fosfomycin and Gram-Negative-Bacterial-Infections

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

In the last decade, an increasing interest in using fosfomycin for the treatment of multidrug-resistant gram-negative (MDR-GNB) infections have been registered, especially when none or only a few other active alternatives remained available.. Fosfomycin may remain active against a considerable proportion of MDR-GNB. In observational studies, a possible curative effect of oral fosfomycin monotherapy has been described for uncomplicated urinary tract infections (UTI) and bacterial prostatitis caused by MDR-GNB, whereas intravenous fosfomycin has been mostly used in combination with other agents for various type of severe MDR-GNB infections. The ZEUS randomized controlled trial (RCT) has started to provide high-level evidence about the possible use of fosfomycin for complicated UTI caused by extended-spectrum β-lactamase-producing GNB, but no results of large RCT are currently available to firmly guide the use of fosfomycin for carbapenem-resistant GNB.. Fosfomycin is an important therapeutic option for MDR-GNB infections. Further pharmacokinetic/pharmacodynamic and clinical research is needed to optimize its use.

Topics: Anti-Bacterial Agents; Clinical Studies as Topic; Drug Resistance, Multiple, Bacterial; Fosfomycin; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests; Randomized Controlled Trials as Topic; Treatment Outcome

There are challenges regarding increased global rates of microbial resistance and the emergence of new mechanisms that result in microorganisms becoming resistant to antimicrobial drugs. Fosfomycin is a broad-spectrum bactericidal antibiotic effective against Gram-negative and certain Gram-positive bacteria, such as Staphylococci, that interfere with cell wall synthesis. During the last 40 years, fosfomycin has been evaluated in a wide range of applications and fields. Although numerous studies have been done in this area, there remains limited information regarding the prevalence of resistance. Therefore, in this review, we focus on the available data concerning the mechanisms and increasing resistance regarding fosfomycin.

Topics: Anti-Bacterial Agents; Drug Resistance, Bacterial; Fosfomycin; Geography; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Prevalence

The alarming increase in antibiotic resistance rates reported for various pathogens has resulted in the use of alternative treatment policies. Given the fairly limited availability of new antimicrobial drugs, the reassessment of older antibiotics is now an interesting option. Fosfomycin, a bactericidal analog of phosphoenolpyruvate that has been previously been employed as an oral treatment for uncomplicated urinary tract infection, has recently raised interest among physicians worldwide. In general, the advanced resistance described in Gram-negative bacteria suggests that fosfomycin can be an appropriate treatment option for patients with highly resistant microbial infections. This review, which refers to key available data, focuses on the possibility of extending the use of fosfomycin beyond urinary tract infections and against multidrug-resistant Gram-negative bacteria.

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

Due to the increase in antimicrobial resistance, strategies such as antimicrobial stewardship programs (ASP) have been developed to improve the clinical results, decrease the adverse effects and the development of resistances and ensure cost-effective therapies. Fosfomycin has a unique mechanism of action against Gram-positive and Gram-negative bacteria. Cross-resistance is uncommon; however, fosfomycin should be used in combination in severe infections to avoid selecting resistant mutations. Fosfomycin's oral formulation facilitates sequential treatment, has low toxicity and high tissue penetration, even in the central nervous system and bone. Fosfomycin is active against resistant Gram-positive bacteria such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin- resistant enterococci and penicillin-resistant Streptococcus pneumoniae, as well as against resistant Gram-negative bacteria such as extended-spectrum beta-lactamase-producing and carbapenemase-producing enterobacteria. Fosfomycin is therefore useful for cases of persistent bacteremia, skin and soft tissue infections, as a glycopeptide-sparing and carbapenem-sparing drug for healthcare-associated infections and for polymicrobial infections. Published studies have demonstrated the synergy between fosfomycin and beta-lactams, daptomycin and glycopeptides against MSSA and MRSA; with linezolid in biofilm-associated infections and with aminoglycosides and colistin against Gram-negative bacteria, providing a nephroprotective effect.

Topics: Animals; Anti-Bacterial Agents; Antimicrobial Stewardship; Bacterial Infections; Drug Resistance, Multiple, Bacterial; Fosfomycin; Gram-Negative Bacterial Infections; Gram-Positive Bacterial Infections; Humans

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

Urinary tract infections (UTIs) caused by antibiotic-resistant Gram-negative bacteria are a growing concern due to limited therapeutic options. Gram-negative bacteria, specifically Enterobacteriaceae, are common causes of both community-acquired and hospital acquired UTIs. These organisms can acquire genes that encode for multiple antibiotic resistance mechanisms, including extended-spectrum-lactamases (ESBLs), AmpC- β -lactamase, and carbapenemases. The assessment of suspected UTI includes identification of characteristic symptoms or signs, urinalysis, dipstick or microscopic tests, and urine culture if indicated. UTIs are categorized according to location (upper versus lower urinary tract) and severity (uncomplicated versus complicated). Increasing rates of antibiotic resistance necessitate judicious use of antibiotics through the application of antimicrobial stewardship principles. Knowledge of the common causative pathogens of UTIs including local susceptibility patterns are essential in determining appropriate empiric therapy. The recommended first-line empiric therapies for acute uncomplicated bacterial cystitis in otherwise healthy adult nonpregnant females is a 5-day course of nitrofurantion or a 3-g single dose of fosfomycin tromethamine. Second-line options include fluoroquinolones and β-lactams, such as amoxicillin-clavulanate. Current treatment options for UTIs due to AmpC- β -lactamase-producing organisms include fosfomycin, nitrofurantion, fluoroquinolones, cefepime, piperacillin-tazobactam and carbapenems. In addition, treatment options for UTIs due to ESBLs-producing Enterobacteriaceae include nitrofurantion, fosfomycin, fluoroquinolones, cefoxitin, piperacillin-tazobactam, carbapenems, ceftazidime-avibactam, ceftolozane-tazobactam, and aminoglycosides. Based on identification and susceptibility results, alternatives to carbapenems may be used to treat mild-moderate UTIs caused by ESBL-producing Enterobacteriaceae. Ceftazidime-avibactam, colistin, polymixin B, fosfomycin, aztreonam, aminoglycosides, and tigecycline are treatment options for UTIs caused by carbapenem-resistant Enterobacteriaceae (CRE). Treatment options for UTIs caused by multidrug resistant (MDR)-Pseudomonas spp. include fluoroquinolones, ceftazidime, cefepime, piperacillin-tazobactam, carbapenems, aminoglycosides, colistin, ceftazidime-avibactam, and ceftolozane-tazobactam. The use of fluoroquinolones for empiric treatment of UTIs should be restricted due to increased rat

Topics: Aminoglycosides; Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; beta-Lactams; Comorbidity; Drug Resistance, Bacterial; Fluoroquinolones; Fosfomycin; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests; Minocycline; Nitrofurantoin; Severity of Illness Index; Urinary Tract Infections

Antimicrobial resistance is a major and emerging threat worldwide. New antimicrobials have been unable to meet the resistance challenge, and treatment options are limited for a growing number of resistant pathogens. More and more clinicians are relying on older antimicrobials for the treatment of multidrug-resistant (MDR) bacteria. Some older antimicrobials have maintained excellent in vitro activity against highly resistant pathogens. In some instances, use of older agents is limited by unfavourable pharmacokinetic/pharmacodynamic characteristics and/or toxicities. In general, clinical data pertaining to the use of older agents for the treatment of MDR pathogens are scarce. Research efforts should be focused on the evaluation of older agents for the treatment of MDR pathogens as well as evaluating how these agents perform in complex patient populations with various and multiple co-morbid conditions.

Topics: Aminoglycosides; Anti-Bacterial Agents; Drug Combinations; Drug Resistance, Multiple, Bacterial; Fosfomycin; Gram-Negative Bacterial Infections; Gram-Positive Bacterial Infections; Humans; Microbial Sensitivity Tests; Minocycline; Polymyxins; Sulfamethizole; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination

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

The aim of this review was to evaluate the susceptibility of contemporary Gram-positive and Gram-negative bacteria to fosfomycin. PubMed and Scopus databases were systematically searched to identify studies published in print or electronically from January 2010 until June 2015. In total, 84 studies were selected. Susceptibility to fosfomycin of Staphylococcus aureus ranged between 33.2% and 100% (frequency=91.7%, 95% confidence interval 88.7-94.9%), of Enterococcus spp. from 30% to 100% (Enterococcus faecium 92.6%, 85.2-100%; Enterococcus faecalis 96.8%, 92.5-100%), of extended-spectrum β-lactamase (ESBL)-producing Escherichia coli from 81% to 100% (95.1%, 94.3-95.9%), of ESBL-producing Klebsiella pneumoniae from 15% to 100% (83.8%, 78.7-89.4%) and of carbapenem-resistant (CR) K. pneumoniae from 39.2% to 100% (73.5%, 66.4-81.4%). Staphylococcus aureus (including meticillin-resistant strains) and E. coli (including ESBL-producing strains) were the most likely to be susceptible with low minimum inhibitory concentrations (MICs). Enterococci (particularly vancomycin-resistant E. faecium) and K. pneumoniae (especially CR strains) were less susceptible with higher MIC50 and MIC90 values. Two studies reported decreasing susceptibility of ESBL-producing E. coli to fosfomycin. In conclusion, guided by local susceptibility data, fosfomycin could be considered for the treatment of patients with infections due to problematic multidrug-resistant bacteria.

Topics: Anti-Bacterial Agents; Fosfomycin; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Microbial Sensitivity Tests

The antimicrobial agent fosfomycin was discovered in 1969, at a time when bacteria had not yet developed extended-spectrum β-lactamases or carbapenemases. Decades later, it is not uncommon for gram-negative organisms to be multidrug-resistant and even pan-resistant to available antibiotic regimens, leaving clinicians with few therapeutic alternatives. Because fosfomycin has been shown to retain activity against these virulent pathogens, there is renewed interest in its use as a therapeutic agent. Fosfomycin formulations including fosfomycin disodium and the newer tromethamine salt are less toxic than other alternatives and are attractive options for resistant gram-negative and gram-positive infections. Oral fosfomycin tromethamine is approved for urinary tract infections in the United States, and an intravenous formulation is also available outside of the United States for systemic disease. The bactericidal action of fosfomycin occurs at an earlier step in cell wall synthesis than that of β-lactam antibiotics. From an in vitro standpoint, fosfomycin generally has high activity against ESBL- and carbapenemase-producing Enterobacteriaceae; multidrug-resistant Pseudomonas aeruginosa susceptibility appears to be more dependent on the local antibiogram. Fosfomycin formulations have a large volume of distribution, penetrate biofilms, and concentrate in the urine. Both oral and intravenous fosfomycin formulations are effective for a wide range of gram-negative infections and disease severities; however, clinical studies are limited. Fosfomycin formulations are well-tolerated, and mild gastrointestinal distress is the most common adverse effect. The primary limitations of fosfomycin are the lack of established regimens for complicated infections and the lack of availability of the intravenous formulation in the United States. Further study of this promising agent seems warranted in the current climate of antibiotic resistance.

Topics: Animals; Anti-Bacterial Agents; Drug Approval; Drug Resistance, Multiple, Bacterial; Fosfomycin; Gram-Negative Bacterial Infections; Humans; United States

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

Fosfomycin has attracted renewed interest for the treatment of lower urinary tract and even systemic infections caused by Gram-negative pathogens with resistance to traditionally used agents. The main concern regarding the clinical utility of fosfomycin refers to the potential for the emergence of resistance during therapy. In this review, we evaluate the available published evidence regarding the mechanisms and the frequency of in vitro mutational resistance to fosfomycin in Gram-negative pathogens. We also review data regarding the emergence of resistance in clinical studies of fosfomycin therapy in various infectious syndromes and data from studies that evaluate the evolution of fosfomycin resistance over time. There appears to be discordance between the high frequency of mutational resistance to fosfomycin in vitro and the lower extent of this phenomenon in clinical studies. This discordance could at least partly be attributed to a biological cost associated with common mutations that confer resistance to fosfomycin, including decreased growth rate and low adherence to epithelial cells for the resistant mutants. The development of resistance appears to be more frequent both in vitro and in clinical studies for Pseudomonas aeruginosa in comparison with Escherichia coli, whereas relevant data for other Enterobacteriaceae are relatively scarce. The urinary tract seems to provide a favourable environment for the use of fosfomycin with a low associated likelihood for the emergence of resistance, owing to high drug concentrations and acidic pH. Additional data are needed to further clarify the optimal use of fosfomycin for different infectious syndromes caused by contemporary multidrug-resistant pathogens.

Topics: Anti-Bacterial Agents; Drug Resistance, Bacterial; Enterobacteriaceae; Fosfomycin; Gram-Negative Bacterial Infections; Humans; Mutation; Pseudomonas aeruginosa

Fosfomycin, originally named phosphonomycin, was discovered in Spain in 1969. There are three forms of fosfomycin: fosfomycin tromethamine (a soluble salt) and fosfomycin calcium for oral use, and fosfomycin disodium for intravenous use. Fosfomycin is a bactericidal antibiotic that interferes with cell wall synthesis in both Gram-positive and Gram-negative bacteria by inhibiting the initial step involving phosphoenolpyruvate synthetase. It has a broad spectrum of activity against a wide range of Gram-positive and Gram-negative bacteria. It is highly active against Gram-positive pathogens such as Staphylococcus aureus and Enterococcus, and against Gram-negative bacteria such as Pseudomonas aeruginosa and Klebsiella pneumoniae. Its unique mechanism of action may provide a synergistic effect to other classes of antibiotics including beta-lactams, aminoglycosides, and fluoroquinolones. Oral fosfomycin is mainly used in the treatment of urinary tract infections, particularly those caused by Escherichia coli and Enterococcus faecalis. Intravenous fosfomycin has been administered in combination with other antibiotics for the treatment of nosocomial infections due to multidrug-resistant (MDR) Gram-positive and Gram-negative bacteria. Fosfomycin has good distribution into tissues, achieving clinically relevant concentrations in serum, kidneys, bladder wall, prostate, lungs, inflamed tissues, bone, cerebrospinal fluid, abscess fluid, and heart valves. Fosfomycin is well tolerated, with a low incidence of adverse events. Further randomized controlled trials are needed in order to evaluate the efficacy of intravenous fosfomycin for the management of nosocomial infections due to MDR pathogens.

Topics: Anti-Bacterial Agents; Cross Infection; Enterococcus faecalis; Escherichia coli; Fosfomycin; Gram-Negative Bacterial Infections; Gram-Positive Bacterial Infections; Humans; Klebsiella pneumoniae; Pseudomonas aeruginosa; Urinary Tract Infections

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

The treatment of multidrug-resistant (MDR), extensively drug-resistant or pandrug-resistant non-fermenting Gram-negative bacterial infections constitutes a challenge in an era of few new antibiotic choices. This mandates the re-evaluation of already existing antibiotics such as fosfomycin. We systematically reviewed the literature to assess the clinical and microbiological effectiveness of fosfomycin in the treatment of these infections by searching PubMed, Scopus and the Cochrane Library databases. In 23 microbiological studies identified, 1859 MDR non-fermenting Gram-negative bacterial isolates were examined. The susceptibility rate to fosfomycin of MDR Pseudomonas aeruginosa isolates was >or=90% and 50-90% in 7/19 and 4/19 relevant studies, respectively. Cumulatively, 511/1693 (30.2%) MDR P. aeruginosa isolates were susceptible to fosfomycin. Serotype O12 isolates exhibited greater susceptibility. Only 3/85 (3.5%) MDR Acinetobacter baumannii and 0/31 MDR Burkholderia spp. isolates were susceptible to fosfomycin. Variable criteria of susceptibility were used in the included studies. Fosfomycin was synergistic in combination with a beta-lactam, aminoglycoside or ciprofloxacin in 46/86 (53.5%) MDR P. aeruginosa isolates. One animal study found a good therapeutic effect of the combination fosfomycin/gentamicin against MDR P. aeruginosa endocarditis. In six clinical studies, 33 patients with MDR P. aeruginosa infections (mainly pulmonary exacerbations of cystic fibrosis) received fosfomycin (25/33 in combination with other antibiotics); 91% of the patients clinically improved. In conclusion, fosfomycin could have a role as a therapeutic option against MDR P. aeruginosa infections. Further research is needed to clarify the potential utility of this agent.

Topics: Acinetobacter baumannii; Animals; Anti-Bacterial Agents; Burkholderia; Drug Resistance, Multiple, Bacterial; Drug Synergism; Endocarditis, Bacterial; Fosfomycin; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections

The emergence of multidrug-resistant (MDR) Gram-negative bacilli creates a challenge in the treatment of nosocomial infections. While the pharmaceutical pipeline is waning, two revived old antibacterials (colistin and fosfomycin), a newer one (tigecycline) and an 'improved' member of an existing class (doripenem) are the only therapeutic options left. The class of polymyxins, known since 1947 and represented mostly by polymyxin B and polymyxin E (colistin), has recently gained a principal role in the treatment of the most problematic MDR Gram-negative pathogens (such as Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae and Stenotrophomonas maltophilia). Future prospective studies are needed to answer important clinical questions, such as the possible benefit of combination with other antimicrobials versus monotherapy, the efficacy of colistin in neutropenic hosts and the role of inhaled colistin. As new pharmacokinetic data emerge, clarification of the pharmacokinetic/pharmacodynamic (PK/PD) profile of colistin as well as appropriate dosing seems urgent, while development of resistance must be carefully monitored. Fosfomycin tromethamine, a synthetic salt of fosfomycin discovered in 1969, has regained attention because of its in vitro activity against extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae and MDR P. aeruginosa. Although in use for decades in oral and parenteral formulations for a variety of infections without significant toxicity, its clinical utility in MDR infections remains to be explored in future studies. Tigecycline, the first representative of the new class of glycylcyclines, holds promise in infections from MDR K. pneumoniae (K. pneumoniae carbapenemase [KPC]- and ESBL-producing strains) and Enterobacteriaceae with various mechanisms of resistance. The in vitro activity of tigecycline against A. baumannii makes it a tempting option, as it is currently the most active compound against MDR strains along with colistin. However, the usual minimum inhibitory concentration values of this pathogen are approximately 2 mg/L and compromise clinical outcomes based on PK/PD issues. Its advantageous penetration into various tissues is useful in infections of the skin and soft tissues as well as intra-abdominal infections (official indications), whereas low serum concentrations compromise its use in bloodstream infections. Therefore, prospective studies with dose escalation are urgently needed, as well as clar

Topics: Anti-Bacterial Agents; Carbapenems; Doripenem; Drug Resistance, Multiple, Bacterial; Fosfomycin; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Minocycline; Polymyxins; Tigecycline

The shortage of new antimicrobial agents has made the scientific community reconsider the potential value of old antibiotics. A search of the literature was performed to compile relevant evidence regarding the effectiveness and safety of fosfomycin for the treatment of patients with gram-positive and/or gram-negative bacterial infections (excluding urinary tract infection and gastrointestinal infection). Of 1311 potentially relevant studies, 62 studies were reviewed in detail. Of 1604 patients with various gram-positive and gram-negative infections of various body sites (including pneumonia and other respiratory infections; osteomyelitis; meningitis; ear, nose, and throat infections; surgical infections; obstetric and gynecological infections; arthritis; septicemia; peritonitis; cervical lymphadenitis; eye infections; diabetic foot infections; and typhoid fever) being treated with fosfomycin alone or in combination with other antibiotics, cure was achieved in 1302 (81.1%) of the patients, and improvement was noted in 47 (2.9%). In comparative perioperative prophylaxis trials that included a total of 1212 patients (mainly patients undergoing colorectal surgery), the fosfomycin-metronidazole combination led to results that were similar to those achieved with the combination of other antibiotics (doxycycline, ampicillin, or cephalothin) and metronidazole. In an era in which there is a shortage of new antibiotics, fosfomycin might be considered to be an alternative treatment agent for infections caused by gram-positive and gram-negative bacteria, in addition to its traditional use in treating uncomplicated urinary tract and gastrointestinal infections. Further research on the in vitro antimicrobial activity of fosfomycin, especially against multidrug-resistant pathogens (such as extended-spectrum beta-lactamase-producing and/or metallo-beta-lactamase-producing enterobacteriaceae and Pseudomonas aeruginosa, and on the effectiveness and safety of the drug in the treatment of patients with such infections may be warranted.

Topics: Anti-Bacterial Agents; Antibiotic Prophylaxis; Drug Therapy, Combination; Fosfomycin; Gram-Negative Bacterial Infections; Gram-Positive Bacterial Infections; Humans

Fosfomycin is an natural antibiotic with an epoxide structure and low molecular weight which acts in the first stage of peptidoglycan synthesis of the bacterial wall. It has a rapid bactericide effect, and a wide spectrum, including methicillin-resistant Staphylococcus aureus and intermediate glycopeptide-susceptible or -resistant enterococci. Over the years it has maintained its activity and has shown stable rates of resistance. It has synergistic action, which is additive or indifferent with glycopeptides, linezolid, quinupristin-dalfopristin, betalactams, aminoglycosides, ansamycines, nitroimidazoles and quinolones, without antagonism. It can be administered orally or parenterally in a wide range of doses, it does not bind to plasma proteins, and has a good distribution volume, reaching high concentrations in the interstitial fluid and tissues. It is eliminated in the kidneys in its active form without metabolites and is dialyzable. It has been used in a number of indications, including urinary, respiratory, intraabdominal, obstetric-gynecologic, central nervous system and osteoarticular infections, with satisfactory overall results in 80% of cases and minimal side effects. It does not cause important changes in the normal human flora. As additional effects it has the capacity to favor phagocytosis, act as an immunomodulator and protect human cells from cisplatin, cyclosporin, aminoglycoside, vancomycin, amphotericin B and polymixin toxicity. Oral fosfomycin is currently clearly indicated in urinary infections and gastroenteritis, and parenteral fosfomycin in high doses and in combination with other drugs in severe inhospital infections caused by problematic pathogens, including multiresistant staphylococci and enterococci, and in immunodepressed patients treated with nephrotoxic drugs.

Topics: Anti-Bacterial Agents; Drug Resistance, Bacterial; Drug Synergism; Drug Therapy, Combination; Fosfomycin; Gram-Negative Bacterial Infections; Gram-Positive Bacterial Infections; Humans

Fosfomycin tromethamine is a phosphonic acid bactericidal agent with in vitro activity against most urinary tract pathogens. It is particularly active against Escherichia coli, and Citrobacter, Enterobacter, Klebsiella, Serratia and Enterococcus spp. There appears to be little cross-resistance between fosfomycin and other antibacterial agents, possibly because it differs from other agents in its general chemical structure and site of action. In its new formulation as the oral tromethamine salt, fosfomycin has 34 to 41% oral bioavailability, has a mean elimination half-life of 5.7 hours, and is primarily excreted unchanged in the urine. Following a single 3 g oral dose, peak urinary concentrations occur within 4 hours and remain high (> 128 mg/L) for 24 to 48 hours, which is sufficient to inhibit most urinary tract pathogens. In clinical trials in patients with acute uncomplicated lower urinary tract infection, single-dose fosfomycin tromethamine therapy was effective, and comparable with several other antibacterial agents given either as single-dose or multiple-dose treatments [e.g. beta-lactam and fluoroquinolone agents, cotrimoxazole (trimethoprim-sulfamethoxazole), nitrofurantoin and pipemidic acid]. Bacteriological eradication rates of 75 to 90% were achieved 5 to 11 days after therapy, with eradication rates of 62 to 93% 4 to 6 weeks after therapy. In 3 large double-blind comparisons with ciprofloxacin, cotrimoxazole and nitrofurantoin, 99% of fosfomycin tromethamine recipients and 100% of patients receiving comparator agents were considered clinically cured or improved after therapy. Fosfomycin tromethamine is well tolerated, with a low incidence of adverse events. These comprise mainly gastrointestinal symptoms that are transient, mild and self-limiting. Thus, fosfomycin tromethamine achieves high clinical and bacteriological cure rates in patients with acute uncomplicated lower urinary tract infection and is well tolerated. The single-dose administration regimen and favourable US pregnancy category rating of fosfomycin tromethamine should also encourage its use in this indication.

Topics: Acute Disease; Administration, Oral; Drug Administration Schedule; Female; Fosfomycin; Gram-Negative Bacterial Infections; Gram-Positive Bacterial Infections; Humans; Pregnancy; Randomized Controlled Trials as Topic; Tromethamine; Urinary Tract Infections

Clinical failures in ventilator-associated pneumonia (VAP) caused by gram-negative bacteria are common and associated with substantial morbidity, mortality, and resource utilization.. We assessed the safety and efficacy of the amikacin fosfomycin inhalation system (AFIS) for the treatment of gram-negative bacterial VAP in a randomized double-blind, placebo-controlled, parallel group, phase 2 study between May 2013 and March 2016. We compared standard of care in each arm plus 300 mg amikacin/120 mg fosfomycin or placebo (saline), delivered by aerosol twice daily for 10 days (or to extubation if < 10 days) via the investigational eFlow Inline System (PARI GmbH). The primary efficacy end point was change from baseline in the Clinical Pulmonary Infection Score (CPIS) during the randomized course of AFIS/placebo, using the subset of patients with microbiologically proven baseline infections with gram-negative bacteria.. There were 143 patients randomized: 71 to the AFIS group, and 72 to the placebo group. Comparison of CPIS change from baseline between treatment groups was not different (P = .70). The secondary hierarchical end point of no mortality and clinical cure at day 14 or earlier was also not significant (P = .68) nor was the hierarchical end point of no mortality and ventilator-free days (P = .06). The number of deaths in the AFIS group was 17 (24%) and 12 (17%) in the placebo group (P = .32). The AFIS group had significantly fewer positive tracheal cultures on days 3 and 7 than placebo.. In this trial of adjunctive aerosol therapy compared with standard of care IV antibiotics in patients with gram-negative VAP, the AFIS was ineffective in improving clinical outcomes despite reducing bacterial burden.. ClinicalTrials.gov; No.: NCT01969799; URL: www.clinicaltrials.gov.

Topics: Administration, Inhalation; Adult; Aged; Amikacin; Anti-Bacterial Agents; APACHE; Chemotherapy, Adjuvant; Double-Blind Method; Female; Fosfomycin; Gram-Negative Bacterial Infections; Humans; Male; Middle Aged; Pneumonia, Ventilator-Associated; Treatment Outcome

Addressing the treatment and prevention of antibacterial-resistant gram-negative bacterial infections is a priority area of the Antibacterial Resistance Leadership Group (ARLG). The ARLG has conducted a series of observational studies to define the clinical and molecular global epidemiology of carbapenem-resistant and ceftriaxone-resistant Enterobacterales, carbapenem-resistant Pseudomonas aeruginosa, and carbapenem-resistant Acinetobacter baumannii, with the goal of optimizing the design and execution of interventional studies. One ongoing ARLG study aims to better understand the impact of fluoroquinolone-resistant gram-negative gut bacteria in neutropenic patients, which threatens to undermine the effectiveness of fluoroquinolone prophylaxis in these vulnerable patients. The ARLG has conducted pharmacokinetic studies to inform the optimal dosing of antibiotics that are important in the treatment of drug-resistant gram-negative bacteria, including oral fosfomycin, intravenous minocycline, and a combination of intravenous ceftazidime-avibactam and aztreonam. In addition, randomized clinical trials have assessed the safety and efficacy of step-down oral fosfomycin for complicated urinary tract infections and single-dose intravenous phage therapy for adult patients with cystic fibrosis who are chronically colonized with P. aeruginosa in their respiratory tract. Thus, the focus of investigation in the ARLG has evolved from improving understanding of drug-resistant gram-negative bacterial infections to positively affecting clinical care for affected patients through a combination of interventional pharmacokinetic and clinical studies, a focus that will be maintained moving forward.

Topics: Adult; Anti-Bacterial Agents; Carbapenems; Drug Resistance, Multiple, Bacterial; Fluoroquinolones; Fosfomycin; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Leadership; Microbial Sensitivity Tests; Pseudomonas aeruginosa

We reviewed the efficacy and safety of intravenous (IV) fosfomycin for the treatment of infections caused by Gram-negative bacteria (GNB) with difficult-to-treat resistance (DTR). Data were retrospectively retrieved for all hospitalized patients who received IV fosfomycin for ≥48 h for the treatment of a DTR GNB between September 27, 2017 and January 31, 2020. A total of 30 patients were included, of which 63.3% were males, and the median age was 63.5 years (IQR 46-73). The median Charlson Comorbidity Score was 6 (IQR 3.8-9). The urinary tract (56.7%) was the most frequent site of infection, and the most frequent target organisms were Klebsiella pneumoniae (56.7%), and Escherichia coli (23.3%). The majority (76.%) received IV fosfomycin in combination with other antibacterial agents. Clinical improvement was observed in 22 (73.3%), eradication of baseline pathogens in 20 (66.7%), 30-day all-cause mortality in 7 (23.3%), and documented emergent resistance to fosfomycin in 5 (16.7%) patients. Treatment-related adverse events were infrequent and generally mild or moderate in severity. In conclusion, IV fosfomycin is a potentially efficacious and safe treatment option for the treatment of DTR GNB infections. Randomized trials are urgently required to confirm the utility of IV fosfomycin as monotherapy and in combination with other agents.

Topics: Anti-Bacterial Agents; Fosfomycin; Gram-Negative Bacterial Infections; Humans; Klebsiella pneumoniae; Male; Microbial Sensitivity Tests; Middle Aged; Retrospective Studies; Urinary Tract Infections

Fosfomycin has re-emerged as a possible therapeutic alternative for the treatment of resistant bacterial pathogens. Its main mechanism of action is the inhibition of the initial step of cell wall synthesis and is active against both Gram-positive and Gram-negative bacteria. However, its clinical effectiveness against multidrug resistant bacteria remains largely unknown. Therefore, we aim to evaluate the clinical and microbiological effectiveness of intravenous fosfomycin as well as its safety in a tertiary care teaching hospital in Lebanon.. This is a retrospective chart review of adult patients who had presented to the hospital and were treated with intravenous fosfomycin for at least 24 hours for any type of infection between 2014 and 2019.. Among 31 episodes treated with intravenous fosfomycin, 68% had an overall favorable clinical response. In 84% of the episodes, fosfomycin was administered in combination with other antibiotics, commonly tigecycline. Of those with available cultures at end of therapy, 73% achieved microbiological success. No relapse was documented within 30 days of completion of therapy. In the episodes secondary to resistant pathogens, the rates of favorable clinical outcome and microbiological success at the end of therapy were 71% and 73%, respectively. Fosfomycin resistance developed in two cases and mild adverse events occurred in 65% of the episodes during the course of treatment.. Fosfomycin is a safe and effective option in the treatment of multi-drug resistant infections. Nevertheless, careful stewardship is important to maintain its efficacy and to reduce the risk of selection of antimicrobial resistance.

Topics: Administration, Intravenous; Adolescent; Adult; Anti-Bacterial Agents; Drug Resistance, Multiple, Bacterial; Female; Fosfomycin; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Lebanon; Male; Middle Aged; Retrospective Studies; Tertiary Care Centers; Young Adult

Oral fosfomycin may constitute an alternative for the treatment of lower urinary tract infections (UTIs) in kidney transplant recipients (KTRs), particularly in view of recent safety concerns with fluroquinolones. Specific data on the efficacy and safety of fosfomycin in KTR are scarce. We performed a retrospective study in 14 Spanish hospitals including KTRs treated with oral fosfomycin (calcium and trometamol salts) for posttransplant cystitis between January 2005 and December 2017. A total of 133 KTRs developed 143 episodes of cystitis. Most episodes (131 [91.6%]) were produced by gram-negative bacilli (GNB), and 78 (54.5%) were categorized as multidrug resistant (including extended-spectrum β-lactamase-producing Enterobacteriaceae [14%] or carbapenem-resistant GNB [3.5%]). A median daily dose of 1.5 g of fosfomycin (interquartile range [IQR]: 1.5-2) was administered for a median of 7 days (IQR: 3-10). Clinical cure (remission of UTI-attributable symptoms at the end of therapy) was achieved in 83.9% (120/143) episodes. Among those episodes with follow-up urine culture, microbiological cure at month 1 was achieved in 70.2% (59/84) episodes. Percutaneous nephrostomy was associated with a lower probability of clinical cure (adjusted odds ratio: 10.50; 95% confidence interval: 0.98-112.29; P = 0.052). In conclusion, fosfomycin is an effective orally available alternative for treating cystitis among KTRs.

Topics: Administration, Oral; Adult; Aged; Anti-Bacterial Agents; Female; Follow-Up Studies; Fosfomycin; Gram-Negative Bacterial Infections; Gram-Positive Bacterial Infections; Humans; Kidney Transplantation; Logistic Models; Male; Middle Aged; Postoperative Complications; Retrospective Studies; Spain; Treatment Outcome; Urinary Tract Infections

In vitro and clinical studies using parenteral fosfomycin have suggested the possibility of using this drug against infections caused by MDR microorganisms. The aim of this study was to describe a case series of patients treated with fosfomycin who had severe infections caused by pan-drug-resistant Gram-negative bacteria.. We describe a prospective series of cases of hospitalized patients with infections caused by Gram-negative bacteria resistant to β-lactams and colistin, treated with 16 g of fosfomycin daily for 10-14 days. Isolates were tested for antimicrobial susceptibility and synergism of fosfomycin with meropenem. We tested for resistance genes and performed typing using PCR and WGS.. Thirteen patients received fosfomycin (seven immunosuppressed); they had bloodstream infections (n = 11; 85%), ventilator-associated pneumonia (n = 1; 8%) and surgical site infection (n = 1; 8%), caused by Klebsiella pneumoniae (n = 9), Serratia marcescens (n = 3) and Pseudomonas aeruginosa (n = 1). Overall, eight (62%) patients were cured. Using time-kill assays, synergism between fosfomycin and meropenem occurred in 9 (82%) of 11 isolates. Typing demonstrated that K. pneumoniae were polyclonal. Eight patients (62%) had possible adverse events, but therapy was not discontinued.. Fosfomycin may be safe and effective against infections caused by pan-drug-resistant Gram-negative microorganisms with different antimicrobial resistance mechanisms and there seems to be synergism with meropenem.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Drug Synergism; Drug-Related Side Effects and Adverse Reactions; Female; Fosfomycin; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Male; Meropenem; Microbial Sensitivity Tests; Microbial Viability; Middle Aged; Pneumonia, Ventilator-Associated; Sepsis; Surgical Wound Infection; Young Adult

Increasing antimicrobial resistance is a major problem worldwide. Many urinary tract infection (UTI) isolates are resistant to all oral antimicrobial agents, necessitating intravenous treatment even for cystitis. Fosfomycin is a broad-spectrum antibiotic that achieves high and prolonged urinary drug concentration and is considered first-line treatment for uncomplicated cystitis. Our aim was to investigate fosfomycin susceptibility among urinary isolates and search for demographic or bacterial characteristics associated with fosfomycin nonsusceptibility.. This is a retrospective study of all Gram-negative urinary isolates at Padeh-Poriya Medical Center in northern Israel. A total of 1503 isolates were tested for fosfomycin susceptibility, as well as susceptibility to other antimicrobial agents, by VITEK2 system and disk diffusion testing. Demographic and clinical data were obtained from patient electronic files.. A total of 1,503 isolates from patients' urine were included. Mean patient age was 64.6 years, 937 (62.3%) were female, 913 (60.7%) were Jews, and in 1,058 (70.4%) cases, the infection was community acquired; 28.1% were extended-spectrum beta lactamase (ESBL)-positive. A total of 1099 (73.1%) isolates were susceptible to fosfomycin. Fosfomycin nonsusceptibility was significantly correlated to year: 124 (20.7%) in 2015 versus 280 (30.9%) in 2016; patient age: 17.6% in patients ≤50 years versus 30% in patients >50 years; hospital-acquired UTI: 34.2% versus 23.8%; and presence of ESBL positivity: 31.1% in ESBL-positive versus 20.9% in ESBL-negative isolates (p for all <0.001).. Fosfomycin nonsusceptibility among urine culture isolates is a worrisome phenomenon that is on the rise and is more often found in elderly patients, patients with nosocomial UTI, and isolates that are ESBL positive.

Topics: beta-Lactamases; Drug Resistance, Multiple, Bacterial; Female; Fosfomycin; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Israel; Male; Microbial Sensitivity Tests; Middle Aged; Retrospective Studies; Urinary Tract Infections

For treatment of peritoneal dialysis-related peritonitis, intraperitoneal administration of antibiotics remains the preferable route. For home-based therapy, patients are commonly supplied with peritoneal dialysis fluids already containing antimicrobial agents. The present study set out to investigate the compatibility of fosfomycin with different peritoneal dialysis fluids, namely, Extraneal

Topics: Anti-Bacterial Agents; Dialysis Solutions; Disk Diffusion Antimicrobial Tests; Drug Interactions; Fosfomycin; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Peritoneal Dialysis; Peritonitis

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

One hospital's experience with procuring i.v. fosfomycin via an expanded-access protocol to treat a panresistant infection is described.. In mid-2014, a patient at a tertiary care institution had an infection caused by a gram-negative pathogen expressing notable drug resistance. Once it was determined by the infectious diseases (ID) attending physician that i.v. fosfomycin was a possible treatment for this patient, the ID pharmacist began the process of drug procurement. The research and ID pharmacists completed an investigational new drug (IND) application, which required patient-specific details and contributions from the ID physician. After obtaining approval of the IND, an Internet search identified a product vendor in the United Kingdom, who was then contacted to begin the drug purchasing and acquisition processes. Authorization of the transaction required signatures from key senior hospital administrators, including the chief financial officer and the chief operating officer. Approximately 6 days after beginning the acquisition process, the research pharmacist arranged for the wholesaler to expedite product delivery. The ID pharmacist contacted the wholesaler's shipping company at the U.S. Customs Office, providing relevant contact information to ensure that any unexpected circumstances could be quickly addressed. The product arrived at the U.S. Customs Office 8 days after beginning the acquisition process and was held in the U.S. Customs Office for 2 days. The patient received the first dose of i.v. fosfomycin 13 days after starting the expanded-access protocol process.. I.V. fosfomycin was successfully procured through an FDA expanded-access protocol by coordinating efforts among ID physicians, pharmacists, and hospital executives.

Topics: Administration, Intravenous; Anti-Bacterial Agents; Compassionate Use Trials; Drug Resistance, Bacterial; Drugs, Investigational; Fosfomycin; Gram-Negative Bacterial Infections; Humans; Investigational New Drug Application; Pharmacists; Pharmacy Service, Hospital; United States; United States Food and Drug Administration

Sphingomonas paucimobilis is an aerobic, oxidase-positive, yellow-pigmented, non-fermentative, Gram-negative opportunistic pathogen that rarely causes infections in humans. It is commonly found in nosocomial environments and, despite its low clinical virulence, it can be responsible for several different infections especially among patients with underlying disease. Here we describe a clinical case of a 46-year-old male paraplegic patient with a history of neurogenic bladder due to insulin-dependent diabetes mellitus and renal failure who was admitted to the urology clinic of a university hospital in Kirsehir, Turkey, with the complaints of urinary tract infection (UTI) including fever, chills, dysuria, abdominal and back pain. The urine culture was positive for Sphingomonas paucimobilis identified by the Vitek-2 system and the patient was successfully treated with oral co-trimoxazole 800/160 mg twice a day for ten days associated to cefixime and fosfomycin. A literature review of UTIs associated to Sphingomonas paucimobilis is reported as well.

Topics: Anti-Bacterial Agents; Cefixime; Community-Acquired Infections; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Disease Susceptibility; Drug Therapy, Combination; Fosfomycin; Gram-Negative Bacterial Infections; Humans; Kidney Failure, Chronic; Male; Middle Aged; Opportunistic Infections; Paraplegia; Recurrence; Sphingomonas; Trimethoprim, Sulfamethoxazole Drug Combination; Turkey; Urinary Bladder, Neurogenic; Urinary Tract Infections

The aim of this study was to evaluate the in vitro susceptibility of MDR gram-negatives bacteria to old drugs such as polymyxin B, minocycline and fosfomycin and new drugs such as tigecycline.. One hundred and fifty-three isolates from 4 Brazilian hospitals were evaluated. Forty-seven Acinetobacter baumannii resistant to carbapenens harboring adeB, blaOxA23, blaOxA51, blaOxA143 and blaIMP genes, 48 Stenotrophomonas maltophilia including isolates resistant to levofloxacin and/or trimethoprim-sulfamethoxazole harboring sul-1, sul-2 and qnrMR and 8 Serratia marcescens and 50 Klebsiella pneumoniae resistant to carbapenens harboring blaKPC-2 were tested to determine their minimum inhibitory concentrations (MICs) by microdilution to the following drugs: minocycline, ampicillin-sulbactam, tigecycline, and polymyxin B and by agar dilution to fosfomycin according with breakpoint criteria of CLSI and EUCAST (fosfomycin). In addition, EUCAST fosfomycin breakpoint for Pseudomonas spp. was applied for Acinetobacter spp and S. maltophilia, the FDA criteria for tigecycline was used for Acinetobacter spp and S. maltophilia and the Pseudomonas spp polymyxin B CLSI criterion was used for S. maltophilia.. Tigecycline showed the best in vitro activity against the MDR gram-negative evaluated, followed by polymyxin B and fosfomycin. Polymyxin B resistance among K. pneumoniae was detected in 6 isolates, using the breakpoint of MIC > 8 ug/mL. Two of these isolates were resistant to tigecycline. Minocycline was tested only against S. maltophilia and A. baumannii and showed excellent activity against both.. Fosfomycin seems to not be an option to treat infections due to the A. baumannii and S. maltophilia isolates according with EUCAST breakpoint, on the other hand, showed excellent activity against S. marcescens and K. pneumoniae.

Topics: Anti-Bacterial Agents; Drug Resistance, Multiple, Bacterial; Fosfomycin; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests; Minocycline; Polymyxin B; Tigecycline

This study describes the population pharmacokinetics of fosfomycin in critically ill patients. In this observational study, serial blood samples were taken over several dosing intervals of intravenous fosfomycin treatment. Blood samples were analyzed using a validated liquid chromatography-tandem mass spectrometry technique. A population pharmacokinetic analysis was performed using nonlinear mixed-effects modeling. Five hundred fifteen blood samples were collected over one to six dosing intervals from 12 patients. The mean (standard deviation) age was 62 (17) years, 67% of patients were male, and creatinine clearance (CLCR) ranged from 30 to 300 ml/min. A two-compartment model with between-subject variability on clearance and volume of distribution of the central compartment (Vc) described the data adequately. Calculated CLCR was supported as a covariate on fosfomycin clearance. The mean parameter estimates for clearance on the first day were 2.06 liters/h, Vc of 27.2 liters, intercompartmental clearance of 19.8 liters/h, and volume of the peripheral compartment of 22.3 liters. We found significant pharmacokinetic variability for fosfomycin in this heterogeneous patient sample, which may be explained somewhat by the observed variations in renal function.

Topics: Aged; Anti-Bacterial Agents; APACHE; Biological Availability; Critical Illness; Drug Administration Schedule; Female; Fosfomycin; Gram-Negative Bacterial Infections; Gram-Positive Bacterial Infections; Greece; Humans; Intensive Care Units; Male; Middle Aged; Models, Statistical; Multiple Organ Failure; Opportunistic Infections

Topics: Anti-Bacterial Agents; Fosfomycin; Gram-Negative Bacterial Infections; Humans; Male; Prostate; Prostatitis

Multidrug-resistant gram-negative bacterial (MDR-GNB) infections of the prostate are an increasing problem worldwide, particularly complicating transrectal ultrasound (TRUS)-guided prostate biopsy. Fluoroquinolone-based regimens, once the mainstay of many protocols, are increasingly ineffective. Fosfomycin has reasonable in vitro and urinary activity (minimum inhibitory concentration breakpoint ≤64 µg/mL) against MDR-GNB, but its prostatic penetration has been uncertain, so it has not been widely recommended for the prophylaxis or treatment of MDR-GNB prostatitis.. In a prospective study of healthy men undergoing a transurethral resection of the prostate for benign prostatic hyperplasia, we assessed serum, urine, and prostatic tissue (transition zone [TZ] and peripheral zone [PZ]) fosfomycin concentrations using liquid chromatography-tandem mass spectrometry, following a single 3-g oral fosfomycin dose within 17 hours of surgery.. Among the 26 participants, mean plasma and urinary fosfomycin levels were 11.4 ± 7.6 µg/mL and 571 ± 418 µg/mL, 565 ± 149 minutes and 581 ± 150 minutes postdose, respectively. Mean overall prostate fosfomycin levels were 6.5 ± 4.9 µg/g (range, 0.7-22.1 µg/g), with therapeutic concentrations detectable up to 17 hours following the dose. The mean prostate to plasma ratio was 0.67 ± 0.57. Mean concentrations within the TZ vs PZ prostate regions varied significantly (TZ, 8.3 ± 6.6 vs PZ, 4.4 ± 4.1 µg/g; P = .001). Only 1 patient had a mean prostatic fosfomycin concentration of <1 µg/g, whereas the majority (70%) had concentrations ≥4 µg/g.. Fosfomycin appears to achieve reasonable intraprostatic concentrations in uninflamed prostate following a single 3-g oral dose, such that it may be a potential option for prophylaxis pre-TRUS prostate biopsy and possibly for the treatment of MDR-GNB prostatitis. Formal clinical studies are now required.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anti-Bacterial Agents; Chromatography, Liquid; Fosfomycin; Gram-Negative Bacterial Infections; Humans; Male; Middle Aged; Prospective Studies; Prostate; Prostatitis; Serum; Tandem Mass Spectrometry; Urine

The amikacin-fosfomycin inhalation system (AFIS) is a combination of 2 antibiotics and an in-line nebulizer delivery system that is being developed for adjunctive treatment of pneumonia caused by Gram-negative organisms in patients on mechanical ventilation. AFIS consists of a combination of amikacin and fosfomycin solutions at a 5:2 ratio (amikacin, 3 ml at 100 mg/ml; fosfomycin, 3 ml at 40 mg/ml) and the PARI Investigational eFlow Inline System. In this antibiotic potentiation study, the antimicrobial activities of amikacin and fosfomycin, alone and in a 5:2 combination, were assessed against 62 Gram-negative pathogens from a worldwide antimicrobial surveillance collection (SENTRY). The amikacin MICs for 62 isolates of Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae were ≥32 μg/ml (intermediate or resistant according to the Clinical and Laboratory Standards Institute [CLSI]; resistant according to the European Committee on Antimicrobial Susceptibility Testing [EUCAST]). Each isolate was tested against amikacin (0.25 to 1,024 μg/ml), fosfomycin (0.1 to 409.6 μg/ml), and amikacin-fosfomycin (at a 5:2 ratio) using CLSI reference agar dilution methods. The median MIC values for amikacin and fosfomycin against the 62 isolates each decreased 2-fold with the amikacin-fosfomycin (5:2) combination from that with either antibiotic alone. Interactions between amikacin and fosfomycin differed by isolate and ranged from no detectable interaction to high potentiation. The amikacin-fosfomycin (5:2) combination reduced the amikacin concentration required to inhibit all 62 isolates from >1,024 to ≤ 256 μg/ml and reduced the required fosfomycin concentration from 204.8 to 102.4 μg/ml. These results support continued development of the amikacin-fosfomycin combination for aerosolized administration, where high drug levels can be achieved.

Topics: Acinetobacter baumannii; Amikacin; Anti-Bacterial Agents; Drug Resistance, Bacterial; Drug Synergism; Fosfomycin; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Respiratory Tract Infections

To determine the in vitro activity of antibiotics, including arbekacin, cefminox, fosfomycin and biapenem which are all still unavailable in India, against Gram-negative clinical isolates.. We prospectively collected and tested all consecutive isolates of Escherichia coli, Klebsiella spp., Pseudomonas aeruginosa and Acinetobacter spp. from blood, urine and sputum samples between March and November 2012. The minimum inhibition concentration (MIC) of 16 antibiotics was determined by the broth micro-dilution method.. Overall 925 isolates were included; 211 E. coli, 207 Klebsiella spp., 153 P. aeruginosa, and 354 Acinetobacter spp. The MIC50 and MIC90 were high for cefminox, biapenem and arbekacin for all pathogens but interpretative criteria were not available. The MIC50 was categorized as susceptible for a couple of antibiotics, including piperacillin/tazobactam, carbapenems and amikacin, for E. coli, Klebsiella spp. and P. aeruginosa. However, for Acinetobacter spp., the MIC50 was categorized as susceptible only for colistin. On the other hand, fosfomycin was the only antibiotic that inhibited 90% of E. coli and Klebsiella spp. isolates, while 90% of P. aeruginosa isolates were inhibited only by colistin. Finally, 90% of Acinetobacter spp. isolates were not inhibited by any antibiotic tested.. Fosfomycin and colistin might be promising antibiotics for the treatment of infections due to E. coli or Klebsiella spp. and P. aeruginosa, respectively, in India; however, clinical trials should first corroborate the in vitro findings. The activity of tigecycline should be evaluated, as this is commonly used as last-resort option for the treatment of multidrug-resistant Acinetobacter infections.

Topics: Acinetobacter; Anti-Bacterial Agents; Cephamycins; Dibekacin; Drug Resistance, Multiple, Bacterial; Escherichia coli; Fosfomycin; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; India; Klebsiella; Microbial Sensitivity Tests; Prospective Studies; Pseudomonas aeruginosa; Thienamycins

To determine the in vitro activity of Fosfomycin tromethamine against extended spectrum beta-lactamase producing uropathogens.. Experimental study.. Department of Microbiology, Armed Forces Institute of Pathology, Rawalpindi, from October 2011 to October 2012.. A total of 381 culture positive ESBL producing isolates from 2400 urine samples submitted over a period of one year were included in this study. Identification of isolates was done by standard biochemical profile of the organisms. The antimicrobial susceptibility of culture positive isolates was performed by disk diffusion method as recommended by Clinical Laboratory Standard Institute guidelines (CLSI).. The antimicrobial activity of Fosfomycin to various isolates revealed that 93% of E. coli, 64% Klebsiella spp. 50% Proteus spp. 75% Enterobacter cloacae, 100% Citrobacter freundii, 100% Burkholderia spp. 100% Serratia spp. and 50% Stenotrophomonas maltophilia were susceptible to this chemical compound.. Fosfomycin showed excellent effectiveness to most of the common ESBL producing bacteria such as E. coli, Klebsiella and Proteus spp.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; beta-Lactamases; Child; Child, Preschool; Drug Resistance, Bacterial; Escherichia coli Infections; Female; Fosfomycin; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Infant; Klebsiella Infections; Klebsiella pneumoniae; Male; Microbial Sensitivity Tests; Middle Aged; Urinary Tract; Urinary Tract Infections; Uropathogenic Escherichia coli; Young Adult

The aim of this study was to evaluate the in vitro activities of antimicrobial agents including fosfomycin tromethamine against Gram-negative isolates recovered from urine samples.. A total of 2334 strains (1562 Escherichia coli, 509 Klebsiella spp, 85 Proteus spp, 75 Pseudomonas spp, 45 Enterobacter spp, 37 Acinetobacter baumannii, 8 Citrobacter spp, 7 Morganella morganii, and 6 Serratia spp) were identified by VITEK 2 during the study period, November 2008 to June 2012. Antimicrobial susceptibilities of the strains were also evaluated using the Kirby-Bauer disk diffusion method, in accordance with the Clinical and Laboratory Standards Institute guidelines.. Overall, 2160 (92.5%) of the isolates tested were susceptible to fosfomycin tromethamine. Higher resistance rates were observed among inpatients compared to outpatients. Resistance rates by strain were: 2.0% for E. coli, 4.4% for Enterobacter spp, 6.9% for Klebsiella spp, 9.4% for Proteus spp, 48.6% for A. baumannii, 56.0% for Pseudomonas spp, and 100% for Morganella morganii. All Serratia spp and Citrobacter spp strains were susceptible. Extended-spectrum beta-lactamase (ESBL)-producing isolates displayed higher fosfomycin resistance rates than negative strains (19.2% vs. 2.9%). The highest in vitro activity was detected for amikacin, piperacillin-tazobactam, and imipenem for all strains including ESBL-producers.. Regardless of ESBL production, the excellent activity of fosfomycin against E. coli, Enterobacter spp, Serratia spp, and Citrobacter spp, indicates that the drug is a valuable therapeutic option for urinary tract infections, even those with co-trimoxazole- and ciprofloxacin-resistant isolates, but not in ESBL-producing Klebsiella spp, Pseudomonas spp, A. baumannii, and Proteus spp. Further studies should be carried out to determine the in vivo drug activity among Enterobacteriaceae other than E. coli.

Topics: Anti-Bacterial Agents; Community-Acquired Infections; Cross Infection; Drug Resistance, Bacterial; Fosfomycin; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests; Urinary Tract Infections

Fosfomycin is an antimicrobial commonly used in uncomplicated urinary tract infections. The microbiological effectiveness of fosfomycin against nonurinary Gram-negative isolates has not been widely investigated. The aim of this study was to evaluate the in vitro activity of fosfomycin against Gram-negative nonurinary isolates in a region of Greece where considerable antimicrobial resistance has been detected.. Data were retrieved from the microbiological library of the University Hospital of Heraklion, Crete. We retrospectively examined the susceptibility of all Gram-negative nonurinary isolates to fosfomycin, collected over 1 year (January-December 2008).. A total of 594 nonurinary Gram-negative isolates were examined. Susceptibility testing was performed for 270 (45.4%) Enterobacteriaceae, 209 (35.2%) Gram-negative nonfermentative bacilli and 115 (19.4%) other Gram-negative bacteria. In total, 385 (64.8%) were susceptible to fosfomycin. Specifically, all Escherichia coli, Proteus mirabilis and Salmonella species isolates were susceptible. Additionally, 73 out of 94 (77.7%) Klebsiella pneumoniae (including carbapenem-resistant strains), 22 out of 32 (68.8%) Enterobacter species and 51 out of 79 (64.5%) Pseudomonas aeruginosa isolates were susceptible to fosfomycin. Susceptibility was highest amongst isolates (45 of 61; 73.8%) taken from outpatients and lowest for intensive care unit isolates (78 of 161; 48.4%). Isolates originating from the pediatric wards exhibited higher susceptibility (45 of 63; 71.4%) than isolates originating from other departments (340 of 531; 64%).. In a region with relatively high levels of antimicrobial resistance, fosfomycin seems to exhibit good levels of in vitro activity against Gram-negative nonurinary isolates. These data justify further evaluation of its potential clinical effectiveness.

Topics: Anti-Bacterial Agents; Fosfomycin; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Greece; Humans; Microbial Sensitivity Tests; Retrospective Studies

Topics: Anti-Bacterial Agents; Bacteriuria; Enterococcus; Escherichia coli; Female; Follow-Up Studies; Fosfomycin; Gram-Negative Bacterial Infections; Gram-Positive Bacterial Infections; Humans; Proteus

The aim of this study was to reassess the activity of fosfomycin against recently isolated uropathogens circulating in Italy and to evaluate the effect of fosfomycin resistance on the expression of several virulence traits using the rare mutant strains. In vitro activity of fosfomycin was evaluated using 441 Gram-negative organisms isolated from patients with uncomplicated urinary tract infections (UTIs). Fosfomycin was the most active antibiotic against Escherichia coli (99% susceptibility). The activity against Proteus mirabilis was more potent than that of co-trimoxazole and nitrofurantoin (87.5, 67 and 0% susceptibility, respectively). The other microorganisms, accounting for about 7% of all pathogens tested, showed variable susceptibilities to fosfomycin. Compared with susceptible strains, fosfomycin-resistant mutants showed a reduced rate of growth and were impaired in their ability to adhere to uroepithelial cells and to urinary catheters. They were also more resistant to UV irradiation and to phage T7 and showed diminished rates of colicin synthesis and transfer of plasmids.

Topics: Aerobiosis; Anti-Bacterial Agents; Bacterial Adhesion; Bacteriophage T7; Bile Acids and Salts; Catheterization; Cell Division; Cells, Cultured; Colicins; Drug Resistance, Bacterial; Epithelial Cells; Fosfomycin; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests; Plasmids; Ultraviolet Rays; Urinary Tract Infections; Urine

Topics: Aged; Anti-Bacterial Agents; Female; Follow-Up Studies; Fosfomycin; Gram-Negative Bacterial Infections; Humans; Moraxella; Time Factors; Urinary Tract Infections; Urine

To investigate at what time the peak level should be determined under conventional thrice daily (t.i.d.) administration of the aminoglycoside netilmicin and to study its serum concentrations under once daily (od) treatment to define the required daily dose and to gain information about convenient drug monitoring.. The design of the study was a consecutive sample trial.. The study took place in a university hospital.. 41 intubated patients of a surgical ICU who received netilmicin as a short-term infusion over 30 min for life-threatening infections were included in the study.. In 21 patients netilmicin was administered t.i.d. The virtual peak levels which had been determined by pharmacokinetic dosage calculation were compared with the serum concentrations obtained directly after the administration as well as after 15, 30, 60 and 180 min. In 20 patients the netilmicin serum concentrations during od treatment were determined directly before and immediately after the application as well as 0.5, 1, 3, 7 and 12 h later. To achieve a virtual peak level of 25 mg/l and a trough level of 0.5 mg/l individual adjustment of the dosage based on pharmacokinetic calculations was performed.. In t.i.d. treatment the serum concentration measured after 30 min was closest to the virtual peak level; therefore, this is the best time to determine the peak level. In od treatment the required daily dose was 7.86 mg/kg body weight (median) in patients with normal renal function. During od dosing the trough level was extremely important in drug monitoring, whereas determination of the high peak level was of doubtful value.. The peak level should be determined during t.i.d. administration at 30 min. In od treatment the initial daily dose should be 7 mg/kg body weight; in drug monitoring the trough level is very important.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Cefotaxime; Cross Infection; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fosfomycin; Gram-Negative Bacterial Infections; Humans; Infusions, Intravenous; Intensive Care Units; Male; Metabolic Clearance Rate; Metronidazole; Middle Aged; Netilmicin; Piperacillin; Respiration, Artificial; Staphylococcal Infections; Teicoplanin