colistin and Gram-Negative-Bacterial-Infections

The increasing prevalence of infections with multidrug-resistant (MDR), extensively-drug resistant (XDR) or difficult-to-treat drug resistant (DTR) Gram-negative bacilli (GNB), including Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae, Enterobacter species, and Escherichia coli poses a severe challenge.. The rapid growing of multi-resistant GNB as well as the considerable deceleration in development of new anti-infective agents have made polymyxins (e.g. polymyxin B and colistin) a mainstay in clinical practices as either monotherapy or combination therapy. However, whether the polymyxin-based combinations lead to better outcomes remains unknown. This review mainly focuses on the effect of polymyxin combination therapy versus monotherapy on treating GNB-related infections. We also provide several factors in designing studies and their impact on optimizing polymyxin combinations.. An abundance of recent in vitro and preclinical in vivo data suggest clinical benefit for polymyxin-drug combination therapies, especially colistin plus meropenem and colistin plus rifampicin, with synergistic killing against MDR, XDR, and DTR P. aeruginosa, K. pneumoniae and A. baumannii. The beneficial effects of polymyxin-drug combinations (e.g. colistin or polymyxin B + carbapenem against carbapenem-resistant K. pneumoniae and carbapenem-resistant A. baumannii, polymyxin B + carbapenem + rifampin against carbapenem-resistant K. pneumoniae, and colistin + ceftolozan/tazobactam + rifampin against PDR-P. aeruginosa) have often been shown in clinical setting by retrospective studies. However, high-certainty evidence from large randomized controlled trials is necessary. These clinical trials should incorporate careful attention to patient's sample size, characteristics of patient's groups, PK/PD relationships and dosing, rapid detection of resistance, MIC determinations, and therapeutic drug monitoring.

Topics: Anti-Bacterial Agents; Anti-Infective Agents; Carbapenems; Colistin; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests; Polymyxin B; Polymyxins; Retrospective Studies; Rifampin

While trimethoprim-sulfamethoxazole (TMP-SMX) is the first-line therapy of Stenotrophomonas maltophilia infections, colistin is one of the therapeutic options in cases of allergy or resistance to TMP-SMX. However, understanding the global status of resistance to colistin amongst S. maltophilia isolates could be helpful for appropriate antibiotic prescription. This study aimed to conduct a systematic review and meta-analysis to examine the prevalence of colistin resistance in clinical S. maltophilia isolates worldwide. According to eligibility criteria, a total of 61 studies were included in the analysis. The pooled prevalence for colistin resistance was 42% (95% CI: 35-49%), ranging from 0.1 to 97%. Subgroups analysis indicated that, the pooled prevalence of colistin resistance was 44% (95% CI: 29-60%) in 15 studies during 2000-2010, and it was estimated to be 41% (95% CI: 33-50%) in 46 articles from 2011 to 2021. It was 46% (95% CI: 35-58%) in the studies that used broth microdilution method, and 39% (95% CI: 30-49%) in the studies with other used methods. The resistance rate in Asian countries was 45% (95% CI: 31-60%), in European countries was 45% (95% CI: 34-56%) and in the countries of North and South America was 33% (95% CI: 20-46%). Our review showed notable resistance to colistin in clinical S. maltophilia isolates. Given the estimated resistance rates, alternative antibiotics could be preferred to treat serious infections due to S. maltophilia.

Topics: Anti-Bacterial Agents; Colistin; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests; Prevalence; Stenotrophomonas maltophilia; Trimethoprim, Sulfamethoxazole Drug Combination

Topics: Anti-Bacterial Agents; Colistin; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacterial Infections; Humans; Polymyxin B; Polymyxins

The superiority of combination therapy for carbapenem-resistant Gram-negative bacilli (CR-GNB) infections remains controversial. In vitro models may predict the efficacy of antibiotic regimens against CR-GNB. A systematic review and meta-analysis was performed including pharmacokinetic/pharmacodynamic (PK/PD) and time-kill (TK) studies examining the in vitro efficacy of antibiotic combinations against CR-GNB [PROSPERO registration no. CRD42019128104]. The primary outcome was in vitro synergy based on the effect size (ES): high, ES ≥ 0.75, moderate, 0.35 < ES < 0.75; low, ES ≤ 0.35; and absent, ES = 0). A network meta-analysis assessed the bactericidal effect and re-growth rate (secondary outcomes). An adapted version of the ToxRTool was used for risk-of-bias assessment. Over 180 combination regimens from 136 studies were included. The most frequently analysed classes were polymyxins and carbapenems. Limited data were available for ceftazidime/avibactam, ceftolozane/tazobactam and imipenem/relebactam. High or moderate synergism was shown for polymyxin/rifampicin against Acinetobacter baumannii [ES = 0.91, 95% confidence interval (CI) 0.44-1.00], polymyxin/fosfomycin against Klebsiella pneumoniae (ES = 1.00, 95% CI 0.66-1.00) and imipenem/amikacin against Pseudomonas aeruginosa (ES = 1.00, 95% CI 0.21-1.00). Compared with monotherapy, increased bactericidal activity and lower re-growth rates were reported for colistin/fosfomycin and polymyxin/rifampicin in K. pneumoniae and for imipenem/amikacin or imipenem/tobramycin against P. aeruginosa. High quality was documented for 65% and 53% of PK/PD and TK studies, respectively. Well-designed in vitro studies should be encouraged to guide the selection of combination therapies in clinical trials and to improve the armamentarium against carbapenem-resistant bacteria.

Topics: Amikacin; Anti-Bacterial Agents; Azabicyclo Compounds; Carbapenems; Ceftazidime; Cephalosporins; Colistin; Drug Combinations; Drug Resistance, Bacterial; Drug Synergism; Drug Therapy, Combination; Fosfomycin; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Imipenem; In Vitro Techniques; Microbial Sensitivity Tests; Polymyxins; Rifampin; Tazobactam; Tobramycin

Antibiotic resistance is a growing global challenge to public health. Polymyxin is considered to be the last-resort antibiotic against most gram-negative bacteria. Recently, discoveries of a plasmid-mediated, transferable mobilized polymyxin resistance gene (mcr-1) in many countries have heralded the increased threat of the imminent emergence of pan-drug-resistant super bacteria. MCR-1 is an inner membrane protein that enables bacteria to develop resistance to polymyxin by transferring phosphoethanolamine to lipid A. However, the mechanism associated with polymyxin resistance has yet to be elucidated, and few drugs exist to address this issue. Here, we review our current understanding regarding MCR-1 and small molecule inhibitors to provide a detailed enzymatic mechanism of MCR-1 and the associated implications for drug design.

Topics: Anti-Bacterial Agents; Bacterial Proteins; Colistin; Drug Design; Drug Resistance, Bacterial; Escherichia coli Proteins; Genes, Bacterial; Gram-Negative Bacterial Infections; Humans; Plasmids; Polymyxins

Sepsis is one of the major causes of neonatal deaths in India and worldwide. Pathogens encountered in neonatal sepsis vary worldwide; reports from developing countries more commonly show Gram negative organisms, most common being Acinetobacter spp., Klebsiella spp. and Escherichia coli. Recent studies show that the incidence of antimicrobial resistance, to third generation cephalosporins and carbapenems, has been on a rise. Because of widespread antimicrobial resistance, 'Higher' or 'Reserve' antibiotics are increasingly being used as first/second line antibiotics. In the past decade, there has been a resurgence in the use of colistin as a result of Extended-spectrum β-lactamase (ESBL)- producing Enterobacteriaceae and carbapenem resistant Enterobacteriaceae (CRE), which retain susceptibility only to colistin. The increasing burden of drug resistant Gram negative organisms, particularly Acinetobacter spp., Klebsiella spp., and E. coli might pose a formidable threat in coming years.

Topics: Anti-Bacterial Agents; beta-Lactamases; Blood Culture; Carbapenems; Colistin; Drug Resistance, Multiple; Enterobacteriaceae; Escherichia coli; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; India; Klebsiella; Neonatal Sepsis

Colistin is the last-resort antimicrobial agent against infections caused by multidrug-resistance Gram-negative bacteria (MDR-GNB). However, a differing risk of colistin-associated acute kidney injury (CA-AKI) has been demonstrated without affecting mortality, thus the association and its importance needs to be questioned. To assess the impact of this adverse effect, a meta-analysis comparing colistin with other antibiotics in treating MDR-GNB infections was conducted. The PubMed, Embase and Cochrane Library electronic databases were searched up to 31 December 2018 for cohort studies and randomised controlled trials with at least two arms with one arm containing colistin-based treatment. The primary endpoint was the incidence of AKI. The secondary endpoint was 30-day all-cause mortality. A total of 34 studies, including 26 regarding colistin-based therapy versus other antibiotics and 9 regarding colistin monotherapy versus combination therapy, were included. The incidence of CA-AKI was 32.3%. Colistin was associated with an 82% higher incidence of AKI than other antibiotics [odd ratio (OR) = 1.82, 95% confidence interval (CI) 1.13-2.92; P = 0.01]. Most CA-AKI events were mild and reversible without a higher rate of mortality or the requirement for renal replacement therapy (RRT). Only 1.0% of patients required RRT for > 4 weeks. Compared with colistin monotherapy, combination therapy was associated with a significantly lower incidence of AKI (OR = 1.46, 95% CI 1.10-1.94; P = 0.009), particularly in combination with a carbapenem (OR = 1.97, 95% CI 1.30-2.99; P = 0.001). In conclusion, CA-AKI might not be an important limitation of colistin in MDR-GNB therapy.

Topics: Acute Kidney Injury; Adult; Anti-Bacterial Agents; Carbapenems; Cohort Studies; Colistin; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Incidence; Renal Replacement Therapy

Increasing antibiotic resistance in multidrug-resistant (MDR) Gram-negative bacteria (MDR-GNB) presents significant health problems worldwide, since the vital available and effective antibiotics, including; broad-spectrum penicillins, fluoroquinolones, aminoglycosides, and β-lactams, such as; carbapenems, monobactam, and cephalosporins; often fail to fight MDR Gram-negative pathogens as well as the absence of new antibiotics that can defeat these "superbugs". All of these has prompted the reconsideration of old drugs such as polymyxins that were reckoned too toxic for clinical use. Only two polymyxins, polymyxin E (colistin) and polymyxin B, are currently commercially available. Colistin has re-emerged as a last-hope treatment in the mid-1990s against MDR Gram-negative pathogens due to the development of extensively drug-resistant GNB. Unfortunately, rapid global resistance towards colistin has emerged following its resurgence. Different mechanisms of colistin resistance have been characterized, including intrinsic, mutational, and transferable mechanisms.In this review, we intend to discuss the progress over the last two decades in understanding the alternative colistin mechanisms of action and different strategies used by bacteria to develop resistance against colistin, besides providing an update about what is previously recognized and what is novel concerning colistin resistance.

Topics: Anti-Bacterial Agents; Colistin; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans

Carbapenem-resistant organisms (CROs), including Pseudomonas aeruginosa, Acinetobacter baumannii and Enterobacterales, are a threat worldwide. This review will cover mechanisms of resistance within CROs and challenges with identification and treatment of these organisms while pointing out unresolved issues and ongoing challenges.. The treatment of CROs has expanded through newer therapeutic options. Guided utilization through genotypic and phenotypic testing is necessary in order for these drugs to target the appropriate mechanisms of resistance and select optimal antibiotic therapy.. Identification methods and treatment options need to be precisely understood in order to limit the spread and maximize outcomes of CRO infections.

Topics: Acinetobacter baumannii; Anti-Bacterial Agents; Bacterial Proteins; beta-Lactam Resistance; beta-Lactamase Inhibitors; beta-Lactamases; beta-Lactams; Carbapenems; Colistin; Drug Resistance, Multiple, Bacterial; Enterobacteriaceae; Genotyping Techniques; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests; Pseudomonas aeruginosa

In this review, we report the available data regarding efficacy, safety and pharmacokinetics of colistin in the treatment of multidrug-resistant Gram-negative bacteria in neonates and infants. Seventeen clinical studies, involving 312 patients, and 3 pharmacokinetics studies were identified. Blood stream infection was the most common source of infection, followed by pneumonia and meningitis/ventriculitis. In most cases, colistin was administered in association with other antibiotics. The most common route of administration was intravenous, with colistimethate doses ranging from 25,000 to 225,000 IU/kg/day divided into 2 or 3 doses. A recent pharmacokinetic study suggested that the appropriate intravenous dose should be >150,000 IU/kg/day. Microbiologic cure was obtained in 94.2% of patients and survival was 76.6%. The combination of intraventricular and intravenous colistin should be used in meningitis/ventriculitis. Nebulized colistin should be used as adjunctive treatment, but not as monotherapy. Nephrotoxicity and apnea were reported in 5.8% and 3.9% of patients respectively.The use of colistin for multidrug-resistant Gram-negative infections in neonates and infants is effective and safe, but the quality of studies is moderate. The optimal intravenous dose should be higher than that indicated in most reports.

Topics: Administration, Intravenous; Anti-Bacterial Agents; Colistin; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacterial Infections; Humans; Infant; Infant, Newborn; Treatment Outcome

Antibiotic resistance is an ever-increasing global problem. Major commercial antibiotics often fail to fight common bacteria, and some pathogens have become multi-resistant. Polymyxins are potent bactericidal antibiotics against gram-negative bacteria. Known resistance to polymyxin includes intrinsic, mutational and adaptive mechanisms, with the recently described horizontally acquired resistance mechanisms. In this review, we present several strategies for bacteria to develop enhanced resistance to polymyxins, focusing on changes in the outer membrane, efflux and other resistance determinants. Better understanding of the genes involved in polymyxin resistance may pave the way for the development of new and effective antimicrobial agents. We also report novel in silico tested primers for PCR assay that may be able distinguish colistin-resistant isolates carrying the plasmid-encoded mcr genes and will assist in combating the spread of colistin resistance in bacteria.

Topics: Anti-Bacterial Agents; Bacterial Proteins; Colistin; Drug Resistance, Bacterial; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests; Polymyxins

Plazomicin is a novel semisynthetic parenteral aminoglycoside that inhibits bacterial protein synthesis. It was approved by the United States Food and Drug Administration for use in adults with complicated urinary tract infections (cUTI), including pyelonephritis. Plazomicin displays potent in vitro activity against Enterobacteriaceae, including both extended-spectrum β-lactamase-producing and carbapenem-resistant isolates. Plazomicin's enhanced Enterobacteriaceae activity is due to its stability to commonly encountered aminoglycoside-modifying enzymes that compromise the activity of traditional aminoglycosides. Plazomicin resistance in Enterobacteriaceae is via modification of the ribosomal binding site due to expression of 16S rRNA methyltransferases. Plazomicin does not display improved activity over traditional aminoglycosides against other problematic resistant Gram-negative bacteria, namely Pseudomonas aeruginosa and Acinetobacter baumannii. Plazomicin has been assessed in two phase III randomized controlled trials. The EPIC trial compared plazomicin and meropenem for the management of cUTI. In this trial, plazomicin demonstrated superiority in composite cure (81.7% vs 70.1%; difference 11.6%; 95% confidence interval [CI] 2.7-25.7) at the test-of-cure visit, which was driven by enhanced sustained microbiological eradication. The CARE trial compared plazomicin-based and colistin-based combinations in patients with serious infections due to carbapenem-resistant Enterobacteriaceae (CRE). In this analysis, plazomicin-based combinations were associated with numerically decreased mortality or serious disease-related complications when compared with colistin-based combinations (23.5% vs 50%, respectively; 90% CI -0.7 to 51.2). Furthermore, plazomicin was also associated with a lower incidence of nephrotoxicity than colistin. However, small sample sizes limit the interpretation of the findings in the CARE trial. Plazomicin is a novel aminoglycoside that offers clinicians an additional option for the management of CRE infections, with superior activity compared with traditional aminoglycosides and potentially improved efficacy and decreased toxicity compared with colistin.

Topics: Animals; Anti-Bacterial Agents; Carbapenems; Clinical Trials as Topic; Colistin; Dose-Response Relationship, Drug; Drug Approval; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Meropenem; Randomized Controlled Trials as Topic; Sisomicin; United States; United States Food and Drug Administration; Urinary Tract Infections

The emergence of multidrug resistant (MDR) infections and the shortage of new therapeutic options have made colistin, a polymyxin antibiotic, the main option for the treatment of MDR Gram-negative bacterial infections in the last decade. However, the rapid onset of renal damage often prevents the achievement of optimal therapeutic doses and/or forces the physicians to interrupt the therapy, increasing the risk of drug resistance. The proper management of colistin-induced nephrotoxicity remains challenging, mostly because the investigation of the cellular and molecular pharmacology of this drug, off the market for decades, has been largely neglected. For years, the renal damage induced by colistin was considered a mere consequence of the detergent activity of this drug on the cell membrane of proximal tubule cells. Lately, it has been proposed that the intracellular accumulation is a precondition for colistin-mediated renal damage, and that mitochondria might be a primary site of damage. Antioxidant approaches (e.g., ascorbic acid) have shown promising results in protecting the kidney of rodents exposed to colistin, yet none of these strategies have yet reached the bedside. Here we provide a critical overview of the possible mechanisms that may contribute to colistin-induced renal damage and the potential protective strategies under investigation.

Topics: Acute Kidney Injury; Animals; Anti-Bacterial Agents; Antioxidants; Cell Membrane; Colistin; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacterial Infections; Humans; Kidney

Data are limited regarding the clinical effectiveness and safety of intravenous colistin for treatment of infections due to MDR Gram-negative bacilli (GNB) in paediatric ICUs (PICUs).. Systematic review of intravenous colistin use in critically ill paediatric patients with MDR-GNB infection in PubMed, Scopus and EMBASE (up to 31 January 2018).. Out of 1181 citations, 7 studies were included on the use of intravenous colistin for 405 patients in PICUs. The majority of patients were diagnosed with lower respiratory tract infections, Acinetobacter baumannii being the predominant pathogen. Colistin dosages ranged between 2.6 and 18 mg/kg/day, with only one case reporting a loading dose. Emergence of colistin resistance during treatment was reported in two cases. Nephrotoxicity and neurotoxicity were reported in 6.1% and 0.5%, respectively, but concomitant medications and severe underlying illness limited our ability to definitively associate use of colistin with nephrotoxicity. Crude mortality was 29.5% (95% CI = 21.7%-38.1%), whereas infection-related mortality was 16.6% (95% CI = 12.2%-21.5%).. While the reported incidence of adverse events related to colistin was low, reported mortality rates for infections due to MDR-GNB in PICUs were notable. In addition to severity of disease and comorbidities, inadequate daily dosage and the absence of a loading dose may have contributed to mortality. As the use of colistin for treatment of MDR-GNB infections increases, it is imperative to understand whether optimal dosing of colistin in paediatric patients differs across different age groups. Thus, future studies to establish the pharmacokinetic properties of colistin in different paediatric settings are warranted.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Administration, Intravenous; Adolescent; Anti-Bacterial Agents; Child; Child, Preschool; Colistin; Critical Illness; Drug Resistance, Multiple, Bacterial; Female; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Intensive Care Units, Pediatric; Male

Recently, multidrug-resistant (MDR) Gram-negative bacteria (GNB) have become a serious concern causing infections in hospitalised burn patients. This meta-analysis was conducted to detect the prevalence of infections caused by MDR-GNB in hospitalised burn patients in Iran.. An electronic search was performed using PubMed, Scopus, Web of Science, EMBASE and Iranian databases. Statistical analysis was performed using STATA13. According to the results of the heterogeneity test, a fixed- or random-effects model was used. Publication bias was detected based on Egger's test. Of 1292 articles identified in the initial search, 107 studies were included in this review.. The prevalence of MDR-GNB in Iranian burn patients is very high. Thus, a comprehensive infectious control programme, a reduction in the use of antibiotic prophylaxis, and thorough information regarding antimicrobial resistance patterns is required.

Topics: Acinetobacter baumannii; Anti-Bacterial Agents; Burns; Colistin; Databases, Factual; Drug Resistance, Multiple, Bacterial; Escherichia coli; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Hospitalization; Humans; Infection Control; Iran; Microbial Sensitivity Tests; Prevalence; Pseudomonas aeruginosa

Polymyxins are naturally occurring cyclic lipopeptides that were discovered more than 60 years ago. They have a narrow antibacterial spectrum, which is mainly against Gram-negative pathogens. The dry antibiotic pipeline, together with the increasing incidence of bacterial resistance in the clinic, has been dubbed 'the perfect storm'. This has forced a re-evaluation of 'old' antibiotics, in particular the polymyxins, which retain activity against many multidrug-resistant (MDR) Gram-negative organisms. As a consequence, polymyxin B and colistin (polymyxin E) are now used as the last therapeutic option for infections caused by 'superbugs' such as Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae. This chapter covers the history, chemistry and antibacterial spectrum of these very important last-line lipopeptide antibiotics.

Topics: Anti-Bacterial Agents; Colistin; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacterial Infections; Humans; Polymyxin B; Polymyxins

Due to lack of better therapeutic options, colistin use for extensively drug-resistant Gram-negative organisms was revived in the past two decades, including in patients in intensive-care units (ICU). There are multiple knowledge gaps pertaining to the clinical use and utility of colistin in critically-ill patients, but due to lack of options, it is used in these high risk patients. In this chapter, we critically review the various topics pertaining to colistin use in critically-ill patients, while highlighting the (lack of) controlled evidence supporting common current practices pertaining to colistin use by clinicians.

Topics: Anti-Bacterial Agents; Colistin; Critical Illness; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacterial Infections; Humans; Intensive Care Units

Polymyxin B is another clinically available polymyxin that has re-emerged in clinical practice to treat infections caused by multi-drug (MDR) or extensively-drug-resistant (XDR) Gram-negative bacteria (GNB). Its chemical structure is very similar to the structure of polymyxin E (colistin). However, since the latter is administered as a prodrug, there are major pharmacokinetic differences between both polymyxins that may potentially determine different clinical and microbiological outcomes. Studies addressing clinical or microbiological outcomes in patients treated with polymyxin B for MDR or XDR GNB are reviewed in this chapter.

Topics: Anti-Bacterial Agents; Colistin; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Polymyxin B

Central nervous system (CNS) infections caused by multi-drug resistant (MDR) Gram-negative bacteria present a major health and economic burden worldwide. Due to the nearly empty antibiotic discovery pipeline, polymyxins (i.e. polymyxin B and colistin) are used as the last-line therapy against Gram-negative 'superbugs' when all other treatment modalities have failed. The treatment of CNS infections due to multi-drug resistant Gram-negative bacteria is problematic and associated with high mortality rates. Colistin shows significant efficacy for the treatment of CNS infections caused by MDR Gram-negative bacteria that are resistant to all other antibiotics. In particular, MDR Acinetobacter baumannii, Pseudomonas aeruginosa and Klebsiella pneumoniae which are resistant to expanded-spectrum and fourth-generation cephalosporins, carbapenems and aminoglycosides, represent a major therapeutic challenge, although they can be treated with colistin or polymyxin B. However, current dosing recommendations of intrathecal/intraventricular polymyxins are largely empirical, as we have little understanding of the pharmacokinetics/pharmacodynamics and, importantly, we are only starting to understand the mechanisms of potential neurotoxicity. This review covers the current knowledge-base on the mechanisms of disposition and potential neurotoxicity of polymyxins as well as the combined use of neuroprotective agents to alleviate polymyxins-related neurotoxicity. Progress in this field will provide the urgently needed pharmacological information for safer and more efficacious intrathecal/intraventricular polymyxin therapy against life-threatening CNS infections caused by Gram-negative 'superbugs'.

Topics: Central Nervous System Infections; Colistin; Drug Resistance, Multiple; Gram-Negative Bacterial Infections; Humans; Injections, Intraventricular; Injections, Spinal; Models, Biological; Neuroprotective Agents; Polymyxin B

We present a case of Gram-negative neurosurgical meningitis in a neonate, refractory to optimal intravenous therapy and removal of ventriculoperitoneal shunt. Cerebrospinal fluid was sterilized within 24 hours using intraventricular colistin. This is the first report of intraventricular colistin use in neonatal meningitis caused by Enterobacter cloacae.

Topics: Anti-Bacterial Agents; Colistin; Gram-Negative Bacterial Infections; Humans; Infant, Newborn; Male; Meningitis; Neurosurgical Procedures; Postoperative Complications; Treatment Outcome; Ventriculoperitoneal Shunt

Colistin, an old cationic polypeptide antibiotic, have been reused due to rising incidence of infections caused by multi-drug resistant (MDR) Gram-negative microorganisms and the lack of new antibiotics. Therefore, we evaluated safety and efficacy of colistin in treatment of these infections. This study included 104 critically ill children with a median age of 55,9 months between January 2011 and January 2016. Nephrotoxicity occurred in 11 (10.5%) patients. Nephrotoxicity occurred between the third and seventh day of treatment in 63% of colistin induced nephrotoxicity episodes. The subgroup analysis between the patients who developed nephrotoxicity during colistin treatment and those that did not, showed no significant difference in terms of age, underlying disease, cause for PICU admission and type of infection required colistin treatment, P values were 0.615, 0.762, 0.621, 0.803, respectively. All patients were receiving a concomitant nephrotoxic agent (P = 0,355). The majority of the patients (52%) were having primary or secondary immune deficiency in treatment failure group and the most common cause of PICU admission was sepsis in treatment failure group, P values were 0.007 and 0.045, respectively. Mortality attributed to colistin failure and crude mortality were 14.4% and 29.8%, respectively. In conclusion, colistin may have a role in the treatment of infections caused by multidrug-resistant Gram-negative bacteria in critically ill children. However, the patients have to be followed for side effects throughout colistin treatment, not for only early stage. And the clinicians should be aware of increase in the rate of nephrotoxicity in patients those have been receiving a concomitant nephrotoxic agent.

Topics: Administration, Intravenous; Child, Preschool; Colistin; Critical Illness; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacterial Infections; Humans; Immunologic Deficiency Syndromes; Intensive Care Units, Pediatric; Kidney; Referral and Consultation; Retrospective Studies; Sepsis; Treatment Outcome

To evaluate whether intravenous plus inhaled combination (IV/INHCC) compared to intravenous monotherapy (IVCM) was associated with patient outcomes and identify factors influencing study outcomes.. PubMed and Scopus were searched till November 2016. Studies were included if they evaluated adult patients with lower respiratory tract infections due to MDR/XDR Gram-negative bacteria and reported comparative mortality data (adjusted and unadjusted) for patients receiving IV/INHCC versus IVCM. Random effects meta-analyses were performed.. Thirteen studies (11 retrospective, 2 prospective) were included. The overall quality of data was low to very low and characterized by the lack of adjusted data. The majority of the studies were designed to evaluate the outcome of the meta-analysis. Both IV and inhaled colistin were administered at variable doses. There was no difference in mortality between IV/INHCC and IVCM when all studies were combined (13 studies, 1115 patients, risk ratio 0.94, 95% confidence interval 0.81-1.08). Only the analysis that included studies with low-dose IV colistin showed significant difference in favor of IV/INHCC versus IVCM (0.65, 0.45-0.94).. Overall, low quality data suggest that IV/INHCC did not lower mortality in patients with MDR Gram negative infections unless low IV colistin dose was administered.

Topics: Administration, Inhalation; Administration, Intravenous; Anti-Bacterial Agents; Colistin; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Pneumonia, Ventilator-Associated; Prospective Studies; Respiratory Tract Infections; Retrospective Studies; Treatment Outcome

Multidrug-resistant (MDR) and extensively-drug-resistant (XDR) Gram-negative bacteria have emerged as a major threat to human health globally. This has resulted in the 're-discovery' of some older antimicrobials and development of new agents, however resistance has also rapidly emerged to these agents. Areas covered: Here we describe recent developments in resistance to three of the most important last-line antimicrobials for treatment of MDR and XDR Gram negatives: fosfomycin, colistin and ceftazidime-avibactam. Expert commentary: A key challenge for microbiologists and clinicians using these agents for treating patients with MDR and XDR Gram negative infections is the need to ensure appropriate reference methods are being used to test susceptibility to these agents, especially colistin and fosfomycin. These methods are not available in all laboratories meaning accurate results are either delayed, or potentially inaccurate as non-reference methods are employed. Combination therapy for MDR and XDR Gram negatives is likely to become more common, and future studies should focus on the clinical effects of monotherapy vs combination therapy, as well as validation of synergy testing methods. Effective national and international surveillance systems to detect and respond to resistance to these last line agents are also critical.

Topics: Animals; Anti-Bacterial Agents; Azabicyclo Compounds; Ceftazidime; Colistin; Drug Combinations; Drug Resistance, Multiple, Bacterial; Fosfomycin; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests

Data on the efficacy and safety of ceftazidime/avibactam (CAZ-AVI) are limited. A systematic review and meta-analysis was conducted to clarify the role of CAZ-AVI for patients with serious Gram-negative bacterial infections. The PubMed, EMBASE and Cochrane Library databases were searched for randomised controlled trials (RCTs) and cohort studies involving CAZ-AVI. Summary risk ratios (RRs) and 95% confidence intervals (CIs) were calculated using a fixed- or random-effects model. Twelve articles (4951 patients) were included, consisting of nine RCTs and three observational studies comparing CAZ-AVI with other regimens, e.g. carbapenems or colistin. CAZ-AVI showed a comparable clinical response (RR = 0.99, 95% CI 0.96-1.02; I

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Carbapenems; Ceftazidime; Colistin; Drug Administration Schedule; Drug Combinations; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests; Patient Safety; Randomized Controlled Trials as Topic; Survival Analysis; Treatment Outcome; Urinary Tract Infections

Polymyxin B and colistin (polymyxin E) were introduced in clinical practice to treat Gram-negative infections in 1950s but their parenteral use waned in 1970s due to toxicity concerns. Resurgence of polymyxins use in Malaysia began approximately in 2009 due to a lack of treatment options for MDR Gram negative superbugs such as Acinetobacter baumannii, Klebsiella pneumoniae and Pseudomonas aeruginosa. However, limited experience and a lack of widespread availability of up-to-date dosing guidelines could potentially result in incorrect use of these last resort antibiotics by managing doctors. The recent report of polymyxin resistant strains is also a cause of concern. Herein, we discuss the importance of preserving the efficacy of polymyxins in hospitals, the similarities and differences between polymyxin B and colistin, issues pertaining to current use of polymxyins and strategies to improve polymyxins' prescription. Polymyxins should only be used to treat significant infections, in optimum doses and if possible, in combination with other antibiotics.

Topics: Administration, Intravenous; Anti-Bacterial Agents; Colistin; Drug Resistance, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Polymyxin B

In this review, we provide an updated summary on colistin pharmacokinetics and pharmacodynamics. Colistin is an old molecule that is frequently used as last-line treatment for infections caused by multidrug-resistant Gram-negative bacteria. Colistin is a decapeptide administered either as a prodrug, colistin methanesulfonate (CMS), when used intravenously, or as colistin sulfate when used orally. Because colistin binds to laboratory materials, many experimental issues are raised and studies on colistin can be tricky. Due to its large molecular weight and its cationic properties at physiological pH, colistin passes through physiological membranes poorly and is mainly distributed within the extracellular space. Renal clearance of colistin is very low, but the dosing regimen should be adapted to the renal function of the patient because CMS is partly eliminated by the kidney. Therapeutic drug monitoring of colistin is warranted because the pharmacokinetics of colistin are very variable, and because its therapeutic window is narrow. Resistance of bacteria to colistin is increasing worldwide in parallel to its clinical and veterinary uses and a plasmid-mediated resistance mechanism (MCR-1) was recently described in animals and humans. In vitro, bacteria develop various resistance mechanisms rapidly when exposed to colistin. The use of a loading dose might reduce the emergence of resistance but the use of colistin in combination also seems necessary.

Topics: Administration, Intravesical; Administration, Oral; Animals; Anti-Bacterial Agents; Colistin; Dose-Response Relationship, Drug; Drug Monitoring; Drug Resistance, Bacterial; Gram-Negative Bacterial Infections; Humans; Molecular Weight; Tissue Distribution

Living in the 'era of antibiotic resistance' and facing the threat of an 'end to antibiotics', physicians in the last decade have revived use of colistin, since the available literature at the clinical level was poor and limited Areas covered: Herein, the authors present the current available knowledge regarding colistin, i.e. in vitro activity and interactions, current pharmacokinetics/pharmacodynamics (PK/PD), clinical efficacy against multidrug-resistant (MDR) and extensively drug-resistant (XDR) Gram-negative bacteria, as well as toxicity issues, whereas the recently published newer plasmid mediated mcr-1 resistance gene is reviewed and discussed. Expert opinion: As proven in a big number of studies and despite their retrospective design, it is surmized that for carbapenemase producing K. pneumoniae, colistin should be given in combination with another active in vitro antibiotic and preferably meropenem/doripenem whenever the relevant minimum inhibitory concentration is ≤8 mg/L. However, colistin monotherapy seems adequate for infections caused by A. baumannii and P. aeruginosa. Based on current knowledge on PK/PD, appropriate dosage schedules are discussed in detail. The worldwide fear of the spread of the plasmid mediated mcr-1 colistin resistance gene is prevailing which, if not limited, the real catastrophy of a life-saver antibiotic will follow soon.

Topics: Animals; Anti-Bacterial Agents; Colistin; Drug Administration Schedule; Drug Interactions; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests

Colistin and polymyxin B (PMB) have different pharmacokinetic profiles and minor differences in antimicrobial activities that may result in discrepancies in mortality and nephrotoxicity. A systematic review and meta-analysis was conducted. PubMed, Scopus and Cochrane Library databases were searched. There was no significant difference in unadjusted mortality between patients treated with colistin and PMB [risk ratio (RR) = 0.71, 95% confidence interval (CI) 0.45-1.13]. Adjusted data were not available. Unadjusted nephrotoxicity was more common in patients treated with colistin than PMB (RR = 1.55, 95% CI 1.36-1.78). According to the RIFLE (Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease) criteria, there was no difference regarding risk, injury or failure between colistin and PMB. Although episodes of loss of renal function were few in general, they developed primarily in colistin-treated patients (RR = 8.55, 95% CI 1.48-49.49). Colistin was associated with more episodes of nephrotoxicity that also occurred sooner in the analysis of adjusted data (hazard ratio = 2.16, 95% CI 1.43-3.27). Colistin administration was an independent risk factor for nephrotoxicity in two studies. Future studies should evaluate in depth the factors associated with mortality and nephrotoxicity in patients treated with polymyxins and the impact of polymyxin-associated nephrotoxicity on mortality.

Topics: Acute Kidney Injury; Anti-Bacterial Agents; Colistin; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Polymyxin B; Survival Analysis; Treatment Outcome

Recently, plasmid-mediated and, therefore, transferable bacterial polymyxin resistance was discovered in strains from both humans and animals. Such a trait may widely spread geographically, while simultaneously crossing microbial species barriers. This may ultimately render the "last resort" polymyxin antibiotics therapeutically useless. Colistin is currently used to treat infections caused by Gram-negative carbapenemase producers and colistin resistance may lead to practical pan-antibiotic resistance. We here analyzed the medical and diagnostic consequences of (emerging) colistin resistance and propose pathways toward adequate diagnostics for timely detection of both asymptomatic carriage and infection. Culture-based testing using chromogenic and selective media for screening clinical (and veterinary) specimens may constitute key tools for that purpose. Relevant molecular tests are also discussed.

Topics: Animals; Anti-Bacterial Agents; Carrier State; Colistin; Drug Resistance, Bacterial; Gene Transfer, Horizontal; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Plasmids

The widespread use of antibiotics in humans and animals has contributed to growing rates of antibiotic resistance. Previously treatable bacterial infections now require the last line of antibiotics or are untreatable. The current antibiotic of last resort for carbapenem-resistant Gram-negative bacterial infections is often colistin. Evidence for the shifting pattern of colistin resistance and how the international community should respond are discussed in this review.. The literature on colistin resistance was reviewed.. Plasmid-mediated colistin resistance encoded by mcr-1 was first documented in China during the routine surveillance of food animals. This has been followed by similar reports across a wide geographic area, in humans, animals, and the environment. The mcr-1 gene has been reported among human isolates in 29 countries, related to environmental samples in four countries, and in food animals and other animals in 28 countries. More recently, a second gene encoding resistance, mcr-2, has been isolated from porcine and bovine Escherichia coli.. The emergence and horizontal transmission of colistin resistance highlights the need for heightened stewardship efforts across the One Health platform for this antibiotic of last resort, and indeed for all antibiotics used in animals and humans.

Topics: Animals; Anti-Bacterial Agents; Colistin; Drug Resistance, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Plasmids

The emergence and spread of multidrug resistant Gram-negative bacteria has led to a resurgence in the clinical use of polymyxin antibiotics. However, the prevalence of polymyxin resistance is on the rise at an alarming rate, motivating the idea of combination therapy to sustain the revival of these "old" antibiotics. Although ample evidence in favor of combination therapy has emerged, it seems impracticable and confusing to find a promising combination from the diverse reports or gain adequate information on the efficacy and safety profile. With a stagnating discovery pipeline of novel antimicrobials, there is a clear need to fill the knowledge gaps in translating these basic research data to beneficial clinical practice. In this review, we examined the factors and ambiguities that stand as major hurdles in bringing polymyxin combination therapy to bedside care, highlighting the importance and urgency of incorporating translational research insights into areas of difficulty. We also discussed future research priorities that are essential to gather the necessary evidence and insights for promoting the best possible use of polymyxins in combination therapy.

Topics: Anti-Bacterial Agents; Colistin; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Klebsiella pneumoniae; Microbial Sensitivity Tests; Polymyxin B; Polymyxins; Pseudomonas aeruginosa; Translational Research, Biomedical

Published literature on the pharmacokinetics and effectiveness of colistin loading doses is reviewed.. Colistin is increasingly used to treat infections caused by multidrug-resistant (MDR) gram-negative bacteria (GNB). A literature search identified seven reports on studies of colistin loading doses. All reviewed studies involved small samples of critically ill patients, with considerable variation in the colistin products and loading doses used. Pharmacokinetic studies indicated that because of the slow rate of conversion of the prodrug colistimethate sodium to the active drug colistin and the long half-life of colistin, it can take two to three days to attain adequate colistin concentrations without a loading dose. The clinical effectiveness of colistin loading doses was evaluated in two studies, neither involving the use of a comparator group. In one of those studies, clinical cure and bacteriological clearance were reported in 82.1% and 73.9% of cases, respectively; in the other, clinical resolution was reported in 77% of patients. Two studies were conducted to compare clinical outcomes of colistin loading-dose regimens and standard regimens with no loading dose; while use of a loading dose was associated with a higher cure rate (63.0% versus 41.3%, p = 0.04) in one study, no improvement in clinical outcomes was reported in the other study.. Published data on the effectiveness of colistin loading doses are limited. The available evidence suggests that it may be necessary to administer a colistin loading dose in severe and life-threatening infections due to MDR GNB.

Topics: Anti-Bacterial Agents; Colistin; Critical Illness; Dose-Response Relationship, Drug; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Prodrugs; Treatment Outcome

Polymyxins have remained the drug of choice for treatment due to carbapenem-resistant Gram-negative bacilli. Unfortunately, the utility of these agents has been limited by a lack of pharmacokinetic understanding, a high toxicity rate, and an extremely narrow therapeutic index. Significant advancements have been achieved in the understanding of the polymyxins over the past decade, and have led to the recognition of several differences between available intravenous formulations. The purpose of this review is to discuss the implications of these differences, assess comparative efficacy and safety of the polymyxins, and provide recommendations for polymyxin dosing and selection.

Topics: Anti-Bacterial Agents; Colistin; Gram-Negative Bacterial Infections; Humans; Kidney; Polymyxins; Treatment Outcome

This review summarizes the main challenges of antimicrobial resistance (AMR) in the neonatal population with a special focus on multidrug-resistant (MDR) Gram-negative pathogens.. MDR-Gram-negative bacteria are a great concern in the neonatal population, with a worldwide rise in the reported incidence and with very limited therapeutic options. Extended-spectrum β-lactamase and carbapenem-resistant Enterobacteriaceae (CRE) have been reported as responsible for neonatal ICU outbreaks. Hospital data from low/middle-income countries show high proportions of isolates from neonates resistant to the WHO first-line and second-line recommended treatments. The spread of CRE has resulted in old antibiotics, such as colistin and fosfomycin, to be considered as alternative treatment options, despite the paucity of available data on safety and appropriate dosage.. Improved global neonatal AMR surveillance programmes including both epidemiology and clinical outcomes are critical for defining the burden and designing interventions. The optimal empiric treatment for neonatal sepsis in settings of high rates of AMR is currently unknown. Both strategic trials of older antibiotics and regulatory trials of new antibiotics are required to improve clinical outcomes in MDR-Gram-negative neonatal sepsis.

Topics: Anti-Bacterial Agents; beta-Lactam Resistance; beta-Lactamases; Carbapenem-Resistant Enterobacteriaceae; Colistin; Drug Resistance, Multiple, Bacterial; Fosfomycin; Gram-Negative Bacterial Infections; Humans; Infant, Newborn

A literature review was undertaken to ascertain the molecular basis for tigecycline and colistin resistance mechanisms and the experimental basis for the detection and delineation of this resistance particularly in carbapenemase-producing Gram-negative bacteria. Pubmed, Google Scholar and Science Direct were searched with the keywords colistin, tigecycline, resistance mechanisms and detection methods. Trans-complementation and comparative MIC studies, mass spectrometry, chromatography, spectrofluorometry, PCR, qRT-PCR and whole genome sequencing (WGS) were commonly used to determine tigecycline and colistin resistance mechanisms, specifically modifications in the structural and regulatory efflux (acrAB, OqxAB, kpgABC adeABC-FGH-IJK, mexAB-XY-oprJM and soxS, rarA robA, ramRAB marRABC, adeLRS, mexRZ and nfxb) and lipid A (pmrHFIJFKLM, lpxA, lpxC lpxD and mgrB, pmrAB, phoPQ,) genes respectively. Mutations in the ribosomal 16S rRNA operon rrnBC, also yielded resistance to tigecycline through target site modifications. The mcr-1 gene conferring resistance to colistin was identified via WGS, trans-complementation and a murine thigh infection model studies. Common detection methods are mainly antibiotic sensitivity testing with broth microdilution while molecular identification tools are mostly PCR and WGS. Spectrofluorometry, MALDI-TOF MS, micro-array and real-time multiplex PCR hold much promise for the future as new detection tools.

Topics: Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Colistin; Drug Resistance, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Lipid A; Membrane Transport Proteins; Microbial Sensitivity Tests; Minocycline; Mutation; RNA, Bacterial; RNA, Ribosomal, 16S; Tigecycline

One of the most important features of the post-antibiotic era in the late 20th century is the resurgence of colistin for the treatment of extensively drug resistant gram-negative bacteria (XDR). Colistin is a narrow spectrum anti-biotic, active against microorganisms with clinical significance such as Acinetobacter baumannii, Pseudomonas aeruginosa and Klebsiella pneumoniae. Nowadays its toxicity is lower, partly explained by better pharmaceuticals and management of the critically ill patients. However, there has been much confusion regarding the dosage of the drug, its name and labeling, therefore, experts have recommended using a common language about this polymyxin. The lack of PK/PD studies for colistin is perhaps the main weakness of this area of knowledge, even though the before mentioned approach has contributed with new ways to manage and calculate the dose of this antimicrobial. Indeed, the efficiency of colistin in association with a second agent in reducing mortality has not been demonstrated.

Topics: Anti-Bacterial Agents; Colistin; Drug Resistance, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Structure-Activity Relationship

Colistin (polymyxin E) has been widely used since the beginning of the century as a last-option antibiotic for the treatment of patients with multidrug-resistant and extensively-drug resistant bacterial infections. However, colistin dosing is troublesome because each batch of the drug contains a mixture of components and because it is administered as the inactive pro-drug colistimethate sodium (CMS), which has different pharmacokinetic (PK) properties from the active drug. Significant inter-individual and intra-individual variability in colistin plasma concentrations have been observed in all available studies. Low plasma concentrations of the drug during the first hours from initiation of administration suggested that a loading dose would be appropriate. However, other PK studies challenge this approach. Clinical data from randomised controlled trials are not available, whilst data from observational studies do not support higher effectiveness of a loading dose. In this review, we summarise the available data regarding the administration of a loading dose and discuss the issues surrounding the potential advantages and disadvantages as well as the context within which such an approach could be beneficial to patients.

Topics: Anti-Bacterial Agents; Colistin; Gram-Negative Bacterial Infections; Humans; Observational Studies as Topic; Plasma; Randomized Controlled Trials as Topic; Time Factors

The polymyxin antibiotics [colistin and polymyxin B (PMB)] are increasingly used as a last-line option for the treatment of infections caused by extensively drug-resistant Gram-negative bacteria. Despite having similar structures and antibacterial activity in vitro, the two clinically available polymyxins have very different pharmacological properties, as colistin (polymyxin E) is intravenously administered to patients in the form of an inactive prodrug colistin methanesulphonate (sodium). This review will discuss recent progress in the pharmacokinetics/pharmacodynamics and toxicity of colistin and PMB, the factors that affect their pharmacological profiles, and the challenges for the effective use of both polymyxins. Strategies are proposed for optimising their clinical utility based upon the recent pharmacological studies in vitro, in animals and patients. In the 'Bad Bugs, No Drugs' era, polymyxins are a critically important component of the antibiotic armamentarium against difficult-to-treat Gram-negative 'superbugs'. Rational approaches to the use of polymyxins must be pursued to increase their effectiveness and to minimise resistance and toxicity.

Topics: Acute Kidney Injury; Anti-Bacterial Agents; Colistin; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Polymyxin B

The polymyxins-colistin and polymyxin B-are an increasingly important part of the antimicrobial arsenal given the rising rate of infections due to multidrug-resistant gram-negative bacteria. Although the drugs have available since the 1950s, only recently have pharmacokinetic and pharmacodynamic data been available to guide appropriate use of these drugs. Far more data and global clinical experience exist for colistin, available as the prodrug colistimethate sodium (CMS), compared with polymyxin B. Concerns raised about variability in the ability to achieve therapeutic drug concentrations when dosing CMS have led many clinicians to desire a more pharmacokinetically reliable product. The pharmacokinetic and pharmacodynamic advantages of polymyxin B compared with CMS are compelling, but clinical experience has not consistently corroborated these data. Prospective, comparative data evaluating both drugs in combination with other antimicrobials as well as comparing polymyxin B and CMS directly will inform optimal use of each drug. Some of these investigations are currently under way. In the meantime, based on current data, both drugs appear to be appropriate for use in the clinical setting.

Topics: Anti-Bacterial Agents; Colistin; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Gram-Negative Bacterial Infections; Humans; Polymyxin B

Infections caused by multi-drug-resistant Gram-negative bacteria, particularly Acinetobacter baumannii, Pseudomonas aeruginosa and Klebsiella pneumoniae, that cause nosocomial infections, represent a growing problem worldwide. The rapid increase in the prevalence of Gram-negative pathogens that are resistant to fluoroquinolones and aminoglycosides as well as all β-lactams, including carbapenems, monobactam, cephalosporins and broad-spectrum penicillins, has prompted the reconsideration of colistin as a valid therapeutic option. Colistin is an old class of cationic, which act by disrupting the bacterial membranes resulting in cellular death. Although there has been a significant recent increase in the data gathered on colistin, focusing on its chemistry, antibacterial activity, mechanism of action and resistance, pharmacokinetics, pharmacodynamics and new clinical application, the prevalence of colistin resistance has been very little reported in the literature. This review concentrates on recent literature aimed at optimizing the clinical use of this important antibiotic.. The available evidence from various studies (microbiological and clinical studies, retrieved from the PubMed, and Scopus databases) regarding the mechanisms and prevalence of resistance was evaluated.. Increasing use of colistin for treatment of infections caused by these bacteria has led to the emergence of colistin resistance in several countries worldwide. Although resistance to polymyxins is generally less than 10%, it is higher in the Mediterranean and South-East Asia (Korea and Singapore), where colistin resistance rates are continually increasing.. There is a critical need for effective infection prevention and control measures and strict use of antibiotics in the world to control the rise and spread of colistin resistance.

Topics: Anti-Bacterial Agents; Colistin; Cross Infection; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Polymyxins; Prevalence

The global spread of multi-drug resistant organisms (MDRO) is a major threat to public health. Fighting MDRO spread requires a multi-faceted approach as summarized in the German Antibiotic Resistance Strategy (DART). In the hospital, this includes antibiotic stewardship concepts and strict infection control measures. Treatment of MDRO is sophisticated. Within the last years, several antibiotics with activity against MRSA were launched and facilitate an individual therapy according to site of infection and co-morbidities. In contrast, novel antibiotics against carbapenemase producing Gram-negatives are still lacking. Current studies have shown, that a colistin-based combination treatment can improve the prognosis in these patients. The following article reviews MDRO definitions, burden of disease, treatment options and general strategies against MDRO.

Topics: Anti-Bacterial Agents; Bacterial Infections; Colistin; Cost of Illness; Cross Infection; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Gram-Negative Bacterial Infections; Humans; Methicillin-Resistant Staphylococcus aureus; Staphylococcal Infections

Increasing number of infection cases caused by multiresistant Gram-negative bacteria or multidrug resistant organism (MDRO) has become a major problem worldwide since there have been a lot of resistance to many classes of antibiotics. Mutant isolates such as fluoroquinolone-resistant and -lactamase-resistant bacteria have been commonly found, particularly in intensive care unit (ICU). During the last two decades, there has been no study of developing antibiotics in search of discovering new type of antibiotics; meanwhile, the resistance of Gram-negative bacteria or MDRO to antibiotics is increasing. Colistin or polymyxin E is an old antibiotic, which has been used since 1959 for treating infection caused by Gram-negative MDRO. It was revealed that colistin has side effects of nephrotoxicity and neurotoxicity; therefore, the use of this antibiotic was stopped and it was replaced by other antibiotics which were effective and were considered safer at that time. There is an increasing number of infections with multi-resistant Gram-negative (MDRO) against the available antibiotics and the availability of alternative antibiotics has not been satisfying; therefore, microbiologists are searching back to the old option, which has been proven to be effective against multi-resistant Gram-negative bacteria, the old antibiotic that has been long forgotten, i.e. colistin, as an alternative treatment against Gram-negative MDRO. It is expected that colistin may have essential and reliable role as future antibiotics for treatment of multi-resistant Gram-negative infections and as an alternative of antibiotics that have been available so far.

Topics: Anti-Bacterial Agents; Colistin; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacterial Infections; Humans; Intensive Care Units

Colistin has been used to treat nosocomial pneumonia (NP) caused by multidrug-resistant (MDR) Gram-negative bacteria (GNB) via different administration routes. Whether patients may benefit from aerosolised colistin as adjunctive treatment was contradictory. We aimed to clarify the safety and efficacy of administering aerosolised and intravenous (IV-AS) colistin versus intravenous (IV) colistin alone in patients with NP caused by MDR-GNB. Two reviewers independently evaluated and extracted data from PubMed, EMBASE and Cochrane databases. Primary outcomes were clinical response rate, all-cause mortality (ICU or hospital), microbiological eradication and nephrotoxicity. Pooled odds ratios (ORs) were calculated and significance was determined by the Z test. Nine eligible studies involving 672 participants were included. The overall clinical response rate (improvement and cure) was significantly higher in the IV-AS group than that in the IV group [OR=1.81, 95% confidence interval (CI) 1.30-2.53; P=0.0005]. Patients treated with IV-AS colistin showed a higher rate of pathogen eradication (OR=1.66, 95% CI 1.11-2.49; P=0.01) and lower all-cause mortality compared with IV colistin (OR=0.69, 95% CI 0.50-0.95; P=0.02). Nephrotoxicity did not differ significantly between IV-AS and IV groups (five studies; 383 patients) (OR=1.11, 95% CI 0.69-1.80; P=0.67). These data indicate that IV-AS colistin has additional benefits compared with IV colistin alone. Clinicians should be encouraged to give combined administration routes in critically ill patients with NP caused by MDR-GNB.

Topics: Administration, Inhalation; Administration, Intravenous; Anti-Bacterial Agents; Colistin; Critical Illness; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Nasal Sprays; Pneumonia, Ventilator-Associated; Treatment Outcome

The widespread use of antibiotics has been associated with the emergence of antimicrobial resistance among bacteria. 'ESKAPE' (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acintobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp.) pathogens play a major role in the rapidly changing scenario of antimicrobial resistance in the 21st century. Chloramphenicol is a broad spectrum antibiotic that was abandoned in developed countries due to its association with fatal aplastic anemia. However, it is still widely used in the developing world. In light of the emerging problem of multi-drug resistant pathogens, its role should be reassessed. Our paper reviews in vitro data on the activity of chloramphenicol against ESKAPE pathogens. Susceptibility patterns for Gram-positives were good, although less favorable for Gram-negatives. However, in combination with colistin, chloramphenicol was found to have synergistic activity. The risk-benefit related to chloramphenicol toxicity has not been analyzed. Therefore, extra precautions should be taken when prescribing this agent.

Topics: Acinetobacter baumannii; Anemia, Aplastic; Anti-Bacterial Agents; Chloramphenicol; Colistin; Drug Resistance, Bacterial; Drug Synergism; Drug Therapy, Combination; Enterobacter; Enterococcus faecium; Gram-Negative Bacterial Infections; Gram-Positive Bacterial Infections; Humans; Klebsiella pneumoniae; Pseudomonas aeruginosa; Staphylococcus aureus

Central nervous system infections caused by Gram-negative bacteria susceptible only to colistin are rare but life-threatening and increasing in prevalence. Given the current antibiotic development pipeline it is likely that the paucity of therapeutic options will continue for the next years. Colistin is an amphipathic bactericidal antibiotic which is administered systemically as colistin methanesulfonate (also known as colistimethate sodium). Colistin methanesulfonate is the inactive prodrug, and in cerebrospinal fluid undergoes spontaneous hydrolysis to colistin (the active form with antimicrobial activity). In this review, we describe and evaluate the clinical and experimental data supporting the use of intraventricular (IVT) or intrathecal (IT) colistin against multidrug-resistant Gram-negative infections of the central nervous system, describe the permeability of the blood-brain barrier to colistin, the pharmacokinetics of colistin after IVT administration of colistin methanesulfonate, its anti-endotoxin activity, discuss the opportunity to administer colistin intraventricularly or intrathecally and the dose regimen, and provide recommendations based on the available evidence.

Topics: Central Nervous System Infections; Colistin; Endotoxins; Gram-Negative Bacterial Infections; Humans; Infusions, Intraventricular; Injections, Spinal

We report three cases of external ventricular derivation infections caused by multidrug-resistant Gram-negative rods and treated successfully with intraventricular colistin. The intrathecal or intraventricular use of colistin have been reported in more than 100 cases without any consensus on dosage, duration and type (monotherapy or combination therapy) of treatment. Based on our comprehensive review of the relevant literature relating to both clinical and pharmacokinetic data, we conclude that the intrathecal/intraventricular administration of colistin is a safe and effective option to treat central nervous system infections caused by multidrug-resistant Gram-negative bacteria.

Topics: Adolescent; Adult; Anti-Bacterial Agents; Central Nervous System Bacterial Infections; Colistin; Cross Infection; Drug Resistance, Multiple, Bacterial; Gram-Negative Aerobic Rods and Cocci; Gram-Negative Bacterial Infections; Humans; Injections, Intraventricular; Injections, Spinal; Male

Polymyxins are 'old' antimicrobials which were abandoned for almost 30 years because of significant renal and neurological toxicity. However, the alarming rise in multiresistant Gram-negative bacterial infections worldwide has revived interest in these 'forgotten' agents. Colistin (polymyxin E) is one of the main antibiotics of this class. It is most often administered as the prodrug colistimethate sodium. Doses for treatment of systemic infections in adults range between 3 and 9 million IU per day. Colistin is increasingly used to treat pneumonia and bacteremia in critically ill patients. During their intensive care unit stay, many of these patients will need continuous renal replacement therapy (CRRT) because of acute kidney injury or an unstable hemodynamic condition. Based on recent pharmacological data and our own experience, we postulate that patients undergoing CRRT may receive substantially higher doses of colistin (i.e. a high loading dose, followed by a maintenance dose of up to 4.5 million IU t.i.d.). Treatment can be continued for a prolonged time period without increasing toxicity. CRRT counteracts colistin accumulation because the drug is continuously filtered and also significantly adsorbed in the bulk of the dialysis membrane. Implementing such a 'CRRT rescue' therapy does require the strict use of highly adsorptive dialysis membranes in association with citrate anticoagulation to increase membrane performance.

Topics: Acute Kidney Injury; Anti-Bacterial Agents; Colistin; Drug-Related Side Effects and Adverse Reactions; Gram-Negative Bacterial Infections; Humans; Kidney; Renal Replacement Therapy; Treatment Outcome

The spread of multidrug-resistant, extensively drug-resistant and pan-drug-resistant pathogens is causing an unprecedented public health crisis. The limited current therapeutic options led to the revival of two 'old' antibiotics - colistin and fosfomycin - for which a better understanding of their pharmacokinetics in the critically ill patient and in specific body compartments is required. Tigecycline's use in clinical practice for nonapproved indication based on its in vitro activity against problematic pathogens requires caution and probably higher doses. Furthermore, all three antibiotics should be used as part of combination regimens in order to prevent resistance and optimize outcomes. The development of new antibacterials in the near future, namely combinations of avibactam, ceftolozane/tazobactam and plazomicin, seems promising; however, they will only partially address current mechanisms of resistance.

Topics: Anti-Bacterial Agents; Colistin; Critical Illness; Drug Resistance, Multiple, Bacterial; Fosfomycin; Gram-Negative Bacterial Infections; Humans; Minocycline; Tigecycline

Colistin is a venerable antibiotic whose fortunes have been revived by its excellent activity, the diminishing output of novel clinically effective antibiotics and the increasing importance of MDR infection in burn surgery, both in the civilian and military arenas. This review synthesizes current evidence on the usage of colistin in burn surgery including the structure-activity relationship; dosing, pharmacokinetics/pharmacodynamic (PK/PD), analytic methods, resistance and current research efforts into the redevelopment of this antibiotic, to distil recommendations for future research and clinical efficacy.

Topics: Anti-Bacterial Agents; Burns; Colistin; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacterial Infections; Humans

Colistin is a re-emerging old antibiotic that is used as a salvage treatment against multidrug-resistant Gram-negative infections. Because it is administrated as an inactive prodrug, colistin methanesulfonate (CMS) that undergoes rapid hydrolyze to colistin, pharmacokinetic studies using biological assays are unreliable. With the recent development of new assays using high performance liquid chromatography (HPLC) accurate pharmacokinetic of CMS and formed colistin is now available in various populations. This article aims to update previous reports on pharmacodynamics, pharmacokinetics, safety and clinical use of colistin, with a special focus on data useful to treat critically ill patients.

Topics: Anti-Bacterial Agents; Colistin; Critical Illness; Drug Resistance, Bacterial; Drug Synergism; Gram-Negative Bacterial Infections; Humans

Colistin is a re-emerging old antibiotic that is used to treat multidrug-resistant infections in critically ill patients. It corresponds to a mixture of at least 30 different compounds administered as inactive derivatives. Therefore, colistin pharmacokinetics are quite difficult to investigate and complex to predict. However specific chromatographic methods have been made available in recent years, leading to a series of modern pharmacokinetic studies after intravenous administration of the prodrug to critical-care patients; these have been conducted by a few groups and have only been recently published. The objective of this article was to conduct a critical review of these very informative modern pharmacokinetic studies and to provide prospective thoughts.

Topics: Animals; Anti-Bacterial Agents; Colistin; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Rats

Colistin has been re-introduced into clinical practice for the treatment of carbapenem-resistant Gram-negative bacteria. Studies in the last decade attempted to reconstruct the path that present-day medications undergo prior to clinical use. In this review, we summarize the results of recent clinical studies. Colistin was associated with lower mortality than no effective treatment and higher unadjusted mortality than β-lactams in non-randomized clinical studies. However, it was administered to sicker patients with carabapenem-resistant bacteria. Overall, nephrotoxicity rates were not higher with colistin in these studies, and colistin-induced nephrotoxicity is reversible in most patients. The emergence of colistin resistance has been described in high-use settings. Synergy with carbapenem, rifampin and other antibiotics has been reported in vitro. Randomized controlled trials are ongoing or in planning to assess this and other aspects of colistin use in clinical practice.

Topics: Anti-Bacterial Agents; beta-Lactams; Carbapenems; Clinical Trials as Topic; Colistin; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans

Although colistin has recently played a key role in the treatment of nosocomial infections due to multidrug resistant Gram-negative pathogens, there is a lack of clinical studies examining colistin pharmacokinetics (PKs) in humans. This refers to all routes of colistin administration in clinical practice. Colistin PK data are also limited in critically ill patients.. Literature search took into account data dealing with colistin PK obtained from animal studies performed during previous decades (1970s, 1980s and 1990s) and from recent human studies performed during the last decade.. Valuable information on pharmacodynamics (PD)/PK of colistin used in the treatments of nosocomial infections due to multidrug resistant Gram-negative pathogens, mostly Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae. A better understanding of PKs could offer significant improvement of colistin use in humans, especially optimization of colistin doses in different routes of administration in order to maximize clinical efficacy and minimize adverse effects and rate of resistance.. There is a lack of human studies on colistin PK and PD. Significant PD parameters best predicting colistin efficacy and their optimal values such as C(max):MIC ratio, AUC/MIC and T > MIC have not yet been clearly defined. It should be noted that further investigation on colistin PK/PD in vitro and in vivo models is required.

Topics: Animals; Anti-Bacterial Agents; Area Under Curve; Clinical Trials as Topic; Colistin; Critical Illness; Cross Infection; Drug Evaluation, Preclinical; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests

Colistin (polymyxin E), an old antibiotic replaced by other less toxic antibiotics in the 1970s, has been increasingly used over the last decade due to multidrug-resistance in Gram-negative bacteria and lack of new antibiotics. However, there is a dearth of information on the pharmacokinetics (PK), pharmacodynamics (PD) and toxicodynamics (TD) of colistin and its non-active prodrug colistimethate sodium (CMS). Optimised dose regimens have not been established for different types of patients. Additionally, most PK data available in the literature were obtained from concentrations derived from potentially misleading microbiological assays. Therefore, it is urgent to conduct prospective studies to optimise CMS/colistin use in patients, in particular the critically ill. This review summarises recent key clinical studies evaluating the efficacy, toxicity and PK/PD of colistin/CMS.

Topics: Animals; Anti-Bacterial Agents; Clinical Trials as Topic; Colistin; Critical Illness; Dose-Response Relationship, Drug; Drug Administration Routes; Drug Evaluation, Preclinical; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Kidney Tubular Necrosis, Acute; Prospective Studies; Retrospective Studies

We are inexorably entering an era where a wide range of multiply antibiotic-resistant bacteria are commonplace. Until recently, multiresistance was mainly seen in Gram-positive bacteria. However, vancomycin remains adequate as a treatment of most infections with these bacteria. The potential threat from vancomycin-resistant bacteria has never fully materialised, and now there is a growing number of new anti-Gram-positive antibiotics. Of these, there is sufficient experience of using linezolid and daptomycin in neonates for these drugs to be recommended for some specific indications. The recent rapid international spread of multiresistant Gram-negative bacteria, including carbapenem-resistant strains, is much more ominous. Treatment options are extremely limited, which has prompted renewed interest in older and more toxic antibiotics such as colistin. However, the optimal management of serious neonatal infections with these bacteria remains to be determined.

Topics: Acetamides; Anti-Bacterial Agents; Carbapenems; Colistin; Daptomycin; Drug Resistance, Bacterial; Gram-Negative Bacterial Infections; Humans; Infant, Newborn; Linezolid; Oxazolidinones; Vancomycin

The increasing prevalence of multidrug-resistant Gram-negative bacteria worldwide has led to a re-evaluation of the previously discarded antibiotic, colistin. Despite its important role as salvage therapy for otherwise untreatable infections, dosage guidelines for the prodrug colistin methanesulfonate (CMS) are not scientifically based and have led to treatment failure and increased colistin resistance. In this review we summarise the recent progress made in the understanding of the pharmacokinetics of CMS and formed colistin with an emphasis on critically ill patients. The pharmacodynamics of colistin is also reviewed, with special attention given to the relationship between pharmacokinetics and pharmacodynamics and how the emerging data can be used to inform design of optimal dosage regimens. Recent data suggest the current dosage regimens of CMS are suboptimal in many critically ill patients.

Topics: Animals; Anti-Bacterial Agents; Colistin; Critical Illness; Dose-Response Relationship, Drug; Drug Administration Schedule; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Prodrugs

The emergence of nosocomial infections due to multidrug-resistant Gram-negative bacteria led to the revival of 'forgotten' antibiotics, such as polymyxins. Colistin, mainly colistimethate sodium (polymyxin E), has been predominantly used. Recent studies suggest that colistin administered as monotherapy or combination therapy is an effective and safe antimicrobial agent for multidrug-resistant Gram-negative bacteria infections. The reported colistin nephrotoxicity is 20% or lower. Although colistin is commonly administered intravenously, it can also be administered via inhalation for pneumonia/ventilator-associated pneumonia treatment or by the intraventricular/intrathecal route for meningitis/ventriculitis treatment. Randomized controlled trials are needed to answer clinical questions such as the appropriate colistin dose, to compare colistin monotherapy with combination therapy, and to determine the exact therapeutic role of aerosolized or intrathecal/intraventricular administration of colistin.

Topics: Administration, Inhalation; Anti-Bacterial Agents; Colistin; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Injections, Intravenous; Injections, Intraventricular; Injections, Spinal

Colistin is a polymyxin antibiotic that was discovered in the late 1940s for the treatment of gram-negative infections. After several years of clinical use, its popularity diminished because of reports of significant nephrotoxicity and neurotoxicity. Recently, the antibiotic has resurfaced as a last-line treatment option for multidrug-resistant organisms such as Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae. The need for antibiotics with coverage of these gram-negative pathogens is critical because of their high morbidity and mortality, making colistin a very important treatment option. Unfortunately, however, resistance to colistin has been documented among all three of these organisms in case reports. Although the exact mechanism causing colistin resistance has not been defined, it is hypothesized that the PmrA-PmrB and PhoP-PhoQ genetic regulatory systems may play a role. Colistin dosages must be optimized, as colistin is a last-line treatment option; in addition, suboptimal doses have been linked to the development of resistance. The lack of pharmacokinetic and pharmacodynamic studies and no universal harmonization of dose units, however, have made it difficult to derive optimal dosing regimens and specific dosing guidelines for colistin. In critically ill patients who may have multiorgan failure, renal insufficiency may alter colistin pharmacokinetics. Therefore, dosage alterations in this patient population are imperative to achieve maximal efficacy and minimal toxicity. With regard to colistin toxicity, most studies show that nephrotoxicity is reversible and less frequent than once thought, and neurotoxicity is rare. Further research is needed to fully understand the impact that the two regulatory systems have on resistance, as well as the dosages of colistin needed to inhibit and overcome these developing patterns.

Topics: Anti-Bacterial Agents; Colistin; Dose-Response Relationship, Drug; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacterial Infections; Humans

The emergence of multidrug-resistant (MDR) Gram-negative bacilli creates a big problem for the treatment of nosocomial infections. As the pharmaceutical pipeline wanes, the only therapeutic options are two revived antibacterials (colistin and fosfomycin), a newer one (tigecycline) and an early-phase neoglycoside (ACHN-490). Polymyxins, known since 1947, are mostly represented by polymyxin E (colistin), which has recently gained a principal position in the management of the most difficult-to-treat MDR Gram-negative pathogens -Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae. However, despite promising therapeutic results in 59-75% of cases, the reported studies share common drawbacks, i.e. the absence of a control group, their retrospective nature, variable dosing and duration of therapy, simultaneous administration of other antibiotics in >70% and a lack of resistance development monitoring. The necessity for well-designed prospective clinical trials is therefore urgent. Fosfomycin is active in vitro against MDR Enterobacteriaceae, including a high proportion of P. aeruginosa; however, clinical experience is lacking with the parenteral formulation in MDR infection and on the best combinations to prevent resistance development. Tigecycline, which is active against MDR Enterobacteriaceae and A. baumannii, has shown satisfactory clinical experience. However, dosage adjustment is required because of low blood levels. ACHN-490, which has promising in vitro activity against MDR K. pneumoniae, is still in early phase II trials in urinary tract infections. Meanwhile, the strict application of infection control measures is the cornerstone of nosocomial infection prevention, and antibiotic stewardship, exemplified by appropriate duration of therapy and de-escalation policies, should not be overlooked.

Topics: Anti-Bacterial Agents; Colistin; Drug Resistance, Multiple, Bacterial; Fosfomycin; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Minocycline; Randomized Controlled Trials as Topic; Tigecycline; Treatment Outcome

Topics: Administration, Inhalation; Anti-Bacterial Agents; Child; Colistin; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans

Colistin is a 50-year-old antibiotic that is being used increasingly as a 'last-line' therapy to treat infections caused by multidrug-resistant Gram-negative bacteria, when essentially no other options are available. Despite its age, or because of its age, there has been a dearth of knowledge on its pharmacological and microbiological properties. This review focuses on recent studies aimed at optimizing the clinical use of this old antibiotic.. A number of factors, including the diversity in the pharmaceutical products available, have hindered the optimal use of colistin. Recent advances in understanding of the pharmacokinetics and pharmacodynamics of colistin, and the emerging knowledge on the relationship between the pharmacokinetics and pharmacodynamics, provide a solid base for optimization of dosage regimens. The potential for nephrotoxicity has been a lingering concern, but recent studies provide useful new information on the incidence, severity and reversibility of this adverse effect. Recent approaches to the use of other antibiotics in combination with colistin hold promise for increased antibacterial efficacy with less potential for emergence of resistance.. Because few, if any, new antibiotics with activity against multidrug-resistant Gram-negative bacteria will be available within the next several years, it is essential that colistin is used in ways that maximize its antibacterial efficacy and minimize toxicity and development of resistance. Recent developments have improved use of colistin in the 21st century.

Topics: Anti-Bacterial Agents; Colistin; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans

Infections by multidrug resistant Gram-negative bacilli (MDR-GNB) have become a major threat for patients hospitalized in intensive care units, representing a prevalent cause of morbimortality in the critically ill, since these microorganisms have developed resistance to most available antimicrobial agents. In this respect, very few therapeutic innovations have been developed in recent years, and it is not foreseen that any new drugs will be commercialized in the near future. Tigecycline represents an effective alternative in this setting, but lacks activity against Pseudomonas aeruginosa, and its use has not been validated for all organ-specific infections. Frequently, only old antibiotics like colistin remain a valid option. New pharmaceutical formulations and dosage regimens of polymyxins have considerably reduced the toxicity previously attributed to these antimicrobials, and have made it possible to reintroduce them into clinical practice. Nonetheless, the effectiveness of polymyxins is still suboptimal, and the expansion of heteroresistance and pan-drug-resistant strains of gram-negative bacilli is of concern. Improvements in dosing, alternative methods of administration and different synergic antimicrobial combinations have been proposed in recent literature, among other measures, to enhance the effectiveness of polymyxins. The latest data regarding polymyxins and their clinical use are discussed in this review.

Topics: Anti-Bacterial Agents; Colistin; Gram-Negative Bacterial Infections; Humans; Polymyxins

Colistin is commonly the last resort for treatment of infections caused by multidrug-resistant Gram-negative bacteria. In clinical practice, it is frequently used as combination therapy in order to improve its antibacterial activity, despite the consequent increase in toxicity. The available evidence from various studies (microbiological, animal and clinical studies, retrieved from the PubMed and Scopus databases) regarding the comparative effectiveness of colistin monotherapy and colistin combination therapy was evaluated. Most of the microbiological studies examined colistin monotherapy vs. combinations with rifampicin (nine studies) or carbapenems (three studies) for Pseudomonas aeruginosa or Acinetobacter baumannii infections. A synergistic effect was detected in all the studies examining the combination of colistin and rifampicin, whereas carbapenems exhibited a synergistic effect in two of three studies. Most of the animal studies examined colistin monotherapy vs. combinations with rifampicin, carbenicillin, piperacillin and imipenem for treatment of P. aeruginosa, A. baumannii or Escherichia coli infections. Mortality rates were significantly lower in the combination treatment arm in three of six relevant studies. However, data from the small number (four) of relevant human studies suggest non-inferiority of colistin monotherapy as compared with combination therapy. In conclusion, microbiological studies suggest superiority of colistin combination treatment, which is in contrast to preliminary data from studies in humans. Results from animal study data are equivocal. There is an urgent need for appropriately designed and powered clinical trials addressing this apparently controversial situation.

Topics: Acinetobacter baumannii; Animals; Anti-Bacterial Agents; Colistin; Drug Synergism; Drug Therapy, Combination; Escherichia coli; Gram-Negative Bacterial Infections; Humans; Pseudomonas aeruginosa

The emergence of gram-negative bacteria resistant to most available antibiotics has led to the readministration of polymyxins B and E (colistin) as "salvage" therapy in critically ill patients. Recent studies demonstrated acceptable effectiveness and considerably less toxicity than reported in older studies of polymyxins. These old antibiotics may be administered for the treatment of intensive care unit-acquired infections of various types, including ventilator-associated pneumonia, urinary tract infections, bacteremia, and meningitis caused by multidrug resistant gram-negative pathogens, such as Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae, and Enterobacter species. Randomized controlled trials are urgently needed to further clarify various issues regarding the effectiveness and safety of polymyxins, however.

Topics: Anti-Bacterial Agents; Colistin; Critical Care; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacterial Infections; Humans; Pneumonia, Ventilator-Associated; Polymyxin B

Hospital-acquired infections due to multidrug-resistant gram-negative bacteria constitute major health problems, since the medical community is continuously running out of available effective antibiotics and no new agents are in the pipeline. Polymyxins, a group of antibacterials that were discovered during the late 1940s, represent some of the last treatment options for these infections. Only two polymyxins are available commercially, polymyxin E (colistin) and polymyxin B. Although several reviews have been published recently regarding colistin, no review has focused on the similarities and differences between polymyxin B and colistin. These two medications have many similarities with respect to mechanism of action, antimicrobial spectrum, clinical uses and toxicity. However, they also differ in several aspects, including chemical structure, formulation, potency, dosage and pharmacokinetic properties.

Topics: Anti-Bacterial Agents; Bacteria; Colistin; Cross Infection; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests; Polymyxin B; Structure-Activity Relationship

The role of colistin in the treatment of infections caused by multidrug-resistant gram-negative microorganisms is discussed.. Colistin is structurally and pharmacologically related to polymyxin B, the other commercially available drug from the polymyxin class. Colistin is bactericidal in nearly all strains of gram-negative bacilli. As with all antibiotics, resistance is of paramount concern. Resistance to colistin has not been frequently documented. Colistin must be administered parenterally, as it is not absorbed from the gastrointestinal tract, mucous membranes, or intact or denuded skin. Parenteral colistin has been replaced by less-toxic antibiotics and should be reserved for life-threatening infections caused by organisms resistant to preferred drugs. A number of published studies and case reports have reevaluated the safety and efficacy of parenteral colistin use in patients with multidrug-resistant infections. In three case series, 58-74% of patients exhibited a clinical response to colistin. Although colistin was previously viewed as reasonably effective but highly nephrotoxic, recent studies have suggested that nephrotoxicity may not be as severe as once thought. Frequent renal function monitoring is necessary in patients receiving colistin, since adverse renal effect may occur, regardless of the dosage given. The recommended dosage of parenteral colistin for adults and children with normal renal function is 2.5-5 mg/kg/day, administered as two to four divided doses. Doses must be adjusted for renal impairment, and dosing recommendations for patients undergoing renal replacement therapy have not been well established.. With vigilant monitoring of renal function and the avoidance of concomitant neurotoxic medications, colistin can be used safely and effectively with minimal adverse outcomes.

Topics: Anti-Bacterial Agents; Colistin; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Kidney

Intravenous and aerosolized polymyxins are being used increasingly, especially in the critical care setting, for treating patients with infections due to multidrug-resistant Gram-negative bacteria, mainly Acinetobacter baumannii and Pseudomonas aeruginosa. Recent literature suggests that intravenous colistin and polymyxin B have acceptable effectiveness for the treatment of patients with bacteremia, as well as infections of various systems and organs, including pneumonia, bacteremia, skin and soft tissue, and urinary tract infections. Although data from recent studies have suggested that the toxicity of intravenous polymyxins is probably less than reported in the older literature, caution should be taken to monitor the renal function of patients who receive these antibiotics.

Topics: Aerosols; Anti-Bacterial Agents; Colistin; Critical Illness; Dose-Response Relationship, Drug; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacterial Infections; Humans; Injections, Intravenous; Polymyxin B; Polymyxins

Increasing multidrug resistance in Gram-negative bacteria, in particular Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae, presents a critical problem. Limited therapeutic options have forced infectious disease clinicians and microbiologists to reappraise the clinical application of colistin, a polymyxin antibiotic discovered more than 50 years ago. We summarise recent progress in understanding the complex chemistry, pharmacokinetics, and pharmacodynamics of colistin, the interplay between these three aspects, and their effect on the clinical use of this important antibiotic. Recent clinical findings are reviewed, focusing on evaluation of efficacy, emerging resistance, potential toxicities, and combination therapy. In the battle against rapidly emerging bacterial resistance we can no longer rely entirely on the discovery of new antibiotics; we must also pursue rational approaches to the use of older antibiotics such as colistin.

Topics: Anti-Bacterial Agents; Colistin; Dose-Response Relationship, Drug; Drug Resistance, Multiple; Gram-Negative Bacterial Infections; Humans

Nitrofurantoin, amikacin, colistin, polymyxin B, doxycycline, and minocycline are antibiotics with proven effectiveness against selected pathogens. These antibiotics have not developed resistance over time. As "low-resistance potential antibiotics" that are effective against an increasing number of infections due to resistant gram-positive or gram-negative pathogens, these antimicrobials remain an important part of the antibiotic armamentarium. They will be used increasingly in the future, as highly resistant organisms continue to be important clinically and therapeutic options remain limited.

Topics: Amikacin; Cell Membrane; Colistin; Doxycycline; Drug Resistance, Microbial; Gram-Negative Bacterial Infections; Humans; Methicillin Resistance; Minocycline; Nitrofurantoin; Polymyxin B; Staphylococcal Infections; Urinary Tract Infections

Infections caused by multi-resistant Gram-negative bacteria, particularly Pseudomonas aeruginosa, are increasing worldwide. In patients with cystic fibrosis (CF), resistance in P. aeruginosa to numerous anti-pseudomonal agents is becoming common. The absence since 1995, of new substances active against resistant Gram-negative bacteria, has caused increasing concern. Colistin, an old antibiotic also known as polymyxin E, has attracted more interest recently because of its significant activity against multi-resistant P. aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae, and the low resistance rates to it. Because its use as an anti-pseudomonal agent was displaced by the potentially less toxic aminoglycosides in 1970s, our knowledge of this drug is limited. However, there has been a significant recent increase in the data gathered on colistin, focussing on its chemistry, antibacterial activity, mechanism of action and resistance, pharmacokinetics, pharmacodynamics and new clinical application. It is likely that colistin will be an important antimicrobial option against multi-resistant Gram-negative bacteria, for some years to come.

Topics: Acinetobacter baumannii; Anti-Bacterial Agents; Colistin; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Klebsiella pneumoniae; Microbial Sensitivity Tests; Pseudomonas aeruginosa

The emergence of multidrug-resistant gram-negative bacteria and the lack of new antibiotics to combat them have led to the revival of polymyxins, an old class of cationic, cyclic polypeptide antibiotics. Polymyxin B and polymyxin E (colistin) are the 2 polymyxins used in clinical practice. Most of the reintroduction of polymyxins during the last few years is related to colistin. The polymyxins are active against selected gram-negative bacteria, including Acinetobacter species, Pseudomonas aeruginosa, Klebsiella species, and Enterobacter species. These drugs have been used extensively worldwide for decades for local use. However, parenteral use of these drugs was abandoned approximately 20 years ago in most countries, except for treatment of patients with cystic fibrosis, because of reports of common and serious nephrotoxicity and neurotoxicity. Recent studies of patients who received intravenous polymyxins for the treatment of serious P. aeruginosa and Acinetobacter baumannii infections of various types, including pneumonia, bacteremia, and urinary tract infections, have led to the conclusion that these antibiotics have acceptable effectiveness and considerably less toxicity than was reported in old studies.

Topics: Anti-Bacterial Agents; Colistin; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacterial Infections; Humans

Polymyxin B sulfate and colistin, also known as colistimethate, have not been used for many years because less toxic antimicrobials are available. Gram-negative bacteria that are resistant to the aminoglycosides, beta-lactams, and fluoroquinolones are becoming more common. These bacteria are often susceptible to the polymyxins.. To present a review of the chemistry, antibacterial spectrum, dosing, pharmacokinetics, toxicity, and indications for polymyxin B sulfate and colistin.. A MEDLINE search (1966-1998) of the English-language literature was performed to identify primary literature on the polymyxins. Older citations ( 1949-1965) were identified through the bibliographies of these articles.. All available reports of in vitro antibacterial activity, animal and clinical trials, and case reports were reviewed.. The polymyxins are amphipathic molecules that interact with lipopolysaccharide in the bacterial outer membrane. They have potent antiendotoxic properties and antibacterial activity against Pseudomonas aeruginosa and many of the Enterobacteriaceae. Polymyxin B and colistin are usually given at a dose of 1.5-2.5 and 5 mg/kg/d, respectively, in two divided doses. Dosing must be altered in renal failure since the kidney is the primary route of elimination. Distribution into pleural fluid, joints, and cerebrospinal fluid is poor. Toxic effects involve the kidney and central nervous system. The polymyxins are recommended for serious systemic infections caused by gram-negative bacteria that are resistant to other agents.. Polymyxin B sulfate and colistin have a role in the therapy of multidrug-resistant gram-negative bacterial infections.

Topics: Anti-Bacterial Agents; Colistin; Drug Resistance, Microbial; Drug Resistance, Multiple; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Polymyxin B

Nephrotoxicity remains a major long-standing concern for colistin, and it is critical to find agents that can prevent it. The present study aims to investigate the effect of vitamin E on the prevention of colistin-induced nephrotoxicity based on its antioxidant and free radical scavenging properties.. A randomized clinical trial was designed for 52 patients taking colistin. These patients were categorized into two groups of equal size, receiving colistin or colistin plus vitamin E (α-Tocopherol). Vitamin E with doses of 400 units was administrated daily either orally or by a nasogastric tube if needed. The incidence of Acute Kidney Injury (AKI) and its duration was recorded based on RIFLE criteria.. The Incidence of AKI based on RIFLE criteria was 42.3% and 46.2% in intervention and control groups, respectively. The analysis showed no significant difference in the prevalence of AKI for the two groups (P = 0.78). There was no significant difference in the duration of AKI neither (P = 0.83).. Although vitamin E is a powerful biological antioxidant, the effects of Vitamin E prophylaxis on colistin-induced nephrotoxicity was not taken into consideration in this study.

Topics: Acute Kidney Injury; Anti-Bacterial Agents; Colistin; Gram-Negative Bacterial Infections; Humans; Pharmaceutical Preparations; Retrospective Studies; Risk Factors; Vitamin E

The RESTORE-IMI 1 phase 3 trial demonstrated the efficacy and safety of imipenem-cilastatin (IMI) combined with relebactam (REL) for treating imipenem-nonsusceptible infections. The objective of this analysis was to compare the outcomes among patients meeting eligibility requirements based on central laboratory susceptibility versus local laboratory susceptibility. Patients with serious infections caused by imipenem-nonsusceptible, colistin-susceptible, and imipenem-REL-susceptible pathogens were randomized 2:1 to IMI-REL plus placebo or colistin plus IMI for 5 to 21 days. The primary endpoint was a favorable overall response. Key endpoints included the clinical response and all-cause mortality. We compared outcomes between the primary microbiological modified intent-to-treat (mMITT) population, where eligibility was based on central laboratory susceptibility testing, and the supplemental mMITT (SmMITT) population, where eligibility was based on local, site-level testing. The SmMITT (

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamase Inhibitors; Cilastatin, Imipenem Drug Combination; Colistin; Drug Resistance, Multiple, Bacterial; Endpoint Determination; Female; Gram-Negative Bacterial Infections; Humans; Imipenem; Kidney; Male; Microbial Sensitivity Tests; Middle Aged; Sex Factors; Treatment Outcome; Young Adult

The aim was to analyse the population pharmacokinetics of colistin and to explore the relationship between colistin exposure and time to death.. Patients included in the AIDA randomized controlled trial were treated with colistin for severe infections caused by carbapenem-resistant Gram-negative bacteria. All subjects received a 9 million units (MU) loading dose, followed by a 4.5 MU twice daily maintenance dose, with dose reduction if creatinine clearance (CrCL) < 50 mL/min. Individual colistin exposures were estimated from the developed population pharmacokinetic model and an optimized two-sample per patient sampling design. Time to death was evaluated in a parametric survival analysis.. Out of 406 randomized patients, 349 contributed pharmacokinetic data. The median (90% range) colistin plasma concentration was 0.44 (0.14-1.59) mg/L at 15 minutes after the end of first infusion. In samples drawn 10 hr after a maintenance dose, concentrations were >2 mg/L in 94% (195/208) and 44% (38/87) of patients with CrCL ≤120 mL/min, and >120 mL/min, respectively. Colistin methanesulfonate sodium (CMS) and colistin clearances were strongly dependent on CrCL. High colistin exposure to MIC ratio was associated with increased hazard of death in the multivariate analysis (adjusted hazard ratio (95% CI): 1.07 (1.03-1.12)). Other significant predictors included SOFA score at baseline (HR 1.24 (1.19-1.30) per score increase), age and Acinetobacter or Pseudomonas as index pathogen.. The population pharmacokinetic model predicted that >90% of the patients had colistin concentrations >2 mg/L at steady state, but only 66% at 4 hr after start of treatment. High colistin exposure was associated with poor kidney function, and was not related to a prolonged survival.

Topics: Anti-Bacterial Agents; Bacteria; Carbapenems; Colistin; Critical Illness; Drug Resistance, Bacterial; Gram-Negative Bacterial Infections; Humans

In vitro models showing synergism between polymyxins and carbapenems support combination treatment for carbapenem-resistant Gram-negative (CRGN) infections. We tested the association between the presence of in vitro synergism and clinical outcomes in patients treated with colistin plus meropenem.. This was a secondary analysis of AIDA, a randomized controlled trial comparing colistin with colistin-meropenem for severe CRGN infections. We tested in vitro synergism using a checkerboard assay. Based on the fractional inhibitory concentration (ΣFIC) index for each colistin-meropenem combination, we categorized results as synergistic, antagonistic or additive/indifferent. The primary outcome was clinical failure at 14 days. Secondary outcomes were 14- and 28-day mortality and microbiological failure.. The sample included 171 patients with infections caused by carbapenem-resistant Acinetobacter baumannii (n = 131), Enterobacteriaceae (n = 37) and Pseudomonas aeuruginosa (n = 3). In vitro testing showed synergism for 73 isolates, antagonism for 20 and additivism/indifference for 78. In patients who received any colistin plus meropenem, clinical failure at 14 days was 59/78 (75.6%) in the additivism/indifference group (reference category), 54/73 (74.0%) in the synergism group (adjusted odds ratio (aOR) 0.76, 95% CI 0.31-1.83), and 11/20 (55%) in the antagonism group (aOR 0.77, 95% CI 0.22-2.73). There was no significant difference between groups for any secondary outcome. Comparing the synergism group to patients treated with colistin monotherapy, synergism was not protective against 14-day clinical failure (aOR 0.52, 95% CI 0.26-1.04) or 14-day mortality (aOR1.09, 95% CI 0.60-1.96).. In vitro synergism between colistin and meropenem via checkerboard method did not translate into clinical benefit.

Topics: Aged; Aged, 80 and over; Carbapenems; Colistin; Cross Infection; Drug Resistance, Bacterial; Drug Synergism; Female; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Male; Meropenem; Microbial Sensitivity Tests; Middle Aged; Pneumonia, Bacterial; Treatment Outcome

Colistin is increasingly used as the last therapeutic option for the treatment of multidrug-resistant, Gram-negative bacterial infections. To ensure safe and efficacious use of colistin, therapeutic drug monitoring (TDM) is needed due to its narrow therapeutic window. This study aimed to evaluate the pharmacokinetic (PK) characteristics of colistin and to guide TDM in colistin-treated patients in Korea.. In a prospective study, we analyzed PK characteristics in 15 patients who intravenously received colistin methanesulfonate twice per day. Colistin methanesulfonate doses were adjusted based on renal function of the subjects. The appropriate blood sampling points for TDM were evaluated by analyzing the correlations between the PK parameters and the plasma concentrations at each time point.. The mean values for the minimum, maximum, and average concentrations (Cmin, Cmax, and Caverage) of colistin at steady state were 2.29, 5.5, and 3.38 mg/L, respectively. The dose-normalized Cmin, Cmax, Caverage, and area under the plasma concentration-time curve from 0 to the last measurable concentration (AUClast) showed negative correlations with the creatinine clearance. The combination of the 0- and 2-hour post-dose plasma concentrations was evaluated as the appropriate sampling point for TDM. Two patients reported nephrotoxic adverse events during colistin administration.. Our study clarifies the PK characteristics of successful colistin treatment using TDM. Further evaluations in a larger patient population are needed to confirm the clinical usefulness of colistin TDM.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Colistin; Drug Monitoring; Drug Resistance, Multiple, Bacterial; Female; Gram-Negative Bacterial Infections; Humans; Infusions, Intravenous; Male; Microbial Sensitivity Tests; Middle Aged; Prospective Studies; Republic of Korea

Colistin-carbapenem combinations are synergistic in vitro against carbapenem-resistant Gram-negative bacteria. We aimed to test whether combination therapy improves clinical outcomes for adults with infections caused by carbapenem-resistant or carbapenemase-producing Gram-negative bacteria.. A randomised controlled superiority trial was done in six hospitals in Israel, Greece, and Italy. We included adults with bacteraemia, ventilator-associated pneumonia, hospital-acquired pneumonia, or urosepsis caused by carbapenem-non-susceptible Gram-negative bacteria. Patients were randomly assigned (1:1) centrally, by computer-generated permuted blocks stratified by centre, to intravenous colistin (9-million unit loading dose, followed by 4·5 million units twice per day) or colistin with meropenem (2-g prolonged infusion three times per day). The trial was open-label, with blinded outcome assessment. Treatment success was defined as survival, haemodynamic stability, improved or stable Sequential Organ Failure Assessment score, stable or improved ratio of partial pressure of arterial oxygen to fraction of expired oxygen for patients with pneumonia, and microbiological cure for patients with bacteraemia. The primary outcome was clinical failure, defined as not meeting all success criteria by intention-to-treat analysis, at 14 days after randomisation. This trial is registered at ClinicalTrials.gov, number NCT01732250, and is closed to accrual.. Between Oct 1, 2013, and Dec 31, 2016, we randomly assigned 406 patients to the two treatment groups. Most patients had pneumonia or bacteraemia (355/406, 87%), and most infections were caused by Acinetobacter baumannii (312/406, 77%). No significant difference between colistin monotherapy (156/198, 79%) and combination therapy (152/208, 73%) was observed for clinical failure at 14 days after randomisation (risk difference -5·7%, 95% CI -13·9 to 2·4; risk ratio [RR] 0·93, 95% CI 0·83-1·03). Results were similar among patients with A baumannii infections (RR 0·97, 95% CI 0·87-1·09). Combination therapy increased the incidence of diarrhoea (56 [27%] vs 32 [16%] patients) and decreased the incidence of mild renal failure (37 [30%] of 124 vs 25 [20%] of 125 patients at risk of or with kidney injury).. Combination therapy was not superior to monotherapy. The addition of meropenem to colistin did not improve clinical failure in severe A baumannii infections. The trial was unpowered to specifically address other bacteria.. EU AIDA grant Health-F3-2011-278348.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; beta-Lactam Resistance; Colistin; Drug Therapy, Combination; Female; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Greece; Humans; Israel; Italy; Male; Meropenem; Middle Aged; Single-Blind Method; Treatment Outcome

Empirical colistin should be avoided. We aimed to evaluate the association between covering empirical antibiotics (EAT) and mortality for infections caused by carbapenem-resistant gram-negative bacteria (CRGNB).. This was a secondary analysis of a randomized controlled trial, including adults with bloodstream infections, pneumonia, or urosepsis caused by CRGNB. All patients received EAT followed by covering targeted therapy. The exposure variable was covering EAT in the first 48 hours. The outcome was 28-day mortality. We adjusted the analyses by multivariable regression analysis and propensity score matching.. The study included 406 inpatients with severe CRGNB infections, mostly Acinetobacter baumannii (312/406 [77%]). Covering EAT was given to 209 (51.5%) patients, mostly colistin (n = 200). Patients receiving noncovering EAT were older, more frequently unconscious and dependent, carrying catheters, and mechanically ventilated with pneumonia. Mortality was 84 of 197 (42.6%) with noncovering vs 96 of 209 (45.9%) with covering EAT (P = .504). Covering EAT was not associated with survival in the adjusted analysis; rather, there was a weak association with mortality (odds ratio [OR], 1.37; 95% confidence interval [CI], 1.02-1.84). Results were similar for colistin monotherapy and colistin-carbapenem combination EAT. In the propensity score-matched cohort (n = 338) covering antibiotics were not significantly associated with mortality (OR, 1.42; 95% CI, .91-2.22). Similar results were obtained in an analysis of 14-day mortality.. Empirical use of colistin before pathogen identification, with or without a carbapenem, was not associated with survival following severe infections caused by CRGNBs, mainly A. baumannii.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Aged; Aged, 80 and over; Anti-Bacterial Agents; Carbapenems; Colistin; Drug Resistance, Bacterial; Drug Therapy, Combination; Female; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Male; Middle Aged; Multivariate Analysis; Prospective Studies; Treatment Outcome

Nephrotoxicity has been a concern with new dosing regimens of colistin. This study was designed to compare nephrotoxicity of high dose and conventional dose of colistin and the ability of detecting it using neutrophil gelatinase-associated lipocalin (NGAL).. A randomized clinical trial was carried out on 40 patients with multidrug-resistant gram-negative infections assigned into 2 groups to receive high and conventional doses of colistin. Blood samples were taken 4 times for measuring serum NGAL. The incidence of acute kidney injury was also evaluated based on the risk, injury, failure, loss, end-stage renal disease (RIFLE) criteria.. Baseline levels of NGAL were not significantly different between the patients on the high dose and conventional dose of colistin. The mean NGAL levels on day 10 were 762.14 ± 415.44 pg/mL and 623.67 ± 272.61 pg/mL, respectively.  However, between-group analysis did not show a significant difference in the NGAL levels. The prevalence of acute kidney injury was 60% and 15% based on the RIFLE criteria, in the high-dose and conventional-dose groups, respectively (P = .003).. Although colistin-induced nephrotoxicity was not confirmed with NGAL levels, our findings, however, showed a higher incidence of acute kidney injury associated with high-dose colistin, defined by the RIFLE criteria. Higher levels of NGAL in the acute kidney injury patients were associated with high-dose regimen of colistin.

Topics: Acute Kidney Injury; Adult; Aged; Anti-Bacterial Agents; APACHE; Biomarkers; Colistin; Drug Resistance, Multiple, Bacterial; Female; Gram-Negative Bacterial Infections; Humans; Incidence; Iran; Lipocalin-2; Male; Middle Aged; Predictive Value of Tests; Prevalence; Risk Factors; Time Factors; Treatment Outcome

Nephrotoxicity is a dose-limiting factor of colistin, a last-line therapy for multidrug-resistant Gram-negative bacterial infections. An earlier animal study revealed a protective effect of ascorbic acid against colistin-induced nephrotoxicity. The present randomized controlled study was conducted in 28 patients and aimed to investigate the potential nephroprotective effect of intravenous ascorbic acid (2 g every 12 h) against colistin-associated nephrotoxicity in patients requiring intravenous colistin. Thirteen patients received colistin plus ascorbic acid, whereas 15 received colistin alone. Nephrotoxicity was defined by the RIFLE classification system. Additionally, urinary neutrophil gelatinase-associated lipocalin (NGAL) and N-acetyl-beta-d-glucosaminidase (NAG) were measured as markers of renal damage, and plasma colistin concentrations were quantified. The baseline characteristics, clinical features, and concomitant treatments of the patients in the two groups were comparable. The incidences of nephrotoxicity were 53.8% (7/13) and 60.0% (9/15) in the colistin-ascorbic acid group and the colistin group, respectively (P = 0.956; relative risk [RR], 0.9; 95% confidence interval, 0.47 to 1.72). In both groups, the urinary excretion rates of NGAL and NAG on day 3 or 5 of colistin treatment and at the end of colistin treatment were significantly higher than those at the respective baselines (P < 0.05). However, the urinary excretion rates of these biomarkers at the various times during colistin treatment did not differ significantly between the groups (P > 0.05). The plasma colistin concentrations in the two groups were not significantly different (P > 0.28). The clinical and microbiological outcomes and mortality of the patients in the two groups were not significantly different. This preliminary study suggests that ascorbic acid does not offer a nephroprotective effect for patients receiving intravenous colistin. (This study has been registered at ClinicalTrials.gov under registration no. NCT01501968.).

Topics: Acetylglucosaminidase; Acute-Phase Proteins; Adult; Aged; Animals; Anti-Bacterial Agents; Ascorbic Acid; Colistin; Female; Gram-Negative Bacterial Infections; Humans; Kidney; Lipocalin-2; Lipocalins; Male; Middle Aged; Proto-Oncogene Proteins

Ventilator-associated pneumonia (VAP) is one of the most common and severe hospital-adquired infections, and multidrugresistant gram-negative bacilli (MDR-GNB) constitute the main etiology in many countries. Inappropriate empiric antimicrobial treatment is associated with increased mortality. In this context, the empirical treatment of choice for VAP is unknown. Colistin, is now the antimicrobial with greatest in vitro activity against MDR-GNB.. The MagicBullet clinical trial is an investigator-driven clinical study, funded by the Seventh Framework Program of the European Commission. This is designed as a phase IV, randomized, controlled, open label, non-inferiority and international trial to assess the safety and efficacy of colistin versus meropenem in late onset VAP. The study is conducted in a total of 32 centers in three European countries (Spain, Italy and Greece) with specific high incidences of infections caused by MDR-GNB. Patients older than 18 years who develop VAP with both clinical and radiological signs, and are on mechanical ventilation for more than 96 hours, or less than 96 hours but with previous antibiotic treatment plus one week of hospitalization, are candidates for inclusion in the study. A total sample size of 496 patients will be randomized according to a severity clinical score (at the time of VAP diagnosis in a 1:1 ratio to receive either colistin 4.5 MU as a loading dose, followed by 3 MU every eight hours (experimental arm), or meropenem 2 g every eight hours (control arm), both combined with levofloxacin. Mortality from any cause at 28 days will be considered as the main outcome. Clinical and microbiological cure will be evaluated at 72 hours, eight days, the finalization of antibiotic treatment, and 28 days of follow-up. The efficacy evaluation will be performed in every patient who receives at least one study treatment drug, and with etiologic diagnosis of VAP, intention-to-treat population and per protocol analysis will be performed.. Currently, there is no study being undertaken which analyzes empiric treatment of (VAP) with a suspicion of multi-resistance. Colistin, an off-patent antibiotic commercialized for more than 60 years, could widen the antibiotic alternatives for a high-mortality illness aggravated by antibiotic resistance.. This trial is registered with ClinicalTrials.gov (identifier: NCT01292031 ; registered on 29 June 2012) and EudraCT (identifier: 2010-023310-31; registered on 7 February 2011).

Topics: Anti-Bacterial Agents; Clinical Protocols; Colistin; Drug Resistance, Multiple, Bacterial; Europe; Gram-Negative Bacterial Infections; Humans; Incidence; Meropenem; Patents as Topic; Pneumonia, Ventilator-Associated; Research Design; Thienamycins; Time Factors; Treatment Outcome

Colistin, which had not been used widely because of nephrotoxicity and neurotoxicity, has gained clinical importance in recent times due to the resurgence of multidrug-resistant Gram-negative bacilli. Very few studies, especially pharmacokinetic studies, have been performed with intravenous colistimethate sodium, and none in India. The aim of our study was to study the single-dose and steady-state pharmacokinetics of colistin in patients with multidrug-resistant Gram-negative bacilli infections.. This was a prospective open-label pharmacokinetic study done in an intensive care unit in a tertiary care hospital on 15 critically ill patients with proven multidrug-resistant Gram-negative bacilli infection. Colistimethate sodium was injected as intermittent intravenous infusions in accordance with the recommendations on the package insert. For patients weighing ≥ 60 kg with a normal renal function or with a creatinine clearance (CL(CR)) of between 20 and 50 ml/min, the drug was administered at 2 million international units (MIU) every 8 h; for those with a CL(CR) of 10-20 ml/min, the dose was 2 MIU every 12 h. Those patients who weighed <60 kg were administered 50,000 IU/kg/day in three divided doses at 8-h intervals. Both single-dose and steady-state pharmacokinetics of colistin were determined and correlated with clinical outcomes.. A wide inter-individual variation was observed in pharmacokinetic parameters. The median (range) of the maximum plasma drug concentration/minimum inhibitory concentration (C(max)/MIC) ratio for Acinetobacter spp. was 13.4 (1.3-40.3) following the administration of a single dose of colistimethate sodium and 26.3 (0.9-64.9) at steady-state. For Pseudomonas spp., these values were 3.18 (1.6-23.1) following the single dose and 3.82 (2.3-10.9) at steady-state. For those patients whose cultures grew Acinetobacter spp., an optimum value of the C(max)/MIC ratio of >8 was achieved in seven of nine patients after the single dose and in seven of eight patients at steady-state. For those patients whose cultures grew Pseudomonas spp, only one patient after the single dose and one patient at steady-state achieved a C(max)/MIC ratio of >8. A significant association was noted between dose and survival, and a trend was observed with patients weighing ≤ 60 kg (who received 50,000 IU/kg/day instead of 6 MIU/day for those >60 kg) having an increased mortality.. The pharmacokinetic parameters of colistin were comparable to those reported in previous studies in critically ill patients. However, the recommended dose may be inadequate to maintain the C(max)/MIC ratio to an optimal level-at least in patients infected with Pseudomonas spp. The dose recommendation should be based only on creatinine clearance and not body weight.

Topics: Acinetobacter; Adolescent; Adult; Anti-Bacterial Agents; Colistin; Drug Resistance, Multiple, Bacterial; Female; Gram-Negative Bacterial Infections; Humans; India; Infusions, Intravenous; Intensive Care Units; Kidney; Klebsiella pneumoniae; Male; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Pseudomonas; Renal Insufficiency; Tertiary Care Centers; Young Adult

Cases of ventilator-associated pneumonia (VAP) due to multidrug-resistant (MDR) Acinetobacter baumannii and Pseudomonas aeruginosa are common in hospitalized patients at Siriraj Hospital, Bangkok, Thailand. Parenteral colistimethate sodium (CMS) has been used for therapy of VAP caused by MDR A. baumannii and P. aeruginosa at Siriraj Hospital over the past few years, with modest favourable outcomes. Objectives To determine whether nebulized CMS as adjunctive therapy of Gram-negative VAP was safe and beneficial.. This was a randomized controlled study in 100 adults who developed Gram-negative VAP (clinical trial registration number: NCT00920270). All patients received systemic antibiotics according to the decisions of their responsible physicians. The patients were randomized to receive an additional 4 mL of nebulized sterile normal saline (NSS) (n = 49) or nebulized CMS equivalent to 75 mg of colistin base in 4 mL of NSS (n = 51) every 12 h until systemic antibiotic therapy of VAP was ended.. The baseline characteristics of the patients and conventional therapy of VAP in both groups were comparable. Most of the cases of VAP were caused by MDR A. baumannii and/or P. aeruginosa. All isolates of Gram-negative bacteria were susceptible to colistin. Favourable clinical outcome was 51.0% in the CMS group and 53.1% in the control group (P = 0.84). Patients in the CMS group had significantly more favourable microbiological outcome when compared with patients in the control group (60.9% versus 38.2%, P = 0.03). Bronchospasm was observed in 7.8% of patients in the CMS group and in 2.0% of patients in the control group (P = 0.36). Renal impairment was observed in 25.5% of patients in the CMS group and in 22.4% of patients in the NSS group (P = 0.82).. Nebulized CMS as adjunctive therapy of Gram-negative VAP seems to be safe. However, a beneficial effect on clinical outcomes of adjunctive nebulized CMS for therapy of Gram-negative VAP was not ascertained.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Colistin; Cross Infection; Female; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Male; Middle Aged; Nebulizers and Vaporizers; Pneumonia, Bacterial; Pneumonia, Ventilator-Associated; Treatment Outcome

Colistin is used to treat infections caused by multidrug-resistant gram-negative bacteria (MDR-GNB). It is administered intravenously in the form of colistin methanesulfonate (CMS), which is hydrolyzed in vivo to the active drug. However, pharmacokinetic data are limited. The aim of the present study was to characterize the pharmacokinetics of CMS and colistin in a population of critically ill patients. Patients receiving colistin for the treatment of infections caused by MDR-GNB were enrolled in the study; however, patients receiving a renal replacement therapy were excluded. CMS was administered at a dose of 3 million units (240 mg) every 8 h. Venous blood was collected immediately before and at multiple occasions after the first and the fourth infusions. Plasma CMS and colistin concentrations were determined by a novel liquid chromatography-tandem mass spectrometry method after a rapid precipitation step that avoids the significant degradation of CMS and colistin. Population pharmacokinetic analysis was performed with the NONMEM program. Eighteen patients (6 females; mean age, 63.6 years; mean creatinine clearance, 82.3 ml/min) were included in the study. For CMS, a two-compartment model best described the pharmacokinetics, and the half-lives of the two phases were estimated to be 0.046 h and 2.3 h, respectively. The clearance of CMS was 13.7 liters/h. For colistin, a one-compartment model was sufficient to describe the data, and the estimated half-life was 14.4 h. The predicted maximum concentrations of drug in plasma were 0.60 mg/liter and 2.3 mg/liter for the first dose and at steady state, respectively. Colistin displayed a half-life that was significantly long in relation to the dosing interval. The implications of these findings are that the plasma colistin concentrations are insufficient before steady state and raise the question of whether the administration of a loading dose would benefit critically ill patients.

Topics: Adult; Aged; Aged, 80 and over; Chromatography, Liquid; Colistin; Critical Illness; Drug Resistance, Multiple, Bacterial; Female; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Infusions, Intravenous; Male; Middle Aged; Tandem Mass Spectrometry

Colistin, an antibiotic almost abandoned for intravenous administration for many years due to its reported toxicity, has been recently reintroduced in clinical practice due to the emergence of multidrug-resistant gram-negative bacteria and the lack of development of new antibiotics to combat them. To assess the safety and effectiveness of intravenous colistin, in combination with other antimicrobial agents, in the treatment of serious infections in patients without cystic fibrosis, a retrospective cohort study in a 450-bed tertiary-care hospital in Athens, Greece, was performed. Patients who were hospitalized from 1 October 2000 to 31 January 2004 and received intravenous colistin for more than 72 h were further analyzed. The primary outcome measure was the in-hospital mortality; secondary end points were the clinical outcome of the infections and the occurrence of colistin toxicity. Fifty patients received intravenous colistin with a median (mean) daily dose of 3 (4.5) million IU for 16.5 (21.3) days for the management of 54 episodes of infections due to multidrug-resistant gram-negative bacteria. The predominant infections were pneumonia (33.3%), bacteremia (27.8%), urinary tract infection (11.1%), and intra-abdominal infection (11.1%). The responsible pathogens were Acinetobacter baumannii (51.9%), Pseudomonas aeruginosa (42.6%), and Klebsiella pneumoniae (3.7%) strains (no pathogen was isolated from one case). In-hospital mortality was 24% (12/50 patients). Clinical response (cure or improvement) of the infection was observed in 66.7% of episodes (36/54). In the studied group, serum creatinine levels were decreased, at the end of colistin treatment, by an average of 0.2 +/- 1.3 mg/dl compared to baseline levels. Deterioration of renal function during colistin therapy was observed in 4/50 patients (8%). Coadministration of other antimicrobial agents with spectrum against gram-negative microorganisms and the absence of a control group constitute the major limitations of this study. The use of intravenous colistin for the treatment of infections due to multidrug-resistant gram-negative bacteria appears to be safe and effective.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Colistin; Cystic Fibrosis; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Female; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Kidney Function Tests; Male; Microbial Sensitivity Tests; Middle Aged; Treatment Outcome

Twenty-one patients who received intravenous colistimethate sodium (CMS) for at least 7 days for the treatment of multidrug-resistant Gram-negative bacterial infections were included in a prospective cohort study at 'Henry Dunant' Hospital in Athens, Greece. The mean (+/- standard deviation) and median daily doses, cumulative doses and duration of treatment of intravenous CMS were, respectively, 5.5 (+/- 1.9) and 6 million IU, 90.2 (+/- 52.0) and 72 million IU, and 17.7 (+/- 11.7) and 15 days (range 7-54 days). Three patients (14.3%) developed nephrotoxicity during treatment with CMS. The cumulative dose of administered CMS was statistically correlated with the difference in values of serum creatinine between the end and start of CMS treatment (r = 0.6, P = 0.004 by Spearman's test).

Topics: Acute Kidney Injury; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Cohort Studies; Colistin; Creatinine; Female; Gram-Negative Bacterial Infections; Greece; Humans; Injections, Intravenous; Kidney Function Tests; Male; Middle Aged; Nephrotic Syndrome; Prospective Studies; Treatment Outcome

The increasing prevalence of multiresistant Gram-negative strains in intensive care units (ICUs) has recently rekindled interest in colistin, a bactericidal antibiotic that was used in the 1960s for treatment of infections caused by Gram-negative bacilli. We conducted the present observational study to evaluate the efficacy of intravenous colistin in the treatment of critically ill patients with sepsis caused by Gram-negative bacilli resistant to all other antibiotics.. Critically ill patients with sepsis caused by Gram-negative bacilli resistant to all antibiotics with the exception of colistin were treated in the six-bed ICU of a trauma hospital. Diagnosis of infection was based on clinical data and isolation of bacteria, and the bacteria were tested with respect to their susceptibility to colistin. Clinical response to colistin was evaluated.. Twenty-four patients (mean age 44.3 years, mean Acute Physiology and Chronic Health Evaluation II score 20.6) received 26 courses of colistin. Clinical response was observed for 73% of the treatments. Survival at 30 days was 57.7%. Deterioration in renal function was observed in 14.3% of 21 patients who were not already receiving renal replacement therapy, but in only one case did this deterioration have serious clinical consequences.. The lack of a control group in the present study does not allow any definite conclusions to be drawn regarding the clinical effectiveness of colistin. On the other hand, this drug has an acceptable safety profile and its use should be considered in severe infections with multiresistant Gram-negative bacilli.

Topics: Acinetobacter baumannii; Adult; Anti-Bacterial Agents; Colistin; Critical Illness; Drug Resistance, Multiple; Female; Gram-Negative Bacterial Infections; Humans; Intensive Care Units; Male; Middle Aged; Pseudomonas aeruginosa; Sepsis

One hundred and eighteen (118) episodes of bacteremia and fungemia in children with cancer were compared to 401 episodes of bacteremia and fungemia in adults with cancer to assess differences in etiology, risk factors and outcome. A retrospective univariate analysis was performed of all episodes of bacteremia in national pediatric and adult cancer institutions appearing in 1990-1996. A total of 519 episodes of bacteremia were assessed and compared. Both cancer centers differed in prophylactic antibiotic policies. About 50% of adults but less than 5% of children received quinolone prophylaxis during neutropenia, even though the empiric antibiotic therapeutic strategy was similar. There were differences in etiology between the groups: staphylococci and Stenotrophomonas maltophilia were more frequently observed in children (P<0.01), Pseudomonas aeruginosa and Acinetobacter spp. in adults (P<0.05). Gram-positive bacteremia was surprisingly more commonly observed in adults (65.7% vs 33.3%, P<0.01). Mixed polymicrobial bacteremia occurred more commonly in adults (31.8% vs 7.6%, P<0.001) than in children. Analysis of risk factors did not observe differences in risk factors except for underlying disease (acute leukemia was more frequently observed in children -48.3% vs adults 33.7%, P<0.05 and prophylaxis: (prior prophylaxis with quinolones was more common in adults (47.5%) than in children (2.5%) P<0.0001). Overall and attributable mortality in pediatric bacteremia was significantly lower than in adults (P<0.03).

Topics: Adult; Analysis of Variance; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotic Prophylaxis; Antifungal Agents; Antineoplastic Agents; Bacteremia; Child; Colistin; Fluconazole; Fungemia; Gram-Negative Bacterial Infections; Gram-Positive Bacterial Infections; Humans; Neoplasms; Neutropenia; Ofloxacin; Penicillin V; Penicillins; Retrospective Studies; Risk Factors; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination

Aztreonam (Az), a minimally absorbable monobactam antibiotic, was compared to colistin plus neomycin (CN), for intestinal decontamination during Bone Marrow Transplantation (BMT) in a controlled study. Thirty-four consecutive patients were randomized in two groups and evaluated for number of febrile episodes, days of fever, fecal cultures and clinical symptoms related to infections or colonizations. No significant differences were observed suggesting that Az is at least as effective as the CN regimen and may be considered as an alternative approach for intestinal decontamination in BMT patients.

Topics: Aztreonam; Bone Marrow Transplantation; Colistin; Digestive System Diseases; Drug Therapy, Combination; Feces; Fever; Gram-Negative Bacterial Infections; Humans; Immunocompromised Host; Neomycin; Risk Factors; Time Factors

230 leukaemic patients were entered into a randomised, prospective, multicentre trial of either ciprofloxacin (1 g/day) or co-trimoxazole (1920 mg/day) plus colistin (800 mg/day) for the prevention of infection during granulocytopenia. Bacteraemia due to resistant gram-negative rods occurred only in the co-trimoxazole-colistin group though both regimens were effective for selective gastrointestinal tract decontamination. However, there were fewer patients without any infective complications (31% vs. 18%: P = 0.02), fewer febrile days [mean (S.D.) 5.9 (1.1) vs. 8.2 (1.4): P = 0.0242], a lower proportion of infective events (0.9 (0.16) vs. 1.2 (0.18): P = 0.005) and fever occurred later (median 19 vs. 14 days: 0.025 less than P less than 0.05) in the co-trimoxazole-colistin group. The choice of prophylactic regimen therefore appears to depend upon whether or not protection against gram-negative infection is required or better systemic prophylaxis overall.

Topics: Administration, Oral; Adolescent; Adult; Aged; Agranulocytosis; Ciprofloxacin; Colistin; Drug Therapy, Combination; Female; Gram-Negative Bacterial Infections; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Premedication; Prospective Studies; Trimethoprim, Sulfamethoxazole Drug Combination

Selective decontamination of the digestive tract with topical nonabsorbable antibiotics has been reported to prevent nosocomial infections in patients receiving mechanical ventilation, and the procedure is used widely in Europe. However, it is unclear whether selective decontamination improves survival.. We conducted a randomized, double-blind multicenter study in which 445 patients receiving mechanical ventilation in 15 intensive care units were given either prophylactic nonabsorbable antibiotics (n = 220) or a placebo (n = 225). Topical antibiotics (tobramycin, colistin sulfate, and amphotericin B) or a placebo was administered through a nasogastric tube and applied to the oropharynx throughout the period of ventilation. The main end points were the mortality rate in the intensive care unit and within 60 days of randomization.. A total of 142 patients died in the intensive care unit; 75 (34 percent) in the treatment group and 67 (30 percent) in the placebo group (P = 0.37). Mortality within 60 days of randomization was similar in the two groups (P = 0.40), even after adjustment for factors that were either unbalanced or individually predictive of survival in the two groups (P = 0.70). Pneumonia developed in 59 patients (13 percent) in the intensive care unit within 30 days of enrollment in the study (33 in the placebo group and 26 in the treatment group, P = 0.42). Pneumonia acquired in the intensive care unit and due to gram-negative bacilli was less frequent (P = 0.01) in the treatment group than in the placebo group. The total charges for antibiotics were 2.2 times higher in the treatment group.. Selective decontamination of the digestive tract does not improve survival among patients receiving mechanical ventilation in the intensive care unit, although it substantially increases the cost of their care.

Topics: Administration, Topical; Amphotericin B; Anti-Bacterial Agents; Colistin; Critical Care; Cross Infection; Digestive System; Double-Blind Method; Female; Gram-Negative Bacterial Infections; Humans; Intensive Care Units; Male; Middle Aged; Multiple Organ Failure; Pneumonia; Respiration, Artificial; Survival Rate; Time Factors; Tobramycin

Polymyxins (polymyxin B and colistin) are lipopeptide antibiotics used as a last-line treatment for life-threatening multidrug-resistant (MDR) Gram-negative bacterial infections. Unfortunately, their clinical use has been affected by dose-limiting toxicity and increasing resistance. Structure-activity (SAR) and structure-toxicity (STR) relationships are paramount for the development of safer polymyxins, albeit very little is known about the role of the conserved position 10 threonine (Thr) residue in the polymyxin core scaffold. Here, we synthesized 30 novel analogues of polymyxin B

Topics: Anti-Bacterial Agents; Colistin; Gram-Negative Bacterial Infections; Humans; Polymyxin B; Polymyxins

The 68-year-old patient presented with fever, general malaise and physical weakness in neutropenia during a known relapse of acute myeloid leukaemia after allogeneic stem cell transplantation.. Due to immune suppression, an empiric antibiotic therapy with piperacillin/tazobactam was started. The 4MRGN screening was positive. For this reason, therapy was switched empirically to ceftazidime/avibactam plus colistin. A tongue ulcer with abscess formation and phlegmonous soft tissue reaction was revealed as the focus of the infection. Several microbiological probes including a blood culture discovered. Die Vorstellung der 68-jährigen Patientin erfolgte bei hohem Fieber, allgemeinem Unwohlseisn und körperlicher Schwäche in der Neutropenie bei Rezidiv einer akuten myeloischen Leukämie nach allogener Stammzelltransplantation.. Aufgrund der bestehenden Immundefizienz wurde eine kalkulierte antibiotische Therapie mit Piperacillin/Tazobactam begonnen. Bei positivem 4MRGN-Screening wurde diese kalkuliert auf Colistin und Ceftazidim/Avibactam umgestellt. Diagnostiziert wurde ein Zungenulkus mit Abszessbildung und phlegmonöser Weichteilreaktion. In mehreren mikrobiologischen Proben, inklusive einer Blutkultur, gelang der Nachweis eines. Vierfach multiresistente gramnegative Bakterien (4MRGN) sind aufgrund ihrer Resistenz gegenüber 4 bakterizid wirkenden Hauptantibiotikagruppen (Acylureidopenicilline, Cephalosporine der 3. Generation, Carbapeneme, Fluorchinolone) nur schwer therapierbar. Der vorliegende Fall zeigt für Cefiderocol eine gute klinische Wirksamkeit – auch bei Erregern, die gegen Antibiotika wie Colistin und Ceftazidim/Avibactam resistent sind und er verdeutlicht, wie wichtig eine antibiogrammgerechte Therapie ist.

Topics: Aged; Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamases; Cefiderocol; Ceftazidime; Cephalosporins; Colistin; Communicable Diseases; Drug Combinations; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Klebsiella pneumoniae; Microbial Sensitivity Tests; Neoplasm Recurrence, Local; Neutropenia

Topics: Anti-Bacterial Agents; Colistin; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Infant, Newborn; Microbial Sensitivity Tests; Tertiary Healthcare

With the difficulties in choosing colistin sulfate and polymyxin B sulfate (PBS) for carbapenem-resistant gram-negative bacteria (CR-GNB), we compared the efficacy and safety of these two old polymyxins in treatment of critically ill patients infected with CR-GNB infection.. One hundred four patients infected with CR-GNB in ICU were retrospectively grouped by PBS (68 patients) or colistin sulfate (36 patients). Clinical efficacy including symptoms, inflammatory parameters, defervescence, prognosis and microbial efficacy were analyzed. Hepatotoxicity, nephrotoxicity, and hematotoxicity were evaluated by TBiL, ALT, AST, creatinine, and thrombocytes.. Demographic characteristics between colistin sulfate and PBS were not significantly different. Most of the CR-GNB were cultured in respiratory tract (91.7% vs 86.8%), and almost all were polymyxin-sensitive (98.2% vs 100%, MIC ≤ 2 μg/ml). The microbial efficacy in colistin sulfate (57.1%) was significantly higher than PBS (30.8%) (p = 0.022), however, no significant difference in clinical success was seen in both groups (33.8% vs 41.7%), as well as mortality, defervescence, imaging remission, days in the hospital, microbial reinfections, and prognosis, and almost all patients defervesce within 7 days (95.6% vs 89.5%).. Both polymyxins can be administrated in critically ill patients infected with CR-GNB and colistin sulfate is superior to PBS in microbial clearance. These results highlight the necessity of identifying CR-GNB patients who may benefit from polymyxin and who are at higher risk of mortality.

Topics: Anti-Bacterial Agents; Carbapenems; Colistin; Critical Illness; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Polymyxin B; Polymyxins; Retrospective Studies

Antibiotic colistin is the last line of defense against multidrug-resistant (MDR) Gram-negative bacterial infections. Emergence of colistin resistance in microbes is a critical challenge. Herein, curcumin is discovered, for the first time, to reverse the resistance phenotype of colistin-resistant bacteria via a checkerboard assay. For the co-delivery of curcumin and colistin, negatively charged poly(ethylene glycol)-functionalized liposomes encapsulating both drugs (Lipo-cc) are prepared. Killing kinetics and live/dead assays confirm the antibacterial activity of Lipo-cc against colistin-resistant bacteria, which is more potent than that of the free curcumin and colistin combination. Mechanistical studies reveal that Lipo-cc restores the affinity of colistin for the bacterial membrane and improves the uptake of curcumin, which leads to reduced efflux pump activity, achieving a synergistic effect of colistin and curcumin. At the effective antibacterial dose, Lipo-cc does not exhibit any toxicity. The therapeutic efficacy of Lipo-cc is further demonstrated in an intestinal bacterial infection model induced with colistin-resistant Escherichia coli. Lipo-cc reduces the bacterial burden with over 6-log reduction and alleviated inflammation caused by infection. Importantly, unlike colistin, Lipo-cc does not affect the homeostasis of the intestinal flora. Taken together, Lipo-cc successfully overcame colistin resistance, indicating its potential for the treatment of colistin-resistant bacterial infections.

Topics: Anti-Bacterial Agents; Colistin; Curcumin; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; Escherichia coli; Gram-Negative Bacterial Infections; Humans; Liposomes; Microbial Sensitivity Tests

Colistin is an antibiotic of last resort for treating Gram-negative bacterial infections, but resistance is spreading rapidly. In a recent issue of Nature, Wang et al. use genome mining to identify and synthesize a natural variant that bypasses colistin resistance and offers new hope for tackling antimicrobial resistance.

Topics: Anti-Bacterial Agents; Colistin; Drug Resistance; Gram-Negative Bacterial Infections; Humans

Preservation fluid (PF) contamination, especially by multidrug-resistant (MDR) Gram-negative bacteria (GNB), poses a high risk of donor-derived infection (DDI) and severe clinical outcomes. We sought to determine whether the use of colistin sulfate to decontaminate PF in kidney transplantation can decrease the incidence of probable DDI (p-DDI) caused by MDR GNB.. In a retrospective study of 916 recipients who received deceased donation, 864 PF samples were collected and cultured, and microbiological contaminants were recorded with the recipients' clinical data and outcomes. From March 2016 to May 2019, 624 samples were decontaminated with ceftizoxime, and from June 2019 to March 2021, 240 samples were decontaminated with colistin sulfate. Between-group comparisons were performed to assess the ability of the two decontamination regimens to decrease the incidence of p-DDI, especially MDR GNB-related infection.. The overall PF contamination rate was 54.51% (471/864), and 80 samples were positive for MDR GNB contamination. All p-DDIs occurred in the ceftizoxime group (p < 0.001), and 67.65% of p-DDIs were MDR GNB-related. In the ceftizoxime group, 23 of 61 cases of MDR GNB contamination led to related p-DDIs, while none occurred in the colistin sulfate group (p = 0.002). Among the 23 patients with p-DDIs, 5 died due to severe infection, and 2 experienced graft loss.. The goal of decontamination should be to decrease the risk of MDR GNB-related p-DDI, and colistin sulfate could be an effective and feasible option.

Topics: Anti-Bacterial Agents; Ceftizoxime; Colistin; Decontamination; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Incidence; Kidney Transplantation; Retrospective Studies

Colistin, considered a drug of last resort as it is effective towards multidrug-resistant Gram-negative bacterial infections. Oral administration of colistin in the poultry industry is a common practice, not only to prevent and reduce bacterial infections, but also as a rapid-growth promoter. Long-term exposure to any antibiotic will eventually lead to the development of bacterial resistance towards all antibiotics through various mechanisms in the physiological system and environment. Chicken is the most consumed source of animal protein for humans throughout the world. In addition, the manure of poultry, containing traces of the used antibiotics, is being used in farming. Exposure to excess amounts of colistin causes a great concern not only to the humans but to the environment as a whole. In the present contribution, colistin has been detected in chicken hepatocyte cells through in vivo confocal microscopy. In addition, the amount of colistin in the chicken excrements has been estimated. A simple chemosensor NAF, a dye-based on napthaldehyde furfural, was developed for the detection of colistin, supplemented with experimental evidence and theoretical calculations.

Topics: Animals; Anti-Bacterial Agents; Bacterial Infections; Colistin; Drug Resistance, Bacterial; Fluorescence; Gram-Negative Bacterial Infections; Microbial Sensitivity Tests

The drug resistance is higher among Gram-negative bacteria and demands the usage of strong antibiotics which can in turn result in systemic toxicity. In the treatment of the chronic wounds harboring pathogenic Gram-negative bacteria, the demand for an antimicrobial product that can be topically administered has been on the rise. In an effort to address the above issue, we have developed Colistimethate sodium (a high-end antibiotic) loaded chitosan hydrogel and characterized. The prepared hydrogel is very stable and observed to be bio- and hemo-compatible in nature. The antibacterial activity of the prepared hydrogel was studied against both ATCC (American Type Culture Collection) strains and clinical isolates of Escherichia coli, Pseudomonas aeruginosa and Klebsiella pneumoniae. The CMS incorporated hydrogel is also capable of inhibiting the biofilm formation. The developed hydrogel can be potentially being used for the treatment of Gram-negative bacterial infected wounds.

Topics: Anti-Bacterial Agents; Chitosan; Colistin; Escherichia coli; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Hydrogels; Microbial Sensitivity Tests; Wound Infection

Delftia acidovorans (

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Ceftazidime; Colistin; Delftia acidovorans; Female; Gentamicins; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Male; Meropenem; Microbial Sensitivity Tests; Middle Aged; Retrospective Studies; Stenotrophomonas maltophilia; Young Adult

The increasing prevalence of resistance against the last-resort antibiotic colistin is a significant threat to global public health. Here, we discovered a novel colistin resistance mechanism via enzymatic inactivation of the drug and proposed its clinical importance in microbial communities during polymicrobial infections.. A bacterial strain of the Gram-negative opportunistic pathogen Stenotrophomonas maltophilia capable of degrading colistin and exhibiting a high-level colistin resistance was isolated from the soil environment. A colistin-degrading protease (Cdp) was identified in this strain, and its contribution to colistin resistance was demonstrated by growth inhibition experiments using knock-out (Δcdp) and complemented (Δcdp::cdp) mutants. Coculture and coinfection experiments revealed that S. maltophilia carrying the cdp gene could inactivate colistin and protect otherwise susceptible Pseudomonas aeruginosa, which may seriously affect the clinical efficacy of the drug for the treatment of cystic fibrosis patients with polymicrobial infection.. Our results suggest that Cdp should be recognized as a colistin resistance determinant that confers collective resistance at the microbial community level. Our study will provide vital information for successful clinical outcomes during the treatment of complex polymicrobial infections, particularly including S. maltophilia and other colistin-susceptible Gram-negative pathogens such as P. aeruginosa. Video abstract.

Topics: Anti-Bacterial Agents; Coinfection; Colistin; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests; Microbiota; Peptide Hydrolases; Pseudomonas aeruginosa; Stenotrophomonas maltophilia

The emergence and spread of the mcr-1 gene and its mutants has immensely compromised the efficient usage of colistin for the treatment of drug-resistant Gram-negative bacterial infection in clinical settings. However, there are currently no clinically available colistin synergis. Here we identify artemisinin derivatives, such as dihydroartemisinin (DHA), that produces a synergistic antibacterial effect with colistin against the majority of Gram-negative bacteria (FIC < 0.5) without induced resistance, particularly those carrying the mcr-1 gene. Mechanism analysis reveals the direct engagement of DHA with the active center of MCR-1 to inhibit the activity of MCR-1. Meanwhile, the results from transcriptome and electron microscope analysis show that DHA could also simultaneously affect the flagellar assembly and the energy metabolism of bacteria. Moreover, in the mouse infection models of Gram-negative bacteria, combination therapy shows remarkable treatment benefits, as shown by an improved survival rate, reduced morbidity, alleviated pathological injury and decreased bacterial loading. Due to the generally safe profile of specialized malaria medication administration in humans, artemisinin derivatives are a promising class of multi-target inhibitors on bacterial resistance and virulence that can be used to extend the usage life of colistin and to tackle the inevitability of serious bacterial infection with colistin.

Topics: Animals; Anti-Bacterial Agents; Artemisinins; Colistin; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Mice; Microbial Sensitivity Tests

Colistimethate sodium (CMS) is the inactive prodrug of colistin, CMS has a narrow antibacterial spectrum with concentration-dependent bactericidal activity against multidrug-resistant gram-negative bacteria, including Pseudomonas aeruginosa and Acinetobacter baumannii. This study aimed to analyze potential correlations between clinical features and the development of CMS-induced nephrotoxicity. This retrospective cohort study was conducted in a tertiary-care university hospital between 1 January 2015 and 31 December 2019. A total of 163 patients received CMS therapy. 75 patients (46%) developed nephrotoxicity attributable to colistin treatment, although only 14 patients (8.6%) discontinued treatment for this reason. 95.7% of CMS were prescribed as target therapy. Acinetobacter baumannii spp. was the most commonly identified pathogen (72.4%) followed by P. aeruginosa (19.6%). Several risk factors associated with nephrotoxicity were identified, among these were age (HR 1.033, 95%CI 1.016-1.052, p < 0.001), Charlson Index (HR 1.158, 95%CI 1.0462-1.283; p = 0.005) and baseline creatinine level (HR 1.273, 95%CI 1.071-1.514, p = 0.006). In terms of in-hospital mortality, risk factors were age (HR 2.43, 95%CI 1.021-1.065, p < 0.001); Charlson Index (HR 1.274, 95%CI 1.116-1.454, p = 0.043), higher baseline creatinine levels (HR 1.391, 95%CI 1.084-1.785, p = 0.010) and nephrotoxicity due to CMS treatment (HR 5.383, 95%CI 3.126-9.276, p < 0.001). In-hospital mortality rate were higher in patients with nephrotoxicity (log rank test p < 0.001). In conclusion, the nephrotoxicity was reported in almost half of the patients. Its complex management, continuous renal dose adjustment and monitoring creatinine levels at least every 48 h leads to a high percentage of inappropriate use and treatment failure.

Topics: Colistin; Creatinine; Gram-Negative Bacterial Infections; Humans; Incidence; Pseudomonas aeruginosa; Renal Insufficiency; Retrospective Studies

Colistin is used against multi-drug resistant pathogens, yet resistance emerges through dissemination of plasmid-mediated genes (mcr) or chromosomal mutation of genes involved in lipopolysaccharide synthesis (i.e. mgrB, phoPQ, pmrCAB). Phenotypic susceptibility testing is challenging due to poor diffusion of colistin in agar media, leading to an underestimation of resistance. Performance of five phenotypic approaches was compared in the context of different molecular mechanisms of resistance. We evaluated Vitek 2® (bioMérieux, AST N242), Colistin MIC Test Strip (Liofilchem Diagnostici), UMIC (Biocentric), and Rapid Polymyxin™ NP test (ELITechGroup) against the standard broth microdilution (BMD) method. We used whole genome sequencing (WGS) to infer molecular resistance mechanisms. We analysed 97 Enterobacterales and non-fermenting bacterial isolates, largely clinical isolates collected up to 2018. Data was analysed by comparing susceptibility categories (susceptible or resistant) and minimal inhibitory concentrations (MIC). Susceptibility category concordance is the percentage of test results sharing the same category to BMD. MIC concordance was calculated similarly but considering ±1 MIC titre error range. We determined genomic diversity by core genome multi locus sequencing typing (cgMLST) and identified putative antimicrobial resistance genes using NCBI and CARD databases, and manual annotation.. Of 97 isolates, 54 (56%) were resistant with standard BMD. Highest susceptibility category concordance was achieved by Rapid Polymyxin™ NP (98.8%) followed by UMIC (97.9%), Colistin E-test MIC strip (96.9%) and Vitek 2® (95.6%). Highest MIC concordance was achieved by UMIC (80.4%), followed by Vitek 2® (72.5%) and Colistin E-test MIC strip (62.9%). Among resistant isolates, 23/54 (43%) were intrinsically resistant to colistin, whereas 31/54 (57%) isolates had acquired colistin resistance. Of these, mcr-1 was detected in four isolates and mcr-2 in one isolate. Non-synonymous mutations in mgrB, phoQ, pmrA, pmrB, and pmrC genes were encountered in Klebsiella pneumoniae, Escherichia coli, and Acinetobacter bereziniae resistant isolates. Mutations found in mgrB and pmrB were only identified in isolates exhibiting MICs of ≥16 mg/L.. The Rapid Polymyxin™ NP test showed highest categorical concordance and the UMIC test provided MIC values with high concordance to BMD. We found colistin resistance in diverse species occurred predominantly through spontaneous chromosomal mutation rather than plasmid-mediated resistance.

Topics: Anti-Bacterial Agents; Bacterial Proteins; Colistin; Drug Resistance, Bacterial; Genomics; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests; Mutation; Phenotype; Plasmids

The efficacy and safety of colistin for the treatment of infections caused by multidrug-resistant gram-negative bacilli have been poorly investigated in Japanese patients. This study was performed to investigate the efficacy and safety of colistin in Japanese patients by analyzing a considerable number of cases. Furthermore, we evaluated the relationship between the plasma concentration and efficacy and safety of colistin in some cases.. A retrospective cohort study was conducted at Hokkaido University Hospital, analyzing patients treated with colistin (colistimethate sodium) during the period from January 2007 to December 2019.. Overall, 42 cases were enrolled. Favorable clinical response was observed in 25 cases (59.5%), with an all-cause 30-day mortality of 33.3% (14/42 cases). Microbiological eradication was achieved in 18 cases (42.9%). Nephrotoxicity was observed in 20 cases (47.6%) and was mild and reversible in all cases. Plasma trough concentrations of colistin determined in nine patients correlated with changes in serum creatinine concentration (⊿) and creatinine clearance (%). The cutoff value of colistin trough concentration for nephrotoxicity was 2.02 μg/mL.. Our results showed approximately 60% clinical efficacy of colistin therapy against infections caused by multidrug-resistant gram-negative bacilli in the patients. Further studies with larger populations are needed to elucidate the efficacy and safety of colistin in Japanese patients.

Topics: Acinetobacter baumannii; Anti-Bacterial Agents; Colistin; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Retrospective Studies; Treatment Outcome

Limited data are present regarding the steady-state pharmacokinetics and pharmacodynamics of colistin in critically ill patients suffering from multi-drug-resistant gram-negative bacterial (MDR-GNB) infections. We aimed to profile the steady-state pharmacokinetics and pharmacodynamics of colistin in critically ill patients with MDR-GNB infections, along with determining the predictors that could influence the clinical, microbiological and safety outcome. We recruited 30 critically ill patients suffering from MDR-GNB infections in our prospective open-label study. Intravenous colistimethate sodium (CMS) 2 million IU was administered concurrently with inhalational CMS 1 million IU every 8 hours. Steady-state plasma colistin levels were measured. Logistic regression analysis was used to identify various predictors of clinical, microbiological and safety outcome. A large variability was observed in the steady-state colistin pharmacokinetic/pharmacodynamic parameters, along with the factors that influenced the clinical, microbiological and safety outcome. In conclusion, steady-state colistin pharmacokinetic and pharmacodynamic parameters observed in our study were largely consistent with those reported in previous studies. High acute physiology and chronic health evaluation II scores were associated with poor clinical outcome. Log-transformed colistin maximum concentration, area under the plasma concentration curve for 8 hours, apparent total body clearance and apparent volume of distribution were significantly associated with the safety outcome.

Topics: Administration, Inhalation; Administration, Intravenous; Adult; Anti-Bacterial Agents; Colistin; Critical Illness; Drug Monitoring; Drug Resistance, Multiple, Bacterial; Female; Gram-Negative Bacterial Infections; Humans; Male; Middle Aged; Patient Safety; Predictive Value of Tests; Prospective Studies; Risk Assessment; Treatment Outcome; Young Adult

Multidrug-resistant Gram-negative bacterial infection is a serious global concern and especially in low and middle-income countries (LMIC) such as India. Colistin, an antimicrobial once abandoned following reports of organ toxicity, has re-emerged as an essential therapeutic agent in the management of these infections. A retrospective review of 162 inpatients was done, focusing on culture-proven multidrug-resistant infections requiring colistin. The overall clinical outcome in 58% of patients was found to be good, with nephrotoxicity and neurotoxicity occurring only in 8 (5%) and 4 (2.5%) patients, respectively. Multivariate analysis revealed an elevated lactate and raised urea to be independent factors associated with poor clinical response. In conclusion, there appears to be strong evidence supporting the use of colistin in the management of multidrug-resistant Gram-negative bacterial infections.

Topics: Anti-Bacterial Agents; Colistin; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Retrospective Studies; Treatment Outcome

To investigate the association between adjunctive nebulized colistin and treatment outcomes in critically ill patients with nosocomial carbapenem-resistant Gram-negative bacterial (CR-GNB) pneumonia.. This retrospective, multi-centre, cohort study included individuals admitted to the intensive care unit with nosocomial pneumonia caused by colistin-susceptible CR-GNB. Enrolled patients were divided into groups with/without nebulized colistin as adjunct to at least one effective intravenous antibiotic. Propensity score matching was performed in the original cohort (model 1) and a time-window bias-adjusted cohort (model 2). The association between adjunctive nebulized colistin and treatment outcomes was analysed.. In total, 181 and 326 patients treated with and without nebulized colistin, respectively, were enrolled for analysis. The day 14 clinical failure rate and mortality rate were 41.4% (75/181) versus 46% (150/326), and 14.9% (27/181) versus 21.8% (71/326), respectively. In the propensity score-matching analysis, patients with nebulized colistin had lower day 14 clinical failure rates (model 1: 41% (68/166) versus 54.2% (90/166), p 0.016; model 2: 35.3% (41/116) versus 56.9% (66/116), p 0.001). On multivariate analysis, nebulized colistin was an independent factor associated with fewer day 14 clinical failures (model 1: adjusted odds ratio (aOR) 0.59, 95% CI 0.37-0.92; model 2: aOR 0.37, 95% CI 0.21-0.65). Nebulized colistin was not associated independently with a lower 14-day mortality rate in the time-dependent analysis in both models 1 and 2.. Adjunctive nebulized colistin was associated with lower day 14 clinical failure rate, but not lower 14-day mortality rate, in critically ill patients with nosocomial pneumonia caused by colistin-susceptible CR-GNB.

Topics: Anti-Bacterial Agents; Carbapenems; Colistin; Critical Illness; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacterial Infections; Healthcare-Associated Pneumonia; Humans; Pneumonia, Bacterial; Retrospective Studies; Treatment Outcome

Polymyxins (colistin) have emerged for the treatment of carbapenem resistant (CR) gram-negative infections. There is a paucity of data on treatment outcomes and adverse effects of high-dose colistin treatment in Pakistan. The aim of this study was to determine the efficacy and toxicity of colistin in CR bacteremia, including patients with renal failure and on hemodialysis, and to determine patient outcomes.. This prospective cohort study was performed from May to December 2017 at Sindh Institute of Urology and Transplantation, Karachi, Pakistan. Patients aged >18 years with documented gram-negative bacteremia were included. Data were compared between those who received colistin and those who did not, including risk factors for CR bacteremia, bacterial clearance, adverse effects, and all-cause mortality up to 14 days of follow-up.. The study included 137 patients, 73 (53.3%) in the colistin group and 64 (46.7%) in the non-colistin group. Patients in the colistin group were 1.47 times more likely to have died by day 14 of follow-up as compared to those in the non-colistin group (19.2% vs 7.8%; relative risk 1.47, p= 0.05). Patients in both groups achieved more than 80% bacteriological clearance. The colistin group patients were less likely to have received appropriate empirical antibiotics as compared to the non-colistin group patients (4.1% vs 62.5%; relative risk 0.09, p< 0.001). Factors significantly associated with mortality were inappropriate empirical antibiotics and acute renal failure. Of the 73 patients in the colistin group, 27 (37.0%) developed reversible neurological adverse effects. Patients with renal insufficiency, not on hemodialysis, were evaluated for colistin nephrotoxicity. Creatinine decreased from 8.08 mg/dl at baseline to 4.85 mg/dl on day 7 in the colistin group, and from 6.5 mg/dl to 3.9 mg/dl in the non-colistin group. Patients with normal renal function had no significant rise in serum creatinine.. Colistin is efficacious in clearing bacteremia even in patients with impaired renal function. The adverse effects were found to be minimal and reversible. We recommend the use of colistin in combination with carbapenems for CR gram-negative bacteria in renal failure. Most importantly, however, this study highlights the role of empirical colistin treatment in patients with risk factors for CR bacteremia.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Bacteremia; Carbapenems; Colistin; Gram-Negative Bacterial Infections; Humans; Male; Middle Aged; Pakistan; Prospective Studies; Treatment Outcome

In this study, the potential of using the novel antibiotic NCL195 combined with subinhibitory concentrations of colistin against infections caused by Gram-negative bacteria (GNB) was investigated. We showed synergistic activity of the combination NCL195 + colistin against clinical multidrug-resistant GNB pathogens with minimum inhibitory concentrations (MICs) for NCL195 ranging from 0.5-4 μg/mL for Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa, whereas NCL195 alone had no activity. Transmission electron microscopy of the membrane morphology of E. coli and P. aeruginosa after single colistin or combination drug treatment showed marked ultrastructural changes most frequently in the cell envelope. Exposure to NCL195 alone did not show any change compared with untreated control cells, whereas treatment with the NCL195 + colistin combination caused more damage than colistin alone. Direct evidence for this interaction was demonstrated by fluorescence-based membrane potential measurements. We conclude that the synergistic antimicrobial activity of the combination NCL195 + colistin against GNB pathogens warrants further exploration for specific treatment of acute GNB infections.

Topics: Animals; Anti-Bacterial Agents; Colistin; Dose-Response Relationship, Drug; Drug Resistance, Multiple, Bacterial; Drug Synergism; Drug Therapy, Combination; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; HEK293 Cells; Hep G2 Cells; Humans; Male; Mice; Microbial Sensitivity Tests; Models, Animal; Robenidine

To compare the effectiveness and safety of aerosolized (AER) plus intravenous (IV) colistin with IV colistin alone in patients with nosocomial pneumonia (NP) due to multidrug-resistant (MDR) Gram-negative bacteria.. This was a retrospective cohort study of adults with NP who received IV colistin alone or in combination with AER colistin. The primary endpoint was clinical cure at end of therapy. Secondary endpoints included microbiological eradication, in-hospital mortality and nephrotoxicity.. In total, 135 patients were included in this study: 65 patients received AER plus IV colistin and 70 patients received IV colistin alone. Baseline characteristics were similar between the two groups. Clinical cure was achieved in 42 (65%) patients who received AER plus IV colistin and 26 (37%) patients who received IV colistin alone (P = 0.01). Among a total of 88 patients who were microbiologically evaluable, 27 (42%) patients who received AER plus IV colistin and 12 (17%) patients who received IV colistin alone attained favourable microbiological outcomes (P = 0.022). In-hospital mortality (43% vs 59%, P = 0.072) was higher in patients who received IV colistin alone, but the difference was not significant. Renal injury occurred in 31% of patients who received AER plus IV colistin and in 41% of patients who received IV colistin alone (P = 0.198).. AER colistin can be considered as salvage therapy as an adjunct to IV administration for the treatment of patients with NP due to MDR Gram-negative pathogens.

Topics: Administration, Inhalation; Adult; Anti-Bacterial Agents; Colistin; Cross Infection; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Healthcare-Associated Pneumonia; Humans; Pneumonia, Ventilator-Associated; Retrospective Studies; Treatment Outcome

The widespread emergence of antibiotic resistance, including multidrug resistance in Gram-negative (G-) bacterial pathogens, poses a critical challenge to the current antimicrobial armamentarium. Antibody-drug conjugates (ADCs), primarily used in anticancer therapy, offer a promising treatment alternative due to their ability to deliver a therapeutic molecule while simultaneously activating the host immune response. The Cloudbreak platform is being used to develop ADCs to treat infectious diseases, composed of a therapeutic targeting moiety (TM) attached via a noncleavable linker to an effector moiety (EM) to treat infectious diseases. In this proof-of-concept study, 21 novel dimeric peptidic molecules (TMs) were evaluated for activity against a screening panel of G- pathogens. The activities of the TMs were not impacted by existing drug resistance. Potent TMs were conjugated to the Fc fragment of human IgG1 (EM), resulting in 4 novel ADCs. These ADCs were evaluated for immunoprophylactic efficacy in a neutropenic mouse model of deep thigh infection. In colistin-sensitive infections, 3 of the 4 ADCs offered protection similar to that of therapeutically dosed colistin, while CTC-171 offered enhanced protection. The efficacy of these ADCs was unchanged in colistin-resistant infections. Together, these results indicate that the ADCs used here are capable of potent binding to G- pathogens regardless of lipopolysaccharide (LPS) modifications that otherwise lead to antibiotic resistance and support further exploration of ADCs in the treatment of infections caused by drug-resistant G- bacteria.

Topics: Animals; Anti-Bacterial Agents; Colistin; Disease Models, Animal; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Lipopolysaccharides; Mice

Levofloxacin has been considered as an alternative treatment for Stenotrophomonas maltophilia infection. However, levofloxacin-resistant S. maltophilia (LRSM) are emerging worldwide.. To investigate LRSM risk factors in hospitalized patients and to determine antibiotic susceptibility patterns of LRSM isolates.. In a retrospective matched case-control-control study, LRSM patients (the case group) were compared with two control groups: levofloxacin-susceptible S. maltophilia (LSSM) patients (control group A) and non-S. maltophilia-infected patients (control group B). Conditional logistic regression was used to analyse risk factors for LRSM occurrence. Tigecycline, ceftazidime, colistin, and trimethoprim/sulfamethoxazole (TMP/SMX) susceptibilities in collected LRSM clinical isolates were determined.. A total of 105 LRSM, 105 LSSM, and 105 non-S. maltophilia-infected patients were analysed. The first multivariate analysis (cases vs group A) revealed that previous fluoroquinolones use was significantly associated with LRSM occurrence, and the second multivariate analysis (cases vs group B) revealed that previous fluoroquinolone use, previous intensive care unit stay, and the number of previous exposures to different classes of antibiotics were significantly associated with LRSM occurrence. Of all the LRSM isolates tested for antibiotic susceptibility, ceftazidime, TMP/SMX, tigecycline, and colistin resistance rates were 42.0, 99.0, 78.0, and 40.0%, respectively.. LRSM antibiotic susceptibility patterns revealed multiple-drug resistance, which further limits treatment options for clinicians. To reduce LRSM occurrence, proper use of antibiotics, especially fluoroquinolones, is mandatory.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Case-Control Studies; Ceftazidime; Colistin; Drug Resistance, Multiple, Bacterial; Female; Fluoroquinolones; Gram-Negative Bacterial Infections; Hospitalization; Humans; Intensive Care Units; Levofloxacin; Male; Microbial Sensitivity Tests; Middle Aged; Retrospective Studies; Risk Factors; Stenotrophomonas maltophilia; Taiwan; Tigecycline; Trimethoprim, Sulfamethoxazole Drug Combination

Despite the increasing reliance on polymyxin antibiotics (polymyxin B and colistin) for treatment of multidrug-resistant Gram-negative infections, many clinical laboratories are unable to perform susceptibility testing due to the lack of accurate and reliable methods. Although gradient agar diffusion is commonly performed for other antimicrobials, its use for polymyxins is discouraged due to poor performance characteristics. Performing gradient agar diffusion with calcium enhancement of susceptibility testing media has been shown to improve the identification of polymyxin-resistant isolates with plasmid-mediated resistance (

Topics: Agar; Anti-Bacterial Agents; Calcium; Colistin; Culture Media; Disk Diffusion Antimicrobial Tests; Drug Resistance, Multiple, Bacterial; Enterobacteriaceae; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Pseudomonas aeruginosa

The aim of this study was to design and characterize dry powder inhaler formulations of ciprofloxacin and colistin co-loaded liposomes prepared by the ultrasonic spray-freeze-drying (USFD) technique. Liposomal formulations and powder production parameters were optimized to achieve optimal characteristics and in-vitro performance such as encapsulation efficiency (EE), particle size, particle distribution index (PDI), fine particle fraction (FPF), emitted dose (ED) and in vitro antibacterial activity. The formulation (F6) with the mannitol (5% w/v) as the internal lyoprotectant and sucrose (5%, w/v), mannitol (10%, w/v) and leucine (5%, w/w) as the external lyoprotectants/aerosolization enhancers showed an optimal rehydrated EE values of ciprofloxacin and colistin (44.9 ± 0.9% and 47.0 ± 0.6%, respectively) as well as satisfactory aerosol performance (FPF: 45.8 ± 2.2% and 43.6 ± 1.6%, respectively; ED: 97.0 ± 0.5% and 95.0 ± 0.6%, respectively). For the blank liposomes, there was almost no inhibitory effect on the cell proliferation in human lung epithelial A549 cells, showing that the lipid materials used in the liposome formulation is safe for use in pulmonary drug delivery. The cytotoxicity study demonstrated that the optimized liposomal formulation (F6) was not cytotoxic at least at the drug concentrations of colistin 5 μg/mL and ciprofloxacin 20 μg/mL. Colistin (2 mg/L) monotherapy showed no antibacterial effect against P. aeruginosa H131300444 and H133880624. Ciprofloxacin (8 mg/L) monotherapy showed moderate bacterial killing for both clinical isolates; however, regrowth was observed in 6 h for P. aeruginosa H133880624. The liposomal formulation displayed superior antibacterial activity against clinical isolates of Pseudomonas aeruginosa H131300444 and P. aeruginosa H133880624 compared to each antibiotic per se. These results demonstrate that the liposomal powder formulation prepared by USFD could potentially be a pulmonary delivery system for antibiotic combination to treat multi-drug resistant Gram-negative lung infections.

Topics: A549 Cells; Administration, Inhalation; Anti-Bacterial Agents; Ciprofloxacin; Colistin; Drug Combinations; Drug Resistance, Bacterial; Drug Resistance, Multiple; Drug Synergism; Gram-Negative Bacterial Infections; Humans; Liposomes; Powders; Pseudomonas aeruginosa; Respiratory Tract Infections

Topics: Anti-Bacterial Agents; Bacterial Outer Membrane; Colistin; Drug Resistance, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Macrocyclic Compounds; Microbial Sensitivity Tests; Peptides; Peptides, Cyclic

Topics: Aminoglycosides; Anti-Bacterial Agents; Colistin; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Pneumonia, Ventilator-Associated

Colistimethate sodium (colistin) is used to treat multidrug-resistant gram negative infections. We describe the profile and outcomes of patients given colistin in a tertiary level government hospital in Manila, Philippines.. We performed a retrospective study of adult patients given intravenous colistin between January 2015 to June 2018 in the Philippine General Hospital. We defined clinical success as a composite of hemodynamic stability, quick Sequential Organ Failure Assessment (qSOFA) score, and microbiological cure.. 250 patients were included, half (49.2%) were admitted in the ICU. Median age was 55 years. There was an increase in qSOFA, APACHE II score, and septic shock from baseline to 24 h prior to colistin use. Most patients had pneumonia (90.8%) with extensively drug-resistant Acinetobacter baumannii as the most common isolate (78.8%). Colistin was given in combination with meropenem (96.4%) for a median of 12 days. Nephrotoxicity was seen in 30.8%, with renal replacement therapy needed in 6%. Clinical success was seen in 61.2% of patients and overall mortality was 41.6%.. Colistin was frequently used in combination with a carbapenem for treatment of XDR-related respiratory infections. Nephrotoxicity was a common adverse effect. Clinical success was modest and overall mortality was high.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Administration, Intravenous; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Carbapenems; Colistin; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Female; Gram-Negative Bacterial Infections; Hospitalization; Humans; Male; Meropenem; Middle Aged; Organ Dysfunction Scores; Philippines; Respiratory Tract Infections; Retrospective Studies; Tertiary Care Centers; Treatment Outcome; Young Adult

To study the prevalence, antibiotic susceptibility profile, clinical outcomes and plasmid-mediated transfer of colistin resistance (CLR) among Gram-negative bacilli (GNB) isolates from different ocular infections.. Prospective case-control study in eastern India.. Consecutive ocular samples with GNB isolates from clinically diagnosed cases of microbial keratitis, infectious endophthalmitis and orbital infections were included. Inclusion criteria were significant GNB growth from ocular samples and > 6 weeks follow-up. Clinical outcomes were determined by disease-specific criteria for each clinical group. Antibiotic susceptibility was tested by broth microdilution for colistin and Kirby-Bauer disc diffusion method for others. Plasmid detection for CLR genes mcr-1 and mcr-2 genes was done by standard protocols.. Sixty GNB isolates were studied. Overall prevalence of CLR (intrinsic plus acquired) was 40% (n = 24), acquired being 37.5% of CLR isolates (n = 9). The prevalence varied from 45.5% (10/22) and 45% (9/20) in microbial keratitis and infectious endophthalmitis, respectively, to 26.3% (5/19) in orbital infections. Clinical outcomes in CLR patients were significantly worse in microbial keratitis (p = 0.018) and orbital infections (p = 0.018), and comparable to colistin-susceptible ones (p = 0.77) in infectious endophthalmitis. CLR isolates had significantly higher resistance to Amikacin, Gentamicin and Ceftazidime but were susceptible to Piperacillin, Carbapenems and fluoroquinolones. Plasmids mcr-1 and mcr-2 were detected in 6.25% (n = 1) and 25%(n = 4), respectively, of the 16 tested isolates.. CLR is highly prevalent in ocular isolates and affects clinical outcomes. CLR isolates may still remain susceptible to Carbapenems, Piperacillin and fluoroquinolones. Plasmid mcr-1- and mcr-2-mediated CLR remains low in ocular infections.

Topics: Anti-Bacterial Agents; Case-Control Studies; Colistin; Drug Resistance, Bacterial; Eye Infections, Bacterial; Follow-Up Studies; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; India; Prevalence; Prognosis; Prospective Studies

Colistin has become a critical antibiotic for fatal Gram-negative infections owing to the proliferation of multidrug-resistant carbapenemase-producing bacteria. Thus, cheaper, faster, efficient and easier-to-use colistin diagnostics are required for clinical surveillance, diagnoses and therapeutics. The sensitivity, specificity, major error (ME), very major error (VME), categorial agreement, essential agreement, turnaround time (TAT), average cost, and required skill for four colistin resistance diagnostics viz., CHROMagar COL-APSE, ComASP Colistin, MicroScan, and Colistin MAC Test (CMT) were evaluated against broth microdilution (BMD) using 84 Gram-negative bacterial isolates. A multiplex PCR (M-PCR) was used to screen all isolates to detect the presence of the mcr-1 to mcr-5 genes. A 15-point grading scale was used to grade the tests under skill, ease, processing time etc. mcr-1 was detected by both M-PCR and CMT in a single E. coli isolate, with other PCR amplicons suggestive of mcr-2, -3 and -4 genes being also observed on the gel. The sensitivity and specificity of CHROMagar COL-APSE, MicroScan, and ComASP Colistin, were 82.05% and 66.67%, 92.31% and 76.92%, and 100% and 88.89% respectively. The MicroScan was the most expensive at a cost (per sampe tested) of R221.6 ($15.0), followed by CHROMagar COL-APSE (R118.3; $8.0), M-PCR (R75.1; $5.1), CMT (R20.1; $1.4) and ComASP Colistin (R2.64; $0.2). CHROMagar was the easiest to perform, followed by ComASP Colistin, M-PCR, MicroScan, CMT and BMD whilst M-PCR and MicroScan required higher skill. The ComASP Colistin was the best performing diagnostic test, with low VME and ME, making it recommendable for routine colistin sensitivity testing in clinical laboratories; particularly, in poorer settings. It is however limited by a TAT of 18-24 hours.

Topics: Anti-Bacterial Agents; Colistin; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests; Reagent Kits, Diagnostic; Sensitivity and Specificity; Time Factors

The rapid emergence and dissemination of multidrug-resistant (MDR) bacterial pathogens pose a serious threat to global healthcare. One particular concern is the carbapenem-resistant Enterobacteriaceae (CRE), a group of Gram-negative bacteria that have evolved resistance to all or nearly all available antibiotics. Coupled with the fact of barren antibiotic development pipeline nowadays, a critical approach is to revitalize existing antibiotics using antibiotic adjuvants. We found a short linear antibacterial peptide (SLAP)-S25 carrying four non-natural amino acids of 2,4-diaminobutanoic acid (Dab), which solely showed weak antibacterial activity but boosted the efficacy of antibiotics covering all major classes, including cefepime, colistin, ofloxacin, rifampicin, tetracycline and vancomycin, against MDR Gram-negative pathogens. Mechanistic studies showed that SLAP-S25 triggers membrane damage by binding to both lipopolysaccharide (LPS) in the outer membrane and phosphatidylglycerol (PG) in bacterial cytoplasmic membrane, to potentiate antibiotic efficacy through collaborative strategies. Lastly, SLAP-S25 effectively enhanced the activity of colistin against MDR Escherichia coli-associated infections in three animal models. Our findings provide a potential therapeutic option using existing antibiotics in combination with broad-spectrum antibiotic adjuvants, to address the prevalent infections caused by MDR Gram-negative pathogens worldwide.

Topics: A549 Cells; Animals; Anti-Bacterial Agents; Carbapenem-Resistant Enterobacteriaceae; Chlorocebus aethiops; Colistin; Disease Models, Animal; Drug Resistance, Multiple, Bacterial; Escherichia coli; Female; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Lipopolysaccharides; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Phosphatidylglycerols; Vero Cells

Intravenous colistin (polymyxin E) has renewed interest as a last-line treatment against antimicrobial-resistant Gram-negative bacterial infections, despite limited literature on pediatric prescribing practices. Point-prevalence surveys were used to obtain intravenous colistin prescribing data from 78 children and neonates, showing high variability, and 60.3% received doses below the Food and Drug Administration and the European Medicines Agency recommendations.

Topics: Adolescent; Anti-Bacterial Agents; Child; Child, Preschool; Colistin; Drug Resistance, Multiple, Bacterial; Europe; Female; Gram-Negative Bacterial Infections; Humans; Infant; Infant, Newborn; Male; United States; United States Food and Drug Administration

Safe and effective use of colistin requires robust pharmacokinetic (PK) and pharmacodynamic (PD) data to guide dosing.. To evaluate the pharmacokinetics of colistimethate sodium and colistin in critically ill patients and correlate with clinical efficacy and renal function.. Twenty critically ill adult patients with colistin-susceptible multidrug-resistant (MDR) infections and normal renal function treated with intravenous colistimethate sodium - at a 9 million units (270 mg CBA) loading dose followed by maintenance (MD) of 3 million units t.i.d, 24 hours later - were evaluated for clinical cure (CC) at the end of therapy. Patient characteristics and plasma colistin levels at 0, 0.5, 1, 2, 4, 8 and 12 hours after the loading dose and at 1, 2 and 8 hours after the eighth and ninth infusion of MD were evaluated. Colistimethate sodium and colistin levels were measured by high-performance liquid chromatography and tandem mass spectrometry (HPLC-MS/MS).. Among the 20 patients who were evaluated, 60% had pneumonia. Predominant pathogens were Klebsiella pneumoniae and Acinetobacter spp. Clinical cure was 50% (10/20). Mean peak loading dose concentrations were 3 ± 1.1 mg/L (1.75-5.14) and 2.37 ± 1.2 mg/L (1.52-5.54) for 'cure' and 'failure' groups, respectively (p = 0.13), while mean steady-state (Cssavg) concentrations were 2.25 ± 1.3 mg/L and 1.78 ± 1.1 mg/L in 'cure' and 'failure' groups, respectively (p = 0.19). Nephrotoxicity was 5% on day 7 of therapy. However, bacteriological cure could not be correlated with PK/PD.. Subtherapeutic Cssavg with clinical failure and lower efficacy without significant nephrotoxicity highlights the need for therapeutic drug monitoring to guide colistin dosing.

Topics: Administration, Intravenous; Adult; Aged; Anti-Bacterial Agents; Colistin; Drug Resistance, Multiple, Bacterial; Female; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Hospitals; Humans; India; Male; Middle Aged; Prospective Studies; Treatment Outcome

Stenotrophomonas maltophilia-induced pulmonary haemorrhage is considered a fatal infection among haematological patients. The outcome can be explained by the patients' immunity status and late diagnosis and treatment.. We present the rare case of successful outcome in a 61-year-old female who developed alveolar haemorrhage and acute respiratory distress syndrome 8 days after a chemotherapy session for her acute lymphoblastic leukaemia, in the context of secondary bone marrow aplasia. Stenotrophomonas maltophilia was isolated in sputum culture. The patient benefitted from early empirical treatment with colistin followed by trimethoprim/sulfamethoxazole, according to the antibiogram. Despite a severe initial clinical presentation in need of mechanical ventilation, neuromuscular blocking agents infusion, and ventilation in prone position, the patient had a favourable outcome and was discharged from intensive care after 26 days.. Stenotrophomonas maltophilia severe pneumonia complicated with pulmonary haemorrhage is not always fatal in haematological patients. Empirical treatment of multidrug-resistant Stenotrophomonas maltophilia in an immunocompromised haematological patient presenting with hemoptysis should be taken into consideration.

Topics: Anti-Bacterial Agents; Colistin; Drug-Related Side Effects and Adverse Reactions; Female; Gram-Negative Bacterial Infections; Hemorrhage; Humans; Immunocompromised Host; Middle Aged; Pneumonia, Bacterial; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pulmonary Alveoli; Respiratory Distress Syndrome; Sputum; Stenotrophomonas maltophilia; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination

Long-term use of colistin for preventing Gram-negative bacterial infections in food animals was prohibited in Thailand in 2017, but it is permitted for short-term treatment. This study aimed to investigate association between the use of colistin for short-term treatment of infection and the emergence of colistin-resistant Enterobacteriaceae in swine. The current study was conducted at 2 selected swine farms in Thailand. Neither farm has used colistin to prevent infection for longer than 1 year. Rectal swabs were collected from the same 66 pigs at birth, and on days 7, 14, 21, 28, and 60. Colistin was used to treat sick pigs for up to 3 days. Additional rectal swabs were collected during colistin treatment. Rectal swabs were analyzed for colistin-resistant Enterobacteriaceae and the mcr-1 gene. Results revealed that colistin-resistant Enterobacteriaceae were absent at birth. Some pigs at both farms had diarrhea and received colistin treatment during days 2-27. Colistin-resistant Enterobacteriaceae were detected in 13.3-50.0% of sick and healthy pigs. No sick pigs were observed during days 28-60, and colistin was not used during that period. Colistin-resistant Enterobacteriaceae were detected in 2.8-10.0% of healthy pigs on day 28, and in 0-3.4% of healthy pigs on day 60. The mcr-1 gene was detected in 57.6% of colistin-resistant Enterobacteriaceae isolates. Short-term treatment with colistin was found to be associated with the emergence of colistin-resistant Enterobacteriaceae in swine. Colistin-resistant Enterobacteriaceae rapidly emerged after colistin use, and rapidly decreased or disappeared after its discontinuation.

Topics: Animals; Animals, Newborn; Anti-Bacterial Agents; Colistin; Drug Resistance, Bacterial; Enterobacteriaceae; Farms; Female; Genes, Bacterial; Gram-Negative Bacterial Infections; Male; Pregnancy; Sus scrofa; Swine; Swine Diseases; Thailand

The aim of this study was to assess colistin use in a country endemic for multidrug-resistant Gram-negative bacteria (MDR-GNB).. Colistin prescription patterns were evaluated in 22 Italian centres. Factors associated with use of colistin in combination with other anti-MDR-GNB agents were also assessed.. A total of 221 adults receiving colistin were included in the study. Their median age was 64 years (interquartile range 52-73 years) and 134 (61%) were male. Colistin was mostly administered intravenously (203/221; 92%) and mainly for targeted therapy (168/221; 76%). The most frequent indications for colistin therapy were bloodstream infection and lower respiratory tract infection. Intravenous colistin was administered in combination with at least another anti-MDR-GNB agent in 80% of cases (163/203). A loading dose of 9 MU of colistimethate was administered in 79% of patients receiving i.v. colistin and adequate maintenance doses in 85%. In multivariable analysis, empirical therapy [odds ratio (OR) = 3.25, 95% confidence interval (CI) 1.24-8.53;P = 0.017] and targeted therapy for carbapenem-resistant Enterobacterales infection (OR = 4.76, 95% CI 1.69-13.43; P = 0.003) were associated with use of colistin in combination with other agents, whilst chronic renal failure (OR = 0.39, 95% CI 0.17-0.88; P =  0.024) was associated with use of colistin monotherapy.. Colistin remains an important option for severe MDR-GNB infections when other treatments are not available. Despite inherent difficulties in optimising its use owing to peculiar pharmacokinetic/pharmacodynamic characteristics, colistin was mostly used appropriately in a country endemic for MDR-GNB.

Topics: Administration, Intravenous; Aged; Anti-Bacterial Agents; Colistin; Cross-Sectional Studies; Drug Prescriptions; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Endemic Diseases; Female; Gram-Negative Bacterial Infections; Humans; Italy; Male; Middle Aged; Respiratory Tract Infections; Sepsis

Topics: Achromobacter; Anti-Bacterial Agents; Chronic Disease; Colistin; Drug Resistance, Multiple, Bacterial; Female; Gram-Negative Bacterial Infections; Humans; Middle Aged; Otitis Media, Suppurative

The objectives of the present study were to identify risk factors for development of acute kidney injury (AKI) during the treatment of bacteraemia due to carbapenem non-susceptible Gram-negative bacteria (CnS-GNB) and its role on mortality. Data of all patients with bacteraemia by CnS-GNB in the intensive care unit of a tertiary hospital from 2012 to 2016 were included. AKI was defined by AKIN criteria. Secondary outcomes were AKI development in patients treated with colistin and predictors of 14-day mortality. Among 285 episodes of bacteraemia due to CnS-GNB, 84 (29.5%) developed AKI. Multivariate analysis revealed that obesity, septic shock, maximum noradrenaline dose and eGFR<60 mL/min/1.73m² upon bacteraemia onset were independently associated with development of AKI. Out of 228 patients receiving colistin, 64 (28.1%) developed AKI. Multivariate analysis found the same factors as before in addition to voriconazole administration. Fourteen-day mortality was 34.2% and was independently associated with bacteraemia by Pseudomonas aeruginosa, AKI during bacteraemia treatment, maximum noradrenaline dose, SAPS II and SOFA scores upon bacteraemia onset, whereas appropriate combination therapy and catheter-related bacteraemia were independently associated with better survival. AKI was a frequent complication of bacteraemia by CnS-GNB and was associated with septic shock and baseline renal function impairment. Mortality was higher among patients that developed AKI due to bacteraemia. Colistin should be considered a safe therapeutic option for treating such infections.

Topics: Acute Kidney Injury; Adult; Aged; Anti-Bacterial Agents; Bacteremia; Carbapenems; Colistin; Critical Illness; Drug Resistance, Bacterial; Female; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Male; Middle Aged; Retrospective Studies; Risk Assessment; Risk Factors

Topics: Aged; Anti-Bacterial Agents; Azabicyclo Compounds; Ceftazidime; Coinfection; Colistin; Drug Combinations; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Enterococcus faecalis; Enterococcus faecium; Eye Neoplasms; Febrile Neutropenia; Gram-Negative Bacterial Infections; Gram-Positive Bacterial Infections; Humans; Klebsiella Infections; Leukemia, Myeloid, Acute; Male; Melanoma; Meropenem; Middle Aged; Neoplasms, Second Primary; Pseudomonas Infections; Tigecycline

Factors influencing treatment outcome of patients with Gram-negative bacterial (GNB) multidrug-resistant (MDR) and extensively drug-resistant (XDR) prosthetic joint infection (PJIs) were analysed. Data were collected (2000-2015) by 18 centres. Treatment success was analysed by surgery type for PJI, resistance (MDR/XDR) and antimicrobials (colistin/non-colistin) using logistic regression and survival analyses. A total of 131 patients (mean age 73.0 years, 35.9% male, 58.8% with co-morbidities) with MDR (n = 108) or XDR (n = 23) GNB PJI were assessed. The most common pathogens were Escherichia coli (33.6%), Pseudomonas aeruginosa (25.2%), Klebsiella pneumoniae (21.4%) and Enterobacter cloacae (17.6%). Pseudomonas aeruginosa predominated in XDR cases. Isolates were carbapenem-resistant (n = 12), fluoroquinolone-resistant (n = 63) and ESBL-producers (n = 94). Treatment outcome was worse in XDR versus MDR cases (P = 0.018). Success rates did not differ for colistin versus non-colistin in XDR cases (P = 0.657), but colistin was less successful in MDR cases (P = 0.018). Debridement, antibiotics and implant retention (DAIR) (n = 67) was associated with higher failure rates versus non-DAIR (n = 64) (OR = 3.57, 95% CI 1.68-7.58; P < 0.001). Superiority of non-DAIR was confirmed by Kaplan-Meir analysis (HR = 0.36, 95% CI 0.20-0.67) and remained unchangeable by time of infection (early/late), antimicrobial resistance (MDR/XDR) and antimicrobials (colistin/non-colistin) (Breslow-Day, P = 0.737). DAIR is associated with higher failure rates even in early MDR/XDR GNB PJIs versus implant removal. Colistin should be preserved for XDR cases as it is detrimental in MDR infections.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Colistin; Drug Resistance, Multiple, Bacterial; Female; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Male; Middle Aged; Prospective Studies; Prosthesis-Related Infections; Retrospective Studies; Survival Analysis; Treatment Outcome

Despite being in clinical use for decades, colistin susceptibility testing remains challenging because of its inherent cationic properties. We aimed to compare the performance characteristics of different methods for testing susceptibility to colistin in a series of clinical isolates of Gram-negative bacilli.. One hundred and nine clinical isolates of Klebsiella pneumoniae (n=34), Escherichia coli (n=20), Acinetobacter baumannii (n=17) and Pseudomonas aeruginosa (n=38) were studied for colistin susceptibility using broth microdilution (BMID), broth macrodilution (BMAD), agar dilution (AD) as well as disc-diffusion (DD) utilizing two different commercial disc sources.. By using BMID as reference method, 88 and 21 isolates were found to be colistin susceptible and resistant, respectively. Overall, acceptable essential agreement (EA) and categorical agreement (CA) were observed between BMAD and reference method (100 %). Whereas the AD method revealed the lowest rate of EA (61.7, 11.7, 5.0 and 5.2 % for K. pneumoniae, A. baumannii, E. coli and P. aeruginosa, respectively), it showed acceptable or near acceptable CA for K. pneumoniae (100 %), E. coli (100 %) and A. baumannii (88.2 %) isolates but not for P. aeruginosa (13.1 %). DD failed to detect resistance in colistin-resistant (colR) P. aeruginosa (n=5, very major errors of 100 %) but successfully identified all high-level colistin-resistant A. baumannii and K. pneumoniae isolates.. We found BMAD to be very reliable for colistin MIC determination. Methods AD and DD should not be used for colistin susceptibility testing in P. aeruginosa isolates as these are associated with false-resistant and -susceptible results, respectively.

Topics: Anti-Bacterial Agents; Colistin; Drug Resistance, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests

Topics: Anti-Bacterial Agents; Autistic Disorder; Bacteremia; Child; Chryseobacterium; Ciprofloxacin; Colistin; Drug Resistance, Bacterial; Female; Gram-Negative Bacterial Infections; Humans; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination

New Delhi metallo-β-lactamase (NDM)-producing bacteria have been identified at a worrying rate in Brazil since 2013. Owing to the need to understand the extent of their spread, this study reports the dissemination of bla

Topics: Amikacin; Anti-Bacterial Agents; beta-Lactamases; Brazil; Colistin; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests; Tertiary Care Centers

Topics: Agriculture; Animals; Antimicrobial Stewardship; Colistin; Drug Resistance, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Lebanon; Livestock

Topics: Acute Kidney Injury; Adult; Aged; Anti-Bacterial Agents; Colistin; Critical Illness; Drug Resistance, Multiple, Bacterial; Female; Gram-Negative Bacterial Infections; Hospitals, University; Humans; Intensive Care Units; Kidney; Latvia; Male; Middle Aged; Renal Dialysis; Retrospective Studies; Tertiary Healthcare

The polymyxin antibiotics colistin (polymyxin E) and polymyxin B became available in the 1950s and thus did not undergo contemporary drug development procedures. Their clinical use has recently resurged, assuming an important role as salvage therapy for otherwise untreatable gram-negative infections. Since their reintroduction into the clinic, significant confusion remains due to the existence of several different conventions used to describe doses of the polymyxins, differences in their formulations, outdated product information, and uncertainties about susceptibility testing that has led to lack of clarity on how to optimally utilize and dose colistin and polymyxin B. We report consensus therapeutic guidelines for agent selection and dosing of the polymyxin antibiotics for optimal use in adult patients, as endorsed by the American College of Clinical Pharmacy (ACCP), Infectious Diseases Society of America (IDSA), International Society of Anti-Infective Pharmacology (ISAP), Society for Critical Care Medicine (SCCM), and Society of Infectious Diseases Pharmacists (SIDP). The European Society for Clinical Microbiology and Infectious Diseases (ESCMID) endorses this document as a consensus statement. The overall conclusions in the document are endorsed by the European Committee on Antimicrobial Susceptibility Testing (EUCAST). We established a diverse international expert panel to make therapeutic recommendations regarding the pharmacokinetic and pharmacodynamic properties of the drugs and pharmacokinetic targets, polymyxin agent selection, dosing, dosage adjustment and monitoring of colistin and polymyxin B, use of polymyxin-based combination therapy, intrathecal therapy, inhalation therapy, toxicity, and prevention of renal failure. The treatment guidelines provide the first ever consensus recommendations for colistin and polymyxin B therapy that are intended to guide optimal clinical use.

Topics: Adult; Anti-Bacterial Agents; Colistin; Dose-Response Relationship, Drug; Gram-Negative Bacterial Infections; Humans; Polymyxin B; Salvage Therapy

The use of colistin in the treatment of multidrug-resistant Gram-negative bacterial infections is restricted due to nephrotoxicity. We investigated the effects of aged black garlic extract (ABGE) on colistin-induced kidney injury in rats. Rats were assigned to four groups. Normal saline was intraperitoneally and intragastrically injected for control group. ABGE was intragastrically injected for garlic group. Ten mg/kg of colistin was intraperitoneally injected for 6 consecutive days for colistin group. One percent of ABGE was done 30 min prior to colistin injection for treatment group. Rats were sacrificed on the next day after last colistin injection. Colistin injection increased the serum levels of blood urea nitrogen and creatinine; however, ABGE prevented deterioration of these serum levels. ABGE also alleviated tubular damage, including vacuolation and necrosis. TUNEL-positive cells were observed less frequently for the ABGE-treated groups. CD68 positive cells were significantly decreased by pretreatment with ABGE. Levels of oxidative stress biomarkers such as 8-hydroxydeoxyguanosine and malondialdehyde were lower in the ABGE-treated groups. Levels of NF-κB, inducible NO synthase, COX-2, and TGF-β1 were lower in rats that had been treated with ABGE injection. Renal levels of IL-1β and TNF-α were increased by colistin administration whereas renal SOD, catalase, and GSH levels were restored by ABGE administration. These results suggest that ABGE, which has antioxidant and anti-inflammatory properties, might be a potential therapeutic agent to prevent renal toxicity of colistin.

Topics: Acute Kidney Injury; Animals; Antioxidants; Colistin; Disease Models, Animal; Garlic; Gram-Negative Bacterial Infections; Humans; Kidney; Male; Oxidative Stress; Plant Extracts; Rats; Rats, Sprague-Dawley; Treatment Outcome; Water

Otto Cars talks to Gary Humphreys about the lack of progress on antimicrobial resistance (AMR) and the urgent need for comprehensive, cross-sectoral action.

Topics: Anti-Bacterial Agents; Antimicrobial Stewardship; Colistin; Drug Resistance, Bacterial; Gram-Negative Bacterial Infections; Health Policy; History, 20th Century; History, 21st Century; Humans

Topics: Acinetobacter baumannii; Anti-Bacterial Agents; Colistin; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Klebsiella pneumoniae; Microbial Sensitivity Tests; Polymyxin B; Pseudomonas aeruginosa

Topics: Adolescent; Anti-Bacterial Agents; Area Under Curve; Carbapenems; Child; Child, Preschool; Colistin; Dose-Response Relationship, Drug; Drug Resistance, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Infant; Injections, Intravenous; Underage Drinking

This article describes the emergence of resistance and predictors of fatality for 1556 cases of healthcare-associated Gram-negative bloodstream infection in 2014 and 2015. The colistin resistance rate in Klebsiella pneumoniae was 16.1%, compared with 6% in 2013. In total, 660 (42.4%) cases were fatal. The highest fatality rate was among patients with Acinetobacter baumannii bacteraemia (58%), followed by Pseudomonas aeruginosa (45%), Klebsiella pneumoniae (41%), Enterobacter cloacae (32%) and Escherichia coli (28%). On multi-variate analysis, the minimum inhibitory concentrations for carbapenems [odds ratio (OR) 1.02, 95% confidence interval (CI) 1.01-1.04; P = 0.002] and colistin (OR 1.1, 95% CI 1.03-1.17; P = 0.001) were found to be significantly associated with fatality.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Bacteremia; Carbapenems; Colistin; Cross Infection; Female; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Retrospective Studies

Colistin is a last resort antibiotic to treat multidrug-resistant Gram-negative bacteria infections. Colistin is administered intravenously in the form of its inactive prodrug colistin methanesulfonate (CMS). For patients with acute kidney impairment and continuous renal replacement therapy high extracorporeal clearance may cause a substantial removal of active colistin from the bloodstream, eventually decreasing its antibacterial efficacy. Currently recommended doses of CMS may therefore be inadequate for these patients. We report on the potential value of a modified regimen that adopts a loading dose of CMS (bolus of 9 MU vs. conventional 3 MU every 8 h), followed by maintenance (3 MU every 8 h). Preliminary pharmacokinetic evidence for the feasibility and efficacy of this regimen is described for 2 patients.

Topics: Acute Kidney Injury; Aged; Anti-Bacterial Agents; Area Under Curve; Colistin; Critical Illness; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Prognosis; Pseudomonas aeruginosa; Renal Dialysis; Renal Replacement Therapy; ROC Curve

To investigate Aeromonas spp. isolates for the presence of the novel resistance gene mcr-3 or variants thereof and to characterize the positive isolates by whole genome sequence analysis.. A total of 479 unrelated Aeromonas isolates were investigated by PCR for the genes mcr-1, mcr-2 and mcr-3. Positive isolates were investigated for their colistin MICs. Species assignment was based on sequence analysis of 16s rRNA and gyrB and rpoB genes. The mcr-carrying contigs obtained by WGS were analysed for the genetic environments of the mcr genes.. Four (0.84%) Aeromonas isolates were positive in the mcr-3-specific PCR assay, whereas none of the isolates harboured mcr-1 or mcr-2. Each of the four mcr-3 genes encoded a novel variant, which showed amino acid identities of 95.0%-98.0% to the original Mcr-3 protein. These variants were designated Mcr-3.6 [Aeromonas allosaccharophila from golden orfe (Leuciscus idus)], Mcr-3.7 [Aeromonas media from turkey (Meleagris gallopavo)], Mcr-3.8 [Aeromonas jandaei from koi carp (Cyprinus carpio)] and Mcr-3.9 [Aeromonas hydrophila from koi carp]. The isolate harbouring the mcr-3.9 gene carried an additional mcr-3.8 gene and showed a distinctly higher colistin MIC of ≥128 mg/L than all other isolates. The genetic environments of the mcr-3 variant genes in all four isolates differed, but in part resembled the flanking regions of mcr-3.3 from Aeromonas veronii of chicken meat.. This study identified four novel Mcr-3 variants. The isolates carrying the respective genes dated back to 2005 suggesting that this gene has existed for more than 12 years.

Topics: Aeromonas; Animals; Anti-Bacterial Agents; Bacterial Proteins; Cluster Analysis; Colistin; DNA, Bacterial; DNA, Ribosomal; Drug Resistance, Bacterial; Fish Diseases; Fishes; Gram-Negative Bacterial Infections; Microbial Sensitivity Tests; Phylogeny; Polymerase Chain Reaction; RNA, Ribosomal, 16S; Sequence Analysis, DNA; Sequence Homology; Turkeys; Whole Genome Sequencing

Topics: Acinetobacter baumannii; Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Colistin; Cross Infection; Drug Resistance, Bacterial; Gram-Negative Bacterial Infections; Health Facilities; Humans; Imipenem; Klebsiella; Libya; Microbial Sensitivity Tests; Multilocus Sequence Typing

The impact of multidrug-resistant organisms (MDROs), including non-fermentative bacilli (NFBs), is rising and underestimated, especially in intensive care units (ICUs). The growing prevalence of multidrug resistance (MDR) and extensive drug resistance (XDR) is challenging for clinicians, as the treatment options are limited.. The purpose of this study was to analyze the extent of the epidemiological problem of multidrugresistant, extensively drug-resistant and pandrug-resistant (PDR) non-fermentative bacilli isolated from pneumonia and bloodstream infections (BSIs) in patients hospitalized in southern Poland.. This study included 253 NFBs belonging to Acinetobacter sp. (ACI), Pseudomonas sp. (PAR), and Stenotrophomonas sp. (STM). The microorganisms were identified, and susceptibility testing was performed using a semi-automatic system. The different patterns of resistance were defined as MDR, XDR, or PDR strains. Epidemiological typing of A. baumannii from ICUs was performed by repetitive polymerase chain reaction (rep-PCR).. More than half of the strains (57.7%) were isolated within ICUs. ACI-strains came significantly more often from ICU wards. The highest prevalence of ACI and PAR was found in pneumonia, whereas STM dominated in BSIs. ACIs were more frequently resistant than other pathogens to all studied antibiotics except colistin (n = 76; 58.9%), and they belonged to the XDR category. DiversiLab demonstrated the presence of 2 dominant clones in the ACI group, both classified as European Clone 2 (EUII).. Our results indicate serious potential therapeutic problems related to high antibiotic resistance of ACI isolates. The stratification of drug resistance (MDR/XDR/PDR) may become an important tool for the assessment of public health epidemiology and microbiological hazards at the local, national, and international level. It allows clear presentation of the issues concerning the epidemiology of highly resistant bacilli, and the exchange of information between medical staff and local representatives of public health for the implementation of effective measures to reduce drug resistance.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Anti-Bacterial Agents; Colistin; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests; Poland; Prevalence; Pseudomonas; Pseudomonas Infections; Stenotrophomonas

Topics: Anti-Bacterial Agents; Ciprofloxacin; Colistin; Cupriavidus; Drug Resistance, Bacterial; Drug Therapy, Combination; Female; Gram-Negative Bacterial Infections; Humans; Meropenem; Microbial Sensitivity Tests; Middle Aged; Shock, Septic; Treatment Outcome

Increasing reliance on antibiotics of last resort to treat the rising numbers of multidrug-resistant bacterial infections in people has focused attention on how shared-use antibiotics are managed and regulated across human and animal health. Discussions at international and national levels have intensified since the identification of new plasmid-mediated genes for colistin resistance in 2016, first in China and subsequently in many other countries, removing the last line of defense against multidrug-resistant Gram-negative bacterial infections with carbapenem resistance. South Africa has reacted to this threat by doing a situational analysis and review of the existing legislation concerning colistin use in animals and people, to inform which course of action to take. The experiences shared in this Personal View outline the process, institution of governance with widespread stakeholder engagement, surveillance, and interventions that South Africa has taken towards optimising the shared use of colistin. The instigation of stewardship guided by the principles of the One Health concept for shared-use antibiotics at the country level is a crucial component of any action plan to combat antibiotic resistance, and is as relevant to other existing antibiotics and new chemical entities that will be forthcoming from an invigorated antibiotic pipeline as it is to colistin.

Topics: Anti-Bacterial Agents; Colistin; Drug Resistance, Bacterial; Gram-Negative Bacterial Infections; Humans; Infection Control; Practice Guidelines as Topic; South Africa

Efflux in bacteria is a ubiquitous mechanism associated with resistance to antimicrobials agents. Efflux pump inhibitors (EPIs) have been developed to inhibit efflux mechanisms and could be a good alternative to reverse colistin resistance, but only CCCP has shown good activity. The aim of our study was to identify CCCP activity in a collection of 93 Gram-negative bacteria with known and unknown colistin resistance mechanisms including isolates with mcr-1 plasmid-mediated colistin resistance.. Colistin MIC was evaluated with and without CCCP and the fold decrease of colistin MIC was calculated for each strain. In order to evaluate the effect of this combination, a time-kill study was performed on five strains carrying different colistin resistance mechanisms.. Overall, CCCP was able to reverse colistin resistance for all strains tested. The effect of CCCP was significantly greater on intrinsically colistin-resistant bacteria (i.e. Proteus spp., Serratia marcescens, Morganella morganii and Providencia spp.) than on other Enterobacteriaceae (P < 0.0001). The same was true for bacteria with a heteroresistance mechanism compared to bacteria with other colistin resistance mechanisms (P < 0.0001). A time-kill study showed the combination was bacteriostatic on strains tested.. These results suggest an efflux mechanism, especially on intrinsically resistant bacteria and Enterobacter spp., but further analysis is needed to identify the molecular support of this mechanism. EPIs could be an alternative for restoring colistin activity in Gram-negative bacteria. Further work is necessary to identify new EPIs that could be used in humans.

Topics: Anti-Bacterial Agents; Bacterial Proteins; Carbonyl Cyanide m-Chlorophenyl Hydrazone; Colistin; Drug Resistance, Multiple, Bacterial; Enterobacteriaceae; Enterobacteriaceae Infections; Escherichia coli; Escherichia coli Proteins; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests; Plasmids; Proton Ionophores

Topics: Animals; Anti-Bacterial Agents; Colistin; Drug Resistance, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans

Given the severity and high mortality of multidrug-resistant Gram-negative bacilli (MDR-GNB) infections, the use of colistin will increase in patients with MDR-GNB infection.. This study aims to assess the efficacy and safety of intravenous colistin in very low birth weight (VLBW; birth weight < 1500 g) preterm infants.. We retrospectively analyzed the medical records of patients who received colistin between June 2016 and December 2017. The patients were assigned to two groups: the VLBW group and the non-VLBW group. Both groups were evaluated for response to treatment and adverse effects.. In total, 66 infants who received colistin therapy were included; of these, 28 infants were VLBW. All of our patients received standard colistin treatment of 5 mg/kg per day in three doses and the median duration of colistin treatment was 14 days. No significant differences were observed between the groups with respect to the efficacy of colistin (defined as showing microbiological clearance in control cultures and the absence of mortality during treatment) (89.3 vs 86.8%, p > 0.99). Serum magnesium and potassium levels were significantly lower in the VLBW group than in the non-VLBW group during colistin therapy (magnesium, 1.30 vs 1.70 mg/dL, p < 0.001; potassium, 3.6 vs 4.6 mEq/L, p < 0.001). Acute kidney injury was observed in four infants in the VLBW group and one in the non-VLBW group, without significant differences (p = 0.15).. Colistin administration appears to be efficacious in VLBW infants; however, renal function tests and serum electrolytes should be monitored more closely in these infants during treatment.

Topics: Acute Kidney Injury; Administration, Intravenous; Anti-Bacterial Agents; Colistin; Drug Resistance, Multiple, Bacterial; Female; Gram-Negative Bacterial Infections; Humans; Infant; Infant, Newborn; Infant, Premature; Infant, Very Low Birth Weight; Male; Retrospective Studies; Treatment Outcome

Background Gram negative pathogens are increasingly resistant to commonly used first line antibiotics and colistin is in most cases the only medicine available. There is very limited information available comparing the effectiveness and costs of low versus high dose colistin with studies showing efficacy with both doses and with variable levels of adverse effects. The absence of a definite dosing strategy makes a model to compare low dose and high dose colistin invaluable in making decisions regarding the appropriate use of colistin. Objective This study was designed to evaluate the cost effectiveness of low versus high dose colistin in the treatment of Pneumonia caused by colistin-only sensitive gram negative bacteria from the perspective of a tertiary care hospital in Saudi Arabia. Setting 300-bed tertiary care hospital in Saudi Arabia. Method A retrospective review was conducted to compare the costs and outcomes of treatment of pneumonia with low versus high dose colistin. The model followed an average patient from initiation of treatment until clinical cure or failure. Main outcome measures The main outcomes were cure, nephrotoxicity, total direct costs per episode, cost per additional cure and cost per nephrotoxicity avoided. Results There was no significant difference between high and low dose colistin with regards to clinical cure (30% vs. 21%; p = 0.292). Significantly more patients experienced nephrotoxicity with high versus low dose colistin (30% vs. 8%; p = 0.004). With low dose colistin the incremental costs per nephrotoxicity avoided was SAR-3056.28. One-way sensitivity analyses did not change the overall results. Conclusion Low dose was not inferior to high dose colistin in terms of clinical cure and had a lower incidence of nephrotoxicity resulting in significant cost avoidance.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Clinical Decision-Making; Colistin; Cost-Benefit Analysis; Dose-Response Relationship, Drug; Drug Resistance, Multiple, Bacterial; Female; Gram-Negative Bacterial Infections; Healthcare-Associated Pneumonia; Humans; Male; Middle Aged; Pneumonia, Bacterial; Retrospective Studies; Saudi Arabia; Treatment Outcome

Bacteria resistant to different classes of antimicrobial agents are a major threat to humanity and risk leading the world towards the return of the pre-antimicrobial era. This study was undertaken to detect the incidence of extensively drug-resistant (XDR) and pandrug-resistant (PDR) bacteria in a tertiary-care hospital in Bhubaneswar, Odisha, India.. Positive bacterial cultures from different clinical samples were identified using a VITEK. A total of 2489 clinical samples were collected and processed for culture during the period January 2013 to April 2017. Of 1103 pure bacterial cultures, 690 (62.6%) were Gram-negative bacteria. The antimicrobial susceptibility profile of Gram-negative bacterial strains revealed that 41.3% (n=285) were XDR and 8.1% (n=56) were PDR. Rates of colistin and tigecycline resistance were 16% and 51.9%, respectively.. This situation demands regular surveillance of antimicrobial resistance of Gram-negative bacteria and implementation of an efficient infection control programme.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Child; Child, Preschool; Colistin; Drug Resistance, Multiple, Bacterial; Female; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; India; Male; Middle Aged; Retrospective Studies; Tertiary Care Centers; Tigecycline; Young Adult

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Colistin; Drug Resistance, Multiple, Bacterial; Drug-Related Side Effects and Adverse Reactions; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Treatment Outcome

Cefiderocol (S-649266), a siderophore cephalosporin, utilizes a novel mechanism of entry into the periplasmic space of Gram-negative bacteria and is broadly stable to ESBLs and carbapenemases.. A collection of carbapenem-resistant Gram-negative bacteria isolated from clinical specimens in 18 Greek hospitals was tested for susceptibility to cefiderocol, meropenem, ceftazidime, cefepime, ceftazidime/avibactam, ceftolozane/tazobactam, aztreonam, amikacin, ciprofloxacin, colistin and tigecycline. Broth microdilution plates were used to determine MICs.. In total 189 non-fermentative Gram-negative bacteria (107 Acinetobacter baumannii and 82 Pseudomonas aeruginosa ) and 282 Enterobacteriaceae (including 244 Klebsiella pneumoniae , 14 Enterobacter cloacae and 11 Providencia stuartii ) were studied. For both A. baumannii and P. aeruginosa the MIC 90 of cefiderocol was 0.5 mg/L. For K. pneumoniae , E. cloacae and P. stuartii the MIC 90 of cefiderocol was 1, 1 and 0.5 mg/L, respectively. Tigecycline was the second most active antibiotic, followed by colistin.. Cefiderocol exhibited greater antimicrobial activity in vitro against carbapenem-resistant Gram-negative bacteria than comparator antibiotics.

Topics: Acinetobacter baumannii; Anti-Bacterial Agents; Bacterial Proteins; beta-Lactam Resistance; beta-Lactamases; Carbapenems; Cefepime; Cefiderocol; Ceftazidime; Cephalosporins; Colistin; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Greece; Humans; Inpatients; Klebsiella pneumoniae; Meropenem; Microbial Sensitivity Tests; Minocycline; Pseudomonas aeruginosa; Thienamycins; Tigecycline

Multi-drug resistant organisms (MDROs) are an increasing concern in health systems. Pathogens such as Pseudomonas aeruginosa, Acinetobacter baumanii, and carbapenamase-producing Enterobacteriaceae hold highest mortality rates especially when the central nervous system is involved. When MDROs are cultured treatment options are limited and reliance on medications such as colistin is becoming more prevalent. Penetration of these therapies into the central nervous system is concerning therefore local administration is a potential concomitant therapy.. This study was a retrospective review from 2009 to 2015 for all patients with documented MDROs gram negative pathogens who received intraventricular colistin.. Seven patients met inclusion criteria. The average age of the patients was 49years old, 4 were males, and the median length of intensive care unit stay was 30days. The duration of therapy ranged from 2 to 14days and all cerebrospinal fluid cultures were sterile at 7days after administration of colistin. Six of the seven patients were discharged from the hospital and one discharged to a skilled nursing facility. The use of intraventricular colistin was not associated with any reported adverse events.. The use of intraventricular colistin was associated with positive clinical outcomes with no reported adverse effects.

Topics: Achromobacter denitrificans; Acinetobacter baumannii; Adult; Aged; Anti-Bacterial Agents; Colistin; Drug Resistance, Multiple, Bacterial; Female; Gram-Negative Bacterial Infections; Humans; Infusions, Intraventricular; Intensive Care Units; Klebsiella pneumoniae; Length of Stay; Male; Meningitis, Bacterial; Middle Aged; Pseudomonas aeruginosa; Retrospective Studies; Young Adult

Optimal dosing for nebulized colistin methanesulfonate (CMS), the prodrug of colistin, is unknown. We describe the pulmonary and systemic pharmacokinetics of CMS and colistin following nebulization of 0.5 million IU (MIU) of CMS in ventilated patients.. Twelve critically ill patients received 0.5 MIU of CMS administered every 8 h as 30 min nebulizations. Blood samples were collected immediately before and until 8 h after first nebulization; mini-bronchoalveolar lavage (mini-BAL) was performed at 1 and 5 h or 3 and 8 h (six patients each) post-dose. Pharmacokinetic analysis was performed for CMS and colistin plasma concentrations using a non-compartmental method. ClinicalTrials.gov: NCT01060891.. After nebulization, CMS concentrations in epithelial lining fluid (ELF) were much higher (100- to 1000-fold) than those in plasma. Concentrations of colistin in ELF should be considered with caution because when <6 mg/L in BAL, colistin bound to mini-BAL devices. Nevertheless, CMS and colistin concentrations in ELF were much lower than expected from previous results with a 2 MIU dose. From CMS plasma pharmacokinetics it was shown that CMS systemic bioavailability was only slightly decreased for the 0.5 MIU dose compared with 2 MIU.. This study shows that CMS concentrations were much higher (100- to 1000-fold) in ELF than in plasma after a 0.5 MIU aerosol of CMS, but much lower (10-fold) than expected from previous results with a 2 MIU dose. Therefore, until new pharmacokinetic and pharmacodynamic assessments of the treatment of ventilator-associated pneumonia with nebulized CMS are performed, the 2 MIU dose should be preferred to the 0.5 MIU dose.

Topics: Administration, Inhalation; Adult; Aerosols; Aged; Aged, 80 and over; Anti-Bacterial Agents; Colistin; Critical Illness; Drug Administration Schedule; Female; Gram-Negative Bacterial Infections; Hospitalization; Humans; Lung; Male; Middle Aged; Nebulizers and Vaporizers; Pneumonia, Ventilator-Associated

Plasmid-mediated and chromosomally-encoded colistin resistance is increasingly being reported worldwide. We aimed to determine the prevalence of faecal carriage of colistin-resistant Gram-negative rod isolates in a university hospital in western France. From February to May 2016, rectal swabs from 653 patients hospitalized in various clinical settings were recovered and subsequently screened for colistin resistance using the SuperPolymyxin medium. Antimicrobial susceptibilities were determined according to EUCAST guidelines. Genetic detection of plasmid-mediated colistin resistance was performed by PCR. The faecal carriage with intrinsic colistin-resistant isolates was high (23 %), while the faecal carriage with Gram-negative rods showing acquired resistance was low (1.4 %). No isolate carried the plasmid-mediated mcr-1/mcr-2 genes. It was noteworthy that none of the patients carrying isolates with acquired colistin resistance had previously received a colistin-based treatment, while these isolates were not multidrug resistant.

Topics: Anti-Bacterial Agents; Carrier State; Colistin; Drug Resistance, Bacterial; Feces; France; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Hospitals, University; Humans; Microbial Sensitivity Tests; Polymerase Chain Reaction; Prevalence

The occurrence of carbapenem- and colistin-resistance among Gram-negative bacteria is increasing worldwide. The aim of this study was to understand the distribution of carbapenem- and colistin-resistance in two areas in Tamil Nadu, India.. The clinical isolates (n=89) used in this study were collected from two diagnostic centres in Tamil Nadu, India. The bacterial isolates were screened for meropenem- and colistin-resistance. Further, resistance genes blaNDM-1, blaOXA-48-like, blaIMP, blaVIM, blaKPC, mcr-1 and mcr-2 and integrons were studied. The synergistic effect of meropenem in combination with colistin was assessed.. A total of 89 bacterial isolates were studied which included Escherichia coli (n=43), Klebsiella pneumoniae (n=18), Pseudomonas aeruginosa (n=10), Enterobacter cloacae (n=6), Acinetobacter baumannii (n=5), Klebsiella oxytoca (n=4), Proteus mirabilis (n=2) and Salmonella paratyphi (n=1). MIC testing showed that 58/89 (65 %) and 29/89 (32 %) isolates were resistant to meropenem and colistin, respectively, whereas 27/89 (30 %) isolates were resistant to both antibiotics. Escherichia coli, K. pneumoniae, K. oxytoca, Pseudomonas aeruginosa, and Enterobacter cloacae isolates were blaNDM-1-positive (n=20). Some strains of Escherichia coli, K. pneumoniae and K. oxytoca were blaOXA-181-positive (n=4). Class 1, 2 and 3 integrons were found in 24, 20 and 3 isolates, respectively. Nine NDM-1-positive Escherichia coli strains could transfer carbapenem resistance via plasmids to susceptible Escherichia coli AB1157. Meropenem and colistin showed synergy in 10/20 (50 %) isolates by 24 h time-kill studies.. Our results highlight the distribution of carbapenem- and colistin-resistance in Gram-negative bacteria isolated from the Tamil Nadu region in South India.

Topics: Anti-Bacterial Agents; Colistin; Drug Resistance, Bacterial; Drug Synergism; Genes, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; India; Meropenem; Microbial Sensitivity Tests; Polymerase Chain Reaction; Thienamycins

Physicians are facing a worldwide increase in multidrug-resistant (MDR) organisms. Eradication of such bacteria, including so called superbugs (XDR), may cause physicians to prescribe last-resort antibiotics. However, experience with these drugs is limited and few data are available.. A before and after retrospective study was conducted from January 2008 to June 2016. Prescriptions of parenteral antimicrobials considered as last-resort antibiotics (colistin, fosfomycin, tigecycline and temocillin) were reviewed by 4 infectious disease specialists (according to microbiology results, susceptibility testing, clinical situation and alternative agents), while doses were analysed by a pharmacist. As a second step, the cohort was split before and after 2013 coinciding with the arrival of a referent in antimicrobial stewardship.. The treatment of 77 patients with a mean age of 55.4 ± 18.7 years was analysed. The majority were treated for gram-negative rods (69.2%), especially Pseudomonas and Klebsiella spp. and Escherichia coli while 20.0% of patients were treated for gram-positive cocci (mainly Staphylococcus aureus) and the remainder were polymicrobial. Of 84 prescriptions, fosfomycin was the most frequently prescribed (47.6%), followed by colistin (40.5%), tigecycline (10.7%) and temocillin (1.2%). Outcomes were favorable in 75.3% of patients. In patients with MDR and XDR infections (n = 54), the mortality rate was 11.1%. After 2013, there were significantly fewer prescriptions of last-resort antibiotics for susceptible microorganisms (29.2% vs 6.9%), in the absence of supporting microbiology results (22.9% vs 3.5%) and fewer dose errors (56.2% vs 27.6%) (P = 0.02).. Reinforcement of the antimicrobial stewardship task force seems to be valuable for promoting the better use of last-resort antibiotics.

Topics: Adult; Advisory Committees; Aged; Aged, 80 and over; Anti-Bacterial Agents; Antimicrobial Stewardship; Colistin; Female; Fosfomycin; Gram-Negative Bacterial Infections; Gram-Positive Bacterial Infections; Humans; Male; Middle Aged; Retrospective Studies; Treatment Outcome

Despite of proven LPS neutralizing activity, intravenous polymyxin use was waned due to experience of associated nephrotoxicity. But, increasing resistance to all available antibiotics has necessitated their resurgence and the prodrug of colistin sulfate (CS), known as colistin-methanesulfonate (CMS), is increasingly used as the only therapeutic option in many infections. Currently available CMS employ very different dose definitions and thus because of complex pharmacokinetics/pharmacodynamics information and short half-life, this drug use remains confusing. We aimed to expose CS in endotoxic shock models by micro-osmotic pump and evaluated its effectiveness.. We used micro-osmotic pumps to deliver either sterile saline or CS at different dosages ranging from 0.25mg/day to 7mg/day for consecutive 3days in LPS (8mg/kg body weight) induced endotoxic mice and observed their outcome twice daily for a week to determine the survival rate. Serum pro-inflammatory cytokine levels and apoptosis in renal tissues in these models were evaluated.. We showed endotoxic shock was reversed and all mice survived with a CS administration at a dosage of 2mg/day for 3 days, in comparison to survival rate with saline administration (p≤0.0001) in endotoxic models. CS infusion in shock models using micro-osmotic pump ameliorated rising of serum TNF-α, IL-12p70 and IL-6 levels. Nephrotoxicity was evident only with a higher dosage, but not with a lower dosage which was optimum to control endotoxic shock in models.. These results highlighted that an optimal dosage of CS effectively improved outcome in endotoxic shock models without causing nephrotoxicity when administered at a slow and sustained manner. And a higher CS dosage administration was nephrotoxic and fatal. Thus this study bought an opportunity to consider future investigations with CS administration in murine Gram-negative bacterial infections in a novel way.

Topics: Animals; Apoptosis; Colistin; Cytokines; Disease Models, Animal; Dose-Response Relationship, Drug; Endotoxins; Gram-Negative Bacterial Infections; Kidney; Lipopolysaccharides; Male; Mice; Mice, Inbred BALB C; Necrosis; Polymyxins; Shock, Septic; Survival Rate

Colistin therapy is used as the last line of defense against life-threatening Gram-negative infections. Nephrotoxicity is the major dose-limiting side effect that impedes optimal dosing of patients. This study aims to examine the nephroprotective effect of the plasma volume expander gelofusine against colistin-induced nephrotoxicity. Renal protection was assessed in mice that were subcutaneously injected with colistin sulfate (14 mg/kg of body weight × 6 doses every 2 h; accumulated dose, 84 mg/kg) and simultaneously injected in the intraperitoneal region with gelofusine (75, 150, 300, or 600 mg/kg × 6). At 2 and 20 h after the last colistin dose, mice were euthanized, and the severity of renal alteration was examined histologically. Histological findings in mice revealed that colistin-induced nephrotoxicity was ameliorated by gelofusine in a dose-dependent manner, whereas significant histological abnormalities were detected in the kidneys of mice in the colistin-only group. The impact of coadministered gelofusine on colistin pharmacokinetics was investigated in rats. Rats were administered a single intravenous dose of gelofusine at 400 mg/kg 15 min prior to the intravenous administration of colistin (1 mg/kg). Gelofusine codosing did not alter the pharmacokinetics of colistin in rats; however, gelofusine did significantly lower the accumulation of colistin in the kidney tissue of mice. This is the first study demonstrating the protective effect of gelofusine against colistin-induced nephrotoxicity. These findings highlight the clinical potential of gelofusine as a safe adjunct for ameliorating the nephrotoxicity and increasing the therapeutic index of polymyxins.

Topics: Animals; Anti-Bacterial Agents; Colistin; Female; Gram-Negative Bacterial Infections; Humans; Kidney; Kidney Cortex Necrosis; Male; Mice; Plasma Substitutes; Polygeline; Protective Agents; Rats; Rats, Sprague-Dawley

Emergence of multidrug-resistant (MDR) gram-negative (GN) pathogens and lack of novel antibiotics have increased the use of colistin, despite unknown optimal dosing. This study aimed to evaluate the safety and efficacy of a colistin loading dose, high-dose (LDHD) maintenance regimen in patients with MDR-GN pneumonia.. A retrospective cohort analysis was performed comparing critically ill patients with MDR-GN pneumonia pre- and postimplementation of a colistin LDHD guideline with a primary outcome of clinical cure. Safety was assessed using incidence of acute kidney injury (AKI) based on RIFLE (risk, injury, failure, loss, end-stage renal disease) criteria.. Seventy-two patients met the inclusion criteria (42 preimplementation and 30 postimplementation). Clinical cure was achieved in 23 (55%) patients in the preimplementation group and 20 (67%) patients in the postimplementation group ( P = .31). AKI occurred in 50% of the patients during the preimplementation period and 58% during the postimplementation period ( P = .59) with no difference in initiation rates of renal replacement therapy.. The increased clinical cure rate after implementation of the colistin LDHD guideline did not reach statistical significance. The LDHD guideline, however, was not associated with an increased incidence of AKI, despite higher intravenous colistin doses. Opportunity exists to optimize colistin dosage while balancing toxicity, but larger studies are warranted.

Topics: Acute Kidney Injury; Adult; Aged; Anti-Bacterial Agents; Colistin; Critical Illness; Drug Resistance, Multiple, Bacterial; Female; Gram-Negative Bacterial Infections; Humans; Male; Middle Aged; Pneumonia; Retrospective Studies

BACKGROUND The emergence of infections related to multidrug-resistant Gram-negative bacilli (MDR-GNB) reintroduced the use of colistin, an antibiotic that was previously abandoned due to adverse effects. However, because of its limited use in neonatal intensive care units, there is very little data about the effectiveness and safety of colistin in children and newborns. In this study, which will be the largest case study in the literature, we aimed to evaluate the effectiveness and safety of colistin in full-term and preterm newborns. MATERIAL AND METHODS The study included patients admitted into 2 level 3 neonatal intensive care units between January 2013 and June 2015. The medical records of patients diagnosed with sepsis, meningitis, pneumonia, and urinary tract infection based on the diagnostic culture results and treated with colistin were analyzed retrospectively. The patients whose infections were not verified were excluded from the study. RESULTS The study included 65 patients (18 term, 47 preterm). The most frequently isolated pathogens were Klebsiella pneumoniae and Acinetobacter baumannii followed by Pseudomonas aeruginosa and Enterobacter cloacae. Mean colistin treatment time was 15±3.5 days. All patients treated with colistin were being treated with at least 1 other antibiotic. While a complete clinical response was achieved in 51 (72.3%) patients, 14 (21.5%) patients died during treatment. Four (7.7%) patients died during as a result of another infection. Three patients developed renal toxicity, another 3 patients had seizures, and apnea was observed in 3 patients. CONCLUSIONS Colistin was found to be effective and safe for treatment of MDR-GNB infections in preterms and infants with very low birth weight. Given the severity of the infection, the adverse effects of colistin were at acceptable levels.

Topics: Anti-Bacterial Agents; Cohort Studies; Colistin; Cross Infection; Drug Resistance, Multiple, Bacterial; Female; Gram-Negative Bacterial Infections; Humans; Infant; Infant, Newborn; Infant, Premature; Intensive Care Units, Neonatal; Male; Retrospective Studies; Treatment Outcome

MICs and biofilm inhibitory concentrations (BICs) were measured for 68 cystic fibrosis (CF) Achromobacter isolates for amikacin, aztreonam, colistin, levofloxacin, and tobramycin. With the exception of colistin and levofloxacin, the remaining antibiotics had MIC90s, BICs at which 50% of the isolates were susceptible (BIC50s), and BICs at which 90% of the isolates were susceptible (BIC90s) equal to or above the highest concentrations tested. In a biofilm model, tobramycin was able to significantly increase killing of bacterial cells compared to controls, for intermediate-resistant strains only, at concentrations of 1,000 and 2,000 μg/ml.

Topics: Achromobacter; Amikacin; Anti-Bacterial Agents; Aztreonam; Biofilms; Colistin; Cystic Fibrosis; Gram-Negative Bacterial Infections; Humans; Levofloxacin; Microbial Sensitivity Tests; Plankton; Tobramycin

The increasing prevalence of multidrug-resistant (MDR) nosocomial infections accounts for increased morbidity and mortality of such infections. Infections with MDR Gram-negative isolates are frequently treated with colistin. Based on recent pharmacokinetic studies, current colistin dosing regimens may result in a prolonged time to therapeutic concentrations, leading to suboptimal and delayed effective treatment. In addition, studies have demonstrated an association between an increased colistin dose and improved clinical outcomes. However, the specific dose at which these outcomes are observed is unknown and warrants further investigation. This retrospective study utilized classification and regression tree (CART) analysis to determine the dose of colistin most predictive of global cure at day 7 of therapy. Patients were assigned to high- and low-dose cohorts based on the CART-established breakpoint. The secondary outcomes included microbiologic outcomes, clinical cure, global cure, lengths of intensive care unit (ICU) and hospital stays, and 7- and 28-day mortalities. Additionally, safety outcomes focused on the incidence of nephrotoxicity associated with high-dose colistin therapy. The CART-established breakpoint for high-dose colistin was determined to be >4.4 mg/kg of body weight/day, based on ideal body weight. This study evaluated 127 patients; 45 (35%) received high-dose colistin, and 82 (65%) received low-dose colistin. High-dose colistin was associated with day 7 global cure (40% versus 19.5%; P = 0.013) in bivariate and multivariate analyses (odds ratio [OR] = 3.40; 95% confidence interval [CI], 1.37 to 8.45; P = 0.008). High-dose colistin therapy was also associated with day 7 clinical cure, microbiologic success, and mortality but not with the development of acute kidney injury. We concluded that high-dose colistin (>4.4 mg/kg/day) is independently associated with day 7 global cure.

Topics: Acute Kidney Injury; Aged; Anti-Bacterial Agents; Bacteremia; beta-Lactam Resistance; Carbapenems; Colistin; Drug Administration Schedule; Drug Dosage Calculations; Female; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Intensive Care Units; Length of Stay; Male; Microbial Sensitivity Tests; Middle Aged; Multivariate Analysis; Retrospective Studies; Survival Analysis; Treatment Outcome

Colistin is currently regarded as one of the 'last-resort' antibiotics used for the treatment of critical infections caused by multidrug-resistant Gram-negative pathogens. There have been numerous reports of the emergence of colistin resistance in patients, most of whom had previously received colistin therapy or with acquisition via nosocomial transmission. However, there are also ample reports of colistin resistance in humans who have not received the drug previously or without nosocomial transmission. We have also observed a similar occurrence in our study involving colistin resistance from several countries along with a similar phenomenon being reported by researchers. The observation of colistin resistance in humans without prior colistin exposure is of particularly great clinical importance and concern because of the current importance of colistin in clinical medicine. Colistin use and colistin-resistant bacteria in animals have been recently reported, suggesting that animals could also be a source of transmission of colistin-resistant bacteria to humans. This is a real worry and calls for clinicians to be aware and vigilant of this phenomenon and of the possibility of independent resistance to colistin in some patients.

Topics: Animals; Anti-Bacterial Agents; Colistin; Drug Resistance, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Prevalence

Colistin is increasingly used as a last option for the treatment of severe infections due to Gram-negative bacteria in critically ill patients requiring intermittent hemodialysis (HD) for acute renal failure. Our objective was to characterize the pharmacokinetics (PK) of colistin and its prodrug colistin methanesulfonate (CMS) in this population and to suggest dosing regimen recommendations. Eight intensive care unit (ICU) patients who were under intermittent HD and who were treated by CMS (Colimycine) were included. Blood samples were collected between two consecutive HD sessions. CMS and colistin concentrations were measured by a specific chromatographic assay and were analyzed using a PK population approach (Monolix software). Monte Carlo simulations were conducted to predict the probability of target attainment (PTA). CMS nonrenal clearance was increased in ICU-HD patients. Compared with that of ICU patients included in the same clinical trial but with preserved renal function, colistin exposure was increased by 3-fold in ICU-HD patients. This is probably because a greater fraction of the CMS converted into colistin. To maintain colistin plasma concentrations high enough (>3 mg/liter) for high PTA values (area under the concentration-time curve for the free, unbound fraction of a drug [fAUC]/MIC of >10 and fAUC/MIC of >50 for systemic and lung infections, respectively), at least for MICs lower than 1.5 mg/liter (nonpulmonary infection) or 0.5 mg/liter (pulmonary infection), the dosing regimen of CMS should be 1.5 million international units (MIU) twice daily on non-HD days. HD should be conducted at the end of a dosing interval, and a supplemental dose of 1.5 MIU should be administered after the HD session (i.e., total of 4.5 MIU for HD days). This study has confirmed and complemented previously published data and suggests an a priori clear and easy to follow dosing strategy for CMS in ICU-HD patients.

Topics: Acute Kidney Injury; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Colistin; Critical Illness; Drug Administration Schedule; Female; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Lung; Male; Microbial Sensitivity Tests; Middle Aged; Renal Dialysis; Respiratory Tract Infections

The Gram-negative bacillus Stenotrophomonas maltophilia (SM) is an emerging MDR opportunistic pathogen. Recent studies identify a potentially relevant activity of azithromycin against Gram-negative bacteria overlooked in standard bacteriological testing. We investigated azithromycin activity against SM in testing conditions incorporating mammalian tissue culture medium and host defence factors.. MIC testing, chequerboard assays, time-kill assays and fluorescence microscopy were performed for azithromycin, the cationic peptide antibiotic colistin and the human defence peptide cathelicidin LL-37 alone or in combination in cation-adjusted Mueller-Hinton broth or mammalian tissue culture media. Azithromycin sensitization of SM to host immune clearance was tested in a human neutrophil killing assay and a murine pneumonia model.. We observed potent bactericidal activity of azithromycin against SM in mammalian tissue culture medium absent in bacteriological medium. Colistin and LL-37 strongly potentiated azithromycin killing of SM by increasing drug entry. Additionally, azithromycin sensitized SM to neutrophil killing and increased SM clearance in the murine pneumonia model.. Despite lack of activity in standard MIC testing, azithromycin synergizes with cationic peptide antibiotics to kill SM in medium mimicking tissue fluid conditions. Azithromycin, alone or in combination with colistin, merits further exploration in therapy of drug-resistant SM infections.

Topics: Animals; Anti-Infective Agents; Antimicrobial Cationic Peptides; Azithromycin; Cathelicidins; Colistin; Disease Models, Animal; Drug Synergism; Gram-Negative Bacterial Infections; Humans; Mice; Microbial Sensitivity Tests; Neutrophils; Pneumonia, Bacterial; Stenotrophomonas maltophilia; Treatment Outcome

Nephrotoxicity is the main adverse effect of colistin and polymyxin B (PMB). It is not clear whether these two antibiotics are associated with different nephrotoxicity rates. We compared the incidences of renal failure (RF) in patients treated with colistimethate sodium (CMS) or PMB for ≥48 h. A multicenter prospective cohort study was performed that included patients aged ≥18 years. The primary outcome was renal failure (RF) according to Risk, Injury, Failure, Loss, and End-stage renal disease (RIFLE) criteria. Multivariate analysis with a Cox regression model was performed. A total of 491 patients were included: 81 in the CMS group and 410 in the PMB group. The mean daily doses in milligrams per kilogram of body weight were 4.2 ± 1.3 and 2.4 ± 0.73 of colistin base activity and PMB, respectively. The overall incidence of RF was 16.9% (83 patients): 38.3% and 12.7% in the CMS and PMB groups, respectively (P< 0.001). In multivariate analysis, CMS therapy was an independent risk factor for RF (hazard ratio, 3.35; 95% confidence interval, 2.05 to 5.48;P< 0.001) along with intensive care unit admission, higher weight, older age, and bloodstream and intraabdominal infections. CMS was also independently associated with a higher risk of RF in various subgroup analyses. The incidence of RF was higher in the CMS group regardless of the patient baseline creatinine clearance. The development of RF during therapy was not associated with 30-day mortality in multivariate analysis. CMS was associated with significantly higher rates of RF than those of PMB. Further studies are required to confirm our findings in other patient populations.

Topics: Acute Kidney Injury; Adult; Age Factors; Aged; Aged, 80 and over; Anti-Bacterial Agents; Body Weight; Colistin; Drug Administration Schedule; Female; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Intensive Care Units; Intraabdominal Infections; Kidney Failure, Chronic; Male; Middle Aged; Multivariate Analysis; Polymyxin B; Prospective Studies; Respiratory Tract Infections; Risk Factors; Survival Analysis

Colistimethate sodium (CMS) is the commercialized form of colistin that is effective against multiresistant Gram-negative bacilli. Its main side effects are nephrotoxicity and neurotoxicity. Pharmacodynamic dosages showed that they were infratherapeutic. Therefore, strategies with higher doses were proposed. The aim of this study was to assess the efficiency and toxicity of higher-dose CMS by comparing two treatment strategies: high-dose CMS versus standard-dose CMS.. A prospective and comparative study of two matched groups was conducted. Fourty-six patients in each group were matched for age, severity and nature of infection. In the high-dose colistin group, CMS was administered at a loading dose of 9 MIU followed by a maintenance dose of 4.5 MIU/12 h. In the second group, retrospectively analyzed, colistin was administered at 6 MIU/day. For each group, clinical results, bacteriological eradication and daily creatinine clearance were recorded. Primary outcome measures were clinical cure defined as disappearance of infectious signs and eradication of microorganisms in all the follow-up cultures. Secondary outcome measures were incidence of acute renal failure and mortality.. Ninety-two patients were analyzed by matching. There was a higher cure rate in the high-dose group (63 vs. 41.3%, p = 0.04). No higher risk of nephrotoxicity was found by increasing daily doses of colistin (32.2 versus 26%, p = 0.64). Similarly, there was no significant difference in the time to onset of renal failure (8.32 vs. 11 days, p = 1) or in the requirement of hemodialysis (26.6 vs. 41%, p = 1).. The high-dose colistin regimen is more efficient, without significant renal or neurological toxicity.

Topics: Acute Kidney Injury; Adult; Aged; Anti-Bacterial Agents; Colistin; Drug Resistance, Multiple, Bacterial; Female; Gram-Negative Bacterial Infections; Humans; Male; Middle Aged; Prospective Studies; Severity of Illness Index

Topics: Animals; Anti-Bacterial Agents; Colistin; Drug Resistance, Bacterial; Escherichia coli Proteins; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Plasmids

The increasing incidence of infections caused by multidrug-resistant (MDR) or extremely drug-resistant (XDR) gram-negative organisms has led to the reemergence of colistin use. Clinical and demographic data were collected on 94 pediatric patients diagnosed with MDR or XDR gram-negative infections and treated with either a colistin-containing regimen (colistin group) or at least one antimicrobial agent other than colistin (noncolistin group). The overall clinical response rates were 65.8% in the colistin group and 70.0% in the noncolistin group (P = 0.33). The infection-related mortality rates were 11% in the colistin group and 13.3% in the noncolistin group (P = 0.74). There was no statistically significant difference in nephrotoxicity in the colistin and noncolistin groups. Colistin therapy was at least as effective and as safe as beta-lactam antibiotics or quinolones, with or without aminoglycosides, in the treatment of infections caused by gram-negative organisms and may be a therapeutic option in children.

Topics: Anti-Bacterial Agents; Child; Child, Preschool; Colistin; Drug Resistance, Multiple, Bacterial; Drug-Related Side Effects and Adverse Reactions; Female; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Infant; Male; Renal Insufficiency; Retrospective Studies; Survival Analysis; Treatment Outcome

Currently, in vitro synergy with colistin has not translated into improved clinical outcomes. This study aimed to compare colistin combination therapy to colistin monotherapy in critically ill patients with multi-drug resistant gram-negative (MDR-GN) pneumonia. This was a retrospective analysis of critically ill adult patients receiving intravenous colistin for MDR-GN pneumonia comparing colistin combination therapy to colistin monotherapy with a primary endpoint of clinical cure. Combination therapy was defined by administration of another antibiotic to which the MDR-GN pathogen was reported as susceptible or intermediate. Ninety patients were included for evaluation (41 combination therapy and 49 monotherapy). Baseline characteristics were similar between groups. No difference in clinical cure was observed between combination therapy and monotherapy in univariate analysis, nor when adjusted for APACHE II score and time to appropriate antibiotic therapy (57.1 vs. 63.4 %, adjusted OR 1.15, p = 0.78). Microbiological cure was significantly higher for combination therapy (87 vs. 35.5 %, p < 0.001). Colistin combination therapy was associated with a significant improvement in microbiological cure, without improvement in clinical cure. Based on the in vitro synergy and improvement in microbiological clearance, colistin combination therapy should be prescribed for MDR-GN pneumonia. Further research is warranted to determine if in vitro synergy with colistin translates into improved clinical outcomes.

Topics: Administration, Intravenous; Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Colistin; Critical Illness; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Female; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Male; Middle Aged; Pneumonia, Bacterial; Retrospective Studies; Treatment Outcome; Young Adult

At the Shaare Zedek Medical Center, we have been using colistimethate sodium (CMS) for empiric as well as pathogen-directed treatment. We present our 10-year experience.. We conducted a retrospective case-series analysis of patients admitted from 1 January 2004 through 1 May 2014 who received at least one dose of CMS. Patient characteristics analysed for all admission for which patients received CMS, included: age, number of re-admissions, admission ward, renal function, disposition and microbiology results. Overall trend in defined daily dose (DDD) for CMS and resistant isolates was analysed.. A total of 5603 admissions met inclusion criteria. Patients' mean (±SD) age was 80 ± 14 years, 1162 (48%) of the admissions were from a healthcare facility and 4367 (78%) of the admissions were to general Internal Medicine wards. The median number of hospital admissions per patient was 5, median admission and discharge creatinine (mg/dl) were 1.05 and 1.01, respectively; 2.3% of admissions required first-time dialysis. The discharge rate from the hospital was 58.4%. Excluding intrinsically CMS-resistant gram-negative organisms, bloodstream and urine isolates were 98% and 100% susceptible, respectively. CMS use (DDDs) increased during the study (p for trend = 0.04) without significant increase in incidence of multidrug-resistant organisms.. Colistimethate sodium use at our institution has increased during this 10-year period. Nevertheless, there is no increasing trend in CMS-resistant organisms, 58% of the patients were discharged alive, and we did not observe significant nephrotoxicity in patients prescribed CMS. CMS should be reserved for microbiologically confirmed extensively drug-resistant gram-negative infections.

Topics: Aged, 80 and over; Anti-Bacterial Agents; Colistin; Community-Acquired Infections; Cross Infection; Drug Resistance, Bacterial; Female; Gram-Negative Bacterial Infections; Hospitalization; Humans; Male; Microbial Sensitivity Tests; Respiratory Tract Infections; Retrospective Studies; Urinary Tract Infections

Stenotrophomonas maltophilia is an emerging multidrug-resistant (MDR) opportunistic pathogen for which new antibiotic options are urgently needed. We report our clinical experience treating a 19-year-old renal transplant recipient who developed prolonged bacteremia due to metallo-β-lactamase-producing S. maltophilia refractory to conventional treatment. The infection recurred despite a prolonged course of colistimethate sodium (colistin) but resolved with the use of a novel drug combination with clinical efficacy against the patient's S. maltophilia isolate.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Aztreonam; Bacteremia; beta-Lactamases; Ceftazidime; Colistin; Drug Combinations; Drug Resistance, Multiple, Bacterial; Drug Substitution; Gene Expression; Gram-Negative Bacterial Infections; Humans; Kidney Transplantation; Male; Polycystic Kidney Diseases; Stenotrophomonas maltophilia; Young Adult

Topics: Anti-Bacterial Agents; Colistin; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacterial Infections; Humans

 Optimizing colistin dosing should translate to improved patient outcomes..  We used data from 2 prospective cohort studies performed between 2006 and 2009 and between 2012 and 2015. In the latter period, a new policy of high-dose colistin (9 million international units [MIU] loading dose followed by 9 MIU daily for normal renal function) was introduced in 2 participating hospitals. We included adult inpatients with invasive infections caused by carbapenem-resistant gram-negative bacteria treated with colistin. Our primary exposure variable was colistin dose, dichotomized to high-dose vs other regimens. The primary outcome was 28-day mortality. We generated a propensity score for high-dose colistin and conducted propensity-adjusted multivariable and matched-cohort analyses for mortality..  Of 529 consecutive patients fulfilling inclusion criteria, 144 were treated with high-dose colistin and 385 with lower-dose colistin regimens. The median daily dose in the high-dose group was 9 MIU (interquartile range [IQR], 9-9) vs 4 MIU (IQR, 3-6) with other regimens. There were 50 of 144 (34.7%) deaths with high-dose colistin vs 165 of 385 (42.9%) with low-dose colistin (P = .1). The propensity-adjusted odds ratio (OR) for mortality was 1.07 (95% confidence interval [CI], .63-1.83) for high-dose colistin. Similar results were obtained when using the study period as the exposure variable, in the subgroup of bacteremic patients (n = 207) and in the propensity-matched cohort (OR, 1.11 [95% CI, .67-1.82]). Nephrotoxicity (RIFLE injury or higher; OR, 2.12 [95% CI, 1.29-3.48]; n = 396) and seizures were significantly more common with high-dose colistin..  In a large cohort, we found no association between high colistin dosing and all-cause mortality. High dosing was associated with more nephrotoxicity.

Topics: Aged; Anti-Bacterial Agents; Carbapenems; Cohort Studies; Colistin; Dose-Response Relationship, Drug; Drug Resistance, Bacterial; Female; Gram-Negative Bacterial Infections; Health Status Indicators; Humans; Male; Mortality; Prospective Studies

Colistin is used as a salvage therapy for multidrug-resistant and extremely drug-resistant gram-negative bacterial infections. Our aim was to evaluate colistin efficiency and toxicity in the treatment of these resistant gram-negative bacterial infections.. This is a retrospective study carried out in a tertiary care hospital during 2011-2013. Study data were collected from the medical records and consultations of the infectious diseases clinic.. The study group included 158 patients with nosocomial infections and 136 (86.1%) of them were hospitalized in the ICU. Respiratory tract infections were the most commonly observed ones (n = 103, 65.2%). The most frequently isolated microorganism was Acinetobacter baumannii (72.2%). A total of 98 (62.0%) patients had clinical cure. There was no statistically significant difference between monotherapy (n = 3/6, 50.0%) and combination therapies (n = 95/152, 62.5%) according to clinical response. Underlying ultimately fatal disease, previous renal disease, and total parenteral nutrition were independent risk factors for poor clinical response. Nephrotoxicity developed in 80 (50.6%) patients and clinical cure was statistically unrelated with nephrotoxicity.. Colistin may be used as an effective agent for multidrug-resistant and extremely drug-resistant gram-negative bacterial infections with close monitoring of renal functions, especially for older and critically ill patients.

Topics: Acinetobacter baumannii; Anti-Bacterial Agents; Colistin; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacterial Infections; Humans; Retrospective Studies; Treatment Outcome

Existing surveillance mechanisms may underestimate the incidence of carbapenem-resistant gram-negative infections (CRGNIs). Although carbapenem resistance increases the risk of death, the trend in mortality over time is unknown.. A retrospective cohort study was conducted at 40 academic medical centers using a discharge database to identify adult hospital admissions without cystic fibrosis in 2006-2012 and received intravenous colistin for >3 consecutive days or died during therapy (termed colistin cases). The primary outcomes were the number of colistin cases per 100,000 admissions per year and change in the hospital mortality rate over time compared with the rate of discharges to home. Secondary outcomes included median overall and intensive care unit lengths of stay.. From 2006 to 2012, a total of 5011 unique patients were identified as colistin cases. The number per 100,000 admissions per year increased from 35.56 to 92.98 during the 7-year study (P < .001). The odds of in-hospital death among colistin cases (compared with discharge to home) decreased by a mean of 5.2%/y (P = .04), whereas discharge to an institution (P = .24) or hospice (P = .89) remained steady over time. The median overall and intensive care unit lengths of stay decreased by 7.5 and 6 days, respectively (P < .001). In a 4-hospital chart review, 81.6% of colistin cases were found to have culture-positive CRGNIs. Conversely, 53% of extensively drug-resistant bloodstream CRGNIs at 2 of these hospitals met colistin case criteria.. Colistin cases represent a severely ill population with a high probability of having culture-confirmed CRGNIs. Colistin tracking is a novel strategy for monitoring the incidence and mortality of CRGNIs, particularly those caused by extensively drug-resistant bacteria. Although the incidence of colistin cases nearly tripled within 7 years, more of these patients are surviving hospitalization and going home.

Topics: Academic Medical Centers; Adult; Aged; Anti-Bacterial Agents; beta-Lactam Resistance; Carbapenems; Cohort Studies; Colistin; Female; Gram-Negative Bacterial Infections; Humans; Incidence; Male; Middle Aged; Retrospective Studies; Survival Analysis; Treatment Outcome; United States

In the face of diminishing therapeutic options for the treatment of infections caused by multidrug-resistant, Gram-negative bacteria, clinicians are increasingly using colistin and polymyxin B. These antibiotics became available clinically in the 1950s, when understanding of antimicrobial pharmacology and regulatory requirements for approval of drugs was substantially less than today. At the 1st International Conference on Polymyxins in Prato, Italy, 2013, participants discussed a set of key objectives that were developed to explore the factors affecting the safe and effective use of polymyxins, identify the gaps in knowledge, and set priorities for future research. Participants identified several factors that affect the optimum use of polymyxins, including: confusion caused by several different conventions used to describe doses of colistin; an absence of appropriate pharmacopoeial standards for polymyxins; outdated and diverse product information; and uncertainties about susceptibility testing and breakpoints. High-priority areas for research included: better definition of the effectiveness of polymyxin-based combination therapy compared with monotherapy via well designed, randomised controlled trials; examination of the relative merits of colistin versus polymyxin B for various types of infection; investigation of pharmacokinetics in special patient populations; and definition of the role of nebulised polymyxins alone or in combination with intravenous polymyxins for the treatment of pneumonia. The key areas identified provide a roadmap for action regarding the continued use of polymyxins, and are intended to help with the effective and safe use of these important, last-line antibiotics.

Topics: Anti-Bacterial Agents; Clinical Trials as Topic; Colistin; Drug Therapy; Gram-Negative Bacterial Infections; Humans; Italy; Microbial Sensitivity Tests; Polymyxin B; Treatment Outcome

Topics: Aged; Bronchitis; Colistin; Drug Resistance, Multiple, Bacterial; Female; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Male; Middle Aged; Respiration, Artificial; Tracheitis

The emergence of multidrug-resistant (MDR) Gram-negative bacteria has become a major public health problem, eliciting renewed interest in colistin, an old antibiotic that is now routinely used to treat MDR bacterial infections. Here we investigated whether colistin use has affected the prevalence of infections due to intrinsic colistin-resistant bacteria (CRB) in university hospitals in Marseille (France) over a 5-year period. All data from patients infected by intrinsic CRB were compiled from January 2009 to December 2013. Escherichia coli infections were used for comparison. Colistin consumption data were also collected from pharmacy records from 2008 to 2013. A total of 4847 intrinsic CRB infections, including 3150 Proteus spp., 847 Morganella spp., 704 Serratia spp. and 146 Providencia spp., were collected between 2009 and 2013. During this period, the annual incidence rate of hospital-acquired CRB infections increased from 220 per 1000 patients to 230 per 1000 patients and that of community-acquired CRB infections increased from 100 per 1000 patients to 140 per 1000 patients. In parallel, colistin consumption increased 2.2-fold from 2008 to 2013, mainly because of an increase in the use of colistin aerosol forms (from 50 unitary doses to 2926 unitary doses; P<10(-5)) that was significantly correlated with an increase in the number of patients positive for CRB admitted to ICUs and units of long-term care between 2009 and 2013 (r=0.91; P=0.03). The global rise in infections due to intrinsic CRB is worrying and surveillance is warranted to better characterise this intriguing epidemiological change.

Topics: Anti-Bacterial Agents; Colistin; Drug Resistance, Bacterial; France; Gram-Negative Bacterial Infections; Hospitals, University; Humans; Incidence; Retrospective Studies; Urinary Tract Infections

Nephrotoxicity is an important adverse effect of colistin methanesulfonate (CMS) therapy. No data exist on rates and risk factors for colistin-related nephrotoxicity in Saudi Arabia (SA). We conducted a prospective cohort study to identify rates and risk factors for CMS nephrotoxicity in our patient population.. We prospectively included adult patients who received ≥48 hours of intravenous CMS therapy. Pregnant patients and those on renal replacement were excluded. Patients received 9 million units (mU) loading dose followed by 3 mU 8 hourly. In renal impairment, CMS dosing was adjusted according to calculated creatinine clearance (CrCl). Nephrotoxicity was defined as per RIFLE criteria (Risk, Injury, Failure, Loss and End-stage renal disease). Statistical analysis was performed using SPSS version 20.0 (IBM, Armonk, New York, USA). The study was approved by the institution's Research Ethics Committee.. A total of 67 patients were included in the study. Mean (±standard deviation) age was 57.5 (±24.0) years, Charlson Co-morbidity Score 2.88 (±2.39), CrCl 133.60 (±92.54) mL/min and serum albumin 28.65 (±4.45) g/L. Mean CMS dose was 0.11 (±0.04) mU/kg/day and mean total CMS dose received was 101.21 (±47.37) mU. Fifty-one (76.1%) patients developed RIFLE-defined nephrotoxicity. Mean total CMS dose and duration of therapy before onset of nephrotoxicity were 66.71 (±43.45) mU and 8.70 (±6.70) days, respectively. In bivariate analysis, patients with nephrotoxicity were significantly older (P 0.013) and had lower baseline serum albumin (P 0.008). Multivariate logistic regression identified serum albumin [odds ratio (OR) 0.72; 95% confidence interval (CI) 0.57-0.93; P 0.010] and intensive care admission (OR 16.38; 95% CI 1.37-195.55; P 0.027) as independent risk factors for CMS nephrotoxicity.. High dose intravenous CMS therapy is associated with high rates of nephrotoxicity in SA. Independent risk factors for colistin nephrotoxicity were baseline hypoalbuminemia and intensive care admission.

Topics: Acute Kidney Injury; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Colistin; Female; Gram-Negative Bacterial Infections; Humans; Male; Mesylates; Middle Aged; Pregnancy; Prospective Studies; Retrospective Studies; Saudi Arabia; Young Adult

To observe the safety and efficacy of Colistimethate sodium in children infected with gram-negative bacteria, susceptible only to colistimethate sodium.. This prospective observational study done over 2 years observed children who received colistin for >48 h, for renal failure as defined by p-RIFLE criteria.. Out of 68 children, 52 (76.5%) survived. There were three children with evidence of acute kidney injury and none had neurotoxicity. Serum creatinine significantly decreased at 48 h and at end of treatment, from that at beginning of therapy (P=0.007).. Colistimethate sodium is effective against carbapenem-resistant Gram-negative bacteria, and is safe in children.

Topics: Acute Kidney Injury; Administration, Intravenous; Adolescent; Anti-Bacterial Agents; Child; Child, Preschool; Colistin; Creatinine; Drug Resistance, Bacterial; Female; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Infant; Infant, Newborn; Male; Microbial Sensitivity Tests; Prospective Studies; Sepsis

To investigate the development of nephrotoxicity associated with colistin dose, and whether this relationship differs depending on renal function.. A retrospective cohort study of patients who received intravenous colistin to treat infections caused by extensively drug-resistant Gram-negative microorganisms. Adult patients receiving colistin for 72 hours or longer were included in this study. Patients who received renal replacement therapy at baseline or were administered colistin for less than 3 days were excluded. Colistin-induced nephrotoxicity was defined as a doubling of baseline serum creatinine. Colistin dosing was evaluated based on both actual body weight and ideal body weight.. Single general hospital between 2010 and 2013.. A total number of 475 patients received colistin therapy. Of these patients, 329 met the inclusion criteria and were included in the analysis.. None.. One hundred forty-three patients (43.5%) experienced nephrotoxicity during colistin treatment. The median onset time of nephrotoxicity was 6 days (interquartile range, 4-8 days). The patients with nephrotoxicity were older. Hematocrit and serum albumin levels were lower in patients with nephrotoxicity. Median daily dosing of colistin based on ideal body weight was significantly higher in patients with nephrotoxicity than in those without nephrotoxicity (4.55 vs 4.43 mg/kg/d, respectively; p=0.021). The cumulative dose was not different between patients with and without nephrotoxicity. In multiple logistic regression analysis, daily colistin dosing based on ideal body weight was only significantly associated with the development of nephrotoxicity in patients with an estimated glomerular filtration rate<60 mL/min/1.73 m2 (odds ratio, 2.34; 95% CI, 1.22-4.5). In these affected patients, based on a receiver operating characteristic plot, the optimal predictive cutoff of colistin dose for the development of nephrotoxicity was 2.87 mg/kg/d of colistin, with a sensitivity of 92.3% and a specificity of 76.7%. In patients with estimated glomerular filtration rate≥60 mL/min/1.73 m, age, serum albumin, hematocrit, and use of glycopeptide were associated with the development of nephrotoxicity.. Development of nephrotoxicity was significantly more strongly associated with the dose of colistin, but only in patients with an estimated glomerular filtration rate<60 mL/min/1.73 m2 and not in those with normal renal function.

Topics: Acute Kidney Injury; Age Factors; Aged; Aged, 80 and over; Anti-Bacterial Agents; Colistin; Creatinine; Dose-Response Relationship, Drug; Drug Resistance, Bacterial; Female; Glomerular Filtration Rate; Gram-Negative Bacterial Infections; Hematocrit; Humans; Male; Middle Aged; Retrospective Studies; Risk Factors; Serum Albumin; Time Factors

Case description The use of i.v. colistin reappeared recently for the treatment of multidrug-resistant Gram negative organisms in the intensive care and cystic fibrosis (CF) setting. According to the latest pharmacokinetic data, a loading dose and high antibiotic doses are given. Two cases of adverse events (paraesthesias, bad taste) were observed immediately after the start of infusion of a high dose of i.v. colistin in adult CF patients at the Ghent University Hospital. Conclusion Recommendations for optimal administration of i.v. colistin in adult CF patients are scarce. This article highlights the importance of mode of administration to avoid toxicity and relates it to recent pharmacokinetic/-dynamic literature.

Topics: Adult; Anti-Bacterial Agents; Colistin; Cystic Fibrosis; Female; Gram-Negative Bacterial Infections; Humans; Infusions, Intravenous; Male; Paresthesia

Critically ill patients with severe sepsis or septic shock may need relatively high colistin daily doses for efficacy against multidrug-resistant and extensively drug-resistant gram-negative rods. However, acute kidney injury (AKI) may represent a major dose-limiting adverse effect of colistin. We sought to determine AKI occurrence and to identify factors influencing AKI risk in severely ill patients receiving colistin according to a recently proposed dosing strategy.. A prospective, observational, cohort study involving patients with severe sepsis or septic shock who received colistin was performed. AKI was defined according to Acute Kidney Injury Network criteria. Colistin administration was driven by a modified pharmacokinetics-pharmacodynamics (PK/PD)-based dosing approach.. Of 70 patients who received colistin at a median daily dose of 9 million IU (MIU; interquartile range, 5.87-11.1 MIU), 31 (44%) developed AKI. In univariate analysis, age, Acute Physiology and Chronic Health Evaluation (APACHE) II score, Sequential Organ Failure Assessment (SOFA), score and baseline renal impairment were significantly associated with AKI. Moreover, patients with AKI were less frequently treated with adjuvant ascorbic acid (P = .003). In multivariate analysis, independent predictors of AKI were baseline renal impairment (adjusted hazard ratio, 4.15; 95% confidence interval, 1.9-9.2; P < .001) and age (1.03; 1.0-1.05; P = .028), whereas a strong independent renal-protective role emerged for ascorbic acid (0.27; .12-.57; P < .001).. In severely ill patients receiving colistin according to a PK/PD-driven dosing approach, baseline renal impairment and older age strongly predict AKI occurrence, but concomitant administration of ascorbic acid markedly reduces AKI risk, allowing safer use of colistin.

Topics: Acute Kidney Injury; Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Antidotes; Ascorbic Acid; Blighia; Colistin; Critical Illness; Female; Gram-Negative Bacterial Infections; Humans; Male; Middle Aged; Prospective Studies; Risk Factors; Sepsis; Young Adult

Colistin has been revived, in the era of extensively drug-resistant (XDR) Gram-negative infections, as the last-resort treatment in critically ill patients. Recent studies focusing on the optimal dosing strategy of colistin have demonstrated the necessity of a loading dose at treatment initiation (D. Plachouras, M. Karvanen, L. E. Friberg, E. Papadomichelakis, A. Antoniadou, I. Tsangaris, I. Karaiskos, G. Poulakou, F. Kontopidou, A. Armaganidis, O. Cars, and H. Giamarellou, Antimicrob Agents Chemother 53:3430-3436, 2009, http://dx.doi.org/10.1128/AAC.01361-08; A. F. Mohamed, I. Karaiskos, D. Plachouras, M. Karvanen, K. Pontikis, B. Jansson, E. Papadomichelakis, A. Antoniadou, H. Giamarellou, A. Armaganidis, O. Cars, and L. E. Friberg, Antimicrob Agents Chemother 56:4241- 4249, 2012, http://dx.doi.org/10.1128/AAC.06426-11; S. M. Garonzik, J. Li, V. Thamlikitkul, D. L. Paterson, S. Shoham, J. Jacob, F. P. Silveira, A. Forrest, and R. L. Nation, Antimicrob Agents Chemother 55:3284-3294, 2011, http://dx.doi.org/10.1128/AAC.01733-10). In 19 critically ill patients with suspected or microbiologically documented infections caused by XDR Gram-negative strains, a loading dose of 9 MU colistin methanesulfonate (CMS) (∼ 270 mg colistin base activity) was administered with a maintenance dose of 4.5 MU every 12 h, commenced after 24 h. Patients on renal replacement were excluded. CMS infusion was given over 30 min or 1 h. Repeated blood sampling was performed after the loading dose and after the 5th or 6th dose. Colistin concentrations and measured CMS, determined after hydrolization to colistin and including the partially sulfomethylated derivatives, were determined with a liquid chromatography-tandem mass spectrometry assay. Population pharmacokinetic analysis was conducted in NONMEM with the new data combined with data from previous studies. Measured colistimethate concentrations were described by 4 compartments for distribution and removal of sulfomethyl groups, while colistin disposition followed a 1-compartment model. The average observed maximum colistin A plus B concentration was 2.65 mg/liter after the loading dose (maximum time was 8 h). A significantly higher availability of the measured A and B forms of colistimethate and colistin explained the higher-than-expected concentrations in the present study compared to those in previous studies. Creatinine clearance was a time-varying covariate of colistimethate clearance. The incidence of acute renal injury was

Topics: Acute Kidney Injury; Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Chromatography, Liquid; Colistin; Creatinine; Critical Illness; Drug Administration Schedule; Drug Resistance, Multiple, Bacterial; Female; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Infusions, Intravenous; Male; Middle Aged; Models, Statistical; Tandem Mass Spectrometry

Gram-negative bacilli (n=15,377) were tested against colistin (polymyxin E) and polymyxin B by a commercial broth microdilution method (Sensititre®). Among Pseudomonas aeruginosa and Acinetobacter spp., colistin and polymyxin B MIC values were within ±1 doubling dilution for >99.0% of strains. Among Klebsiella spp. and Escherichia coli, 55.0 and 53.2% of strains displayed a colistin MIC 2-fold lower than polymyxin B, but polymyxin B was slightly more potent than colistin against strains with decreased susceptibility to either polymyxin.

Topics: Colistin; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests; Polymyxin B

Infections caused by carbapenem-resistant bacteria constitute a major challenge for current medical practice.. To describe treatment and outcome of carbapenem-resistant Gram-negative bacilli (GNB) blood-stream infection (BSI) caused by these organisms at a tertiary care hospital in Mumbai.. Carbapenem-resistant isolates from blood cultures were collected from January 2013 to April 2013. Identification and antimicrobial susceptibility testing were performed using Vitek 2 analyzer (Biomerieux Ltd.). Carbapenemase production was detected by modified Hodge's test (MHT). Patient's medical history, treatment and co-morbid conditions were noted. Outcomes of BSIs were evaluated.. Forty-two isolates of carbapenem-resistant GNB isolated from BSIs were Enterobacteriaceae spp. (19), Acinetobacter baumannii (15), and Pseudomonas aeruginosa (8). Colistin had maximum in vitro activity with 97% against Enterobacteriaceae, 100% against Acinetobacter, and 100% activity against Pseudomonas aeruginosa isolates. Positivity of MHT was 92.9%. Outcome of colistin mono and combination therapy was comparable with 83% and 79%, respectively. Outcome of colistin and carbapenem combination therapy was found to be 100 percent.. High incidences of bacteremia by carbapenem-resistant GNB including Enterobacteriaceae is a worrisome trend. Treatment options are compromised and only available option is colistin which has its own limitation. Colistin monotherapy may be non-inferior compared to combination therapy for treating BSIs caused by isolates with minimum inhibitory concentration (MIC) for colistin as ≤0.5 mg/l. Combined use of the colistin and carbapenem may provide good therapeutic options for BSI caused by carbapenem-resistant GNB and warrants further investigations.

Topics: Acinetobacter baumannii; Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Bacteremia; beta-Lactam Resistance; Carbapenems; Child; Child, Preschool; Colistin; Enterobacteriaceae; Female; Gram-Negative Bacterial Infections; Humans; India; Infant; Male; Microbial Sensitivity Tests; Middle Aged; Pseudomonas aeruginosa; Tertiary Care Centers; Treatment Outcome; Young Adult

Infections caused by multi-drug resistant bacteria, particularly Gram-negative bacteria, are an ever-increasing problem. While the development of new antibiotics remains one option in the fight against bacteria that have become resistant to currently available antibiotics, an attractive alternative is the development of adjuvant therapeutics that restore the efficacy of existing antibiotics. We report a small molecule adjuvant that suppresses colistin resistance in multidrug resistant Acinetobacter baumannii and Klebsiella pneumoniae by interfering with the expression of a two-component system. The compound downregulates the pmrCAB operon and reverses phosphoethanolamine modification of lipid A responsible for colistin resistance. Furthermore, colistin-susceptible and colistin-resistant bacteria do not evolve resistance to combination treatment. This represents the first definitive example of a compound that breaks antibiotic resistance by directly modulating two-component system activity.

Topics: Anti-Bacterial Agents; Bacterial Proteins; Colistin; Down-Regulation; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Lipid A; Small Molecule Libraries; Transcription Factors

Nosocomially acquired multidrug-resistant (MDR) Gram-negative bacteria are important contributors to paediatric intensive care unit (PICU) mortality and morbidity, with limited treatment options.. To investigate the outcomes of all children treated with colistin for infection with MDR Gram-negative bacteria while admitted to PICU.. Retrospective observational study of 19 months. Primary endpoints were all-cause intensive care unit mortality and safety. Secondary endpoints evaluated clinical and microbiological outcomes. Cases were stratified according to HIV status.. Twenty-seven children received 30 colistin courses during the study period. Eight patients (29.6%) were HIV infected, six (22.2%) were HIV uninfected but exposed, and 11 (40.7%) were HIV uninfected and unexposed. Common MDR Gram-negative bacteria cultured were: Acinetobacter species (n=22, 81.5%), Pseudomonas aeruginosa (n=11, 40.7%) and Klebsiella pneumoniae (n=7, 25.9%). Mortality was 37%, with no significant difference between HIV strata. No adverse drug reactions were noted. A composite clinical improvement was noted in 16 courses (53.3%) of colistin. Only 30% of colistin courses used in HIV-infected children resulted in an improved clinical assessment as compared with 83.3% of courses in HIV-uninfected/unexposed children (p=0.04). In HIV-infected children, five of 10 (50%) courses of colistin showed bacteriological clearance compared to the HIV uninfected/unexposed group where all cases showed bacterial eradication (p=0.02).. HIV-infected children had poorer clinical and bacteriological responses to colistin treatment than HIV uninfected/unexposed. These results require confirmation with prospective studies to determine whether findings are due to poor microbial response, immunodeficiency or repeated reinfections.

Topics: Anti-Bacterial Agents; Child Mortality; Child, Preschool; Colistin; Drug Resistance, Multiple, Bacterial; Female; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; HIV Infections; Humans; Infant; Intensive Care Units, Pediatric; Male; Retrospective Studies; South Africa; Treatment Outcome

A colistin-glycopeptide combination (CGC) has been shown in vitro to be synergistic against multidrug-resistant Gram-negative bacteria (MDR GNB), especially Acinetobacter baumannii, and to prevent further resistance. However, clinical data are lacking. We carried out a retrospective multicenter study of patients hospitalized in intensive care units (ICUs) who received colistin for GNB infection over a 1-year period, to assess the rates of nephrotoxicity and 30-day mortality after treatment onset among patients treated with and without CGC for ≥48 h. Of the 184 patients treated with colistin, GNB infection was documented for 166. The main causative agents were MDR A. baumannii (59.6%), MDR Pseudomonas aeruginosa (18.7%), and carbapenem-resistant Klebsiella pneumoniae (14.5%); in 16.9% of patients, a Gram-positive bacterium (GPB) coinfection was documented. Overall, 68 patients (40.9%) received CGC. Comparison of patients treated with and without CGC showed significant differences for respiratory failure (39.7% versus 58.2%), ventilator-associated pneumonia (54.4% versus 71.4%), MDR A. baumannii infection (70.6% versus 52%), and GPB coinfection (41.2% versus 0%); there were no differences for nephrotoxicity (11.8% versus 13.3%) and 30-day mortality (33.8% versus 29.6%). Cox analysis performed on patients who survived for ≥5 days after treatment onset showed that the Charlson index (hazard ratio [HR], 1.26; 95% confidence interval [CI], 1.01 to 1.44; P = 0.001) and MDR A. baumannii infection (HR, 2.51; 95% CI, 1.23 to 5.12; P = 0.01) were independent predictors of 30-day mortality, whereas receiving CGC for ≥5 days was a protective factor (HR, 0.42; 95% CI, 0.19 to 0.93; P = 0.03). We found that CGC was not associated with higher nephrotoxicity and was a protective factor for mortality if administered for ≥5 days.

Topics: Acinetobacter baumannii; Aged; Anti-Bacterial Agents; Colistin; Critical Illness; Drug Therapy, Combination; Female; Glycopeptides; Gram-Negative Bacterial Infections; Humans; Kidney; Klebsiella pneumoniae; Male; Middle Aged; Pneumonia, Ventilator-Associated; Proportional Hazards Models; Pseudomonas aeruginosa; Survival Analysis; Treatment Outcome

The aim of our study was to evaluate the in vitro activity of IB-367 and its bactericidal effect for Pseudomonas aeruginosa and Escherichia coli, associated to a synergic study to test the antibiotic combinations between the peptide and colistin or imipenem. Minimum inhibitory concentrations (MICs), the minimum bactericidal concentrations (MBCs), the synergy test and killing study were carried out to evaluate the IB-367 activity. In the in vivo model, a wound was incised through the panniculus carnosus of BALB/c mice, and then inoculated with 5 × 107 colony-forming units of P. aeruginosa and E. coli. For each strain, the study included an infected or not infected group that did not receive any treatment, and five contaminated groups treated with local IB- 367, intraperitoneal imipenem, intraperitoneal colistin, topical IB-367 local plus intraperitoneal imipenem or intraperitoneal colistin. All isolates were inhibited by IB-367 at concentrations of 4-64 mg/l. Killing by IB-367 was shown to be very rapid: its activity on all Gram-negative bacteria was completed within a 40 min exposure period at a concentration of 2 × MIC/l. Synergy was demonstrated when IB-367 was combined with colistin or imipenem. In in vivo studies, the groups treated with topical IB-367 and intraperitoneal colistin showed the best results in terms of bacterial load inhibition either for Pseudomonas or for E. coli. The good in vitro activity and in vivo efficacy, as well as, the synergic interactions with antibiotics suggest that IB-367 is a promising candidate for potential application in the treatment of wound Gram-negative infections.

Topics: Acinetobacter baumannii; Administration, Topical; Animals; Anti-Bacterial Agents; Antimicrobial Cationic Peptides; Colistin; Disease Models, Animal; Drug Therapy, Combination; Escherichia coli; Gram-Negative Bacterial Infections; Humans; Imipenem; Injections, Intraperitoneal; Klebsiella pneumoniae; Mice, Inbred BALB C; Microbial Sensitivity Tests; Pseudomonas aeruginosa

Infections due to multidrug-resistant gram-negative bacteria (MDR-GNB) are a significant burden to the healthcare system globally. Colistin is the drug of choice for MDR-GNB and recent studies recommend high doses. This study investigated the safety of low-dose colistin and the relationship of minimum inhibitory concentration (MIC) of colistin with bacterial cure in the treatment for MDR-GNB infections.. Computerized dispensing records identified all patients who received colistin during January 2010 and December 2011. Patients who were aged < 12 years old, who received colistin for < 72 h or had moderate to severe renal impairment were excluded. Medical records of the remaining patients were reviewed for the necessary data to determine the bacterial cure and nephrotoxicity of colistin. Multivariate logistic regression analysis was used to determine the predictors of bacterial cure.. A total of 125 evaluable patients received colistin during the study period. Ninety-four of 125 (75·2%) patients achieved bacterial cure. No statistically significant differences were observed between patients who achieved and failed to achieve bacterial cure with regards to age, gender, site of infection, mg/kg dose or duration of colistin use. The average MIC in the bacterial cure group was significantly lower than the MIC in the bacterial failure group (P = 0·002). Similarly, 30-day mortality from the last dose of colistin was significantly lower in the bacterial cure group (P = 0·002). Nephrotoxicity occurred in 12·8% of patients and was not associated with the dose of colistin or concomitant use of nephrotoxic medications. MIC of <1 μg/mL was the only significant independent predictor of bacterial cure in the multivariate logistic regression analysis (P = 0·015), whereas infection caused by MDR Klebsiella pneumonia was an independent risk factor for bacterial failure (P = 0·049).. Low-dose colistin is an effective option in the treatment for infections caused by MDR-GNB with a low incidence of nephrotoxicity. Patients who achieved bacterial cure had significantly lower MIC values of colistin against MDR-GNB than those who failed to achieve it. Colistin dose should be based on the MIC data of a given patient or local antimicrobial sensitivity data to maximize its efficacy.

Topics: Acute Kidney Injury; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Colistin; Dose-Response Relationship, Drug; Drug Resistance, Multiple, Bacterial; Female; Gram-Negative Bacterial Infections; Humans; Male; Microbial Sensitivity Tests; Middle Aged

The initial use of polymyxins, polymyxin B and colistin (administered as a pro-drug colistin methanesulfonate sodium [CMS]), mostly relied on old pharmacokinetic (PK) studies that lacked appropriate methodology. In recent years, many PK studies in both animals and humans have provided more consistent evidence supporting better use of these invaluable antibiotics. However, translating preclinical data to clinical practice is not always an easy task and some may experience difficulties on how recent knowledge on polymyxins can be applied into the patients' care. Although many questions are still unresolved, there are consistent data able to improve clinical practice when prescribing initial and maintenance doses of both polymyxin B and CMS. Considering the importance of optimal use of polymyxins, this editorial discusses recent PK findings and how to take advantage of them at the bedside to improve the treatment of patient with extensively-drug-resistant Gram-negative bacterial infections.

Topics: Anti-Bacterial Agents; Area Under Curve; Colistin; Drug Administration Schedule; Drug Dosage Calculations; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests; Polymyxin B

The antimicrobial treatment of Stenotrophomonas maltophilia infections is complicated by intrinsic multidrug resistance and a lack of reliable susceptibility data. We assessed the activity of colistin (COL), rifampicin (RIF) and tigecycline (TGC) alone and in combination using a range of in vitro susceptibility testing methodologies and a simple invertebrate model of S. maltophilia infection (Galleria mellonella). Synergy [fractional inhibitory concentration indices (FICIs) ≤0.5] between COL and either RIF or TGC was observed against 92 % and 88 % of 25 S. maltophilia isolates, respectively, despite resistance to one or another of the single agents alone. In time-kill assays, COL combined with either RIF or TGC was superior to single agents, but only the COL/RIF regimen was reliably bactericidal. The in vitro findings correlated with treatment outcomes in G. mellonella, with heightened survival observed for larvae treated with COL/RIF or COL/TGC compared with COL, RIF or TGC alone. COL combined with RIF was the most effective combination overall in both in vitro and in vivo (p < 0.05) assays. Given the difficulty in selecting appropriate therapy for S. maltophilia infections, regimens consisting of COL combined with RIF or TGC could be considered for clinical use.

Topics: Animals; Colistin; Disease Models, Animal; Drug Resistance, Multiple, Bacterial; Drug Synergism; Drug Therapy, Combination; Gram-Negative Bacterial Infections; Lepidoptera; Microbial Viability; Minocycline; Rifampin; Stenotrophomonas maltophilia; Survival Analysis; Tigecycline; Treatment Outcome

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Topics: Anti-Bacterial Agents; Colistin; Female; Gram-Negative Bacterial Infections; Humans; Injections, Intraventricular; Meningoencephalitis; Middle Aged; Stenotrophomonas maltophilia; Subarachnoid Hemorrhage

In intensive care units (ICUs), the most important causes of nosocomial bacterial infections are mainly multidrug-resistant (MDR) and extensively drug-resistant (XDR) Acinetobacter baumannii and Klebsiella pneumoniae strains. Mortality related to these infections is very high due to lack of effective therapy and the severity of patient conditions. This study aimed to assess the prevalence of carbapenem resistance genes in 77 carbapenem-resistant Gram-negative bacteria isolated from severe infections (bloodstream, pulmonary and urinary tract) during the period 1 January to 31 July 2013 in a general ICU in Catania, Italy, and to examine their susceptibility to tigecycline and colistin using two different methods. In total, 52 A. baumannii belonging to the same sequence type (ST) 2 clone and carrying the bla(OXA-23) gene as well as 25 K. pneumoniae carrying bla(KPC-3) were isolated. Four distinct pulsotypes were identified in K. pneumoniae, which correlated with four distinct STs: ST258 and ST512, spread worldwide, and ST147 and ST395 detected for the first time in Italy. A. baumannii isolates showed an XDR profile and were fully susceptible only to colistin; all KPC-producing K. pneumoniae isolates were MDR, whilst colistin was active against 19 of 25 strains. These results show that broth microdilution (BMD) is a reliable in vitro susceptibility test for colistin, above all K. pneumoniae, whilst both the gradient test and BMD are suitable for tigecycline susceptibility testing of A. baumannii.

Topics: Acinetobacter baumannii; Anti-Bacterial Agents; beta-Lactamases; Carbapenems; Colistin; Drug Resistance, Multiple, Bacterial; Electrophoresis, Gel, Pulsed-Field; Genotype; Gram-Negative Bacterial Infections; Humans; Intensive Care Units; Italy; Klebsiella pneumoniae; Microbial Sensitivity Tests; Minocycline; Multilocus Sequence Typing; Tigecycline

Despite concerns about its nephrotoxicity, colistin often remains the only effective agent for treating multidrug-resistant Gram-negative infections. Published studies have reported a wide range of nephrotoxicity risk factors. To assess the clinical utility of various models, we compared their performances for predicting the risk of nephrotoxicity. We identified a model demonstrating reasonable overall risk assessment, with an observed/expected ratio of 1.29 (95% confidence interval [CI], 0.68 to 1.90) and a positive predictive value of 87.5% for identifying patients at high risk of developing nephrotoxicity.

Topics: Anti-Bacterial Agents; Colistin; Drug Resistance, Multiple, Bacterial; Female; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Kidney; Male; Middle Aged; Risk; Risk Assessment

Colistin is an old antibiotic that has recently gained a considerable renewal of interest for the treatment of pulmonary infections due to multidrug-resistant Gram-negative bacteria. Nebulization seems to be a promising form of administration, but colistin is administered as an inactive prodrug, colistin methanesulfonate (CMS); however, differences between the intrapulmonary concentrations of the active moiety as a function of the route of administration in critically ill patients have not been precisely documented. In this study, CMS and colistin concentrations were measured on two separate occasions within the plasma and epithelial lining fluid (ELF) of critically ill patients (n = 12) who had received 2 million international units (MIU) of CMS by aerosol delivery and then intravenous administration. The pharmacokinetic analysis was conducted using a population approach and completed by pharmacokinetic-pharmacodynamic (PK-PD) modeling and simulations. The ELF colistin concentrations varied considerably (9.53 to 1,137 mg/liter), but they were much higher than those in plasma (0.15 to 0.73 mg/liter) after aerosol delivery but not after intravenous administration of CMS. Following CMS aerosol delivery, typically, 9% of the CMS dose reached the ELF, and only 1.4% was presystemically converted into colistin. PK-PD analysis concluded that there was much higher antimicrobial efficacy after CMS aerosol delivery than after intravenous administration. These new data seem to support the use of aerosol delivery of CMS for the treatment of pulmonary infections in critical care patients.

Topics: Administration, Inhalation; Administration, Intravenous; Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Biotransformation; Colistin; Critical Illness; Drug Administration Schedule; Drug Dosage Calculations; Extracellular Fluid; Female; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Half-Life; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Models, Statistical; Pneumonia, Ventilator-Associated

Colistin is an old antibiotic that has recently gained a considerable renewal of interest as the last-line defense therapy against multidrug-resistant Gram-negative bacteria. It is administered as colistin methanesulfonate (CMS), an inactive prodrug, and it was shown that due to slow CMS conversion, colistin plasma concentrations increase very slowly after treatment initiation, which constitutes the rationale for a loading dose in critically ill patients. However, faster CMS conversion was observed in healthy volunteers but using a different CMS brand, which may also have a major impact on colistin pharmacokinetics. Seventy-three critically ill patients not undergoing dialysis received multiple doses of CMS. The CMS concentrations were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and a pharmacokinetic analysis was conducted using a population approach. We confirmed that CMS renal clearance and colistin concentrations at steady state are mostly governed by creatinine clearance, but we predict a typical maximum concentration of drug in serum (Cmax) of colistin close to 2 mg/liter, occurring 3 h after an initial dose of 2 million international units (MIU) of CMS. Accordingly, the estimated colistin half-life (t1/2) was relatively short (3.1 h), with rapid attainment of steady state. Our results are only partially consistent with other recently published results. We confirm that the CMS maintenance dose should be adjusted according to renal function in critically ill patients. However, much higher than expected colistin concentrations were observed after the initial CMS dose, with rapid steady-state achievement. These discrepancies challenge the pharmacokinetic rationale for a loading dose, which may still be appropriate for rapid bacterial eradication and an improved clinical cure rate.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Biotransformation; Colistin; Critical Illness; Drug Administration Schedule; Drug Dosage Calculations; Female; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Half-Life; Humans; Lung; Male; Microbial Sensitivity Tests; Middle Aged

Most patients with cystic fibrosis (CF) have chronic rhinosinusitis; their sinuses are often colonized with bacteria that can initiate and maintain deleterious pulmonary infections. Theoretically, eradication of the sinus bacteria should reduce the frequency of lung infections and thereby reduce pulmonary morbidity. This article addressed whether bacteria in CF sinuses are eligible for eradication by sinus surgery and postoperative treatment.. A prospective study including 58 CF patients, who had extensive sinus surgery and growth of Pseudomonas aeruginosa, Achromobacter xylosoxidans, and/or Burkholderia multivorans in their sinuses, was initiated. All patients followed a systematic postoperative treatment program of nasal irrigations with saline and colistimethate sodium and systematic endoscopic cleansing. All patients had follow-up examinations including sinus cultures; each side of the nose was cultured separately.. At the 6-month follow-up visit, 49 patients were cultured; 66 of 98 maxillary-ethmoidal complexes (67%) showed no growth of pathogenic bacteria. Some patients were not free from CF pathogenic bacteria at all cultures; however, 20 (41%) patients had no bilateral regrowth (p < 0.01) and 4 patients had no unilateral regrowth at any time during 6 months of follow-up. The eradication of CF pathogens was accomplished in patients from all three lung infection groups: intermittently colonized, chronically infected, and lung transplanted. The patient with the longest follow-up had no bacterial growth for 3 years.. Extensive sinus surgery combined with intensive follow-up can eradicate pathogenic bacteria from CF sinuses.

Topics: Achromobacter denitrificans; Adolescent; Adult; Burkholderia; Burkholderia Infections; Child; Chronic Disease; Colistin; Cystic Fibrosis; Female; Follow-Up Studies; Gram-Negative Bacterial Infections; Humans; Male; Middle Aged; Nasal Lavage; Paranasal Sinuses; Prospective Studies; Pseudomonas aeruginosa; Pseudomonas Infections; Rhinitis; Sinusitis; Treatment Outcome; Young Adult

Colistin is increasingly used as a salvage therapy for nosocomial infections caused by multidrug-resistant Gram-negative bacteria such as Pseudomonas aeruginosa and Acinetobacter baumannii. However, the available pharmacokinetic (PK) data for colistin are limited to guide dosing. The aim of this study was to develop a population PK model of colistin and to identify the optimal dosage regimens for burn patients. Fifty patients with burns ranging from 4% to 85% of total body surface area who had been treated with colistimethate sodium (CMS) were studied. CMS, which is hydrolyzed in vivo to an active metabolite, was intravenously administered every 12 h. Blood samples were collected at 0, 1, 2, 4, 6, and 8 h after more than five infusions to measure the colistin concentration using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) system. The population PK model was developed using nonlinear mixed effect modeling (NONMEM, v. 6.2). A one-compartment linear PK model for colistin best described the data. The covariates included in the final model were creatinine clearance for the relative fraction of CMS converted into colistin and the presence of edema for the turnover rate constant of CMS converted into colistin. A steady-state 24-h area under the concentration-time curve was simulated from 1,000 virtual patients receiving 150 mg colistin base activity every 12 h using the final model. Relative to previous studies with critically ill patients, the elimination half-life of colistin (6.6 h) was much shorter, and continuous renal replacement therapy was not a significant covariate for any PK parameters.

Topics: Acinetobacter baumannii; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Area Under Curve; Biological Availability; Biotransformation; Burns; Colistin; Drug Administration Schedule; Female; Gram-Negative Bacterial Infections; Half-Life; Humans; Injections, Intravenous; Male; Middle Aged; Models, Statistical; Pseudomonas aeruginosa; Treatment Outcome

In vitro evaluation of colistin susceptibility is fraught with complications, due in part to the inherent cationic properties of colistin. In addition, no reference method has been defined against which to compare the results of colistin susceptibility testing. This study systematically evaluated the available methods for colistin MIC testing in two phases. In phase I, colistin MICs were determined in 107 fresh clinical isolates of multidrug-resistant (MDR) Gram-negative bacilli (GNB) by broth microdilution with polysorbate 80 (BMD-T), broth macrodilution (TDS), and the Etest. In phase II, 50 of these isolates, 10 of which were colistin resistant, were tested in parallel using BMD-T, TDS, agar dilution, broth microdilution without polysorbate 80 (BMD), and the TREK Gram-negative extra MIC format (GNXF) Sensititre. The Etest was also performed on these 50 isolates using Mueller-Hinton agar (MHA) from three different manufacturers. Colistin MIC results obtained from the five methods were compared to the MIC results obtained using BMD-T, the method that enables the highest nominal concentration of colistin in the test medium. Essential agreement ranged from 34% (BMD) to 83% (TDS), whereas categorical agreement was >90% for all methods except for BMD, which was 88%. Very major errors (VMEs) (i.e., false susceptibility) for the Etest were found in 47 to 53% of the resistant isolates, depending on the manufacturer of the MHA that was used. In contrast, VMEs were found for 10% (n = 1) of the resistant isolates by BMD and 0% of the isolates by the TDS, agar dilution, and Sensititre methods. Based on these data, we urge clinical laboratories to be aware of the variable results that can occur when using different methods for colistin MIC testing and, in particular, to use caution with the Etest.

Topics: Anti-Bacterial Agents; Colistin; Diagnostic Errors; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests

The activity of colistin in combination with daptomycin was assessed using 30 Gram-negative type strains and multidrug-resistant isolates with defined mechanisms of resistance. Daptomycin minimum inhibitory concentrations (MICs) were determined with and without sub-inhibitory concentrations of colistin. The activity of daptomycin was not affected with respect to Escherichia coli, Klebsiella pneumoniae or Pseudomonas aeruginosa. For colistin-susceptible Acinetobacter baumannii, sensitisation factors ranged from 8 to 128 (median 32), with the daptomycin MIC being reduced to the Clinical and Laboratory Standards Institute (CLSI) enterococci susceptibility breakpoint of 4 μg/ml for the ATCC 19606 type strain. A combination of daptomycin and colistin may be useful for the treatment of A. baumannii but not infections due to other Gram-negative species.

Topics: Colistin; Daptomycin; Drug Synergism; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests

Colistin is increasingly used as the last-resort treatment option against infections caused by multidrug-resistant (MDR) Gram-negative pathogens, but its nephrotoxicity is of concern, especially in severely ill patients. The aim of this study was to analyze the toxicity of colistin therapy in adults and children with hematological malignancies (HM) and hematopoietic stem cell transplantation (HSCT) recipients.. Data on HSCT recipients and HM patients, treated with intravenous colistin (2.5-5 mg/kg/day in children and 3-6 million international units (IU) in adults, adjusted to renal function) during the period 2008-2011 in our center, were retrospectively collected and analyzed. Nephrotoxicity was defined according to the RIFLE criteria (Risk, Injury, Failure, Loss, and End-stage kidney disease).. Twenty-nine children and adults received 38 courses of intravenous colistin (2.5-5 mg/kg/day in children and 3-6 × 10(6) IU in adults, adjusted to renal function) [allogeneic HSCT (22 courses) and HM (16 courses)] for 3-28 days (median 10 days) for empirical therapy for nosocomial clinical sepsis (28) or local infection (6), and bacteremia with MDR Gram-negative rods (4). Nephrotoxicity was observed at the end of 4 (10.5%) courses. In 32 (84%) courses, nephrotoxic medications were concomitantly administered. Two patients had convulsions, probably unrelated to colistin. Seven patients (18%) died while on colistin therapy. No death was attributed to an adverse effect of colistin.. Treatment with intravenous colistin, with dosage adjusted to renal function, was relatively safe for HM/HSCT patients, even with concomitantly administered nephrotoxic medications. Concern about nephrotoxicity should not justify a delay in initiating empirical colistin treatment in situations where infection with MDR Gram-negative rods is likely.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Bacteremia; Child; Child, Preschool; Colistin; Female; Gram-Negative Bacterial Infections; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Infant; Male; Middle Aged; Retrospective Studies; Treatment Outcome

Nosocomial infection due to multidrug-resistant Gram-negative pathogens in ICUs is a challenge for clinicians and microbiologists and has led to the resurgence of IV colistin use in the last decade. The aim of this study was to assess the efficacy of IV colistin in the treatment of critically ill children with multidrug-resistant Gram-negative infections.. Retrospective descriptive study conducted in the PICU of Maulana Azad Medical College and associated Chacha Nehru Bal Chikitsalaya, Delhi, India, during the period of January 2010 to December 2011.. The records of critically ill children with multidrug-resistant Gram-negative infections treated with IV colistin were reviewed.. Fifty critically ill children received IV colistin; their median age was 36 months (range: 1 mo-12 yr), with male:female ratio of 3:2. The isolated pathogens were Acinetobacter baumannii, Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, and Enterobacter cloacae. Mean duration of colistin therapy was 14.3 days (range, 7-21). A favorable clinical outcome occurred in 36 children (72%), and 14 children (28%) died due to severe sepsis with multiple-organ dysfunction syndrome. Renal toxicity occurred in five children and was associated with multiple-organ dysfunction syndrome in three and coadministration of vancomycin in two. No neurotoxic adverse effects due to colistin therapy were reported.. Our study suggests that IV colistin may have a role in the treatment of infections caused by multidrug-resistant Gram-negative bacteria in critically ill children, but further prospective and randomized control trials are needed to confirm its efficacy and safety in children.

Topics: Anti-Bacterial Agents; Child; Child, Preschool; Colistin; Critical Illness; Cross Infection; Drug Administration Schedule; Drug Resistance, Multiple, Bacterial; Female; Gram-Negative Bacterial Infections; Humans; Infant; Infusions, Intravenous; Intensive Care Units, Pediatric; Male; Retrospective Studies; Treatment Outcome

The emergence of multidrug-resistant (MDR) bacteria in cystic fibrosis (CF) patients has led to the use of colistin drug and the emergence of colistin-resistant Gram-negative bacteria. The aim of this study was to compare the disk diffusion and Etest methods for colistin susceptibility testing on MDR bacteria associated with CF from Marseille, France. Forty-nine MDR clinical isolates (27 Stenotrophomonas maltophilia, 22 Achromobacter xylosoxidans) were used in this study. Disk diffusion and Etest assays were used to assess the reliability of these two techniques. For S. maltophilia, 25 out of 27 isolates had low minimum inhibitory concentrations (MICs, 0.125-0.75 mg/L), whereas two isolates displayed high MICs (32 mg/L). Similarly, 19 out of 22 A. xylosoxidans isolates had low MICs (0.75-3.0 mg/L), whereas three isolates had high MICs (32-256 mg/L). The diameters of zone inhibition with a 50-μg colistin disk displayed a good correlation with the MICs obtained by the Etest. Susceptible and resistant strains were eventually separated using a disk diffusion assay at a cut-off of ≤ 12 mm for a 50-μg disk. Colistin displayed excellent activity against S. maltophilia and A. xylosoxidans and the disk diffusion assay could be confidently used to determine the susceptibility to colistin for MDR Gram-negative bacteria in the context of CF.

Topics: Achromobacter denitrificans; Anti-Bacterial Agents; Colistin; Cystic Fibrosis; Drug Resistance, Multiple, Bacterial; France; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests; Stenotrophomonas maltophilia

Following a bloodstream infection in June 2011 with Ralstonia mannitolilytica in a premature infant treated with a humidifying respiratory therapy device, an investigation was initiated at the Hadassah Medical Centres in Jerusalem. The device delivers a warmed and humidified mixture of air and oxygen to patients by nasal cannula. The investigation revealed colonisation with R. mannitolilytica of two of 15 patients and contamination of components of five of six devices deployed in the premature units of the Hadassah hospitals. Ten isolates from the investigation were highly related and indistinguishable from isolates described in an outbreak in 2005 in the United States (US). Measures successful in containing the US outbreak were not included in user instructions provided to our hospitals by the distributor of the device.

Topics: Anti-Bacterial Agents; Colistin; Disease Outbreaks; Disinfection; Drug Resistance, Bacterial; Equipment Contamination; Gram-Negative Bacterial Infections; Humans; Humidity; Infant, Newborn; Infant, Premature; Israel; Oxygen Inhalation Therapy; Ralstonia pickettii; Respiratory Tract Infections

Owing to its activity against multidrug-resistant gram-negative bacteria, colistin (like other older antibiotics) is experiencing a surprising resurgence. In the 50 years following its discovery, little effort was put into studying its dosing and pharmacodynamic properties. Recent data have been filling the gaps, and individualized dosing recommendations targeting an optimal AUC/MIC ratio have been published. According to these data, pharmacokinetic targets will clearly be missed without exceeding the currently recommended dosages. Even the highest doses studied so far do not universally result in sufficient drug levels. Therefore, colistin remains a last-resort drug which should be used in combination with other antibiotics only. Regardless of the presence of resistance, carbapenems seem to be the most promising combination partners.

Topics: Anti-Bacterial Agents; Colistin; Dose-Response Relationship, Drug; Drug Resistance, Multiple, Bacterial; Evidence-Based Medicine; Gram-Negative Bacterial Infections; Humans

Data regarding the most efficacious and least toxic schedules for the use of colistin are scarce. The aim of this study was to determine the incidence and the potential risk factors of colistin-associated nephrotoxicity including colistin plasma levels.. A prospective observational cohort study was conducted for over one year in patients receiving intravenous colistin methanesulfonate sodium (CMS). Blood samples for colistin plasma levels were collected immediately before (Cmin) and 30 minutes after CMS infusion (Cmax). Renal function was assessed at baseline, on day 7 and at the end of treatment (EOT). Severity of acute kidney injury (AKI) was defined by the RIFLE (risk, injury, failure, loss, and end-stage kidney disease) criteria.. One hundred and two patients met the inclusion criteria. AKI related to CMS treatment on day 7 and at the end of treatment (EOT) was observed in 26 (25.5%) and 50 (49.0%) patients, respectively. At day 7, Cmin (OR, 4.63 [2.33-9.20]; P < 0.001) was the only independent predictor of AKI. At EOT, the Charlson score (OR 1.26 [1.01-1.57]; P = 0.036), Cmin (OR 2.14 [1.33-3.42]; P = 0.002), and concomitant treatment with ≥ 2 nephrotoxic drugs (OR 2.61 [1.0-6.8]; P = 0.049) were independent risk factors for AKI. When Cmin was evaluated as a categorical variable, the breakpoints that better predicted AKI were 3.33 mg/L (P < 0.001) on day 7 and 2.42 mg/L (P < 0.001) at EOT.. When using the RIFLE criteria, colistin-related nephrotoxicity is observed in a high percentage of patients. Cmin levels are predictive of AKI. Patients who receive intravenous colistin should be closely monitored and Cmin might be a new useful tool to predict AKI.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Colistin; Female; Gram-Negative Bacterial Infections; Humans; Kidney Diseases; Male; Middle Aged; Prospective Studies; Risk Factors; Spain

Topics: Aged; Analysis of Variance; Anti-Bacterial Agents; Colistin; Cross Infection; Drug Resistance, Multiple, Bacterial; Female; Gram-Negative Bacterial Infections; Hospitalization; Humans; Male; Middle Aged; Retrospective Studies; Risk Factors; Treatment Outcome

Antibiotic-resistant bacterial infection is one of the most serious clinical problems worldwide. Vancomycin, teicoplanin, daptomycin, and colistin are glycopeptide and lipopeptide antibiotics that are frequently used to treat multidrug-resistant bacterial infections. Therapeutic drug monitoring is recommended to ensure both safety and efficacy and to improve clinical outcomes. This study developed a fast, simple, and sensitive ultra-high-pressure liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method for the simultaneous determination of the concentrations of these four drugs in human plasma. The sample preparation process includes a simple protein denaturation step using acetonitrile, followed by an 11-fold dilution with 0.1% formic acid. Eight target peaks for the four drugs can be analyzed within 3 min using a Kinetex™ 2.6 μm C18 column. The mass spectrometry parameters were optimized, and two transitions for each target peak were used for multiple reaction monitoring, which provided high sensitivity and specificity. The UHPLC-MS/MS method was validated over clinical concentration ranges. The intra-day and inter-day precisions for the ratio of the peak area of each analyte to the peak area of the internal standard were all below 12.7 and 14.7% relative standard deviations, respectively. The accuracy at low, medium, and high concentrations of the eight target peaks was between 89.3 and 110.7%. The standard curves for the analytes were linear and had coefficients of determination higher than 0.997. The limits of detection were all below 70 ng mL(-1). The use of this method to analyze patient plasma samples confirmed that it is effective for the therapeutic drug monitoring of these four drugs and can be used to improve the therapeutic efficacy and safety of treatment with antibiotics.

Topics: Acetonitriles; Anti-Bacterial Agents; Calibration; Chromatography, High Pressure Liquid; Colistin; Daptomycin; Drug Monitoring; Drug Resistance, Multiple, Bacterial; Formates; Gram-Negative Bacterial Infections; Gram-Positive Bacterial Infections; Humans; Limit of Detection; Protein Denaturation; Reproducibility of Results; Tandem Mass Spectrometry; Teicoplanin; Vancomycin

Polymyxins have recently again become important because of multidrug-resistant (MDR) gram-negative pathogens. The aim of this study was to evaluate the clinical and microbiological efficacy and toxicity of different dosages of colistin in patients infected with MDR microorganisms that were sensitive only to colistin. The study was conducted in the 1,200-bed Ankara Numune Training and Research Hospital. Patients with normal renal function who received colistin for 48 h or more were retrospectively evaluated. Clinical response was defined as resolution of fever and clinical and laboratory findings. Microbiological response was defined as bacteriological eradication from the infection site. Nephrotoxicity was defined as at least two consecutive serum creatinine measurements with an increase of 0.5 mg/dl from baseline at least 24 h apart after 2 or more days of colistin therapy. Twenty-four patients were included in the study: total clinical response was obtained in 17 of 24 (70.8 %) patients and microbiological response in 15 of 24 (62.5 %) patients. Patients were grouped according to colistin dosage of 3 × 1 million units (MU) versus 3 × 2 MU. Clinical response rates were 69.2 % and 72.7 %, respectively (p = 0.65). Microbiological response rate was similar (p = 0.62). Nephrotoxicity was revealed in 1 of 13 patients (7.7 %) for the 3 × 1 MU group and 2 of 11 patients (18.2 %) in the 3 × 2 MU group (p = 0.57). The nephrotoxicity rate was greater with higher dosages of colistin, but the difference was not statistically significant. Renal function of patients receiving higher dosages of colistin should be more closely monitored.

Topics: Adult; Aged; Anti-Bacterial Agents; Bacteremia; Colistin; Drug Resistance, Multiple, Bacterial; Female; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Male; Middle Aged; Pneumonia, Bacterial; Treatment Outcome; Urinary Tract Infections; Young Adult

Colistin is increasingly used for the treatment of multidrug-resistant gram-negative infections. However, colistin dosing varies greatly and the optimal regimen is unknown. The purpose of this study was to determine if colistin dosing correlates with patient outcomes.. This retrospective study included patients with gram-negative bacteremia treated with intravenous colistin for at least 72 hours. The primary objective was to determine if colistin dose (mg of colistin base activity/kg/day) independently predicts day-7 microbiological success. Secondary objectives included evaluation for an association between colistin dose and 7-day mortality, 28-day mortality, and the development of acute kidney insufficiency (AKI).. Seventy-six patients were included in the analysis, with 52 patients (68%) achieving 7-day microbiological success. The median colistin dose was significantly higher in patients who achieved microbiological success (2.9 vs 1.5 mg/kg/day; P = .011). After adjusting for baseline severity of illness and concomitant tigecyline use, higher colistin dose independently correlated with microbiological success (adjusted odds ratio per 1 mg/kg/day = 1.74; 95% confidence interval, 1.11-2.71; P = .015). The median colistin dose was also significantly higher among survivors at day 7 (2.7 vs 1.5 mg/kg/day; P = .007). However, no difference was observed in colistin dose when comparing survivors and nonsurvivors at day 28. A significantly higher colistin dose was given to patients who developed AKI during therapy (3.8 vs 1.6 mg/kg/day; P < .001).. Higher colistin dose independently predicted microbiological success, which may partially explain the similar association with 7-day mortality. However, higher colistin doses may also precipitate worsening renal function.

Topics: Anti-Bacterial Agents; Bacteremia; Colistin; Dose-Response Relationship, Drug; Drug Resistance, Multiple, Bacterial; Female; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Injections, Intravenous; Male; Middle Aged; Retrospective Studies; Treatment Outcome

Topics: Adult; Aged; Anti-Bacterial Agents; Cohort Studies; Colistin; Drug Resistance, Multiple, Bacterial; Drug-Related Side Effects and Adverse Reactions; Female; France; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Infusions, Intravenous; Male; Middle Aged; Osteoarthritis; Retrospective Studies; Switzerland; Time Factors; Treatment Outcome

Topics: Anti-Bacterial Agents; Bronchitis; Colistin; Drug Resistance, Multiple; Female; Gram-Negative Bacterial Infections; Humans; Male; Respiration, Artificial; Tracheitis

In this prospective multicentric study, we assessed the in vitro antimicrobial activity of carbapenems (imipenem, meropenem, and doripenem), tigecycline, and colistin against 166 unusual nonfermenting Gram-negative bacilli (NF-GNB) clinical isolates collected from nine French hospitals during a 6-month period (from December 1, 2008, to May 31, 2009). All NF-GNB isolates were included, except those phenotypically identified as Pseudomonas aeruginosa or Acinetobacter baumannii. Minimal inhibitory concentrations (MICs) of antimicrobial agents were determined by using the E-test technique. The following microorganisms were identified: Stenotrophomonas maltophilia (n=72), Pseudomonas spp. (n=30), Achromobacter xylosoxidans (n=25), Acinetobacter spp. (n=18), Burkholderia cepacia complex (n=9), Alcaligenes faecalis (n=7), and Delftia spp. (n=5). All isolates of Acinetobacter spp., A. faecalis, and Delftia spp. were susceptible to the three carbapenems. Imipenem exhibited the lowest MICs against Pseudomonas spp., and meropenem, as compared with imipenem and doripenem, displayed an interesting antimicrobial activity against A. xylosoxidans and B. cepacia complex isolates. Conversely, no carbapenem exhibited any activity against S. maltophilia. Except for S. maltophilia isolates, tigecycline and colistin exhibited higher MICs than carbapenems, but covered most of the microorganisms tested in this study. To our knowledge, no prior study has compared antimicrobial activity of these five antibiotics, often considered as "last-resort" treatment options for resistant Gram-negative infections, against unusual NF-GNB clinical isolates. Further studies should be carried out to assess the potential clinical use of these antibiotics for the treatment of infections due to these microorganisms.

Topics: Anti-Bacterial Agents; Bacterial Typing Techniques; Carbapenems; Colistin; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests; Minocycline; Tigecycline

Gram-negative bacteria susceptible only to colistin (COS) are emerging causes of severe nosocomial infections, reviving interest in the use of colistin. However, consensus on the most effective way to administer colistin has not yet been reached.. All patients who had sepsis due to COS gram-negative bacteria or minimally susceptible gram-negative bacteria and received intravenous colistimethate sodium (CMS) were prospectively enrolled. The CMS dosing schedule was based on a loading dose of 9 MU and a 9-MU twice-daily fractioned maintenance dose, titrated on renal function. For each CMS course, clinical cure, bacteriological clearance, daily serum creatinine clearance, and estimated creatinine clearance were recorded.. Twenty-eight infectious episodes due to Acinetobacter baumannii (46.4%), Klebsiella pneumoniae (46.4%), and Pseudomonas aeruginosa (7.2%) were analyzed. The main types of infection were bloodstream infection (64.3%) and ventilator-associated pneumonia (35.7%). Clinical cure was observed in 23 cases (82.1%). Acute kidney injury developed during 5 treatment courses (17.8%), did not require renal replacement therapy, and subsided within 10 days from CMS discontinuation. No correlation was found between variation in serum creatinine level (from baseline to peak) and daily and cumulative doses of CMS, and between variation in serum creatinine level (from baseline to peak) and duration of CMS treatment.. Our study shows that in severe infections due to COS gram-negative bacteria, the high-dose, extended-interval CMS regimen has a high efficacy, without significant renal toxicity.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Cohort Studies; Colistin; Critical Illness; Cross Infection; Female; Gram-Negative Bacterial Infections; Humans; Kidney Diseases; Male; Middle Aged; Prospective Studies; Sepsis; Treatment Outcome

Topics: Anti-Bacterial Agents; Colistin; Cross Infection; Female; Gram-Negative Bacterial Infections; Humans; Male; Sepsis

A previous pharmacokinetic study on dosing of colistin methanesulfonate (CMS) at 240 mg (3 million units [MU]) every 8 h indicated that colistin has a long half-life, resulting in insufficient concentrations for the first 12 to 48 h after initiation of treatment. A loading dose would therefore be beneficial. The aim of this study was to evaluate CMS and colistin pharmacokinetics following a 480-mg (6-MU) loading dose in critically ill patients and to explore the bacterial kill following the use of different dosing regimens obtained by predictions from a pharmacokinetic-pharmacodynamic model developed from an in vitro study on Pseudomonas aeruginosa. The unbound fractions of colistin A and colistin B were determined using equilibrium dialysis and considered in the predictions. Ten critically ill patients (6 males; mean age, 54 years; mean creatinine clearance, 82 ml/min) with infections caused by multidrug-resistant Gram-negative bacteria were enrolled in the study. The pharmacokinetic data collected after the first and eighth doses were analyzed simultaneously with the data from the previous study (total, 28 patients) in the NONMEM program. For CMS, a two-compartment model best described the pharmacokinetics, and the half-lives of the two phases were estimated to be 0.026 and 2.2 h, respectively. For colistin, a one-compartment model was sufficient and the estimated half-life was 18.5 h. The unbound fractions of colistin in the patients were 26 to 41% at clinical concentrations. Colistin A, but not colistin B, had a concentration-dependent binding. The predictions suggested that the time to 3-log-unit bacterial kill for a 480-mg loading dose was reduced to half of that for the dose of 240 mg.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Colistin; Critical Illness; Dose-Response Relationship, Drug; Female; Gram-Negative Bacterial Infections; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Prospective Studies; Protein Binding; Pseudomonas aeruginosa

Stenotrophomonas maltophilia is acquiring increasing importance as a nosocomial pathogen.. We retrospectively studied the characteristics and outcome of patients with any type of S. maltophilia infection at the University Hospital of Heraklion, Crete, Greece, between 1/2005-12/2010. S. maltophilia antimicrobial susceptibility was tested with the agar dilution method. Prognostic factors for all-cause in-hospital mortality were assessed with multivariate logistic regression.. Sixty-eight patients (median age: 70.5 years; 64.7% males) with S. maltophilia infection, not related to cystic fibrosis, were included. The 68 patients were hospitalized in medical (29.4%), surgical (26.5%), hematology/oncology departments (23.5%), or the intensive care units (ICU; 20.6%). The most frequent infection types were respiratory tract (54.4%), bloodstream (16.2%), skin/soft tissue (10.3%), and intra-abdominal (8.8%) infection. The S. maltophilia-associated infection was polymicrobial in 33.8% of the cases. In vitro susceptibility was higher to colistin (91.2%), trimethoprim/sulfamethoxazole and netilmicin (85.3% each), and ciprofloxacin (82.4%). The empirical and the targeted treatment regimens were microbiologically appropriate for 47.3% and 63.6% of the 55 patients with data available, respectively. Most patients received targeted therapy with a combination of agents other than trimethoprim/sulfamethoxazole. The crude mortality and the mortality and the S. maltophilia infection-related mortality were 14.7% and 4.4%, respectively. ICU hospitalization was the only independent prognostic factor for mortality.. S. maltophilia infection in a general hospital can be associated with a good prognosis, except for the patients hospitalized in the ICU. Combination reigmens with fluoroquinolones, colistin, or tigecycline could be alternative treatment options to trimethoprim/sulfamethoxazole.

Topics: Aged; Ciprofloxacin; Colistin; Colony Count, Microbial; Cross Infection; Drug Resistance, Multiple, Bacterial; Female; Gram-Negative Bacterial Infections; Greece; Humans; Logistic Models; Male; Netilmicin; Retrospective Studies; Statistics, Nonparametric; Stenotrophomonas maltophilia; Treatment Outcome; Trimethoprim

Intraventricular colistin, administered as colistin methanesulfonate (CMS), is the last resource for the treatment of central nervous system infections caused by panresistant Gram-negative bacteria. The doses and daily regimens vary considerably and are empirically chosen; the cerebrospinal fluid (CSF) pharmacokinetics of colistin after intraventricular administration of CMS has never been characterized. Nine patients (aged 18 to 73 years) were treated with intraventricular CMS (daily doses of 2.61 to 10.44 mg). Colistin concentrations were measured using a selective high-performance liquid chromatography (HPLC) assay. The population pharmacokinetics analysis was performed with the P-Pharm program. The pharmacokinetics of colistin could be best described by the one-compartment model. The estimated values (means ± standard deviations) of apparent CSF total clearance (CL/Fm, where Fm is the unknown fraction of CMS converted to colistin) and terminal half-life (t(1/2λ)) were 0.033 ± 0.014 liter/h and 7.8 ± 3.2 h, respectively, and the average time to the peak concentration was 3.7 ± 0.9 h. A positive correlation between CL/Fm and the amount of CSF drained (range 40 to 300 ml) was observed. When CMS was administered at doses of ≥5.22 mg/day, measured CSF concentrations of colistin were continuously above the MIC of 2 μg/ml, and measured values of trough concentration (C(trough)) ranged between 2.0 and 9.7 μg/ml. Microbiological cure was observed in 8/9 patients. Intraventricular administration of CMS at doses of ≥5.22 mg per day was appropriate in our patients, but since external CSF efflux is variable and can influence the clearance of colistin and its concentrations in CSF, the daily dose of 10 mg suggested by the Infectious Diseases Society of America may be more prudent.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Adolescent; Adult; Aged; Central Nervous System Bacterial Infections; Colistin; Female; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Injections, Intraventricular; Klebsiella Infections; Klebsiella pneumoniae; Male; Microbial Sensitivity Tests; Middle Aged; Pseudomonas aeruginosa; Pseudomonas Infections

Colistin resistance, although uncommon, is increasingly being reported among Gram-negative clinical pathogens, and an understanding of its impact on the activity of antimicrobials is now evolving. We evaluated the potential for synergy of colistin plus trimethoprim, trimethoprim-sulfamethoxazole (1/19 ratio), or vancomycin against 12 isolates of Acinetobacter baumannii (n = 4), Pseudomonas aeruginosa (n = 4), and Klebsiella pneumoniae (n = 4). The strains included six multidrug-resistant clinical isolates, K. pneumoniae ATCC 700603, A. baumannii ATCC 19606, P. aeruginosa ATCC 27853, and their colistin-resistant derivatives (KPm1, ABm1, and PAm1, respectively). Antimicrobial susceptibilities were assessed by broth microdilution and population analysis profiles. The potential for synergy of colistin combinations was evaluated using a checkerboard assay, as well as static time-kill experiments at 0.5× and 0.25× MIC. The MIC ranges of vancomycin, trimethoprim, and trimethoprim-sulfamethoxazole (1/19) were ≥128, 4 to ≥128, and 2/38 to >128/2,432 μg/ml, respectively. Colistin resistance demonstrated little impact on vancomycin, trimethoprim, or trimethoprim-sulfamethoxazole MIC values. Isolates with subpopulations heterogeneously resistant to colistin were observed to various degrees in all tested isolates. In time-kill assays, all tested combinations were synergistic against KPm1 at 0.25× MIC and 0.5× MIC and ABm1 and PAm1 at 0.5× MIC. In contrast, none of the tested combinations demonstrated synergy against any colistin-susceptible P. aeruginosa isolates and clinical strains of K. pneumoniae isolates. Only colistin plus trimethoprim or trimethoprim-sulfamethoxazole was synergistic and bactericidal at 0.5× MIC against K. pneumoniae ATCC 700603. Colistin resistance seems to promote the in vitro activity of unconventional colistin combinations. Additional experiments are warranted to understand the clinical significance of these observations.

Topics: Acinetobacter baumannii; Anti-Bacterial Agents; Colistin; Drug Resistance, Multiple, Bacterial; Drug Synergism; Gram-Negative Bacterial Infections; Humans; Klebsiella pneumoniae; Microbial Sensitivity Tests; Microbial Viability; Pseudomonas aeruginosa; Trimethoprim, Sulfamethoxazole Drug Combination; Vancomycin

Available data on colistin pharmacokinetics in patients undergoing continuous renal replacement therapy (CRRT) are limited. Our aim was to study colistin pharmacokinetics in critically ill patients treated with colistin methane sulphonate for Gram-negative sepsis and undergoing continuous venovenous haemodiafiltration for acute renal failure.. Three patients were studied. The colistin methane sulphonate dose administered was at the discretion of the attending physician and was in all cases lower than that recommended for individuals with intact renal function. Colistin methane sulphonate was administered intravenously over 30 min, and blood samples were collected from each patient pre- and post-filter for the HPLC determination of colistin levels in serum before infusion, at 10, 60, 120, 240, 360, 480 and 600 min from the end of infusion, and immediately before the next dose. Concurrently, spot samples of effluent from the haemofilter were also collected and analysed. Both colistin total extracorporeal clearance and clearance in the effluent were calculated.. Extracorporeal clearance resulted in substantial removal of colistin (43%-59% of total colistin clearance). Total colistin clearance was found to be reduced (varying between 3.3 and 4.5 L/h), compared with patients with normal renal function. Colistin methane sulphonate dosage resulted in clearly suboptimal colistin steady-state concentrations.. In spite of substantial extracorporeal clearance, total colistin clearance was reduced, compared with patients with normal renal function. Colistin adsorption by the haemofilter contributed to its extracorporeal clearance to a large extent. Studies on other patients receiving colistin methane sulphonate and undergoing CRRT are required before more appropriate dosage regimens can be recommended.

Topics: Anti-Bacterial Agents; Chromatography, High Pressure Liquid; Colistin; Critical Illness; Gram-Negative Bacterial Infections; Hemodiafiltration; Humans; Infusions, Intravenous; Intensive Care Units; Male; Metabolic Clearance Rate; Middle Aged; Sepsis; Serum; Time Factors

Topics: Anti-Bacterial Agents; Colistin; Cross Infection; Female; Gram-Negative Bacterial Infections; Humans; Male; Sepsis

The purpose of this study was to describe inhaled colistin pharmacokinetics in patients with ventilator-associated tracheobronchitis (VAT) due to polymyxin-only susceptible Gram-negative bacteria (GNB).. Inhaled colistimethate sodium (CMS) was administered at a dose of 80 mg every 8 h for 7 days. Mini bronchoalveolar lavage (BAL) was performed before and at 1, 4 and 8 h, while blood samples were collected before and at 0.16, 0.5, 1, 2, 4 and 8 h after the first dose. Colistin concentrations in BAL and serum were determined by high-performance liquid chromatography.. Our study population included 20 patients. At the end of treatment, cure was achieved in 16 patients and favorable microbiological response in 12 patients. Median (25-75 % interquartile range) colistin concentrations in epithelial lining fluid (ELF) were 6.7 (4.8-10.1), 3.9 (2.5-6.0) and 2.0 (1.0-3.8) μg/ml at 1, 4 and 8 h, respectively, and fivefold higher than those achieved in serum. Median ELF concentrations at 1 and 4 h were above the minimum inhibitory concentrations of all isolated pathogens; however, the 4-h median was below the European Committee on Antimicrobial Susceptibility Guidelines (EUCAST) breakpoints for Pseudomonas aeruginosa and the 8-h median was low relative to EUCAST breakpoints for all GNB. Colistin pharmacokinetic/pharmacodynamic parameters in ELF were associated with favorable microbiological response at the end of treatment.. Inhaled colistin may achieve high drug concentrations in the lung. However, a dose of 80 mg of inhaled CMS every 8 h may not be adequate for the treatment of lower respiratory tract infections due to multi-drug resistant GNB.

Topics: Acinetobacter baumannii; Administration, Inhalation; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Bronchitis; Colistin; Drug Resistance, Multiple; Female; Gram-Negative Bacterial Infections; Humans; Klebsiella pneumoniae; Male; Middle Aged; Pseudomonas aeruginosa; Respiration, Artificial; Tracheitis

Nosocomial infection due to multidrug-resistant Gram-negative pathogens in intensive care units is a challenge for clinicians and microbiologists, and has led to resurgence of parenteral colistin use in the last decade. Safety and efficacy data regarding intravenous colistin (colistimethate) use in neonates is sparse. We present our experience of efficacy and safety of colistimethate in the treatment of sepsis in critically sick term and preterm neonates.. The records of the neonates who received colistimethate in a neonatal intensive care unit of a tertiary care center from January 2009 to December 2009 were reviewed.. Eighteen critically sick neonates (10 term and 8 preterm) received 21 courses of colistimethate (dose ranging from 50,000 to 75,000 IU/kg/d) for treatment of pneumonia, blood stream infections, meningitis, and empyema thoracis. The isolated pathogens in decreasing order of frequency were Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonos aeruginosa, and Enterobacter. Mean duration of colistimethate was 13.1 days/course (range: 5-21 days). At least one other antibiotic was coadministered in all courses. A favorable clinical outcome occurred in 16 of 21 (76%) courses, 5 patients died due to severe sepsis with multiple organ dysfunction. Microbiologic clearance was documented in 17 courses. Increase in serum creatinine by > 0.5 mg/dL above baseline in 2 babies was associated with the presence of multiple organ dysfunction syndrome in both and coadministration of netilmicin in one.. Colistimethate intravenous administration appears to be safe and efficacious for multidrug-resistant Gram-negative infections in neonates, including preterm and extremely low birth weight neonates.

Topics: Acinetobacter baumannii; Anti-Bacterial Agents; Bacteremia; Colistin; Critical Care; Cross Infection; Drug Resistance, Multiple, Bacterial; Enterobacter; Female; Gram-Negative Bacterial Infections; Humans; Infant, Newborn; Infusions, Intravenous; Klebsiella pneumoniae; Male; Pseudomonas aeruginosa; Treatment Outcome

To analyze the efficacy of nebulized colistin in the microbiological eradication and clinical improvement of patients with pulmonary infection by multi-resistant Acinetobacter baumannii (MAB).. A retrospective study.. Intensive Care Unit of a Tertiary hospital.. Hospitalized patients on invasive mechanical ventilation with positive MAB cultures of the airway.. All received treatment with colistin (CL). Nosocomial pneumonia (NP) or Tracheobronchitis (TB) was determined according to routine criteria and colonization (CO) was determined in the case of a positive culture in the absence of infection criteria. Three groups of patients were defined: those treated with nebulized CL, those treated with IV CL and those treated with IV CL plus nebulized CL.. Baseline characteristics. Microbiological eradication and clinical recovery were evaluated according to routine criteria.. 83 patients were studied, 54 of whom were treated, with the following diagnoses: 15 (27.8%) with NP, 16 (29.6%) with TB and 23 patients (42.6%) with CO. Nebulized CL was used in 36 patients (66.7%): 66.7% of which for CO, 33.3% in treatment for TB and in no case of NP. In 61.1% of the patients, IV CL was used: 22.2% of which for CO, 38.9% for TB and 38.9% in NP. The combination of IV CL and nebulized CL was used in 15 patients (27.8%): 5 patients (33.3%) CO, 2 patients (13.3%) TB and 8 patients (53.3%) NP. Microbiological eradication was achieved in 32 patients (59.3%), with the following distribution: 8 (47.1%) with IV CL, 15 (83.3%) with nebulized CL and 9 patients (69.2%) with a combination of IV CL and nebulized CL. Clinical recovery was achieved in 42 patients (77.8%): 12 (80%) with IV CL, 18 (94.7%) with nebulized CL and 12 (85.7%) with a combination of nebulized and IV CL. These differences were not significant. In the group of patients with infection due to TB and NP (31 patients, 57.4%), microbiological eradication was achieved in 5 patients (100%) treated with nebulized CL and in 6 of the 9 patients (42.9%) treated with IV CL, the difference being significant (P<.05). Clinical recovery in this group was 100% (6 patients) treated with nebulized CL and 75% (9 of the 12 patients) in the IV CL group. This difference was not significant.. Our study suggests that treatment with colistin in patients with pulmonary infection with multi-resistant Acinetobacter baumannii could be more efficient if it were to be administrated solely nebulized or in combination with IV colistin rather than administered solely intravenously.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Administration, Inhalation; Adult; Aged; Bronchitis; Colistin; Critical Illness; Cross Infection; Dose-Response Relationship, Drug; Drug Evaluation; Drug Resistance, Multiple, Bacterial; Female; Gram-Negative Bacterial Infections; Humans; Injections, Intravenous; Male; Middle Aged; Nebulizers and Vaporizers; Pneumonia, Bacterial; Pneumonia, Ventilator-Associated; Retrospective Studies; Tracheitis; Tracheotomy

Topics: Anti-Bacterial Agents; Colistin; Cross Infection; Drug Resistance, Multiple, Bacterial; Female; Gram-Negative Bacterial Infections; Humans; Male

Topics: Administration, Inhalation; Aerosols; Anti-Bacterial Agents; Colistin; Gram-Negative Bacterial Infections; Humans; Pneumonia, Bacterial; Pneumonia, Ventilator-Associated; Statistics as Topic; Treatment Outcome

Topics: Administration, Inhalation; Aged; Anti-Bacterial Agents; Bronchitis; Colistin; Drug Resistance, Multiple, Bacterial; Female; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Male; Middle Aged; Respiration, Artificial; Tracheitis; Treatment Outcome

To comparatively evaluate the antimicrobial activities of colistin and polymyxin B with those of other antimicrobials against a worldwide collection of 40 625 Gram-negative bacilli.. Antimicrobial susceptibility testing was performed and interpreted using the CLSI broth microdilution method except for colistin against Enterobacteriaceae.. The polymyxins showed potent in vitro activities (MIC₉₀, ≤ 0.5-1 mg/L) against this large collection of clinical isolates, with very low resistance rates (< 0.1%-1.5%). Resistance to the polymyxins remained stable among organisms tested except for Klebsiella spp. isolates collected from the Asia-Pacific and Latin American regions, where a trend towards greater resistance was observed (P  ≤  0.05). In addition, an important reduction in imipenem susceptibility among Acinetobacter spp. and Klebsiella spp. was demonstrated in most geographical regions.. Although the polymyxins showed excellent in vitro activity against the vast majority of Gram-negative bacilli evaluated, a trend to greater resistance was observed in the Asia-Pacific and Latin American regions. Therefore, the clinical use of polymyxins must be cautious and surveillance monitored.

Topics: Anti-Bacterial Agents; Brazil; Colistin; Drug Resistance, Bacterial; Europe; Geography; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests; Polymyxin B; Population Surveillance

In recent years there has been renewed interest in colistin for the treatment of infections by multidrug-resistant Gram-negative bacteria, causing concern that increasing use may be accompanied by the emergence of resistance. This is a retrospective cohort study of colonization and infection by colistin-resistant (CR) gram-negative bacteria in critically ill patients. Colonization data were based on surveillance culture results. Among 150 patients, 78 (52%) were colonized by CR Gram-negative bacteria. Among them, 30 (20%) were colonized by Klebsiella pneumoniae isolates and 51 (34%) were colonized by intrinsically resistant to colistin (CIR) enterobacteriaceae. Seven cases of infection were caused by CR K. pneumoniae and 12 cases by CIR strains. The main risk factor for colonization by CR pathogens was colistin treatment.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Cohort Studies; Colistin; Critical Illness; Drug Resistance, Bacterial; Female; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Male; Middle Aged; Retrospective Studies; Risk Factors; Young Adult

It is unclear whether the effectiveness of polymyxins depends on the site of infection, the responsible pathogen, dosage, and monotherapy vs. combination therapy. We investigated colistin therapy in a large, retrospective, single-centre, cohort study. Primary analysis outcomes were infection outcome, survival and nephrotoxicity. Over a 7-year period (October 2000 to October 2007), 258 patients received intravenous (i.v.) colistin for at least 72h for microbiologically documented multidrug-resistant Gram-negative bacterial infections, comprising 170 (65.9%) Acinetobacter baumannii, 68 (26.4%) Pseudomonas aeruginosa, 18 (7.0%) Klebsiella pneumoniae, 1 (0.4%) Stenotrophomonas maltophilia and 1 (0.4%) Enterobacter cloacae. Cure of infection occurred in 79.1% of patients, nephrotoxicity in 10% and hospital survival in 65.1%. In the multivariate analysis, independent predictors of survival were colistin average daily dose [adjusted odds ratio (aOR)=1.22, 95% confidence interval (CI) 1.05-1.42] and cure of infection (aOR=9, 95% CI 3.6-23.1), whilst the proportion of creatinine change (aOR=0.21, 95% CI 0.1-0.45), Acute Physiology and Chronic Health Evaluation (APACHE) II score (aOR=0.89, 95% CI 0.84-0.95) and haematological disease (aOR=0.23, 95% CI 0.08-0.66) were associated with mortality. Effectiveness of colistin was not dependent on the type of pathogen. No independent predictors for nephrotoxicity were observed. The findings of the largest cohort study to date on i.v. colistin show that colistin is a valuable antibiotic with acceptable nephrotoxicity and considerable effectiveness that depends on the daily dosage and infection site.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Cohort Studies; Colistin; Drug Resistance, Multiple, Bacterial; Female; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Infusions, Intravenous; Kidney; Male; Middle Aged; Retrospective Studies; Treatment Outcome; Young Adult

Multidrug-resistant (MDR) bacterial infections are increasing in Taiwan hospitals, prompting the common use of colistin. In this study, the safety and efficacy of intravenous (i.v.) colistin was assessed. The medical records of patients receiving colistin for treatment of MDR Gram-negative bacterial infections between January 2006 and September 2008 at a Taiwan medical centre were reviewed retrospectively. Demographics, clinical presentation, causative organism, adverse events and outcomes were recorded. Of the 115 patient records analysed, 74 patients (64%) were treated in the Intensive Care Unit. Common underlying diseases were hypertension (49%), chronic pulmonary disease (46%), chronic kidney disease (33%) and malignancy (31%). Lower respiratory tract infections were most common (71%), followed by primary bloodstream infections (12%), urinary tract infections (8.7%) and others (7.8%). Successful treatment with i.v. colistin against MDR Gram-negative bacterial infections occurred in 59 patients (51%). Multivariate analysis showed that a higher Acute Physiology and Chronic Health Evaluation (APACHE) II score (odds ratio=1.14; 95% confidence interval 1.02-1.28; P=0.02) was independently associated with a poor clinical response. Overall, 12 (14%) of 84 patients presented nephrotoxicity and 4 patients (3.5%) had neurotoxicity. In conclusion, colistin is an effective antimicrobial agent for severe infections caused by MDR Gram-negative bacteria. Clinical outcomes are associated with the severity of infection and underlying diseases. Compared with previous reports, this study showed a lower incidence of nephrotoxicity and neurotoxicity.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Central Nervous System; Central Nervous System Diseases; Colistin; Drug Resistance, Multiple, Bacterial; Female; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Infusions, Intravenous; Kidney; Kidney Diseases; Male; Middle Aged; Retrospective Studies; Taiwan; Treatment Outcome

In recent reports polymyxins have been considered an effective and safe treatment option for the management of multidrug-resistant (MDR) Gram-negative bacterial infections. Here we report our clinical experience with the use of intravenous colistin sulfate in critically ill patients hospitalized from January 2006 to October 2008, as a last treatment resort in China, and assess its effectiveness and adverse effects. Fifteen patients who suffered from severe infections caused by MDR or pandrug-resistant (PDR) Gram-negative bacteria (13 isolates of Acinetobacter baumannii, 4 isolates of Pseudomonas aeruginosa and 2 isolates of Klebsiella pneumoniae), unresponsive to the initial empirical regimens, were treated with colistin sulfate (daily dose of 1.28 +/- 0.25 million IU and duration of 22.3 +/- 6.2 days), based on sensitivity results. The treatment resulted in a good clinical response in 73.3%, microbiological clearance in 60% and mortality in 20%. Possible nephrotoxicity occurred in 1 patient and no patients developed neurotoxicity. In conclusion, intravenous colistin sulfate is a safe and viable alternative for the treatment of severe infections due to sensitive MDR Gram-negative bacteria.

Topics: Adult; Aged; Anti-Bacterial Agents; Central Nervous System Diseases; China; Colistin; Critical Illness; Drug Resistance, Multiple, Bacterial; Female; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Injections, Intravenous; Kidney; Kidney Diseases; Male; Middle Aged; Retrospective Studies; Treatment Outcome

Emergence of multidrug-resistant Gram-negative nosocomial pathogens has led to resurgence of colistin use. Safety and efficacy data regarding colistin use in pediatric patients are sparse, while optimal dosage has not been defined. We present a case series of neonates and children without cystic fibrosis treated with various doses of colistin intravenously. The records of patients who received colistin in a tertiary-care hospital from January 2007 to March 2009 were reviewed. Thirteen patients (median age 5 years, range 22 days to 14 years) received 19 courses of colistin as treatment of pneumonia, central nervous system infection, bacteremia, or complicated soft tissue infection. The isolated pathogens were Acinetobacter baumannii, Enterobacter cloacae, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Stenotrophomonas maltophilia. Daily dose of colistin (colistimethate) ranged between 40,000 and 225,000 IU/kg. Duration of administration ranged from 1 to 133 days. Other antimicrobials were co-administered in 18/19 courses. Increase of serum creatinine in one patient was associated with co-administration of colistin and gentamicin. Sixteen of 19 courses had a favorable outcome, and only two of the three deaths were infection-related. Colistin intravenous administration appears well tolerated even at higher than previously recommended doses and of prolonged duration.

Topics: Administration, Inhalation; Adolescent; Aerosols; Anti-Bacterial Agents; Child; Child, Preschool; Colistin; Cross Infection; Drug Resistance, Multiple, Bacterial; Female; Gram-Negative Bacterial Infections; Humans; Infant; Infant, Newborn; Infusions, Intravenous; Injections, Intraventricular; Male; Retrospective Studies; Treatment Outcome

Colistin has re-entered clinical use by necessity. We aimed to assess its effectiveness and safety compared with newer antibiotics.. This was a single-centre, prospective cohort study. Inclusion criteria were microbiologically documented pneumonia, urinary tract infection, surgical site infection, meningitis or bacteraemia treated appropriately with colistin versus imipenem, meropenem or ampicillin/sulbactam (comparators). All consecutive patients were included, only once, between May 2006 and July 2009. The primary outcome was 30 day mortality. Multivariable and Cox regression survival analyses were used to adjust comparisons between groups. Odds ratios (ORs) or hazard ratios (HRs) with 95% confidence intervals are reported.. Two hundred patients treated with colistin and 295 patients treated with comparators were included. Treatment with colistin was associated with older age, admission from healthcare facilities, mechanical ventilation and lower rate of early appropriate antibiotic treatment. The 30 day mortality was 39% (78/200) for colistin versus 28.8% (85/295) for comparators; unadjusted OR 1.58 (1.08-2.31). In the adjusted analysis the OR was 1.44 (0.91-2.26) overall and 1.99 (1.06-3.77) for bacteraemic patients (n = 220). At the end of follow-up, treatment with colistin was significantly associated with cumulative mortality; adjusted HR 1.27 (1.01-1.60) overall and 1.65 (1.18-2.31) among patients with bacteraemia. Nephrotoxicity at the end of treatment was more frequent with colistin; OR adjusted for other risk factors for nephrotoxicity 3.31 (1.54-7.08). Treatment with colistin was followed by increased incidence of Proteus spp. infections during a 3 month follow-up.. The need for colistin treatment is associated with poorer survival. Adjusted analyses suggest that colistin is less effective and more toxic than beta-lactam antibiotics.

Topics: Adult; Aged; Anti-Bacterial Agents; Cohort Studies; Colistin; Cross Infection; Drug Resistance, Multiple, Bacterial; Female; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Male; Middle Aged; Prospective Studies; Survival Analysis; Treatment Outcome

Antibiotic susceptibility methods that are commonly used to test bacterial isolates from patients with cystic fibrosis are of uncertain reliability for the polymyxins. To assess the reliability of four standard testing methods, this pilot study used a challenge set that included polymyxin-resistant isolates of Pseudomonas aeruginosa and Stenotrophomonas maltophilia.. Twenty-five P. aeruginosa and 12 S. maltophilia isolates were tested for susceptibility to colistin (polymyxin E). Repeatability (concordance of replicates performed concurrently), reproducibility (concordance of replicates performed over time) and comparability (concordance of different methods) of agar dilution, broth microdilution, Etest and disc diffusion were assessed through the use of descriptive statistics and scatterplot analyses.. All four methods displayed excellent repeatability (overall concordance rate of 99%). However, analysis of reproducibility revealed substantially lower rates of concordance (74% for agar dilution, 84% for broth microdilution and Etest, and 91% for disc diffusion). In addition, comparability to agar dilution of the three other methods was generally poor, with overall rates of very major error ranging from 12% for broth microdilution to 18% for Etest and disc diffusion.. Compared with agar dilution, other susceptibility testing methods give high rates of apparent false polymyxin susceptibility for cystic fibrosis isolates of P. aeruginosa and S. maltophilia. Prospective study of the correlation between in vitro susceptibility and clinical response is needed to clarify whether these discrepancies reflect oversensitivity of the agar dilution method or insensitivity of the other methods.

Topics: Anti-Bacterial Agents; Colistin; Cystic Fibrosis; False Positive Reactions; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Reproducibility of Results; Sensitivity and Specificity; Stenotrophomonas maltophilia

Infections caused by multidrug-resistant gram-negative bacteria have caused a resurgence of interest in colistin. To date, information about pharmacokinetics of colistin is very limited in critically ill patients, and no attempts have been made to evaluate its concentration in BAL.. In this prospective, open-label study, 13 adult patients with ventilator-associated pneumonia caused by gram-negative bacteria were treated with colistin methanesulfonate (CMS) IV, 2 million International Units (174 mg) q8h, a usually recommended dose, for at least 2 days. Blood samples were collected from each patient at time intervals after the end of infusion. BAL was performed at 2 h. Colistin was measured by a selective, sensitive high-performance liquid chromatography-based method. Pharmacokinetic parameters were determined by noncompartmental analysis.. Patients received 2.19 ± 0.38 mg/kg (range, 1.58-3.16) of CMS per dose. At steady state, mean ± SD plasma colistin maximum (Cmax) and trough (Ctrough) concentrations were 2.21 ± 1.08 and 1.03 ± 0.69 μg/mL, respectively. Mean ± SD area under the plasma concentration-time curve from 0 to 8 h (AUC(0-8)), apparent elimination half-life, and apparent volume of distribution were 11.5 ± 6.2 μg × h/mL, 5.9 ± 2.6 h, and 1.5 ± 1.1 L/kg, respectively. Cmax/minimum inhibitory concentration (MIC) ratio and AUC(0-24)/MIC ratio (MIC = 2 μg/mL) were 1.1 ± 0.5 and 17.3 ± 9.3, respectively. Colistin was undetectable in BAL. Nephrotoxicity was not observed.. Although the pharmacodynamic parameters that better predict the efficacy of colistin are not known in humans, in critically ill adult patients the IV administration of CMS 2 million International Units (174 mg) q8h results in apparently suboptimal plasma concentrations of colistin, which is undetectable in BAL. A better understanding of the pharmacokinetic-pharmacodynamic relationship of colistin is urgently needed to determine the optimal dosing regimen.

Topics: Adult; Aged; Anti-Bacterial Agents; Bronchoalveolar Lavage Fluid; Colistin; Critical Illness; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Infusions, Intravenous; Intensive Care Units; Male; Middle Aged; Pneumonia, Ventilator-Associated; Prospective Studies; Survival Rate; Treatment Outcome; Young Adult

Using a liquid chromatography-tandem mass spectrometry method, the serum and cerebrospinal fluid (CSF) concentrations of colistin were determined in patients aged 1 months to 14 years receiving intravenous colistimethate sodium (60,000 to 225,000 IU/kg of body weight/day). Only in one of five courses studied (a 14-year-old receiving 225,000 IU/kg/day) did serum concentrations exceed the 2 microg/ml CLSI/EUCAST breakpoint defining susceptibility to colistin for Pseudomonas and Acinetobacter. CSF colistin concentrations were <0.2 microg/ml but increased in the presence of meningitis (approximately 0.5 microg/ml or 34 to 67% of serum levels).

Topics: Adolescent; Anti-Bacterial Agents; Child; Child, Preschool; Colistin; Female; Gram-Negative Bacterial Infections; Humans; Infant; Male; Treatment Outcome

To report a case of recurrent Stenotrophomonas maltophilia ventilator-associated pneumonia (VAP) that was successfully treated with doxycycline and aerosolized colistin.. A 28-year-old male was admitted with a severe head injury and required mechanical ventilation. The patient developed S. maltophilia VAP on hospital day 17, which was cured after 7 days of treatment with high-dose intravenous trimethoprim/sulfamethoxazole (TMP/SMX). However, on day 34, the patient developed recurrent S. maltophilia VAP that did not respond clinically or demonstrate eradication on follow-up culture after 10 days of TMP/SMX. At that time, TMP/SMX was discontinued and treatment was initiated with intravenous doxycycline and aerosolized colistin. The VAP episode was cured after 14 days of treatment with doxycycline/aerosolized colistin.. S. maltophilia is an emerging cause of VAP in some centers. This organism is associated with high mortality rates and has few treatment options because it is intrinsically resistant to most drug classes. Recent data suggest that doxycycline and aerosolized colistin each are effective in treatment of other multidrug-resistant organisms, such as Pseudomonas aeruginosa and Acinetobacter baumannii. However, this is the first report describing the use of this antibiotic regimen for S. maltophilia. High-dose TMP/SMX is considered to be the drug of choice primarily based on excellent in vitro activity. Few data exist on how to treat patients who fail therapy with TMP/SMX or cannot receive that drug because of resistance, allergy, or adverse events. Thus, it is important to report alternative methods for treating this infection.. The positive clinical response to doxycycline and aerosolized colistin seen in the patient described here suggests that this combination may be an alternative treatment in patients who fail initial treatment or cannot receive standard therapies.

Topics: Administration, Inhalation; Adult; Aerosols; Anti-Bacterial Agents; Anti-Infective Agents; Colistin; Doxycycline; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Gram-Negative Bacterial Infections; Humans; Injections, Intravenous; Male; Pneumonia, Bacterial; Pneumonia, Ventilator-Associated; Stenotrophomonas maltophilia; Trimethoprim, Sulfamethoxazole Drug Combination

The incidence of ventilator-associated pneumonia (VAP) due to multidrug-resistant (MDR) organisms is increasing. Intravenous (IV) colistin or aerosolized (AS) plus IV colistin have been recently used to treat these life-threatening infections. The purpose of this study was to compare the efficacy and safety of AS plus IV colistin versus IV colistin alone for patients with MDR VAP due to gram-negative bacteria.. A retrospective matched case-control study was performed at the Intensive Care Unit of the University Hospital of Heraklion, Greece, from January 2005 through December 2008. Forty-three patients with VAP due gram-negative MDR pathogens received AS plus IV colistin and were matched on the basis of age and Acute Physiology and Chronic Health Evaluation II score with 43 control patients who had received IV colistin alone.. Demographic characteristics, clinical status, and gram-negative isolated pathogens were similar between the 2 treatment groups. Acinetobacter baumannii (66 cases [77%]) was the most common pathogen, followed by Klebsiella pneumoniae (12 cases [14%]) and Pseudomonas aeruginosa (8 cases [9.3%]). No colistin-resistant strains were isolated from patients in either group. No significant differences between the 2 groups were observed regarding eradication of pathogens (P = .679), clinical cure (P = .10), and mortality (P = .289). Eight patients (19%) in each treatment group developed reversible renal dysfunction. No AS colistin-related adverse events were recorded.. Addition of AS colistin to IV colistin did not provide additional therapeutic benefit to patients with MDR VAP due to gram-negative bacteria.

Topics: Administration, Inhalation; Aged; Anti-Bacterial Agents; Case-Control Studies; Colistin; Female; Gram-Negative Bacterial Infections; Greece; Hospitals, University; Humans; Injections, Intravenous; Intensive Care Units; Male; Middle Aged; Pneumonia, Ventilator-Associated; Retrospective Studies; Treatment Outcome

We sought to evaluate the safety and feasibility of inhaled aminoglycosides or colistin in cancer patients with ventilator-associated pneumonia (VAP) due to Gram-negative bacteria (GNB). A retrospective case-matched study was obtained after obtaining IRB approval in patients at the intensive care unit at our NCI-designated comprehensive cancer center between 1999 and 2005. Sixteen patients with GNB-VAP who received inhaled aminoglycosides or colistin were compared with 16 patients who had received these antibiotics intravenously alone. Eligible patients were required to have received at least six doses of inhaled therapy, or 3 or more days of intravenous therapy. Clinical Pulmonary Infection Scores were used to assess pneumonia severity. Standard ATS criteria were used to define VAP. Patients treated with inhaled antibiotics were less likely to have received corticosteroids (13% vs 50%; P < 0.02) and had a higher median baseline creatinine level (0.85 vs 0.6 mg/dL; P < 0.02) than patients treated intravenously. Pseudomonas aeruginosa (69%) was the most common cause of VAP. There were no serious adverse events associated with inhaled antibiotics. Patients who received these antibiotics intravenously developed renal dysfunction (31%); none of the patients treated with inhaled antibiotics developed nephrotoxicity (P < or = 0.04). Patients treated with inhaled antibiotics were more likely to have complete resolution of clinical (81% vs 31% in the intravenous antibiotic group; P < 0.01) and microbiologic infection (77% vs 8% in the intravenous antibiotic group: P < 0.0006). In a multivariate analysis adjusted for corticosteroid use, inhaled antibiotic therapy was predictive of complete clinical resolution (odds ratio [OR], 6.3; 95% confidence interval [CI], 1.1, 37.6; P < 0.04) and eradication of causative organisms (OR 36.7; 95% CI, 3.3, 412.2; P < 0.003). In critically ill cancer patients with Gram-negative VAP, inhaled aminoglycosides were tolerated without serious toxicity and may lead to improved outcome.

Topics: Administration, Inhalation; Adult; Aged; Aminoglycosides; Anti-Bacterial Agents; Case-Control Studies; Colistin; Critical Illness; Drug Resistance; Female; Gram-Negative Bacterial Infections; Humans; Immunologic Factors; Male; Middle Aged; Neoplasms; Pneumonia, Bacterial; Pneumonia, Ventilator-Associated; Retrospective Studies; Severity of Illness Index; Steroids; Treatment Outcome

The increasing frequency of infections caused by multidrug-resistant (MDR) Gram-negative bacteria has led to the reappraisal of colistimethate use.. We present a case series of critically ill pediatric patients without cystic fibrosis who received intravenous colistimethate treatment. All available relevant medical records were reviewed.. Seven children without cystic fibrosis (mean age 7.7 years; 2 female), admitted to the intensive care unit of a tertiary-care pediatric hospital in Athens, Greece, were identified to have received intravenous colistimethate during October 2004 to May 2008. MDR Acinetobacter baumannii, Pseudomonas aeruginosa, and/or Klebsiella pneumoniae were isolated from blood and/or bronchial secretions specimens in 6 of 7 reported patients. All isolates were susceptible to colistin. All 7 patients received intravenous colistimethate in a dosage of 5 mg/kg daily (divided in 3 equal doses, administered every 8 hours). Five children received colistimethate for 10 days and the remaining 2 for 2 and 23 days, respectively. The infections caused by MDR Gram-negative bacteria were improved in 6 children with microbiologically documented infections. Five of the 7 children were discharged from the ICU. The remaining 2 children died (1 of them had received colistimethate for 2 days); their death was not attributed to MDR Gram-negative infection. No nephrotoxicity or other type of toxicity of colistimethate was noted in this case-series.. Although the small number of included cases precludes any firm conclusions, our study suggests that colistimethate may have a role for the treatment of infections caused by MDR Gram-negative bacteria in critically ill pediatric patients.

Topics: Adolescent; Anti-Bacterial Agents; Child; Child, Preschool; Colistin; Critical Illness; Cystic Fibrosis; Drug Resistance, Multiple, Bacterial; Female; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Infant; Infant, Newborn; Injections, Intravenous; Male

Reports of patients with polymyxin-only susceptible gram-negative nosocomial pneumonia treated with inhaled, but without concurrent intravenous, colistin are rare.. Patients admitted in a tertiary 450-bed tertiary care centre during the period 05/01/2005-05/31/2007 and receiving colistin through nebulization, but not systemically, were included in this retrospective case series.. Five patients (three with ventilator-associated pneumonia and two with nosocomial pneumonia) received colistin through nebulization without concomitant intravenous colistin. The isolated pathogens were Acinetobacter baumannii (three cases), Pseudomonas aeruginosa (one case) and the combination of Klebsiella pneumoniae, A. baumannii and P. aeruginosa (one case). They were susceptible only to colistin (three cases) or to colistin and gentamicin (two cases). Intravenous antimicrobial agents given concurrently were piperacillin/tazobactam, meropenem, ceftriaxone and ciprofloxacin; isolated pathogens were resistant to these agents. Four (80%) out of the five patients were cured, survived and were discharged. One patient died. No colistin-related adverse event was observed.. The experience from this case series and other relevant recent reports suggest that treatment of pneumonia due to polymyxin-only susceptible gram-negative bacilli with inhaled colistin (without concurrent systemic administration) deserves further careful investigation.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Administration, Inhalation; Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Colistin; Cross Infection; Drug Resistance, Multiple, Bacterial; Female; Gram-Negative Bacterial Infections; Humans; Klebsiella Infections; Klebsiella pneumoniae; Male; Pneumonia, Bacterial; Pneumonia, Ventilator-Associated; Pseudomonas aeruginosa; Pseudomonas Infections; Retrospective Studies; Treatment Outcome

Achromobacter xylosoxidans (formerly Alcaligenes xylosoxidans) is a rare but important nosocomial pathogen. Antibiotic resistance has been increasing during the past decade. A. xylosoxidans may be confused with Pseudomonas spp. but, unlike Pseudomonas spp., this organism has peritrichous flagella. Complicated intra-abdominal infection with A. xylosoxidans has rarely been reported in the literature. This report is of an immunocompetent patient with acute cholecystitis complicated by an intra-abdominal abscess after surgery. Culture of both blood and ascites yielded extended drug-resistant A. xylosoxidans, which was only sensitive to colistin. The clinical and laboratory characteristics of A. xylosoxidans are presented.

Topics: Abdominal Abscess; Achromobacter denitrificans; Adult; Anti-Bacterial Agents; Ascites; beta-Lactamases; Blood; Cholecystitis; Colistin; Cross Infection; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacterial Infections; Humans; Male

Since multidrug-resistant gram-negative organisms have been increasing, polymyxin E (colistin) has been reintroduced despite its nephrotoxicity. A case-control study was performed to investigate the incidence, clinical characteristics and risk factors of colistin-induced nephrotoxicity. From August 2006 to June 2008, 47 cases receiving at least one defined daily dose (DDD) of intravenous colistin were included; 15 (31.9%) of the 47 cases developed nephrotoxicity with preserved urine output, 3 (20%) of whom underwent renal replacement therapy. The mean dosage of colistimethate sodium was 2.25 g (22.5 DDD; range 0.6-8.7 g) at the time of nephrotoxicity. Of 10 patients who were re-assessed for renal function after 1 month, 9 (90%) recovered their renal function. In the univariate analysis, site of infection, hypoalbuminaemia and cumulative dosage of the second-generation fluoroquinolones, aminoglycosides and non-steroidal anti-inflammatory drugs (NSAIDs) co-administered during colistin treatment as well as concomitant use of NSAIDs were risk factors for nephrotoxicity. However, in the logistic regression hypoalbuminaemia and the use of NSAIDs were significant risk factors for increased nephrotoxicity during colistin administration, suggesting that free colistin might cause renal toxicity. In conclusion, colistin-induced nephrotoxicity occurred at a high rate, and hypoalbuminaemia and concomitant use of NSAIDs were significant risk factors.

Topics: Adult; Aged; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Case-Control Studies; Colistin; Female; Gram-Negative Bacterial Infections; Humans; Hypoalbuminemia; Incidence; Kidney; Kidney Diseases; Male; Middle Aged; Risk Factors

To investigate the therapeutic effect and side effects of colistin in treating infections caused by multidrug-resistant (MDR) gram-negative bacillus in patients with severe burn in order to provide the basis for reasonable application of this antibiotic in clinic.. Nine burn patients suffered from infections caused by MDR gram-negative bacillus admitted to our institute from August 2005 to January 2009 were involved in this study. On the premises that isolated bacteria were only sensitive to colistin or not sensitive to other antibiotics, patients were treated with intravenous drip of colistin (100 x 10(4) - 150 x 10(4) U/d), or intravenous drip combined with administration of the drug into respiratory tract by atomization or instillation (50 x 10(4) - 100 x 10(4) U/d). The bacteriologic and therapeutic effects and side effects (including neurotoxicity and nephrotoxicity, rise in serum levels of creatinine, urea nitrogen and cystatin C were detected and compared before and after administration) of colistin were observed.. Out of 9 patients, 7 patients were with bloodstream and pulmonary infections, 1 patient was with bloodstream, pulmonary, and invasive wound infections, and 1 patient was with bloodstream and urinary tract infections. The pathogenic bacteria were proved to be Pseudomonas aeruginosa, Acinetobacter baumannii and Pseudomonas maltophilia. After the administration of colistin, bacteria clearance rate of blood reached 92.3% in 9 patients; isolation rate of MDR gram-negative bacillus of sputum was significantly decreased in 7 patients with pulmonary infection (before treatment 58.2% v.s. after treatment 14.6%, P < 0.01); a complete MDR gram-negative bacillus clearance of urine was observed in 1 patient with urinary tract infection. Colistin was clinically effective in 8 patients but ineffective in 1 patient (effective rate 88.9%). Compared with those before administration, serum levels of creatinine and urea nitrogen were decreased after administration in all patients; no significant difference in serum level of cystatin C among 8 patients was detected, except an obvious elevation in serum level of cystatin C in 1 patient after colistin therapy, and it lowered 1 month after discontinuation. No neurotoxicity or other side effect was observed during medication and 5 days after discontinuation in all patients.. Reasonable application of colistin is a good option for treating infections caused by MDR gram-negative bacillus in patients with severe burn, as no other more effective drug is found.

Topics: Adult; Anti-Bacterial Agents; Burns; Colistin; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Male; Middle Aged; Treatment Outcome

The aim of the present work was to evaluate clinical efficacy of the biospecific hemosorbent "Liposorb". The main component of "Liposorb" is polyacrylamide gel containing an immobilized affine ligand (antibiotic polymyxin E-colistyne). 40 patients with abdominal sepsis and peritonitis of different genesis underwent a total of 52 seances of vein-venous extracorporeal hemoperfusion of hemosorbent "Liposorb". Endotoxin level (lipopolysaccharide - LPS) was measured by the turbodimetric method. Blood perfusion through a "Liposorb" column at 50-70 ml/min during 90 minutes permitted to reach stabilization of parameters of systemic hemodynamics. All the patients showed positive dynamics of general well-being, blood gas composition, clinical and biochemical blood analyses. The endotoxin (LPS) level of Gramm-negative flora significantly decreased. It is concluded that hemosorbtion using biospecific polymyxin-containing hemosorbent "Liposorb" effectively removes Gramm-negative endotoxin and leads to stabilization of hemodynamic in patients with Gramm-negative abdominal sepsis.

Topics: Acrylic Resins; Anti-Bacterial Agents; Colistin; Drug Combinations; Endotoxemia; Follow-Up Studies; Gels; Gram-Negative Bacterial Infections; Hemoperfusion; Humans; Middle Aged; Treatment Outcome

Topics: Anti-Bacterial Agents; Colistin; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans

Colistin methanesulfonate (CMS) has the potential to hydrolyze in aqueous solution to liberate colistin, its microbiologically active and more toxic parent compound. While conversion of CMS to colistin in vivo is important for bactericidal activity, liberation of colistin during storage and/or use of pharmaceutical formulations may potentiate the toxicity of CMS. To date, there has been no information available regarding the stability of CMS in pharmaceutical preparations. Two commercial CMS formulations were investigated for stability with respect to colistin content, which was measured by a specific high-performance liquid chromatography method. Coly-Mycin M Parenteral (colistimethate lyophilized powder) was stable (<0.1% of CMS present as colistin) for at least 20 weeks at 4 degrees C and 25 degrees C at 60% relative humidity. When Coly-Mycin M was reconstituted with 2 ml of water to a CMS concentration of 200 mg/ml for injection, Coly-Mycin M was stable (<0.1% colistin formed) for at least 7 days at both 4 degrees C and 25 degrees C. When further diluted to 4 mg/ml in a glucose (5%) or saline (0.9%) infusion solution as directed, CMS hydrolyzed faster at 25 degrees C (<4% colistin formed after 48 h) than at 4 degrees C (0.3% colistin formed). The second formulation, CMS Solution for Inhalation (77.5 mg/ml), was stable at 4 degrees C and 25 degrees C for at least 12 months, as determined based on colistin content (<0.1%). This study demonstrated the concentration- and temperature-dependent hydrolysis of CMS. The information provided by this study has important implications for the formulation and clinical use of CMS products.

Topics: Anti-Bacterial Agents; Chemistry, Pharmaceutical; Colistin; Drug Stability; Drug Storage; Gram-Negative Bacterial Infections; Humans; Hydrolysis; Pharmaceutical Solutions; Solutions; Temperature

To determine the in vitro activity of various antimicrobial agents including ertapenem, imipenem, meropenem, fosfomycin, netilmicin, colistin, and piperacillin/tazobactam against clinical isolates of cephalosporin-resistant gram-negative bacteria.. All clinical isolates of gram-negative bacteria obtained from patients receiving care at Queen Sirikit National Institute of Child Health (QSNICH), Bangkok, Thailand, from 2006-2007 were evaluated for antimicrobial susceptibility. Those resistant to all cephalosporins were further assessed for additional disc susceptibility and MIC test using E-tests.. Each of the fifty-five strains of extended spectrum beta-lactamase (ESBL) producing K. pneumoniae and E. coli were tested. The results showed excellent in vitro activity of the studied drugs against ESBL-producing K. pneumoniae with percent susceptibility of 100, 100, 100, 89.8, and 92.7 for ertapenem, imipenem, meropenem, fosfomycin, and colistin, respectively. MIC90 of ertapenem, imipenem, meropenem, fosfomycin, and colistin against K. pneumoniae were 0.23, 0.09, 0.38, 59.2, and 0.75 microg/ml, respectively. Piperacillin/tazobactam inhibited 68.2% of the tested isolates of K. pneumoniae. All studied drugs, except netilmicin, exhibited good activity against ESBL-producing Escherichia coli with 100% sensitivity for carbapenem, fosfomycin, colistin and 95.8% for piperacillin/tazobactam. MIC90 of ertapenem, imipenem, meropenem, fosfomycin, and colistin against Escherichia coli were 0.177, 0.25, 0.064, 2.85, and 0.58 microg/ml, respectively. Six strains of cephalosporin-resistant P. aeruginosa were isolated and tested for MIC. The results showed percent susceptibility of 66.7 and 33.3 for piperacillin/tazobactam and colistin, respectively. MIC90 of piperacillin/tazobactam and colistin against P. aeruginosa were 256 and 8 microg/ml, respectively. Twenty-four strains of cephalosporin-resistant Acinetobacter spp. were isolated with percent susceptibility of 17.6 and 95.5 for piperacillin/tazobactam and colistin, respectively. MIC90 of piperacillin/tazobactam and colistin against Acinetobacter spp. were 256 and 1.4 microg/ml, respectively.. Carbapenems, fosfomycin, and colistin exhibited excellent in vitro activity against both ESBL-producing K. pneumoniae and E. coli. Piperacillin/tazobactam exhibited good in vitro susceptibility against ESBL- producing E. coli, but not K. pneumoniae. Colistin was the most potent in vitro activity of antibiotics against cephalosporins-resistant Acinetobacter spp. However, cephalosporin-resistant Pseudomonas aeruginosa remained problematic, we recommend performing in vitro susceptibility test to determine appropriate antibiotic uses. E-test methods have been shown to be more accurate than disc diffusion test for evaluating colistin susceptibility.

Topics: Anti-Bacterial Agents; Cephalosporins; Colistin; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacterial Infections; Humans; In Vitro Techniques; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Thailand

Ventilator-associated pneumonia (VAP) remains the leading cause of death in patients with intensive care unit (ICU) acquired infections associated with an attributable mortality around 30%. Increasing antimicrobial resistance in patients with VAP challenges intensivists to search for alternative therapeutic options. There is scarcity of data in the literature concerning the administration of aerosolized colistin in critically ill patients with VAP due to multidrug-resistant (MDR) Gram-negative pathogens.. To assess the safety and effectiveness of aerosolized colistin as an adjunctive to the intravenous antimicrobial therapy for the treatment of VAP due to MDR Gram-negative pathogens, we prospectively examined all patients, who received inhaled colistin.. Sixty critically ill patients with a mean APACHE II score 16.7, received aerosolized colistin for the treatment of VAP due to MDR pathogens [Acinetobacter baumannii (37/60 cases), Pseudomonas aeruginosa (12/60 cases) and Klebsiella pneumoniae strains (11/60 cases)]. Half of the isolated pathogens were susceptible only to colistin. Mean (+/-SD) daily dosage of aerosolized colistin was 2.2 (+/-0.7) million international units (IU). All patients received 2946 inhalations of colistin and the mean duration of administration was 16.4 days. Fifty-seven patients received concomitant intravenous treatment with colistin or other antimicrobial agents. Bacteriological and clinical response of VAP was observed in 50/60 (83.3%) patients. No adverse effects related to inhaled colistin were recorded. All cause hospital mortality was 25% while mortality attributable to VAP was 16.7%.. Aerosolized colistin may be considered as adjunctive to intravenous treatment in patients with VAP due to MDR Gram-negative bacteria susceptible to colistin in critically ill patients. Although colistin is safe and effective, the best route of administration remains unclear. In addition, controlled comparative studies are needed to establish its effectiveness and safety.

Topics: Administration, Inhalation; Adult; Aerosols; Aged; Anti-Bacterial Agents; Colistin; Drug Resistance, Multiple; Female; Gram-Negative Bacterial Infections; Humans; Intensive Care Units; Male; Middle Aged; Pneumonia, Bacterial; Pneumonia, Ventilator-Associated; Prospective Studies; Treatment Outcome

To assess the efficacy and toxicity of intravenous colistin in the treatment of infections due to multidrug-resistant gram-negative bacteria.. Retrospective cohort study.. Sixty patients received colistin sulphomethate sodium (mean dose, 4.4mg/kg/day; median duration, 20days). The main infections were pneumonia or tracheobronchitis (63.3%), intra-abdominal (10%), urinary tract (8.3%), and surgical site infection (6.6%), primary bacteremia (5%), catheter infection (3.3%), meningitis (1.6%), and soft-tissue infection (1.6%). The responsible bacteria were Acinetobacter spp. (50%), P. aeruginosa (23.3%), K. pneumoniae (13.3%), Enterobacter spp. (10%), E. coli (1.6%), and S. maltophilia (1.6%). Eight patients (13%) received colistin monotherapy, and 52 (87%) received combination therapy with other antibiotics such as beta-lactams (15 cases), aminoglycosides (14), beta-lactams and aminoglycosides (15), or ciprofloxacin (8). A favourable response was observed in 43 cases (71.7%). Overall mortality was 26.7%. Despite the common use of combination therapy with aminoglycosides (48%), nephrotoxicity during colistin therapy was observed in only 10.9% of patients; most of them had previous renal failure.. Colistin appears to be an effective and safe drug for therapy of severe infections due to multidrug-resistant gram-negative bacteria. Despite the concomitant use of aminoglycosides in a high proportion of patients, renal toxicity was an uncommon adverse event.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Child; Child, Preschool; Colistin; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Female; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Infant; Injections, Intravenous; Kidney; Male; Middle Aged; Retrospective Studies

The accuracy of disk susceptibility methods for colistin against 778 bacterial pathogens was evaluated in comparison with Etest using interpretive criteria available from the Clinical and Laboratory Standards Institute (CLSI). Colistin exhibited excellent activity against Acinetobacter baumannii and Escherichia coli isolates (minimum inhibitory concentration for 90% of the organisms (MIC(90))=0.5 mg/L), whilst it was less active both against Enterobacter spp. and Klebsiella pneumoniae (MIC for 50% of the organisms (MIC(50))=0.5 mg/L, MIC(90)=16 mg/L). Colistin also showed good activity against Pseudomonas aeruginosa (MIC(90)=2 mg/L, MIC(50)=1 mg/L) but poor activity against Stenotrophomonas maltophilia (MIC(50)=8 mg/L, MIC(90)=128 mg/L). Only 0.8% of minor errors were observed between the studied methods for P. aeruginosa isolates when the CLSI criteria were applied. All A. baumannii isolates with a zone diameter < or =12 mm were resistant and those with a zone diameter > or =14 mm were susceptible according to MIC breakpoints established by the CLSI. Among nine isolates exhibiting a zone diameter of 13 mm, one was resistant to colistin (MIC=8 mg/L) and eight isolates were susceptible (MIC=0.5 mg/L). Applying a MIC breakpoint of < or =2 mg/L for susceptibility in Enterobacteriaceae, all isolates with a zone diameter > or =14 mm were susceptible, whilst all isolates with a zone diameter < or =11 mm were resistant. Among isolates with zone diameters of 12-13 mm, 59% were characterised as susceptible. Major errors were observed only in K. pneumoniae isolates at a rate of 0.8%. The poor agar diffusion characteristics of colistin limit the predictive accuracy of the disk diffusion test and consequently values of 12-13 mm should be confirmed with MIC determination by Etest or broth dilution method.

Topics: Anti-Bacterial Agents; Colistin; Diagnostic Errors; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests

Topics: Afghanistan; Anti-Bacterial Agents; Colistin; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Hospitals, Military; Humans; Iraq; Male; Military Personnel

Topics: Animals; Anti-Bacterial Agents; Colistin; Drug Resistance, Multiple, Bacterial; Drug Synergism; Drug Therapy, Combination; Gram-Negative Bacterial Infections; Humans; Pseudomonas Infections; Rats; Rifampin; Sepsis; Treatment Failure

Multidrug resistant Gram-negative rods are increasingly isolated from clinical specimens, especially from hospitalized patients. The aim of this study was to evaluate the prevalence of imipenem resistant strains of Gram-negative rods isolated in dr. A. Jurasz University Hospital in Bydgoszcz between 1999 and 2005 and imipenem consumption in this period. Out of 109614 isolated microorganisms, Gram-negative rods were 28,5%, 637 (2,0%) of strains were resistant to imipenem. These strains were isolated mostly from patients hospitalized in intensive care and rehabilitation clinics. Among imipenem-resistant strains Pseudomonas aeruginosa prevailed (88,9%). P. aeruginosa strains were sensitive to colistin, 45,5% of them to aztreonam and 44,0% to ceftazidime. The imipenem consumption in the appropriate years included in this study was: 805,00; 1201,25; 940,00; 1390,00; 1660,00; 1341,25; 1841,25 DDD respectively, and was strictly connected with increasing imipenem-resistant Gram-negative rods isolation.

Topics: Anti-Bacterial Agents; Aztreonam; beta-Lactam Resistance; Carbapenems; Colistin; Cross Infection; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacterial Infections; Humans; Imipenem; Intensive Care Units; Microbial Sensitivity Tests; Retrospective Studies

Topics: Anti-Bacterial Agents; Bacteremia; Ciprofloxacin; Colistin; Drug Resistance, Bacterial; Gram-Negative Anaerobic Bacteria; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests; Neoplasms

Topics: Colistin; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacterial Infections; Humans; Kidney Diseases; Polymyxin B

The prospective case series study presented here was conducted to assess the outcome of patients with infections caused by polymyxin-only-susceptible (POS) gram-negative bacteria managed with intravenous colistin. Between July 2003 and April 2005 a total of 27 patients were infected with a POS gram-negative bacterium and received intravenous colistin at a dose of 2 million international units (MIU) (160 mg or 66.7 mg colistin base) every 8 h for a mean (+/-SD) duration of 13.9 (+/-7.5) days. Nine patients had ventilator-associated pneumonia and received, in addition to the intravenous colistin therapy, 1 MIU (80 mg or 33.3 mg colistin base) aerosolized colistin every 12 h for a mean (+/-SD) duration of 13 (+/-6.5) days. The predominant pathogens were Pseudomonas aeruginosa (n = 17) and Acinetobacter baumannii (n = 12); in two patients both pathogens were isolated from one clinical specimen. In-hospital mortality and clinical response were 15% and 85%, respectively. Colistin-associated nephrotoxicity was observed in two of the 27 patients. POS gram-negative pathogens represent a major threat for hospitalized patients. Colistin appears to be an effective and safe treatment, even in patients with severe underlying diseases.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Colistin; Drug Resistance, Multiple, Bacterial; Female; Gram-Negative Bacterial Infections; Humans; Infusions, Intravenous; Kidney Diseases; Male; Middle Aged; Pneumonia, Ventilator-Associated; Prospective Studies; Pseudomonas aeruginosa; Treatment Outcome

A retrospective cohort study evaluated the effectiveness and nephrotoxicity of intravenous colistin monotherapy vs. colistin-meropenem combination therapy for patients with multidrug-resistant Gram-negative bacterial infections. Fourteen patients received intravenous colistin monotherapy and 57 received colistin-meropenem. No significant differences were found concerning clinical response of the infection (12/14 (85.7%) vs. 39/57 (68.4%), p 0.32) and development of nephrotoxicity (0/14 (0%) vs. 4/57 (7%), p 0.58). A favourable association was revealed between survival and treatment with colistin monotherapy compared to colistin-meropenem (0/14 (0%) vs. 21/57 (36.8%) deaths, p 0.007), even after adjusting for the variables for which significant differences were found.

Topics: Acute Kidney Injury; Adult; Aged; Anti-Bacterial Agents; Cohort Studies; Colistin; Drug Resistance, Multiple; Drug Therapy, Combination; Female; Gram-Negative Bacterial Infections; Humans; Male; Meropenem; Middle Aged; Retrospective Studies; Thienamycins; Treatment Outcome

A retrospective case series study was performed in a 30-bed general intensive care unit (ICU) of a tertiary care hospital to assess the effectiveness and safety of colistin in 43 critically ill patients with ICU-acquired infections caused by multiresistant Gram-negative bacteria. Various ICU-acquired infections, mainly pneumonia and bacteraemia caused by multiresistant strains of Pseudomonas aeruginosa and/or Acinetobacter baumannii, were treated with colistin. Good clinical response (cure or improvement) was noted in 74.4% of patients. Deterioration of renal function occurred in 18.6% of patients during colistin therapy. Nephrotoxicity was elevated significantly in those patients with a history of renal failure (62.5%). All-cause mortality amounted to 27.9%. In this group of critically ill patients, an age of >50 years (OR, 5.4; 95% CI 1.3-24.9) and acute renal failure (OR, 8.2; 95% CI 2.9-23.8) were independent predictors of mortality. Colistin should be considered as a treatment option in critically ill patients with infection caused by multiresistant Gram-negative bacilli.

Topics: Adult; Aged; Anti-Bacterial Agents; Colistin; Cross Infection; Drug Resistance, Multiple, Bacterial; Female; Gram-Negative Bacterial Infections; Humans; Intensive Care Units; Male; Middle Aged; Retrospective Studies

A 28-year-old man developed five episodes of meningitis, all due to multiresistant Gram-negative rods during his 7-month hospitalisation after head trauma. This patient's recurrent meningitis was solved only when colistin and amikacin were given by the intraventricular in addition to the intravenous route for a long period of time, specifically 6 weeks.

Topics: Adult; Colistin; Craniocerebral Trauma; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacterial Infections; Humans; Injections, Intraventricular; Male; Meningitis, Bacterial; Neurosurgical Procedures; Recurrence

Topics: Colistin; Drug Resistance, Bacterial; Gram-Negative Bacterial Infections; Humans

Topics: Aerosols; Anti-Bacterial Agents; Chemistry, Pharmaceutical; Colistin; Drug Administration Routes; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacterial Infections; Humans; Pneumonia, Bacterial

Among the six species characterized within the genus Ochrobactrum, Ochrobactrum anthropi and Ochrobactrum intermedium are currently reported as opportunistic pathogens in humans. Since the species identification is mainly based on 16S rDNA analysis, the aim of this study was to search for other characteristics useful for Ochrobactrum species discrimination. Ribotyping, morphological and biochemical analyses, and antimicrobial susceptibility testing were performed for a panel of 35 clinical isolates, first identified to the species level using 16S rDNA sequencing. Type and reference strains of five Ochrobactrum species were comparatively analysed. Commercial identification systems such as API 20NE and VITEK 2 were tested for their ability to identify Ochrobactrum anthropi and to detect other members of the genus Ochrobactrum. An improved protocol for the identification of Ochrobactrum spp. by routine medical microbiology practices is proposed: isolation of a non-fastidious non-fermenting oxidase-positive Gram-negative rod resistant to all beta-lactams except imipenem indicates the genus Ochrobactrum, and the API 20NE system confirms the genus identification for most strains, whereas the VITEK 2 system using ID-GNB cards was less powerful. Urease activity, the mucoidy of the colonies, growth at 45 degrees C on tryptic soy agar, and susceptibility to colistin, tobramycin and netilmicin should be considered as differential characteristics for identification of O. anthropi and O. intermedium to the species level. However, definitive identification depends on genotyping methods.

Topics: Anti-Bacterial Agents; Bacterial Typing Techniques; beta-Lactams; Colistin; Culture Media; DNA, Bacterial; DNA, Ribosomal; Fermentation; Gentian Violet; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests; Molecular Sequence Data; Netilmicin; Ochrobactrum; Opportunistic Infections; Oxidoreductases; Phenazines; Ribotyping; RNA, Ribosomal, 16S; Sequence Analysis, DNA; Temperature; Tobramycin; Urease

With their potent activity against Gram-negative bacteria, the polymyxins are important alternative antibiotics for cystic fibrosis (CF) patients. A retrospective evaluation of polymyxin activity against 6001 Pseudomonas aeruginosa, 150 Achromobacter xylosoxidans and 506 Stenotrophomonas maltophilia CF isolates was initiated. In addition, we looked at how polymyxin susceptibility testing was affected by the testing method (agar dilution versus microdilution), the agent (polymyxin E versus polymyxin B), incubation time (24 h versus 48 h) and by different interpretative criteria (German DIN, French FSM, British BSAC).. Polymyxin B exhibited reasonable activity against P. aeruginosa (MIC(90)< or =2 mg/L), whereas it was less active against A. xylosoxidans (MIC(90)< or =16 mg/L) and S. maltophilia (MIC(90)< or =16 mg/L). During 2000-2002, polymyxin B resistance in P. aeruginosa, S. maltophilia and A. xylosoxidans was found to be 6.7%, 17.0% and 29.9% (corresponding to 12.4%, 20.7% and 35.4% of infected patients), respectively. When the agar dilution method was used, polymyxin E exhibited higher MICs than polymyxin B. The microdilution method produced lower polymyxin MICs than the agar dilution method. Therefore, the microdilution MICs after prolonged incubation (48 h) and the agar dilution MICs of polymyxin B correlated best (AUC of 0.93, r(2) of 0.44 and s of 0.83).. Polymyxin resistance among common CF pathogens is not rare, thus underlining the necessity of accurate susceptibility testing. When compared with the agar dilution method, it was found that the microdilution method is a valid, rapid and cost effective alternative for the determination of polymyxin activity. The performance of the microdilution method was most reliable after prolonged incubation (48 h) at a susceptibility breakpoint of < or =4 mg/L according to the BSAC guidelines (specificity 91%, sensitivity 89%, 1.5% very major errors).

Topics: Achromobacter denitrificans; Adolescent; Adult; Anti-Bacterial Agents; Child; Child, Preschool; Colistin; Cystic Fibrosis; Drug Resistance, Bacterial; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests; Polymyxins; Pseudomonas aeruginosa; Quality Control; Stenotrophomonas maltophilia

Stenotrophomonas maltophilia is characterized by intrinsic resistance to a variety of antimicrobials. Therapeutic options are often limited particularly after the emergence of isolates resistant to trimethoprim/sulfamethoxazole. The application of colistin for infections caused by multidrug-resistant Gram-negative pathogens is limited due to its toxicity. In order to evaluate the activity of the interaction of colistin with rifampin or trimethoprim/sulfamethoxazole on S. maltophilia, 24 different isolates resistant to trimethoprim/sulfamethoxazole were in vitro exposed over-time to the combination of 1x and 4 x MIC of colistin with 2 microg/ml of rifampin or 2/38 microg/ml of trimethoprim/sulfamethoxazole. The applied concentrations for rifampin and trimethoprim/sulfamethoxazole reflect their mean serum levels. Synergy of colistin and rifampin was documented after the first two hours of bacterial growth for approximately 60% of isolates and it occurred with both applied concentrations of colistin. The interaction of colistin and rifampin prevented regrowth observed when single colistin was applied. Synergy of colistin and trimethoprim/sulfamethoxazole was mainly found when colistin was applied at a concentration of 4 x MIC involving 41.7% of isolates after 24 h of growth. In the presence of trimethoprim/sulfamethoxazole bacterial regrowth, observed when single colistin was applied, was prevented. It is concluded that growth of multidrug-resistant S. maltophilia is significantly inhibited by the interaction of colistin and rifampin and to a lesser extent of colistin and trimethoprim/sulfamethoxazole. These results merit further study in both the animal model and the clinical setting.

Topics: Anti-Bacterial Agents; Colistin; Colony Count, Microbial; Cross Infection; Drug Resistance, Multiple, Bacterial; Drug Synergism; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests; Rifampin; Stenotrophomonas maltophilia; Trimethoprim, Sulfamethoxazole Drug Combination

The emergence of infections caused by multidrug-resistant Pseudomonas aeruginosa and Acinetobacter spp. has necessitated the search for alternative parenteral agents such as the polymyxins. The National Committee for Clinical Laboratory Standards (NCCLS) documents do not currently provide interpretative criteria for the testing of the polymyxins, colistin and polymyxin B. Therefore, an evaluation of the antimicrobial activity of colistin and polymyxin B was initiated using 200 bloodstream infection pathogens collected through the SENTRY Antimicrobial Surveillance Program. All susceptibility tests were performed according to the NCCLS recommendations. Polymyxin B and colistin displayed a nearly identical spectrum of activity, exhibiting excellent potency against P. aeruginosa (MIC(90), 2 microg/ml) and Acinetobacter sp. (MIC(90), 2 microg/ml). In contrast, they showed limited activity against some other nonfermentative bacilli such as Burkholderia cepacia (MIC(90), >/=128 microg/ml). Excellent correlation was achieved between broth microdilution and agar dilution tests (r = 0.96 to 0.98); 94.3% of the results were +/-1 log(2) dilution between the methods used for both compounds. At a resistance breakpoint of >/=4 microg/ml for both agents, unacceptable false-susceptible or very major errors were noted for colistin (5%) and polymyxin B (6%). Modified zone criteria for colistin (/=14 mm) and polymyxin B (/=14 mm) were suggested, but some degree of error persisted (>/=3.5%). It is recommended that all susceptible disk diffusion results be confirmed by MIC tests using the preferred reference NCCLS method. The quality control (QC) ranges listed in the product package insert require an adjusted range by approximately 3 mm for both NCCLS gram-negative quality control strains. This evaluation of in vitro susceptibility test methods for the polymyxin class drugs confirmed continued serious testing error with the disk diffusion method, the possible need for breakpoint adjustments, and the recalculation of disk diffusion QC ranges. Clinical laboratories should exclusively use MIC methods to assist the therapeutic application of colistin or polymyxin B until disk diffusion test modifications are sanctioned and published by the NCCLS.

Topics: Anti-Bacterial Agents; Bacteremia; Colistin; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests; Microbiology; Polymyxin B; Quality Control

Topics: Adult; Anti-Bacterial Agents; Colistin; Drug Resistance, Microbial; Drug Resistance, Multiple; Female; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Injections, Spinal; Meningitis, Bacterial; Microbial Sensitivity Tests

With an anti-infectious and an antithrombotic prophylaxis aims, a locked flush solution including heparin and vancomycin, was used systematically for implantable venous access system for each patient, from january to april 1995. Since the 6th of april 1995, in order to widen the antibiotic spectrum on Gram negative bacteriae, we added colimycin at the flush solution. In 1995, 342 hospitalised patients held this type of venous access and received chemotherapy and/or radiochemotherapy for cancer. Two thousand six hundred thirty three manipulations were done, 575 with the first flush solution, 2058 with the second. During the year, 15 implantable access system (4.4%) were considered as infected, only 3 (0.9%) were removed, in the first period. THe infectious rate seemed to be stable, but the bacterial assessment to be modified between the two periods. The Gram negative bacterial infections seemed to decrease with colimycin addition (33% versus 50%). These results must be confirmed by a long term and/or randomized study.

Topics: Anti-Bacterial Agents; Catheterization, Central Venous; Catheters, Indwelling; Colistin; Drug Combinations; Female; Fibrinolytic Agents; Gram-Negative Bacterial Infections; Heparin; Humans; Male; Middle Aged; Neoplasms; Pilot Projects; Vancomycin

To evaluate the effect of total bowel decontamination (TD) and selective bowel decontamination (SD) in a non-protective environment clinical and laboratory data of children treated for acute leukaemia between 1983 and 1991 were analysed retrospectively. From 1983 until 1989 34 patients [18 acute non-lymphoblastic leukaemia (ANLL) patients, 16 acute lymphoblastic leukaemia (ALL) patients] received TD and 31 patients (8 ANLL patients, 23 ALL patients) received SD from 1987 until 1991. TD consisted of colistin sulphate, neomycin, cephaloridine and amphotericin B orally as well as Orabase and sterilized food, while the patients were nursed in a single room. SD consisted of oral colistin sulphate, neomycin and amphotericin B. Those patients with ANLL were nursed in a single room; patients with ALL were nursed in a single room during remission induction therapy only. All patients except those with ANLL receiving TD received Pneumocystis carinii pneumonia prophylaxis with cotrimoxazole. Because the two groups were heterogeneous for diagnosis and chemotherapy the occurrence of fever (central body temperature at least 38.5 degrees C) and major infections (septicaemia of infections of the deep tissues or organs) were registered during periods of neutropenia (neutrophilic granulocytes < or = 500/mm3 for at least 8 days). Patients on TD had 55 periods of neutropenia, patients on SD 80. Patients on TD had 89.1 periods of fever/100 periods of neutropenia whereas patients on SD had 56.3. Also patients on TD had 27.3 major infections/100 periods of neutropenia whereas patients on SD had 11.3. Major infections predominantly consisted of septicaemia caused by gram-positive bacteria. We conclude that, in this study, TD in a non-protective environment does not offer better protection against major infections that SD in patients with ALL or ANLL.

Topics: Adolescent; Amphotericin B; Anti-Bacterial Agents; Bacteremia; Bacterial Infections; Carboxymethylcellulose Sodium; Cephaloridine; Cephalosporins; Child; Child, Preschool; Colistin; Drug Therapy, Combination; Food Handling; Gram-Negative Bacterial Infections; Humans; Infant; Intestines; Leukemia, Myeloid, Acute; Neomycin; Neutropenia; Pneumonia, Pneumocystis; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Retrospective Studies; Sterilization; Trimethoprim, Sulfamethoxazole Drug Combination

Gram-negative septic episodes are a potential risk of small-bowel transplantation; bacterial translocation through the graft is considered the mechanism. As a measure to prevent this complication, we evaluated postoperative selective bowel decontamination (SBD) in the rat model of orthotopic small-bowel transplantation [Lewis (LEW) and Brown-Norway (BN) rats as donors and recipients]. For 4 days after transplantation we gave FK 506, 2 mg/kg, which prevents rejection and results in indefinite recipient survival. For SBD, 24 mg/kg/day polymyxin E and 20 mg/kg/day tobramycin were administered via orogastric gavage to allograft recipients, both with and without FK 506 therapy. On Day 9, all rats were sacrificed, the peritoneal cavity was swabbed, and mesenteric lymph nodes (MLN), spleen, liver, and ileum were harvested for microbial qualitative and quantitative analysis. Animals with positive peritoneal swab cultures were excluded. SBD resulted in a significant reduction of the quantitative gram-negative bacterial flora in the ileum and cecum and of bacterial translocation to the MLN [0% versus 50% (no FK 506 therapy) and 8% versus 50% (FK 506 treated)]. In the allograft groups not treated with FK 506, SBD failed to significantly prolong survival, suggesting that acute rejection is not hastened by infection (bacterial translocation). We conclude that SBD in small-bowel-graft recipients prevents bacterial translocation by reducing intestinal gram-negative bacterial flora; this may reduce local and systemic infections by gut-derived organisms.

Topics: Animals; Cell Movement; Colistin; Colony Count, Microbial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Intestine, Small; Liver; Lymph Nodes; Mesentery; Postoperative Care; Rats; Rats, Inbred Lew; Spleen; Tacrolimus; Tobramycin

To evaluate the efficiency of intratracheal colistin in preventing nosocomial bronchopneumonia (BPN) in the critically ill.. Study evaluating the clinical incidence of nosocomial BPN in 2 groups of critically ill patients who receive or did not receive intratracheal colistin. BPN was assessed clinically in survivors and histologically in non-survivors.. A 14-bed surgical intensive care unit.. 598 consecutive critically ill patients were studied during a prospective non-randomized study over a 40-month period.. 251 patients--31 non-survivors and 220 survivors--did not receive intratracheal colistin and 347-42 non-survivors and 305 survivors--received intratracheal colistin for a 2-week period (1,600,000 units per 24 h).. The incidence of nosocomial BPN was evaluated clinically in survivors, using repeated protected minibronchoalveolar lavages, and histologically in non-survivors via an immediate postmortem pneumonectomy (histologic and semi-quantitative bacteriologic analysis of one lung). The clinical incidence of nosocomial BPN was of 37% in coli (-) survivors and of 27% in coli (+) survivors (p < 0.01). This result was histologically confirmed in non-survivors, where the incidence of histologic BPN was of 61% in coli (-) patients and of 36% in coli (+) patients (p < 0.001). Emergence of BPN due to colistin-resistant micro-organisms was not observed. Because colistin was successful in preventing Gram-negative BPN and did not change the absolute number of Gram-positive BPN, the proportion of BPN caused by staphylococcus species was higher in group coli (+) patients (33% vs 16%). Mortality was not significantly influenced by the administration of colistin.. This study suggests that the administration of intratracheal colistin during a 2-week period significantly reduces the incidence of Gram-negative BPN without creating an increasing number of BPN due to colistin-resistant micro-organisms.

Topics: Aged; Bronchoalveolar Lavage Fluid; Colistin; Critical Illness; Cross Infection; Drug Evaluation; Drug Resistance, Microbial; Female; Gram-Negative Bacterial Infections; Humans; Incidence; Instillation, Drug; Intubation, Intratracheal; Male; Microbial Sensitivity Tests; Middle Aged; Pneumonectomy; Pneumonia; Prospective Studies; Respiration, Artificial; Survival Rate

Triethylene thiophosphoramide, an alkylating agent of value as a palliative in cases of neoplastic disease and reticulosis, has been effective in preventing vascularization of the cornea when used locally. Since recurrent pterygium, a persistent clinical problem, particularly in the Western states, is preceded by corneal vascularization and fibroplastic proliferation, it is possible that this drug when used topically may be useful in obviating to some extent the use of radiation, which must be used with great caution to avoid the production of cataract. In the treatment of gram-negative bacterial infection, especially Pseudomonas aeruginosa, the drug colistin has been known to be effective in some cases which were not helped by other antibiotics, including polymixin B. In the field of virus infections, a major breakthrough may have come about by the discovery that 5-iodo-2-deoxyuridine (IDU) attacks the herpes cirrus in the cornea as a metabolic antagonist. Animal experiments and some clinical studies have confirmed its effectiveness as compared with other therapeutic measures in selected cases. In the treatment of ocular problems resulting from systemic disease fibrinolysin (plasmin) has apparently caused dissolution of the clot and restoration of circulation in some cases of retinal artery occlusion. Severe diabetic retinopathy in younger diabetic patients has been shown to regress in certain cases treated by hypophysectomy or radiation of the pituitary gland employing the cyclotron. This gland is also associated intimately with the exophthalmos of thyroid origin, and its action may be aggravated by the use of ACTH or steroids.

Topics: Animals; Anti-Bacterial Agents; Colistin; Cornea; Gram-Negative Bacterial Infections; Humans; Ophthalmology; Pseudomonas aeruginosa