minocycline and Klebsiella-Infections

The spread of carbapenemase-producing K. pneumoniae (CPKP) has become a significant problem worldwide. Combination therapy for CPKP is encouraging, but polymyxin resistance to many antibiotics is hampering effective treatment. Combination therapy with three or more antibiotics is being increasingly reported, therefore we performed a systematic review of triple combination cases in an effort to evaluate their clinical effectiveness for CPKP infections.. The PubMed database was searched to identify all published clinical outcomes of CPKP infections treated with triple combination therapy. Articles were stratified into two tiers depending on the level of clinical detail provided. A tier 1 study included: antibiotic regimen, regimen-specific outcome, patient status at onset of infection, and source of infection. Articles not reaching these criteria were considered tier 2.. Thirty-three studies were eligible, 23 tier 1 and ten tier 2. Among tier 1 studies, 53 cases were included in this analysis. The most common infection was pneumonia (31%) followed by primary or catheter-related bacteremia (21%) and urinary tract infection (17%). Different combinations of antibiotic classes were utilized in triple combinations, the most common being a polymyxin (colistin or polymyxin B, 86.8%), tigecycline (73.6%), aminoglycoside (43.4%), or carbapenem (43.4%). Clinical and microbiological failure occurred in 14/39 patients (35.9%) and 22/42 patients (52.4%), respectively. Overall mortality for patients treated with triple combination therapy was 35.8% (19/53 patients).. Triple combination therapy is being considered as a treatment option for CPKP. Polymyxin-based therapy is the backbone antibiotic in these regimens, but its effectiveness needs establishing in prospective clinical trials.

Topics: Aminoglycosides; Anti-Bacterial Agents; Bacteremia; Bacterial Proteins; beta-Lactamases; Carbapenems; Colistin; Drug Combinations; Female; Humans; Klebsiella Infections; Klebsiella pneumoniae; Male; Microbial Sensitivity Tests; Minocycline; Pneumonia; Polymyxin B; Polymyxins; Tigecycline; Treatment Outcome; Urinary Tract Infections

Carbapenem-resistant organisms are increasingly common worldwide, particularly in India and are associated with high mortality rates especially in patients with severe infection such as bacteremia. Existing drugs such as carbapenems and polymyxins have a number of disadvantages, but remain the mainstay of treatment. The tetracycline class of antibiotics was first produced in the 1940s. Minocycline, tetracycline derivative, although licensed for treatment of wide range of infections, has not been considered for treatment of multidrug-resistant organisms until recently and needs further in vivo studies. Tigecycline, a derivative of minocycline, although with certain disadvantages, has been frequently used in the treatment of carbapenem-resistant organisms. In this article, we review the properties of minocycline and tigecycline, the common mechanisms of resistance, and assess their role in the management of carbapenem-resistant organisms.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Anti-Bacterial Agents; Carbapenems; Case-Control Studies; Drug Resistance, Multiple, Bacterial; Genes, MDR; Humans; India; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Minocycline; Tigecycline

The wide dissemination of carbapenemase producing K. pneumoniae (KPC-Kp) has caused a public health crisis of global dimensions, due to the serious infections in hospitalized patients associated with high mortality. In 2014, we aim to review clinical data on KPC-Kp at a time when a pro-active strategy (combating the problem before it is established) is no longer useful, focusing on epidemiology, patient risk profile, infection control, digestive tract colonization and treatment issues such as the role of carbapenems or carbapenem sparing strategies, colistin and resistance, dual carbapenem administration and the role of tigecycline. All these issues are illustrated prospectively to provide a forum for a Consensus strategy when not only intensive care units but also medical and surgical wards are affected by the epidemics.

Topics: Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Carbapenems; Colistin; Cross Infection; Drug Therapy, Computer-Assisted; Humans; Infection Control; Klebsiella Infections; Klebsiella pneumoniae; Minocycline; Risk Factors; Tigecycline

Klebsiella pneumoniae producing KPC-type carbapenemase causes severe nosocomial infection at a high mortality rate. Nosocomial pneumonia in particular is associated with high mortality, likely due to the unfavorable pulmonary pharmacokinetics of the antibiotics used against this agent. Therefore, early and accurate microbiological identification and susceptibility evaluation are crucial in order to optimize antibiotic therapy. We report a case of ventilator-associated pneumonia caused by colistin-resistant K. pneumoniae producing KPC-type carbapenemase treated using a carbapenem-sparing therapy and tailored according to the serum procalcitonin concentration in order to limit the duration of antibiotic therapy.

Topics: Adult; Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Calcitonin; Calcitonin Gene-Related Peptide; Colistin; Cross Infection; Drug Resistance, Bacterial; Drug Therapy, Combination; Equipment Contamination; Fosfomycin; Humans; Klebsiella Infections; Klebsiella pneumoniae; Male; Minocycline; Pneumonia, Bacterial; Protein Precursors; Tigecycline; Treatment Outcome; Ventilators, Mechanical

Here we review the effectiveness and safety of high-dose tigecycline (200mg daily). A systematic search was performed in PubMed and Scopus databases as well as of abstracts presented at scientific conferences. Eight studies (263 patients; 58% critically ill) were included, comprising one randomised controlled trial (RCT), four non-randomised cohorts and three case reports. Klebsiella pneumoniae was the most commonly isolated pathogen (reported in seven studies). In the RCT, response in the clinically evaluable patients was 85.0% (17/20) in the 100mg every 12h (q12h) group and 69.6% (16/23) in the 75mg q12h group (P=0.4). More episodes of diarrhoea, treatment-related nausea and vomiting developed in the high-dose group (14.3% vs. 2.8%, 8.6% vs. 2.8% and 5.7% vs. 2.8%, respectively; P>0.05 for all comparisons). Three (8.6%) and 7 (19.6%) patients died in the 200mg and 150mg daily dose groups, respectively. The cohort studies enrolled patients with severe infections, including ventilator-associated pneumonia and complicated intra-abdominal infections. Mortality with high-dose tigecycline (100mg q12h) in the cohort studies ranged from 8.3% to 26%; mortality in the low-dose groups (50mg q12h) ranged from 8% to 61% and depended on the severity of the underlying infection. There are limited available data regarding the effectiveness and safety of high-dose tigecycline. Most of the data come from critically ill patients with difficult-to-treat infections. Pharmacokinetic/pharmacodynamic properties of tigecycline suggest that high-dose regimens may be more effective than low-dose regimens. Candidates for administration of high-dose tigecycline should be also defined.

Topics: Adult; Aged; Anti-Bacterial Agents; Critical Illness; Drug Administration Schedule; Female; Humans; Intraabdominal Infections; Klebsiella Infections; Klebsiella pneumoniae; Male; Microbial Sensitivity Tests; Middle Aged; Minocycline; Pneumonia, Ventilator-Associated; Survival Analysis; Tigecycline; Treatment Outcome

The increasing incidence of carbapenem-resistant Klebsiella pneumoniae (CR-KP) fundamentally alters the management of patients at risk to be colonized or infected by such microorganisms. Owing to the limitation in efficacy and potential for toxicity of the alternative agents, many experts recommend using combination therapy instead of monotherapy in CR-KP-infected patients. However, in the absence of well-designed comparative studies, the best combination for each infection type, the continued role for carbapenems in combination therapy and when combination therapy should be started remain open questions. Herein, the authors revise current microbiological and clinical evidences supporting combination therapy for CR-KP infections to address some of these issues.

Topics: Aminoglycosides; Anti-Bacterial Agents; Carbapenems; Colistin; Drug Therapy, Combination; Fosfomycin; Humans; Klebsiella Infections; Klebsiella pneumoniae; Minocycline; Rifampin; Risk Factors; Tigecycline

Klebsiella pneumoniae carbapenemases (KPCs) were originally identified in the USA in 1996. Since then, these versatile β-lactamases have spread internationally among Gram-negative bacteria, especially K pneumoniae, although their precise epidemiology is diverse across countries and regions. The mortality described among patients infected with organisms positive for KPC is high, perhaps as a result of the limited antibiotic options remaining (often colistin, tigecycline, or aminoglycosides). Triple drug combinations using colistin, tigecycline, and imipenem have recently been associated with improved survival among patients with bacteraemia. In this Review, we summarise the epidemiology of KPCs across continents, and discuss issues around detection, present antibiotic options and those in development, treatment outcome and mortality, and infection control. In view of the limitations of present treatments and the paucity of new drugs in the pipeline, infection control must be our primary defence for now.

Topics: Aminoglycosides; Anti-Bacterial Agents; Bacteremia; Bacterial Proteins; beta-Lactamases; Colistin; Communicable Disease Control; Geography; Humans; Klebsiella Infections; Klebsiella pneumoniae; Minocycline; Tigecycline; Treatment Outcome

The emergence of Klebsiella pneumoniae carbapenemases (KPCs) producing bacteria has become a significant global public health challenge while the optimal treatment remains undefined. We performed a systematic review of published studies and reports of treatment outcomes of KPC infections using MEDLINE (2001-2011). Articles or cases were excluded if one of the following was fulfilled: no individual patient data provided, no treatment regimen specified, no treatment outcome specified, report of colonization, or greater than three antibiotics were used to treat the KPC infection. Data extracted included patient demographics, site of infection, organism, KPC subtype, antimicrobial therapy directed at KPC-infection, and treatment outcome. Statistical analysis was performed in an exploratory manner. A total of 38 articles comprising 105 cases were included in the analysis. The majority of infections were due to K. pneumoniae (89%). The most common site of infection was blood (52%), followed by respiratory (30%), and urine (10%). Forty-nine (47%) cases received monotherapy and 56 (53%) cases received combination therapy directed at the KPC-infection. Significantly more treatment failures were seen in cases that received monotherapy compared to cases who received combination therapy (49% vs 25%; p= 0.01). Respiratory infections were associated with higher rates of treatment failure with monotherapy compared to combination therapy (67% vs 29% p= 0.03). Polymyxin monotherapy was associated with higher treatment failure rates compared to polymyxin-based combination therapy (73% vs 29%; p= 0.02); similarly, higher treatment failure rates were seen with carbapenem monotherapy compared to carbapenem-based combination therapy (60% vs 26%; p= 0.03). Overall treatment failure rates were not significantly different in the three most common antibiotic-class combinations: polymyxin plus carbapenem, polymyxin plus tigecycline, polymyxin plus aminoglycoside (30%, 29%, and 25% respectively; p=0.6). In conclusion, combination therapy is recommended for the treatment of KPC infections; however, which combination of antimicrobial agents needs to be established in future prospective clinical trials.

Topics: Adult; Aged; Aminoglycosides; Anti-Bacterial Agents; Bacteremia; Bacterial Proteins; beta-Lactamases; Carbapenems; Drug Combinations; Female; Humans; Klebsiella Infections; Klebsiella pneumoniae; Male; Microbial Sensitivity Tests; Middle Aged; Minocycline; Polymyxins; Tigecycline; Treatment Outcome

Bacteria producing Klebsiella pneumoniae carbapenemases (KPCs) are rapidly emerging as a cause of multidrug-resistant infections worldwide. Bacterial isolates harbouring these enzymes are capable of hydrolysing a broad spectrum of beta-lactams including the penicillins, cephalosporins, carbapenems and monobactam. Detection of isolates harbouring carbapenemases can be inconsistent using automated systems, often requiring subsequent confirmatory tests. Phenotypic methods utilizing boronic acid disc tests have demonstrated promising results and appear practical for use in clinical microbiology laboratories. Treatment of infection caused by KPC bacteria is particularly worrisome as the carbapenems are often agents of the last resort for resistant Gram-negative infections. The optimal treatment of infections caused by KPC bacteria is not well established and clinical outcome data remain sparse. We reviewed the current literature regarding clinical outcomes following KPC infections, with a specific effort to summarize the clinical data available for specific antimicrobial agents. A total of 15 papers involving 55 unique patient cases were reviewed. While the total number of patients is relatively small, some useful insights could still be gathered to guide clinicians in the management of KPC infections. Tigecycline and the aminoglycosides were associated with positive outcomes in the majority of cases. Clinical success rates were low when the polymyxins were used as monotherapy, but were much higher when they were used in combination. Studies examining combination therapy and well-controlled clinical trials are needed to ascertain the optimal treatment of infections caused by KPC bacteria.

Topics: Aminoglycosides; Anti-Bacterial Agents; Bacterial Proteins; beta-Lactam Resistance; beta-Lactamases; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Humans; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Minocycline; Polymyxins; Tigecycline; Treatment Outcome

Clinical treatment for blaKPC-positive Klebsiella pneumoniae isolates is challenging because the recommended antibiotic options are limited and are extraordinarily expensive. This study aimed to explore a new therapy for infection caused by KPC-producing K. pneumoniae.. Patients with blaKPC-positive K. pneumoniae infection, were prospectively screened and were categorised into two groups: patients in the study group received a combination-based therapy of cefepime and amoxicillin/clavulanic acid and the control group received tigecycline-based therapy. The pathogen clearance rate, 28-day mortality and cost of the antibiotic treatment were compared between the two groups. Moreover, the checkerboard microdilution method was performed to determine the synergy between cefepime and amoxicillin/clavulanic acid in vitro.. Twenty-six and 25 cases were enrolled in the study and control groups. The mortality and the overall pathogen clearance rate showed no significant differences (P=0.311 and P=0.447). Both the total cost and the portion of the cost not covered by insurance were higher for the control group compared to the study group (both P<0.001). Consistently, synergy (65.4%) and partial synergy (26.9%) were the main effects.. In contrast to the currently recommended tigecycline-based therapy, cefepime and amoxicillin/clavulanic acid combination was an effective and economical option to KPC-KP infection in China.

Topics: Adult; Aged; Amoxicillin-Potassium Clavulanate Combination; Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Cefepime; Cephalosporins; Drug Therapy, Combination; Female; Humans; Klebsiella Infections; Klebsiella pneumoniae; Male; Middle Aged; Minocycline; Tigecycline

Clinical isolates of Klebsiella pneumoniae were tested for a correlation between tigecycline MIC and expression of ramA by using real-time PCR. At MICs of 4 and 8 microg/ml, the expression of ramA was statistically significantly different from MICs of 2 microg/ml or less, supporting the tigecycline susceptibility breakpoint of

Topics: Anti-Bacterial Agents; Bacterial Proteins; Drug Resistance, Multiple, Bacterial; Humans; Klebsiella Infections; Klebsiella pneumoniae; Membrane Transport Proteins; Microbial Sensitivity Tests; Minocycline; Polymerase Chain Reaction; Tigecycline

The continuous emergence of tigecycline-resistant bacteria is undermining the effectiveness of clinical tigecycline. Environmental tigecycline-resistant bacteria have the potential to infect humans through human-environment interactions. Furthermore, the mechanisms of tigecycline resistance in Enterobacterales are complicated. In this study, we aimed to investigate the additional pathways of tigecycline resistance in environmental Enterobacterales besides tet(X) and tmexCD-toprJ. During the years 2019-2020, tigecycline-resistant Enterobacterales (n = 45) negative for tet(X) and tmexCD-toprJ were recovered from 328 different samples from two slaughterhouses. Five distinct bacteria species were identified, of which Klebsiella pneumoniae (n = 37) was the most common, with K. pneumoniae ST45 and ST35 being the predominant clones. Tigecycline resistance determinants analysis showed that tet(A) mutations and ramR inactivation were the most prevalent mechanisms for tigecycline resistance in the 45 strains. Two known tet(A) variants (type 1 and tet(A)-v) and one novel tet(A) variant (type 3) were identified. Cloning experiments confirmed that the novel type 3 tet(A) could enhance the 4-fold MIC for tigecycline. Inactivation of ramR was induced by either point mutations or indels of sequences, which could result in the overexpression of AcrAB pump genes leading to tigecycline resistance. In addition, all isolates were resistant to a wide range of antimicrobials and carried various resistance genes. These findings enriched the epidemiological and genomic characterizations of tigecycline-resistant Enterobacterales from slaughterhouses and contributed to a better understanding of the complex mechanisms of tigecycline resistance in environmental bacteria.

Topics: Abattoirs; Animals; Anti-Bacterial Agents; Bacteria; Drug Resistance, Bacterial; Gammaproteobacteria; Genomics; Humans; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Minocycline; Swine; Tigecycline

The increasing incidence of tigecycline resistance undoubtedly constitutes a serious threat to global public health. The combination therapies had become the indispensable strategy against this threat. Herein, 11 clinical tigecycline-resistant

Topics: Anti-Bacterial Agents; Azepines; Drug Resistance, Bacterial; Humans; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Minocycline; Naphthalenes; Tigecycline

Tigecycline is an antibacterial agent restricted for use against carbapenem-resistant Klebsiella pneumoniae (CRKP). This study aimed to identify the tigecycline resistance mechanism in clinical CRKP isolates obtained from a 60-year-old femalepatient during tigecycline treatment.. Three K. pneumoniae isolates obtained during tigecycline treatment were subjected to antimicrobial susceptibility testing, pulsed-field gel electrophoresis (PFGE), multilocus sequence typing, and whole-genome sequencing and analysis. The function of ramR was confirmed by gene complementation.. Three K. pneumoniae isolates (W814, W112 and W113) were collected from the patient on Days 0, 10 and 13, respectively, of ongoing tigecycline treatment. Antimicrobial susceptibility testing showed resistance to all antibiotics except tigecycline and ceftazidime/avibactam. The tigecycline minimum inhibitory concentration (MIC) for strains W814 and W112 was 4 mg/L compared with 16 mg/L for strain W113. The three strains belonged to sequence type 11 (ST11) and had a similar PGFE pattern. Insertion sequence (IS) element ISKpn18 in ramR was identified in strain W113. A parent strain transformed with plasmid pCR2.1-Hyg carrying ramR enhanced tigecycline susceptibility, thus confirming that a loss-of-function insertion in ramR contributes to tigecycline resistance.. ISKpn18 insertion in the ramR gene contributes to the tigecycline resistance mechanism in the isolated K. pneumoniae strains.

Topics: Carbapenems; Drug Resistance, Bacterial; Female; Humans; Klebsiella Infections; Klebsiella pneumoniae; Middle Aged; Minocycline; Tigecycline

Lack of effective treatment for multidrug-resistant Klebsiella pneumoniae (MDR-Kp) necessitates finding and optimising combination therapies of old antibiotics. The aims of this study were to quantify the combined effect of polymyxin B and minocycline by building an in silico semi-mechanistic pharmacokinetic/pharmacodynamic (PKPD) model and to predict bacterial kinetics when exposed to the drugs alone and in combination at clinically achievable unbound drug concentration-time profiles. A clinical K. pneumoniae strain resistant to polymyxin B [minimum inhibitory concentration (MIC) = 16 mg/L] and minocycline (MIC = 16 mg/L) was selected for extensive in vitro static time-kill experiments. The strain was exposed to concentrations of 0.0625-48 × MIC, with seven samples taken per experiment for viable counts during 0-28 h. These observations allowed the development of the PKPD model. The final PKPD model included drug-induced adaptive resistance for both drugs. Both the minocycline-induced bacterial killing and resistance onset rate constants were increased when polymyxin B was co-administered, whereas polymyxin B parameters were unaffected. Predictions at clinically used dosages from the developed PKPD model showed no or limited antibacterial effect with monotherapy, whilst combination therapy kept bacteria below the starting inoculum for >20 h at high dosages [polymyxin B 2.5 mg/kg + 1.5 mg/kg every 12 h (q12h); minocycline 400 mg + 200 mg q12h, loading + maintenance doses]. This study suggests that polymyxin B and minocycline in combination may be of clinical benefit in the treatment of infections by MDR-Kp and for isolates that are non-susceptible to either drug alone.

Topics: Anti-Bacterial Agents; Drug Resistance, Multiple, Bacterial; Drug Synergism; Drug Therapy, Combination; Humans; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Minocycline; Models, Biological; Polymyxin B

Intracranial infections, especially multidrug-resistant (MDR) bacterial meningitis, are one of the most severe complications after craniotomy and may greatly impact patient outcomes.. We report a case of severe MDR Klebsiella pneumonia meningitis after craniotomy that was treated with three different dosages of tigecycline (Pfizer, New York, NY, U.S.A.)via a combined intravenous (IV) and intracerebroventricular (ICV) administration. Here, we discuss the pharmacokinetics (PK) of a combined IV and ICV tigecycline administration for a patient with an intracranial infection after craniotomy.. In the present case, three different dosages of tigecycline were administered: 49 mg IV plus 1 mg ICV q12 h, 45 mg IV plus 5 mg ICV q12 h, 40 mg IV plus 10 mg ICV q12 h. The combined IV and ICV administration might improve CSF tigecycline concentrations, and in this case, the methods of administration were safe and effective.

Topics: Aged; Anti-Bacterial Agents; Craniotomy; Drug Resistance, Multiple, Bacterial; Humans; Infusions, Intravenous; Injections, Intraventricular; Klebsiella Infections; Klebsiella pneumoniae; Male; Meningitis, Bacterial; Microbial Sensitivity Tests; Minocycline; Postoperative Complications; Tigecycline

To evaluate the impact of high-dose (HD) carbapenem-based combination therapy on clinical outcome in patients with monomicrobial carbapenem-resistant Klebsiella pneumoniae (CR-KP) bloodstream-infection (BSI).. Post hoc analysis of all adult patients with CR-KP BSI who were treated with a combination antibiotic regimen, collected over a six-year period in six large Italian teaching hospitals. To control for confounding effects of HD carbapenem combination on 14-day mortality, a multivariate Cox regression analysis was performed. Due to imbalances between patients, a propensity score for receiving HD carbapenem was added to the model.. 595 patients with CR-KP BSI were analysed, 77% of isolates showed a carbapenem MIC ≥16 mg/L, 428 (71.9%) received HD carbapenem-based combination therapy. Overall, 127 patients (21.3%) died within 14 days after BSI onset. Multivariate analysis showed the Charlson comorbidity index (HR 1.31, 95%CI 1.20-1.43, P <0.001), septic shock at BSI onset (HR 3.14, 95%CI 2.19-4.50, P <0.001), and colistin-resistant strain (HR 1.52, 95%CI 1.02-2.24, P = 0.03) were independently associated with 14-day mortality, whereas admission to surgical ward (HR 0.44, 95%CI 0.25-0.78, P = 0.005) and HD carbapenem use (HR 0.69, 95%CI 0.47-1.00, P = 0.05) were protective factors. When adjusted for the propensity score, HD carbapenem use showed a greater protective effect (HR 0.64, 95%CI 0.43-0.95, P = 0.03). Stratifying the model for carbapenem MIC, the benefit of HD carbapenem was also observed for strains with carbapenem MIC ≥16 mg/L.. In patients receiving combination therapy for CR-KP BSI, the use of HD carbapenem seems to be associated with better outcome, even in the presence of high-level carbapenem resistance.

Topics: Aged; Bacteremia; Carbapenem-Resistant Enterobacteriaceae; Carbapenems; Colistin; Drug Resistance, Bacterial; Drug Therapy, Combination; Female; Gentamicins; Humans; Klebsiella Infections; Klebsiella pneumoniae; Male; Middle Aged; Minocycline; Propensity Score; Tertiary Care Centers; Tigecycline; Treatment Outcome

Pneumonia caused by carbapenemase-producing Klebsiella pneumoniae (CP-KP) are increasingly encountered in hospitals worldwide, causing high mortality due to lack of treatment options. The goal of this study was to assess the efficacy of tigecycline and minocycline for CP-KP hospital-acquired pneumonia (HAP) by using Monte Carlo simulation.. A total of 164 non-duplicated CP-KP strains were collected from sputum or blood in patients with HAP. The MICs for antimicrobials were determined by the agar dilution method. A 10,000-patient Monte Carlo Simulation based on a PK/PD model incorporating the MICs and population pharmacokinetic parameters were conducted to calculate probability of target attainment (PTA) at each MIC value and total cumulative fraction of response (CFR).. The susceptibility rate of tigecycline and minocycline were 79.9% and 41.5%, respectively. At recommended doses, an optimal PTA of 90% was obtained for treating HAP caused by CP-KP with MICs of tigecycline ≤0.5 mg/L or minocycline ≤4 mg/L. The CFR of tigecycline at the recommended dose and double dose (100 mg q12h) were 71.2% and 90.2%, respectively. The CFR of minocycline at recommended dose and double dose (200 mg q12h) was 53.4% and 77.2%, respectively.. The findings of this study suggest that the recommended dose of tigecycline was not effective in HAP caused by CP-KP, and a higher CFR indicating a better clinical efficacy can be gained by doubling the dose (100 mg q12h). minocycline (200 mg q12h) might be a potential alternative of tigecycline to against strains with MICs ≤ 8 mg/L.

Topics: Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Cross Infection; Humans; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Minocycline; Models, Statistical; Monte Carlo Method; Pneumonia, Bacterial; Sputum; Tigecycline

This study assessed the in vitro antibacterial activity of minocycline-aminoglycoside combination against Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae. Seventy non-duplicate clinical isolates of KPC-producing K. pneumoniae were collected from patients with bloodstream infections. The synergistic activity of minocycline-aminoglycoside combination was studied by the checkerboard method and time-kill assays in strains with different susceptibilities, and the mutant prevention concentration (MPC) and mutant selection window (MSW) of drugs alone and in combination were determined. The checkerboard method found this combination displayed synergistic and partial synergistic activity against aminoglycoside-susceptible isolates, but indifferent activity against aminoglycoside-resistant isolates. Time-kill assays further demonstrated strong synergistic and bactericidal effect of this combination existed against isolates which were susceptible to both drugs. But for resistant isolates, the time-kill assays showed no synergy. The MPCs of minocycline or aminoglycosides were 8- to 32-fold higher than the MICs, suggesting the MSWs of these drugs were quite wide. For the antibiotic combinations, the addition of 1×MIC concentration of amikacin or gentamicin could reduce the MPCs of minocycline by 4- to 16-fold. Generally, no mutants recovered in the plates containing 1×MIC concentration of minocycline and 2×MIC concentration of amikacin or gentamicin. In summary, these results suggest that minocycline-aminoglycoside combination can be an alternative for infections caused by KPC-producing K. pneumoniae because this combination displays strong synergistic and bactericidal activity in susceptible isolates, and can effectively prevent the emergence of resistant mutants. Further in vitro pharmacokinetic/pharmacodynamic studies and clinical trials should be performed to fully evaluate the efficacy of this drug combination.

Topics: Aminoglycosides; Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; Drug Synergism; Humans; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Minocycline

Carbapenem-resistant Klebsiella pneumoniae (CRKP) bloodstream infection (BSI) has become increasingly frequent threat recently, especially in the intensive care unit (ICU). High-dose tigecycline (TGC) regimen is proposed due to the limitation of treatment options. We investigated the efficacy and safety of high-dose TGC combination regimens for treating CRKP BSI. Furthermore, the risk factors for mortality were also determined.This was a single center retrospective cohort study conducted from 2014 to 2016. A total of 40 patients with nosocomial CRKP BSI admitted to the ICU were included; they were classified into two groups according to the treatment regimens with high-dose TGC (HD group) or not (non-HD group). In-hospital mortality rates and microbiologic responses from both groups were reviewed and compared. Besides, the survival and non-survival groups were compared to identify the risk factors of mortality.Twenty-three patients constituted the HD group (high-dosage TGC regimen was administered as 200 mg loading dose followed by 100 mg every 12 h) and 17 patients constituted the non-HD group (standard dose TGC therapy as 100 mg loading dose followed by 50 mg every 12 h and other antibiotics). The in-hospital mortality was 52.2% in the HD group and 76.5% in the non-HD group (P = .117). The Kaplan-Meier test showed significantly longer survival times in the HD group (mean: 83 days vs 28 days; P = .027). Microbiological eradication was observed in 13 patients (56.5%) in the HD group and 6 patients (36.3%) in the non-HD group (P = .184). A smaller fraction of patients in the HD group were subjected to vasoactive therapy (52.2% vs 88.2%; P = .016) compared to the non-HD group. There was no significant difference in the manifestation of adverse effects between the two groups. In the multivariate analysis, multiple organ dysfunction syndrome (MODS), vasoactive therapy, and exposure to carbapenems were regarded as the independent predictors of mortality.A therapeutic regimen consisting of a high dose of TGC was associated with significantly longer survival time and numerically lower mortality in CRKP BSI. Adverse events were not increased with the double dose therapy.

Topics: Aged; Anti-Bacterial Agents; Bacteremia; Carbapenem-Resistant Enterobacteriaceae; Cross Infection; Female; Hospital Mortality; Humans; Kaplan-Meier Estimate; Klebsiella Infections; Klebsiella pneumoniae; Male; Middle Aged; Minocycline; Retrospective Studies; Tigecycline; Treatment Outcome

Febrile neutropenic patients are at a high risk of life-threatening bacterial infections. Tigecycline was developed to treat multidrug-resistant isolates, however resistance to tigecycline in Klebsiella pneumoniae has been reported. Here, we investigated tigecycline resistance among K. pneumoniae isolated from febrile neutropenic patients admitted to Hematology ICU, Egypt. Out of 75 enrolled febrile neutropenic patients, 48 cases showed bacteriologically confirmed infection. The majority of cases were infected with K. pneumoniae, of which nine were tigecycline non-susceptible. Expression levels of the efflux pump genes acrB and oqxB and their regulatory genes ramA and rarA were analysed. Six isolates had overexpression of the four efflux-related genes while one showed baseline expression. This study emphasizes the importance of growing tigecycline resistance in K. pneumoniae infecting febrile neutropenic patients. Concerning the mechanism of resistance, it was clear that the ramA gene plays the major role, although alternative resistance mechanisms may also exist.

Topics: Adult; Animals; Anti-Bacterial Agents; Bacterial Proteins; Drug Resistance, Bacterial; Egypt; Female; Humans; Klebsiella Infections; Klebsiella pneumoniae; Male; Microbial Sensitivity Tests; Middle Aged; Minocycline; Neutropenia; Tigecycline; Young Adult

Emergence of carbapenem-resistant Klebsiella pneumoniae (CRKP) strains that also exhibit resistance to tigecycline and colistin have become a major clinical concern, as these two agents are the last-resort antibiotics used for treatment of CRKP infections. A leukemia patient infected with CRKP was subjected to follow-up analysis of variation in phenotypic and genotypic characteristics of CRKP strains isolated from various specimens at different stages of treatment over a period of 3 years. Our data showed that (1) carbapenem treatment led to the emergence of CRKP in the gastrointestinal (GI) tract of the patient, which subsequently caused infections at other body sites as well as septicemia; (2) treatment with tigecycline led to the emergence of tigecycline-resistant CRKP, possibly through induction of the expression of a variant tet(A) gene located in a conjugative plasmid; (3) colistin treatment was effective in clearing CRKP from the bloodstream but led to the emergence of mcr-1-positive Enterobacteriaceae strains as well as colistin-resistant CRKP in the GI tract due to inactivation of the mgrB gene; and (4) tigecycline- and colistin-resistant CRKP could persist in the human GI tract for a prolonged period even without antibiotic selection pressure. In conclusion, clinical CRKP strains carrying a conjugative plasmid that harbors the bla

Topics: Adult; Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; Carbapenems; Caspofungin; Colistin; Diarrhea; Drug Resistance, Bacterial; Echinocandins; Feces; Gastrointestinal Tract; Humans; Klebsiella Infections; Klebsiella pneumoniae; Leukemia, Monocytic, Acute; Lipopeptides; Male; Microbial Sensitivity Tests; Minocycline; Tigecycline; Treatment Outcome

Nine Klebsiella pneumoniae isolates coproducing NDM-1 and OXA-232 carbapenemases were successively isolated from a single patient. Although they were isolated simultaneously and were isogenic, they presented different colony phenotypes (matt and mucoid). All nine isolates were resistant to most antibiotics except colistin and fosfomycin. In addition, matt-type isolates were resistant to tigecycline. No differences were detected in the cps cluster sequences, except for the insertion of IS5 in the wzb gene of two matt-type isolates. In vitro virulence assays based on production of capsular polysaccharide, biofilm formation, and resistance to human serum indicated that the mucoid-type isolates were significantly more virulent than the matt-type. In addition, mucoid-type isolates showed higher survival rates than the matt-type ones in infection experiments in the fruit fly, suggesting a higher virulence of K. pneumoniae isolates with a mucoid phenotype. To our knowledge, this is the first report of K. pneumoniae colonies with different phenotypes being isolated from the same sample. In addition, we show that virulence varies with colony phenotype. Dissemination of K. pneumoniae isolates expressing both antibiotic resistance and high virulence would constitute a great threat.

Topics: Animals; Anti-Bacterial Agents; Bacterial Capsules; Bacterial Proteins; beta-Lactamases; Biofilms; Colistin; Drosophila melanogaster; Drug Resistance, Multiple, Bacterial; Fosfomycin; Gene Expression Regulation, Bacterial; Genes, Bacterial; Genotype; Humans; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Minocycline; Phenotype; Serotyping; Survival Rate; Tigecycline; Virulence; Virulence Factors

Tigecycline is a treatment option for infections caused by carbapenem-resistant Klebsiella pneumoniae (CRKP). Emerging tigecycline resistance in CRKP represents a growing threat. Knowledge of the clinical, microbiological, and molecular characteristics of tigecycline- and carbapenem-resistant Klebsiella pneumoniae (TCRKP) is limited.. Patients infected with TCRKP were identified from a Taiwanese national surveillance study. Clinical data were collected from medical records. We performed susceptibility tests, carbapenemase gene detection, pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST). Furthermore, we performed quantitative real-time polymerase chain reaction (qRT-PCR) analyses to assess the expression levels of the efflux pump genes acrB and oqxB.. We identified 16 patients infected with TCRKP, with urinary tract infection (UTI) being the most common type of infection (63%). The all-cause 30-day mortality rate was 44% in patients with TCRKP infection. Patients with a site of infection other than the urinary tract had a significantly higher mortality rate than patients with UTIs (83% vs. 20%, p = 0.035). PFGE and MLST revealed no dominant clone or sequence type. Using qRT-PCR, overexpression of both the acrB and oqxB genes was identified in seven isolates, and overexpression of the oqxB gene was observed in another seven. There was poor correlation between acrB or oqxB expression and tigecycline MICs (r = -0.038 and -0.166, respectively).. The mortality rate in patients infected with TCRKP in this study was 44% and this is an important subset of patients. The absence of a linear relationship between efflux pump genes expression and MICs indicates that tigecycline resistance may be mediated by other factors. Continuous monitoring of tigecycline resistance among CRKP isolates and resistance mechanisms are necessary.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Biological Transport; Carbapenems; Drug Resistance, Bacterial; Female; Genes, Bacterial; Humans; Klebsiella Infections; Klebsiella pneumoniae; Male; Middle Aged; Minocycline; Real-Time Polymerase Chain Reaction; Tigecycline; Urinary Tract Infections

Tigecycline is regarded as a last-resort treatment for carbapenem-resistant

Topics: Anti-Bacterial Agents; Carbapenem-Resistant Enterobacteriaceae; Carbapenems; Drug Resistance, Bacterial; Humans; Klebsiella Infections; Klebsiella pneumoniae; Membrane Transport Proteins; Microbial Sensitivity Tests; Minocycline; Multidrug Resistance-Associated Proteins; Mutation; Plasmids; Tetracycline Resistance; Tigecycline; Trans-Activators

To assess risk factors for recurrent carbapenem-resistant Klebsiella pneumoniae bloodstream-infection (CR-KP BSI), we performed a prospective observational cohort study of all consecutive adult patients cured of a CR-KP BSI at our hospital over a six-year period (June 2010 to June 2016). Maximum follow-up per patient was 180 days from the index blood cultures (BCs). Recurrent CR-KP BSI was defined as new evidence of positive BCs in patients with documented clinical response after completing a course of anti-CR-KP therapy. Univariate and multivariate cause-specific Cox proportional hazards analysis were performed. During the study period 249 patients were diagnosed with a CR-KP BSI, 193 were deemed as cured within 14 days after index BCs and were analysed. Recurrence occurred in 32/193 patients (16.6%) within a median of 35 (IQR 25-45) days after index BCs. All but one of the recurrences occurred within 60 days after the index BCs. Comparison of recurrent and non-recurrent cases showed significant differences for colistin use (84.4% vs. 62.2%, p = 0.01), meropenem-colistin-tigecycline regimen (43.8% vs. 24.8%, p = 0.03) and length of therapy for the index BSI episode (median 18 vs. 14 days, p = 0.004). All-cause 180-day mortality (34.4% vs. 16.1%, p = 0.02) was higher in recurrent cases. In the multivariate analysis, the only independent variable was source control as a protective factor for recurrence. Recurrence is frequent among patients cured of a CR-KP BSI and is associated with higher long-term mortality. When feasible, source control is mandatory to avoid recurrence. The role of antibiotic treatment should be further investigated in large multicentre studies.

Topics: Aged; Anti-Bacterial Agents; beta-Lactam Resistance; Colistin; Cross Infection; Female; Hospitals; Humans; Incidence; Klebsiella Infections; Klebsiella pneumoniae; Male; Meropenem; Middle Aged; Minocycline; Prospective Studies; Recurrence; Risk Factors; Sepsis; Thienamycins; Tigecycline; Time Factors

To investigate the synergistic and bactericidal effects of antimicrobial combinations of any two of colistin, fosfomycin and tigecycline against the nine extended-spectrum β-lactamase (ESBL)-producing Klebsiella pneumoniae (KP) clinical isolates, including 4 carbapenem-susceptible strains and five imipenem and/or meropenem-resistant strains.. The most active combination group was colistin plus tigecycline, showing synergy in 8 isolates and bactericidal activities in 6 isolates by using concentrations of 1/2× MIC and 1/4× MIC, respectively. The least active combination was tigecycline plus fosfomycin, which showed synergy in only 4 isolates and no bactericidal activities by using concentrations of 1/2× MIC and 1/4× MIC, respectively.. The combination of tigecycline and colistin may be considered as a last-resort approach to the ESBL-producing KP infections, especially those isolates with carbapenem resistance.

Topics: Anti-Bacterial Agents; beta-Lactamases; Carbapenem-Resistant Enterobacteriaceae; Colistin; Drug Combinations; Drug Resistance, Multiple, Bacterial; Drug Synergism; Fosfomycin; Humans; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Minocycline; Tigecycline

In recent years, Klebsiella pneumoniae has emerged as a leading cause of nosocomial infection owing to the rising prevalence of multidrug-resistant strains, particularly carbapenem-resistant isolates. In this study, the complete genome sequence of carbapenem-resistant K. pneumoniae SWU01 was determined.. Antimicrobial susceptibilities and hypermucoviscous phenotype were determined by the disk diffusion method and positive string test, respectively. Multilocus sequence typing (MLST) was performed using the K. pneumoniae MLST database, and capsular serotype was analysed using the BIGSdb-Kp database with the nucleotide sequence of the variable region (CD1-VR2-CD2) of wzc. The complete genome sequence was obtained via the PacBio RS II platform, and antimicrobial resistance genes were identified using ResFinder 2.1.. SWU01 was resistant to all antibiotics tested except polymyxin B and minocycline. This strain showed a hypermucoviscous phenotype with serotype K47 belonging to the ST11 clone. The complete genome consists of a 5536506-bp circular chromosome and a 162552-bp plasmid, with a G+C content of 57.4%. A total of 5537 protein-coding sequences, 85 tRNAs, 25 rRNAs, 12 non-coding RNA genes and 157 pseudogenes were identified in the genome. Thirteen acquired antibiotic resistance genes were detected (eight in the chromosome and five in the plasmid).. Here we present the first whole-genome sequence of a carbapenem-resistant hypermucoviscous K. pneumoniae isolate SWU01 with capsular serotype K47 belonging to ST11 from a patient in China, which may serve as a reference sequence for further understanding of the pathogenesis and multidrug resistance mechanisms of this species.

Topics: Anti-Bacterial Agents; Base Composition; Carbapenem-Resistant Enterobacteriaceae; China; Cross Infection; Drug Resistance, Multiple, Bacterial; Humans; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Minocycline; Multilocus Sequence Typing; Plasmids; Polymyxin B; RNA, Bacterial; Serogroup; Whole Genome Sequencing

Topics: Anti-Bacterial Agents; Austria; Chromosomes, Bacterial; Drug Resistance, Bacterial; Humans; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Minocycline; Mutation; Rivers; Tetracycline; Tigecycline; Water Microbiology

Tigecycline is one of the few therapeutic options that are available for treating serious clinical infections. However, tigecycline nonsusceptible Enterobacteriaceae has emerged recently in China. In this study, a total of 28 clinical Klebsiella pneumoniae isolates that were not previously exposed to tigecycline were collected and confirmed for tigecycline minimum inhibitory concentrations (MICs) using standard broth microdilution tests. To elucidate the mechanisms underlying molecular resistance to tigecycline, the expression levels of efflux pumps AcrAB and OqxAB and their regulators RamA, MarA, RarA, and SoxS were determined by quantitative polymerase chain reaction. The expression levels of the genes acrB, ramA, marA, and soxS were statistically different in different MIC groups (p < 0.05). Sequence analysis of the acrR and ramR genes revealed several nonsynonymous mutations in the nine resistance isolates. The values of MIC in these isolated strains with ramR mutations were significantly higher than those without ramR mutation (p = 0.029). Moreover, mutations in the ramR gene led to the overexpression of RamA. These results indicated that the mutation of the ramR gene through the upregulated expression of RamA contributed to tigecycline resistance and that several of the newly identified types of mutations in ramR and acrR were not previously reported in K. pneumoniae clinical isolates.

Topics: Anti-Bacterial Agents; Bacterial Proteins; China; Drug Resistance, Bacterial; Humans; Klebsiella Infections; Klebsiella pneumoniae; Membrane Transport Proteins; Microbial Sensitivity Tests; Minocycline; Multilocus Sequence Typing; Tigecycline

The objective of this study was to assess the achievement of pharmacokinetic/pharmacodynamic (PK/PD) targets of meropenem (MEM) in critically-ill patients with bloodstream infections (BSI) due to Klebsiella pneumoniae-carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) with MEM minimum inhibitory concentrations (MICs) ≥16 mg/L. Nineteen critically-ill patients with KPC-Kp BSI were given combination therapy including MEM, tigecycline, plus colistin or gentamicin (according to susceptibility testing). MEM was administered as an extended 3-hour infusion of 2 g every 8 hours, or adjusted according to renal function. MEM plasma concentrations were determined by high-performance liquid chromatography. PK/PD targets for MEM were defined as T > 40% 1×MIC and T > 40% 4×MIC. Possible synergisms between MEM and coadministered agents were assessed by time-kill assays based on plasma levels for MEM and on fixed plasma concentrations for the other agents. In none of 19 patients MEM reached any PK/PD target. The actual MEM MICs were 256, 512, and 1024 mg/L in 1, 3, and 15 isolates, respectively. However, theoretically, the PK/PD target of T > 40% 1×MIC could have been achieved in 95%, 68%, 32% and 0% of the isolates for MIC equal to 8, 16, 32, and 64 mg/L, respectively. No synergisms were observed between MEM and coadministered agents. In conclusion, high-dose MEM failed to reach PK/PD targets in 19 patients with BSI due to KPC-Kp with very high MEM MICs. On a theoretical basis, our results suggest a possible usefulness of MEM against resistant blood isolates with MICs up to 32 mg/L.

Topics: Aged; Anti-Bacterial Agents; Bacteremia; Bacterial Proteins; beta-Lactamases; Colistin; Critical Illness; Drug Synergism; Drug Therapy, Combination; Female; Gentamicins; Humans; Klebsiella Infections; Klebsiella pneumoniae; Male; Meropenem; Microbial Sensitivity Tests; Middle Aged; Minocycline; Thienamycins; Tigecycline

Topics: Anti-Bacterial Agents; Carbapenems; Ceftazidime; Doripenem; Drug Resistance, Bacterial; Drug Synergism; Humans; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Minocycline; Rifampin; Tigecycline

In this study, we have attempted to report the first clonal spread of colistin-resistant Klebsiella pneumoniae coproducing KPC and VIM carbapenemases in the neonatal unit of Rabta Teaching Hospital of Tunis (Tunisia). This retrospective study was performed from January 1, 2014 to December 31, 2014 in the Microbiology Laboratory at the Rabta University Hospital of Tunis. Twenty-one nonreplicate colistin-resistant K. pneumoniae were isolated from 19 patients hospitalized in the neonatal unit and 2 patients in the adult intensive care unit (ICU). Most of the strains were isolated from invasive specimens. Pulsed-field gel electrophoresis (PFGE) and PCR analysis and nucleotide sequencing of the blaKPC and blaVIM genes were performed. Mortality was reported in 92% of cases. All the strains were resistant to colistin (minimum inhibitory concentration [MICs] ranged from 8 to 12 mg/L). The MICs for imipenem of K. pneumoniae isolates ranged from 3 to 256 mg/L for 13 strains that were characterized as intermediate or resistant. The MICs for ertapenem were higher than 32 mg/L for the 19 resistant strains. All the isolates were sensitive to tigecycline and chloramphenicol. PFGE analysis revealed two clones (I and II). Twenty of the 21 colistin-resistant, carbapenem-resistant K. pneumoniae isolates belonged to clone I. Only one strain was related to clone II. PCR analysis and nucleotide sequencing revealed that the 20 isolates belonged to clone I, coproduced the blaKPC and blaVIM genes. A single strain (clone II), which was isolated in the ICU, did not produce KPC and VIM carbapenemases. All strains did not produce OXA-48.

Topics: Adult; Anti-Bacterial Agents; Bacterial Proteins; Bacterial Typing Techniques; beta-Lactamases; beta-Lactams; Chloramphenicol; Clone Cells; Colistin; Drug Resistance, Multiple, Bacterial; Electrophoresis, Gel, Pulsed-Field; Ertapenem; Female; Gene Expression; Hospitals, University; Humans; Imipenem; Infant, Newborn; Klebsiella Infections; Klebsiella pneumoniae; Male; Minocycline; Retrospective Studies; Survival Analysis; Tigecycline; Tunisia

Shunt infections are seen in 3% to 20% of patients who have cerebrospinal fluid (CSF) shunts. Although the staphylococcal species are the most common cause of shunt-related infections, Gram-negative bacteria are increasingly reported with higher mortality rates. Tigecycline, a glycylcycline, is not approved for children. But in the era of nosocomial infections due to multidrug-resistant pathogens, it can be the life-saving option. We report an infant with ventriculoperitoneal shunt-related meningitis treated with a tigecycline combination regimen. A 5-month-old boy who had a ventriculoperitoneal shunt was admitted with meningitis. Extended spectrum β-lactamase-producing Klebsiella pneumoniae grew in the CSF. At the end of the fourth week of intravenous meropenem plus gentamicin therapy, carbapenem-resistant K pneumoniae grew in the CSF (mean inhibitory concentration value for meropenem >4 μg/mL, by E-test). The infected shunt was removed, and an external ventricular drainage catheter was inserted. With permission, intravenous tigecycline (1.2 mg/kg per dose twice a day) and intrathecal amikacin were added to the meropenem. Intrathecal amikacin could be given for only 7 days. On the sixth day of tigecycline treatment, the CSF was sterilized. Antibiotic therapy was given and consisted of a total of 60 days of meropenem and 20 days of tigecycline therapy. Because no available efficacy and safety data from randomized-controlled studies exist, tigecycline must be used only as salvage therapy, in combination with other drugs, for critically ill children who have no alternative treatment options.

Topics: Amikacin; Drug Therapy, Combination; Humans; Hydrocephalus; Infant; Infant, Premature, Diseases; Infusions, Intravenous; Injections, Spinal; Klebsiella Infections; Klebsiella pneumoniae; Male; Meningitis, Bacterial; Meropenem; Microbial Sensitivity Tests; Minocycline; Off-Label Use; Salvage Therapy; Thienamycins; Tigecycline; Ventriculoperitoneal Shunt

Urinary tract infections (UTIs) are a common reason for empirical treatment with broad-spectrum antibiotics worldwide. However, population-based antimicrobial resistance (AMR) prevalence data to inform empirical treatment choice are lacking in many regions, because of limited surveillance capacity. We aimed to assess the prevalence of AMR to commonly used antimicrobial drugs in Escherichia coli and Klebsiella pneumoniae isolated from patients with community- or healthcare-associated UTIs on two islands of Indonesia.. We performed a cross-sectional patient-based study in public and private hospitals and clinics between April 2014 and May 2015. We screened patients for symptoms of UTIs and through urine dipstick analysis. Urine culture and susceptibility testing were supported by telemicrobiology and interactive virtual laboratory rounds. Surveillance data were entered in forms on mobile phones.. Of 3424 eligible patients, 3380 (98.7%) were included in the final analysis, and yielded 840 positive cultures and antimicrobial susceptibility data for 657 E. coli and K. pneumoniae isolates. Fosfomycin was the single oral treatment option with resistance prevalence <20% in both E. coli and K. pneumoniae in community settings. Tigecycline and fosfomycin were the only options for treatment of catheter-associated UTIs with resistance prevalence <20%, whilst the prevalence of resistance to meropenem was 21.3% in K. pneumoniae .. Patient-based surveillance of AMR in E. coli and K. pneumoniae causing UTIs indicates that resistance to the commonly available empirical treatment options is high in Indonesia. Smart AMR surveillance strategies are needed to inform policy makers and to guide interventions.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Catheter-Related Infections; Cross-Sectional Studies; Drug Resistance, Multiple, Bacterial; Epidemiological Monitoring; Escherichia coli; Escherichia coli Infections; Female; Fosfomycin; Humans; Indonesia; Klebsiella Infections; Klebsiella pneumoniae; Male; Meropenem; Middle Aged; Minocycline; Population Surveillance; Tertiary Care Centers; Thienamycins; Tigecycline; Urinary Tract Infections; Young Adult

We characterized NDM-1-producing

Topics: Amikacin; Anti-Bacterial Agents; Bacterial Typing Techniques; beta-Lactamases; Brazil; Clone Cells; DNA Transposable Elements; Drug Resistance, Multiple, Bacterial; Electrophoresis, Gel, Pulsed-Field; Fosfomycin; Gene Expression; Genotype; Humans; Klebsiella Infections; Klebsiella pneumoniae; Minocycline; Multilocus Sequence Typing; Phylogeny; Plasmids; Polymyxin B; Tigecycline

Various transmission routes contribute to spread of carbapenem-resistant Klebsiella pneumoniae (CRKP) in hospitalized patients. Patients with readmissions during which CRKP is again isolated ("CRKP readmission") potentially contribute to transmission of CRKP.. To evaluate CRKP readmissions in the Consortium on Resistance against Carbapenems in K. pneumoniae (CRaCKLe).. Cohort study from December 24, 2011, through July 1, 2013.. Multicenter consortium of acute care hospitals in the Great Lakes region.. All patients who were discharged alive during the study period were included. Each patient was included only once at the time of the first CRKP-positive culture.. All readmissions within 90 days of discharge from the index hospitalization during which CRKP was again found were analyzed. Risk factors for CRKP readmission were evaluated in multivariable models.. Fifty-six (20%) of 287 patients who were discharged alive had a CRKP readmission. History of malignancy was associated with CRKP readmission (adjusted odds ratio [adjusted OR], 3.00 [95% CI, 1.32-6.65], P<.01). During the index hospitalization, 160 patients (56%) received antibiotic treatment against CRKP; the choice of regimen was associated with CRKP readmission (P=.02). Receipt of tigecycline-based therapy (adjusted OR, 5.13 [95% CI, 1.72-17.44], using aminoglycoside-based therapy as a reference in those treated with anti-CRKP antibiotics) was associated with CRKP readmission.. Hospitalized patients with CRKP-specifically those with a history of malignancy-are at high risk of readmission with recurrent CRKP infection or colonization. Treatment during the index hospitalization with a tigecycline-based regimen increases this risk.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; beta-Lactam Resistance; Case-Control Studies; Cross Infection; Female; Humans; Kaplan-Meier Estimate; Klebsiella Infections; Klebsiella pneumoniae; Logistic Models; Longitudinal Studies; Male; Microbial Sensitivity Tests; Middle Aged; Minocycline; Multivariate Analysis; Odds Ratio; Patient Readmission; Prospective Studies; Risk Factors; Tigecycline; United States

Currently, tigecycline-nonsusceptible Klebsiella pneumoniae (TNSKP) is mainly reported to emerge following clinical use of tigecycline and is usually polyclonal. This study aimed to characterize TNSKP isolated from patients without prior tigecycline use.. Twenty-six TNSKP clinical isolates were collected, and carbapenemase and 16S rRNA methylase genes were identified by polymerase chain reaction and sequencing. Molecular typing was conducted by pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST). Clinical data of patients in the carbapenem-susceptible TNSKP group and the tigecycline- and carbapenem-nonsusceptible K. pneumoniae (TCNSKP) group were compared.. TNSKP can occur without tigecycline use, and TCNSKP ST11 is predominant among them. Further, this report proposes potential risk factors for the occurrence of carbapenem-nonsusceptibility in TNSKP.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Carbapenems; Female; Humans; Intensive Care Units; Klebsiella Infections; Klebsiella pneumoniae; Male; Methyltransferases; Microbial Sensitivity Tests; Middle Aged; Minocycline; Multilocus Sequence Typing; Polymerase Chain Reaction; Tigecycline; Young Adult

We evaluated the antimicrobial susceptibility of 1,454 organisms consecutively collected from patients with bacteremia associated with skin and skin structure infections. The most common organisms obtained wereStaphylococcus aureus(670 organisms [46.1%]),Escherichia coli(200 organisms [13.8%]), β-hemolytic streptococci (βHS) (138 organisms [9.5%]), andKlebsiella pneumoniae(109 organisms [7.5%]). The susceptibility rates for ceftaroline were 97.9% forS. aureus(95.9% among methicillin-resistantS. aureus[MRSA]), 100.0% for βHS, 86.5% forE. coli, and 89.0% forK. pneumoniae Ceftaroline and tigecycline provided the best overall coverage.

Topics: Academic Medical Centers; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Community-Acquired Infections; Escherichia coli; Escherichia coli Infections; Humans; Klebsiella Infections; Klebsiella pneumoniae; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Minocycline; Skin; Staphylococcal Skin Infections; Streptococcal Infections; Streptococcus; Tigecycline; United States

The lack of treatment for multidrug-resistant (MDR) Enterobacteriaceae often leads to the use of double or triple antibiotic combinations to increase the option of clinical success. This study analyzes multiple combination bactericidal testing (MCBT) to screen double and triple antibiotic combinations, at standard peak serum concentration, for bactericidal activity against 21 MDR Klebsiella pneumoniae isolates. This method was compared with time-killing curves. The full bactericidal activity against all strains was obtained only by adding colistin. MCBT has a potential to become a rapid method for testing multiple antibiotic combinations for MDR microorganisms when colistin is used, providing clinicians with in vitro cidal data within 48 hr of strain isolation.

Topics: Anti-Bacterial Agents; beta-Lactams; Colistin; Culture Media; Dose-Response Relationship, Drug; Drug Resistance, Multiple, Bacterial; Drug Synergism; Drug Therapy, Combination; Ertapenem; Humans; Klebsiella Infections; Klebsiella pneumoniae; Meropenem; Microbial Sensitivity Tests; Minocycline; Predictive Value of Tests; Rifampin; Thienamycins; Tigecycline

Tigecycline is one of the drugs used to treat multi-drug resistant Klebsiella pneumoniae (K. pneumoniae) infections, including complicated skin and soft tissue infections, complicated intra-abdominal infection, and community-acquired pneumonia in the Republic of Korea. However, since its commercial release, K. pneumoniae resistance against tigecycline has been reported, and there is a serious concern about the spread of tigecycline resistant bacteria.. In this study, we collected and analyzed 342 isolates from 23 hospitals in the Republic of Korea to determine the mechanisms of tigecycline susceptibility and their clonal types. The hospitals include several from each province in the Republic of Korea, except Jeju, an island province, and nonsusceptibility among the isolates was tested by the disk diffusion method. In our lab, susceptibility was checked again using the broth dilution method, and clonal types were determined using the multilocus sequence typing protocol. Real-time PCR was performed to measure the ramR mutation in the isolates nonsusceptible to tigecycline, which would suggest an increased expression of the AcrAB multidrug pump.. Fifty-six K. pneumoniae isolates were found to be nonsusceptible, 16% of the 342 collected. Twenty-seven and nine isolates of the tigecycline nonsusceptible isolates had mutations in the ramR and rpsJ genes, respectively; while 18 nonsusceptible isolates harbored the tetA gene. Comparison of isolates with and without ramR mutation showed a significant statistical difference (p<0.05) for expression of AcrAB. Moreover, the most common clonal types, as observed in our study, appear to be ST11 and ST789.. Several dominate clonal types infer tigecycline resistance to K. pneumoniae, including ST11, ST768, ST15, ST23, ST48, and ST307. There does not seem to be a transferrable medium, such as plasmid, for the resistance yet, although mutation of the ramR gene may be a common event, accounting for 48% of the nonsusceptibility in this study.

Topics: Anti-Bacterial Agents; Bacterial Proteins; Drug Resistance, Bacterial; Humans; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Minocycline; Multilocus Sequence Typing; Plasmids; Polymerase Chain Reaction; Real-Time Polymerase Chain Reaction; Republic of Korea; Tigecycline

Infections caused by carbapenemase-producing Klebsiella pneumoniae resistant to tigecycline, colistin, or aminoglycosides are a growing health concern. In our retrospective chart review, we noted increased resistance to colistin compared with tigecycline, despite limited prior use of colistin. This may affect the choice of presumptive antibiotics used in these hard to treat infections. Improved infection control and antimicrobial stewardship practices are essential to prevent the spread of these multidrug-resistant organisms.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Colistin; Drug Resistance, Multiple, Bacterial; Female; Humans; Klebsiella Infections; Klebsiella pneumoniae; Male; Middle Aged; Minocycline; Retrospective Studies; Tigecycline; Young Adult

Topics: Ceftriaxone; Female; Humans; Klebsiella Infections; Klebsiella pneumoniae; Laparoscopy; Liver Abscess; Microbial Sensitivity Tests; Middle Aged; Minocycline; Tigecycline

Serious infections in intensive care unit patients caused by multidrug-resistant (MDR) Klebsiella pneumoniae represent a major threat worldwide owing to increased mortality and limited treatment options. With the application of tigecycline for MDR pathogens, tigecycline-non-susceptible K. pneumoniae isolates have recently emerged in China. To identify the susceptibility profile of MDR K. pneumoniae to tigecycline and evaluate the molecular characterization of tigecycline resistance, 214 MDR K. pneumoniae isolates were collected from blood samples of patients in intensive care units. MICs and clonal relatedness were determined by standard broth microdilution and multilocus sequence typing, respectively. Expression levels of efflux pumps and their global regulators were examined using real-time PCR. Mutations of local repressor were identified by PCR and sequencing. Our results show that the tigecycline resistance rate of 214 MDR K. pneumoniae isolates was 6.07 %. ST11 was the predominant clone type of tigecycline-non-susceptible K. pneumoniae isolates. Expression of efflux pump AcrB and global regulator RamA correlated with tigecycline MICs (AcrB: x2=8.91, P=0.03; RamA: x2=13.91, P<0.01), and mean expression levels of AcrB for the MICs ≥4 mg l-1 were significantly higher than MICs ≤2 mg l-1 (t=2.48, P=0.029). In addition, one tigecycline-resistant isolate harboured a deletion mutation in the ramR gene. These data indicated a linear correlative trend for overexpression of the AcrB and the tigecycline MICs resulting from the upregulation of RamA. The emergence of molecular type ST11 of MDR K. pneumoniae isolates should be monitored to identify factors that contribute to tigecycline resistance in intensive care units.

Topics: Anti-Bacterial Agents; Bacteremia; China; DNA Mutational Analysis; Drug Resistance, Multiple, Bacterial; Gene Expression Profiling; Genes, Regulator; Humans; Intensive Care Units; Klebsiella Infections; Klebsiella pneumoniae; Membrane Transport Proteins; Microbial Sensitivity Tests; Minocycline; Multidrug Resistance-Associated Proteins; Multilocus Sequence Typing; Real-Time Polymerase Chain Reaction; Sequence Analysis, DNA; Tigecycline

Donor-derived infections with multidrug-resistant gram-negative bacteria are associated with poor outcomes, in part because of limited treatment options. Here, we describe a case of donor-derived, disseminated infection with colistin-resistant, carbapenemase-producing Klebsiella pneumoniae in a liver transplant recipient that was cured with addition of intravenous fosfomycin to a multidrug regimen, in conjunction with aggressive surgical source control. Intravenous fosfomycin represents a promising adjunctive agent for use in treatment of extensively drug-resistant infections in immunocompromised hosts.

Topics: Aged; Allografts; Anti-Bacterial Agents; Antibiotic Prophylaxis; Bacterial Proteins; beta-Lactamases; Colistin; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Female; Fibrosis; Fosfomycin; Humans; Klebsiella Infections; Klebsiella pneumoniae; Liver Transplantation; Microbial Sensitivity Tests; Minocycline; Tigecycline

Tigecycline resistance among Klebsiella pneumoniae isolates has been increasingly reported. We aimed to investigate the relationship among in vivo acquisition of tigecycline resistance in K. pneumoniae clinical isolates, the underlying molecular mechanisms and bacterial virulence. Clinical isolates of K. pneumoniae from the same patient in a medical centre in Taiwan that were initially tigecycline-susceptible (TS) and then became tigecycline-non-susceptible (TNS) were identified. Clinical data were collected. All isolates were subjected to MIC determination by Etest, pulsed-field gel electrophoresis (PFGE), multilocus sequence typing (MLST), virulence factor determination, and growth rate and mouse lethality studies. Quantitative RT-PCR was performed to analyse acrA, oqxA, ramA and rarA expressions. The presence of mutations in acrR, ramR, oqxR and rpsJ were analysed by DNA sequencing. Five isogenic paired isolates were determined by PFGE fingerprinting. TNS K. pneumoniae appeared after treatment with a variety of antibiotics among patients infected with TS K. pneumoniae. TNS K. pneumoniae isolates were associated with upregulation of RamA and/or RarA and the corresponding AcrAB and/or OqxAB efflux pump(s), respectively. Various mutations in negative regulatory genes (ramR and oqxR) accounted for overexpression of ramA and rarA, respectively. Three of the five paired isolates showed similar growth rates and virulence between TS and TNS isolates. Two TNS K. pneumoniae strains belonging to capsular types K1 and K20 retained their high virulence. In conclusion, some TNS K. pneumoniae strains derived from TS isolates did not compromise their virulence. Dissemination of these highly pathogenic and resistant strains would be of major concern in the future.

Topics: Aged; Animals; Anti-Bacterial Agents; Disease Models, Animal; Drug Resistance, Bacterial; Electrophoresis, Gel, Pulsed-Field; Female; Humans; Klebsiella Infections; Klebsiella pneumoniae; Male; Mice, Inbred C57BL; Microbial Sensitivity Tests; Middle Aged; Minocycline; Multilocus Sequence Typing; Survival Analysis; Taiwan; Tigecycline; Virulence; Virulence Factors

A rise in tigecycline resistance in Klebsiella pneumoniae has been reported recently worldwide. We sought to identify risk factors, outcomes, and mechanisms for adult patients with tigecycline-nonsusceptible K. pneumoniae bacteremia in Taiwan. We conducted a matched case-control study (ratio of 1:1) in a medical center in Taiwan from January 2011 through June 2015. The cases were patients with tigecycline-nonsusceptible K. pneumoniae bacteremia, and the controls were patients with tigecycline-susceptible K. pneumoniae bacteremia. Logistic regression was performed to evaluate the potential risk factors for tigecycline-nonsusceptible K. pneumoniae bacteremia. Quantitative reverse transcription-PCR was performed to analyze acrA, oqxA, ramA, rarA, and kpgA expression among these isolates. A total of 43 cases were matched with 43 controls. The 14-day mortality of patients with tigecycline-nonsusceptible K. pneumoniae bacteremia was 30.2%, and the 28-day mortality was 41.9%. The attributable mortalities of tigecycline-nonsusceptible K. pneumoniae at 14 and 28 days were 9.3 and 18.6%, respectively. Fluoroquinolone use within 30 days prior to bacteremia was the only independent risk factor for tigecycline-nonsusceptible K. pneumoniae bacteremia. The tigecycline-nonsusceptible K. pneumoniae bacteremia was mostly caused by overexpression of AcrAB and/or OqxAB efflux pumps, together with the upregulation of RamA and/or RarA, respectively. One isolate demonstrated isolated overexpression of kpgA In conclusion, tigecycline-nonsusceptible K. pneumoniae bacteremia was associated with high mortality, and prior fluoroquinolone use was the independent risk factor for the acquisition of tigecycline-nonsusceptible K. pneumoniae The overexpression of AcrAB and/or OqxAB contributes to tigecycline nonsusceptibility in K. pneumoniae.

Topics: Aged; Anti-Bacterial Agents; Bacteremia; Case-Control Studies; Drug Resistance, Bacterial; Female; Humans; Klebsiella Infections; Klebsiella pneumoniae; Male; Membrane Transport Proteins; Microbial Sensitivity Tests; Minocycline; Risk Factors; Taiwan; Tigecycline; Transcription Factors

We first describe two novel variants of blaKPC, blaKPC-16 and blaKPC-17, which were identified in three Klebsiella pneumoniae isolates from a patient in Taiwan. KPC-16 and KPC-17 differed from KPC-2 by two (P202S and F207L) and a single (F207L) amino acid substitutions, respectively. All three isolates with identical pulsotype belonged to sequence type 11. The MICs of the three isolates for colistin and tigecycline were 0.5 μg/mL and 2 μg/mL, respectively. Moreover, an outbreak of at least 39 blaKPC-17-containing K. pneumoniae isolates is ongoing in southern Taiwan in 2014. Physicians should know that blaKPC-17-containing isolates can substantially threaten public health.

Topics: Aged; Anti-Bacterial Agents; beta-Lactamases; Colistin; Disease Outbreaks; Electrophoresis, Gel, Pulsed-Field; Genotype; Humans; Klebsiella Infections; Klebsiella pneumoniae; Male; Microbial Sensitivity Tests; Minocycline; Molecular Typing; Taiwan; Tigecycline

Laboratory-derived Klebsiella pneumoniae mutants demonstrated that the ramA locus mediated low-level tigecycline resistance. The aim of this study was to elucidate the underlying mechanisms of tigecycline resistance in clinical K. pneumoniae isolates. In total, 106 isolates with tigecycline MICs ranging from 0.125 mg/L to 16 mg/L were collected to determine the correlations between expression of the global regulon ramA, marA, soxS, the acrB pump gene and tigecycline MICs. PCR was used to determine whether mutations in ramR, acrR or the rpsJ gene encoding 30S ribosomal protein S10 were responsible for tigecycline resistance. ramA or ramR inactivation and corresponding trans-complemented strains were used to characterise the contribution of RamA and RamR to tigecycline resistance. Tigecycline MICs were correlated with transcriptional levels of ramA and acrB, but were negatively correlated with marA and soxS. Disrupting ramA strikingly reduced the tigecycline MIC by 16-fold, accompanied by a 0.5-fold downregulation of acrB expression and 3.14- and 3.80-fold upregulation of marA and soxS, respectively. Complementation with plasmid-borne ramA restored the original parental phenotype of decreased tigecycline susceptibility. Of 34 tigecycline-non-susceptible isolates, 21 harbouring diverse mutations in RamR led to ramA overexpression. Disrupting the mutated ramR gene and complementing the mutated ramR gene with a wild-type gene downregulated expression of ramA but maintained the same tigecycline-resistant phenotype as the parental strain; the complemented strain exhibited 4.21- and 27.51-fold increased expression of acrB and marA, respectively. In conclusion, for the majority of tigecycline-resistant K. pneumoniae, ramA, depressed by ramR, was the major factor accounting for tigecycline resistance.

Topics: Anti-Bacterial Agents; Bacterial Proteins; Drug Resistance, Bacterial; Gene Knockout Techniques; Genetic Complementation Test; Humans; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Minocycline; Polymerase Chain Reaction; Regulon; Tigecycline; Trans-Activators; Transcriptome

Topics: Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Colistin; Cross-Sectional Studies; Gentamicins; Hospitals; Humans; Italy; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Minocycline; Tigecycline

Topics: Anti-Bacterial Agents; Bacteriuria; Drug Resistance, Bacterial; Female; Humans; Klebsiella Infections; Klebsiella pneumoniae; Male; Minocycline

KPC-producing Klebsiella pneumoniae isolates have emerged as important pathogens of nosocomial infections, and tigecycline is one of the antibiotics recommended for severe infections caused by KPC-producing K. pneumoniae. To identify the susceptibility profile of KPC-producing K. pneumoniae to tigecycline and investigate the role of efflux pumps in tigecycline resistance, a total of 215 KPC-producing K. pneumoniae isolates were collected. The minimum inhibitory concentration (MIC) of tigecycline was determined by standard broth microdilution tests. Isolates showing resistance to tigecycline underwent susceptibility test with efflux pump inhibitors. Expression levels of efflux pump genes (acrB and oqxB) and their regulators (ramA, marA, soxS and rarA) were examined by real-time PCR, and the correlation between tigecycline MICs and gene expression levels were analysed. Our results show that the tigecycline resistance rate in these isolates was 11.2%. Exposure of the tigecycline-resistant isolates to the efflux pump inhibitor NMP resulted in an obvious decrease in MICs and restored susceptibility to tigecycline in 91.7% of the isolates. A statistically significant association between acrB expression and tigecycline MICs was observed, and overexpression of ramA was found in three tigecycline-resistant isolates, further analysis confirmed ramR mutations existed in these isolates. Transformation of one mutant with wild-type ramR restored susceptibility to tigecycline and repressed overexpression of ramA and acrB. These data indicate that efflux pump AcrAB, which can be up-regulated by ramR mutations and subsequent ramA activation, contributed to tigecycline resistance in K. pneumoniae clinical isolates.

Topics: Anti-Bacterial Agents; beta-Lactamases; Drug Resistance, Bacterial; Gene Expression Regulation, Bacterial; Genes, MDR; Genes, Regulator; Humans; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Minocycline; Multidrug Resistance-Associated Proteins; Piperazines; Tigecycline; Transformation, Bacterial

The emergence and spread of carbapenems-resistant Klebsiella pneumoniae (CRKP) in burn ward is an important threat to burn management. CRKP isolates are resistant to almost all available antibiotics and are susceptible only to polymyxins and tigecycline. The mechanism of the drug resistance of CRKP is associated with the plasmid-encoded carbapenemase Klebsiella pneumoniae carbapenemase (KPC), a carbapenem-hydrolyzing β-lactamase. Antibiotics which can currently be used to treat CRKP infection include polymyxins, tigecycline, and some aminoglycosides. The efficacy of using antibiotics in combination is better than that of single-agent therapy for the treatment of CRKP infection in bloodstream. In order to control CRKP infection in burn patients, strategies for preventing CRKP dissemination in burn ward are strongly advocated.

Topics: Anti-Bacterial Agents; Bacterial Proteins; beta-Lactam Resistance; beta-Lactamases; Burns; Carbapenems; Drug Resistance, Bacterial; Humans; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Minocycline; Tigecycline

A 68-year-old male underwent a right hepatectomy, resection of the biliary convergence, and a left hepatic jejunostomy for a Klatskin tumour. The postoperative course was complicated by biliary abscesses with relapsing bloodstream infections due to Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae (KPC-Kp). A 2-week course of combination antibiotic therapy failed to provide source control and the bacteraemia relapsed. Success was obtained with a regimen of tigecycline 100mg daily for 2 months, followed by tigecycline 50mg daily for 6 months, then 50mg every 48h for 3 months. No side effects were reported.

Topics: Aged; Anti-Bacterial Agents; Bacteremia; Bacterial Proteins; beta-Lactamases; Humans; Klebsiella Infections; Klebsiella pneumoniae; Liver; Male; Minocycline; Postoperative Complications; Tigecycline

Topics: Aged; Carbapenems; Drug Resistance, Bacterial; Drug Therapy, Combination; Female; Humans; Intensive Care Units; Klebsiella Infections; Klebsiella pneumoniae; Male; Middle Aged; Minocycline; Tigecycline

To determine the rates of and risk factors for tigecycline nonsusceptibility among carbapenem-resistant Klebsiella pneumoniae (CRKPs) isolated from hospitalized patients.. Multicenter prospective observational study.. Acute care hospitals participating in the Consortium on Resistance against Carbapenems in Klebsiella pneumoniae (CRaCKle).. A cohort of 287 patients who had CRKPs isolated from clinical cultures during hospitalization.. For the period from December 24, 2011 to October 1, 2013, the first hospitalization of each patient with a CRKP during which tigecycline susceptibility for the CRKP isolate was determined was included. Clinical data were entered into a centralized database, including data regarding pre-hospital origin. Breakpoints established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) were used to interpret tigecycline susceptibility testing.. Of 287 patients included in the final cohort, 155 (54%) had tigecycline-susceptible CRKPs. Of all index isolates, 81 (28%) were tigecycline-intermediate and 51 (18%) were tigecycline resistant. In multivariate modeling, independent risk factors for tigecycline nonsusceptibility were (1) admission from a skilled nursing facility (OR, 2.51; 95% CI, 1.51-4.21; P=.0004), (2) positive culture within 2 days of admission (OR, 1.82; 95% CI, 1.06-3.15; P=.03), and (3) receipt of tigecycline within 14 days (OR, 4.38, 95% CI, 1.37-17.01, P=.02).. In hospitalized patients with CRKPs, tigecycline nonsusceptibility was more frequently observed in those admitted from skilled nursing facilities and occurred earlier during hospitalization. Skilled nursing facilities are an important target for interventions to decrease antibacterial resistance to antibiotics of last resort for treatment of CRKPs.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; beta-Lactam Resistance; Carbapenems; Drug Resistance, Multiple, Bacterial; Female; Humans; Klebsiella Infections; Klebsiella pneumoniae; Male; Microbial Sensitivity Tests; Middle Aged; Minocycline; Prospective Studies; Risk Factors; Skilled Nursing Facilities; Tigecycline; Time Factors

In 2010 the Hellenic center for disease control and prevention launched the "Prokroustes" nationwide action plan to tackle the increasing rates of carbapenem resistance among gram-negative nosocomial pathogens. In the present report, data from a Greek tertiary-care hospital are presented three years after the adoption of the infection control measures. Carbapenem resistance rates have been contained for Klebsiella pneumoniae and Acinetobacter baumannii but not for Pseudomonas aeruginosa. More worryingly, in accordance with their overuse against carbapenem-resistant bacteria, resistance rates to colistin and tigecycline have risen significantly.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Anti-Bacterial Agents; Carbapenems; Colistin; Containment of Biohazards; Cross Infection; Drug Resistance, Multiple, Bacterial; Gentamicins; Greece; Humans; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Minocycline; Tertiary Care Centers; Tigecycline

New antibiotic options are urgently needed for the treatment of carbapenem-resistant Enterobacteriaceae infections. We report a 64-year-old female with prolonged hospitalization following an intestinal transplant who developed refractory bacteremia due to a serine carbapenemase-producing pandrug-resistant isolate of Klebsiella pneumoniae. After failing multiple antimicrobial regimens, the patient was successfully treated.

Topics: Anti-Bacterial Agents; Antiviral Agents; Azabicyclo Compounds; Bacteremia; Bacterial Proteins; beta-Lactamases; Carbapenems; Ceftazidime; Colectomy; Colistin; Drug Combinations; Drug Resistance, Multiple, Bacterial; Female; Ganciclovir; Humans; Immunosuppressive Agents; Intestine, Small; Klebsiella Infections; Klebsiella pneumoniae; Meropenem; Microbial Sensitivity Tests; Middle Aged; Minocycline; Thienamycins; Tigecycline; Trimethoprim, Sulfamethoxazole Drug Combination; Valganciclovir

Catheter-related bacteremias carry high mortality rates in hematological patients. When a multidrug-resistant microorganism is involved, the catheter should ideally be removed; however, this approach is not always possible. Tigecycline lock therapy was used in two pediatric oncohematological patients with intravascular catheter-related infection due to KPC-producing Klebsiella pneumoniae. The catheter was salvaged in both cases, and the patients were later discharged. Our experience suggests the usefulness of this approach in treating this type of infection.

Topics: Adolescent; Anemia, Aplastic; Anti-Bacterial Agents; Antineoplastic Agents; Bacteremia; Catheter-Related Infections; Central Venous Catheters; Drug Administration Schedule; Female; Humans; Immunosuppressive Agents; Infant; Klebsiella Infections; Klebsiella pneumoniae; Minocycline; Tigecycline; Treatment Outcome

Topics: Anti-Bacterial Agents; Drug Resistance, Bacterial; Humans; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Minocycline; Mutation; Tigecycline

Fosfomycin is active in vitro against extensively drug-resistant (XDR) and pandrug-resistant (PDR) Pseudomonas aeruginosa and Klebsiella pneumoniae carbapenemase-producing strains; however, the in vivo effectiveness against such pathogens is almost unknown. A multicentre, observational, prospective case-series study was performed in 11 ICUs. All consecutive fosfomycin-treated patients suffering from XDR or PDR fosfomycin-susceptible, microbiologically documented infections were recorded. Clinical and microbiological outcomes were assessed. A safety analysis was performed. In total, 68 patients received fosfomycin during the study period, 48 of whom were considered suitable for effectiveness analysis based on predefined criteria. Bacteraemia and ventilator-associated pneumonia were the main infections. Carbapenemase-producing K. pneumoniae and P. aeruginosa were isolated in 41 and 17 cases, respectively. All isolates exhibited an XDR or PDR profile, being fosfomycin-susceptible by definition. Fosfomycin was administered intravenously at a median dose of 24g/day for a median of 14 days, mainly in combination with colistin or tigecycline. Clinical outcome at Day 14 was successful in 54.2% of patients, whilst failure, indeterminate outcome and superinfection were documented in 33.3%, 6.3% and 6.3%, respectively. All-cause mortality at Day 28 was 37.5%. Bacterial eradication was observed in 56.3% of cases. Fosfomycin resistance developed in three cases. The main adverse event was reversible hypokalaemia. In conclusion, fosfomycin could have a place in the armamentarium against XDR and PDR Gram-negative infections in the critically ill. Resistance development during therapy, which has been a matter of concern in previous studies, did not occur frequently. The necessity of combination with other antibiotics requires further investigation.

Topics: Administration, Intravenous; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Colistin; Critical Illness; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Female; Fosfomycin; Humans; Intensive Care Units; Klebsiella Infections; Klebsiella pneumoniae; Male; Middle Aged; Minocycline; Prospective Studies; Pseudomonas aeruginosa; Pseudomonas Infections; Tigecycline; Treatment Outcome

The aim of this study was to assess the efficacy of tigecycline in the treatment of infections due to carbapenemase-producing Klebsiella pneumoniae (CPKP) in critically ill patients.. A retrospective observational study was conducted in critically ill patients receiving different tigecycline doses for severe CPKP infections. We evaluated demographic data, localization and severity of infection, response to therapy, and mortality.. Fifteen patients received tigecycline for 16 episodes of CPKP infection. The main infections were pneumonia (31%), urinary tract infection (31%), peritonitis (20%), catheter-related bacteraemia (12%), and meningitis (6%). Most infections were complicated with severe sepsis (44%), septic shock (12%), and/or bacteraemia (19%). The daily maintenance dose of tigecycline was 200 mg in 10 episodes and 100 mg in 6 episodes. The overall 30-day mortality rate was 25%. Univariate analysis showed that mortality was significantly associated (p < 0.01) with mean APACHE II and SOFA scores and the presence of immunosuppression, but not with the tigecycline dose.. Tigecycline appears to be an effective therapy for severe infections due to CPKP in critically ill patients. Mortality is related to the severity of the underlying disease. We observed no benefit from a higher maintenance dose of tigecycline, although the number of patients included in the study was too small to draw any general conclusions in this regard.

Topics: Adult; Aged; Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Critical Illness; Drug Resistance, Multiple, Bacterial; Female; Humans; Klebsiella Infections; Klebsiella pneumoniae; Male; Middle Aged; Minocycline; Retrospective Studies; Tigecycline

We report the epidemiological and clinical features of the first outbreak of Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (KPC-KP) type 2 in Switzerland. The outbreak took place in the medical intensive care unit (MICU) of our tertiary care hospital and affected three severely ill patients. After the implementation of strict infection control measures, no further patients colonised with KPC-KP could be detected by the screening of exposed patients. Successful treatment of patients infected with KPC-KP consisted of a combination therapy of meropenem, colistin and tigecycline.

Topics: Adult; Aged; Anti-Bacterial Agents; beta-Lactamases; Colistin; Disease Outbreaks; Electrophoresis, Gel, Pulsed-Field; Genotype; Humans; Infection Control; Intensive Care Units; Klebsiella Infections; Klebsiella pneumoniae; Male; Meropenem; Middle Aged; Minocycline; Molecular Typing; Switzerland; Tertiary Care Centers; Thienamycins; Tigecycline; Treatment Outcome

Five carbapenem-resistant strains (three Klebsiella pneumoniae, one Escherichia coli, and one Enterobacter aerogenes) were isolated between 2009 and 2012 at the Verona University Hospital, Italy, during an epidemiological analysis of antibiotic resistance determinants and plasmid profiles in Enterobacteriaceae. Two out of the five strains, K. pneumoniae E530 and E. coli E558, were cultured from bile and abdominal drainage, respectively, of a single patient. The strains were resistant to beta-lactams and fluoroquinolones, and susceptible to tigecycline and colistin. All the strains harboured bla(KPC-3), bla(TEM-1), and bla(OXA-9), and the three K. pneumoniae additionally carried blaSHV-11 and aac(6')Ib. The bla(KPC-3) was inserted in transposon Tn4401a. All the strains hosted an FIIk-type plasmid, and the three K. pneumoniae coharboured an colE-type plasmid. Transconjugants, besides bla(KPC-3), harboured bla(TEM-1) and bla(OXA-9) genes on FIIk-type plasmid. K. pneumoniae E301 was ST258, while strain E530 and C525 belonged to the ST512, and E. coli E558 was ST43. To our best knowledge, this is the first report that strongly supports the transmission of bla(KPC-3) from ST512 K. pneumoniae to E. coli ST43 in a single patient, a phenomenon of both clinical and microbiological importance.

Topics: Abdominal Abscess; Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; beta-Lactams; Bile; Colistin; Conjugation, Genetic; DNA Transposable Elements; Drug Resistance, Multiple, Bacterial; Enterobacter aerogenes; Enterobacteriaceae Infections; Escherichia coli; Escherichia coli Infections; Fluoroquinolones; Gene Expression; Humans; Klebsiella Infections; Klebsiella pneumoniae; Minocycline; Plasmids; Tigecycline

Combination therapy is recommended for the treatment of KPC-producing Klebsiella pneumoniae (KPC-Kp), but the optimal regimen for colistin-resistant strains is unknown. We compared the synergistic activity and post-antibiotic effect (PAE) of colistin in combination with other antimicrobials against colistin-susceptible and -resistant KPC-Kp bloodstream isolates.. The genotypes of nine colistin-susceptible and eight colistin-resistant KPC-Kp bloodstream isolates were analysed using PCR and amplicon sequencing. Combinations of colistin, meropenem, tigecycline, rifampicin and teicoplanin were then screened using the Etest, a chequerboard assay and time-kill studies. Synergistic combinations were also analysed with respect to the PAE in time-kill curves and the PAE at clinically achievable concentrations.. Insertional inactivation of the PhoQ/PhoB two-component regulatory system by mgrB-IS5 was identified in 6/8 (75%) colistin-resistant KPC-Kp. Colistin/rifampicin combinations resulted in no interactions [fractional inhibitory concentration (FIC) indices 1.5-2] for colistin-susceptible strains, but were uniformly synergistic (FIC indices 0.1-0.4) against colistin-resistant KPC-Kp. Time-kill kinetic analysis, at clinically achievable fixed concentrations of rifampicin and colistin, confirmed synergy and produced persistent growth inhibition (3 h) of colistin-resistant KPC-Kp strains exposed to colistin/rifampicin or colistin/rifampicin/tigecycline combinations.. Combinations of colistin plus rifampicin, and less frequently tigecycline, exhibited synergistic activity in vitro against colistin-resistant KPC-Kp strains.

Topics: Anti-Bacterial Agents; Bacteremia; beta-Lactamases; Colistin; DNA, Bacterial; Drug Resistance, Bacterial; Drug Synergism; Genotype; Humans; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Minocycline; Polymerase Chain Reaction; Rifampin; Sequence Analysis, DNA; Tigecycline

Carbapenem-resistant Klebsiella pneumoniae (CRKP) is an increasing global threat. Here, we describe the prevalence and impact of tigecycline use in a cohort of patients with CRKP bacteriuria nested within a multicentre, prospective study. In the 21-month study period, 260 unique patients were included. Tigecycline was given to 80 (31%) patients. The use of tigecycline during the index hospitalization was significantly associated with the subsequent development of tigecycline resistance in the same patient (OR, 6.13; 95% CI, 1.15-48.65; p 0.03). In conclusion, the use of tigecycline with CRKP bacteriuria is common, and is associated with the subsequent development of tigecycline resistance.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Bacteriuria; Carbapenems; Cohort Studies; DNA, Bacterial; Drug Resistance, Bacterial; Female; Humans; Klebsiella Infections; Klebsiella pneumoniae; Male; Middle Aged; Minocycline; Molecular Sequence Data; Sequence Analysis, DNA; Tigecycline

To identify the risk factors for incident enteric colonization by KPC-producing Klebsiella pneumoniae (KPC-Kp) resistant to colistin or tigecycline during Intensive Care Unit (ICU) stay.. A prospective observational study of patients admitted to the ICU was conducted during a 27-month period. Rectal samples taken upon admission and weekly afterwards were inoculated on selective chromogenic agar. K. pneumoniae isolates were characterized by standard methodology. Mean inhibitory concentration (MIC) to colistin and tigecycline were determined by E-test. The presence of bla KPC gene was confirmed by PCR.. Among 254 patients, 62 (24.4%) became colonized by colistin- resistant KPC-Kp during their stay. Multivariate analysis revealed that corticosteroid, colistin administration and number of colonized patients in nearby beds per day were significantly associated with colonization. Among 257 patients, 39 (17.9%) became colonized by tigecycline resistant KPC-Kp during their stay. Risk factors identified by multivariate analysis were: days at risk, obesity, number of colonized patients treated in nearby beds per day and administration of tigecycline.. The high prevalence of colistin or tigecycline resistant KPC-Kp enteric carriage in ICU patients indicate that dissemination is due to their transfer from patient to patient via the personnel and indicates the importance of strict infection control protocols.

Topics: Adult; Aged; Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Colistin; Drug Resistance, Bacterial; Female; Greece; Hospitalization; Hospitals, University; Humans; Intensive Care Units; Klebsiella Infections; Klebsiella pneumoniae; Male; Middle Aged; Minocycline; Prospective Studies; Risk Factors; Tertiary Care Centers; Tigecycline

Of 26 tigecycline-nonsusceptible Klebsiella pneumoniae (TNSKP) clinical isolates, 25 had nonsynonymous mutations in ramR and/or acrR (23 in ramR and 10 in acrR). Eight TNSKP isolates possessed overexpression of ramA, acrB, rarA, and oqxB simultaneously, while 8 and 1 TNSKP strains had upregulation of ramA and acrB and of rarA and oqxB, respectively. Thus, resistance mechanisms of 9 TNSKP isolates cannot be explained by the present pathways. This study underscores the role of RamA in TNSKP and suggests the presence of novel tigecycline resistance mechanisms.

Topics: Anti-Bacterial Agents; Drug Resistance, Multiple, Bacterial; Humans; Klebsiella Infections; Klebsiella pneumoniae; Membrane Transport Proteins; Microbial Sensitivity Tests; Minocycline; Multidrug Resistance-Associated Proteins; Tigecycline

Solid organ transplantation (SOT) is a risk factor for the acquisition of carbapenem-resistant Klebsiella pneumoniae. This infection is associated with a high mortality rate given the limited armamentarium of antibiotics for multidrug-resistant organisms along with continued immunosuppression to prevent graft rejection. We report a case of carbapenem-resistant K. pneumoniae pneumonia, bacteraemia and intra-abdominal infection in a newly transplanted liver recipient. The patient was successfully treated with a long course of high-dose tigecycline and colistin, along with surgical drainage. We discuss SOT-relevant epidemiology, therapeutic options and the rationale for our treatment choice.

Topics: Anti-Bacterial Agents; Colistin; Dose-Response Relationship, Drug; Drug Therapy, Combination; Humans; Klebsiella Infections; Klebsiella pneumoniae; Liver Transplantation; Male; Middle Aged; Minocycline; Opportunistic Infections; Tigecycline

This 3-year prospective, observational, single-center study was undertaken to describe prescription, microbiology findings, tolerance, and efficacy of tigecycline for carbapenem-resistant Klebsiella pneumoniae (CRKP) infections after liver transplantation in the intensive care unit (ICU).. All patients after liver transplantation treated with tigecycline for ≥3 days for CRKP infections in our ICU from January 1, 2010, to December 31, 2012, were studied. Patient characteristics, indication of treatment, bacteriology, and ICU mortality were collected. The main end points were clinical and microbiologic efficacy and tolerance of tigecycline.. Over the study period, 8 men and 2 women (18 CRKP isolates), aged 54.3 ± 7.7 years, were included in the study. Acute Physiology and Chronic Health Evaluation and Sequential Organ Failure Assessment scores on ICU admission were 13.7 ± 2.7 and 10 ± 2.2, respectively. In 7 isolates, tigecycline was prescribed for CRKP blood stream infection (BSI), in 6 for complicated intra-abdominal infection (IAI), in 2 for ventilator-associated pneumonia (VAP), in 2 for surgical site infection, and in 1 for urinary tract infection. In 4 cases, tigecycline was prescribed for secondary BSI followed by VAP and/or IAI. All isolates were susceptible to tigecycline, 83.4% to colistin, 44.5% to gentamicin, and 27.8% to amikacin. In 2 patients, tigecycline was prescribed as monotherapy. Three patients had clinical failure. The microbiologic response rate was 70%. Superinfection was detected in 5 patients, and Pseudomonas aeruginosa was the most frequently isolated pathogen. Tigecycline was generally well tolerated. The ICU mortality rate was 60% with attributable mortality rate 30%.. Our pilot study suggests that tigecycline shows a good safety and tolerance profile in patients with CRKP infections in the ICU after orthotopic liver transplantation. Limited therapeutic options for such infections leave physicians no choice but to use tigecycline for off-label indications such as urinary tract and blood stream infections.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; beta-Lactam Resistance; Carbapenems; Female; Follow-Up Studies; Greece; Humans; Incidence; Intensive Care Units; Klebsiella Infections; Klebsiella pneumoniae; Liver Transplantation; Male; Middle Aged; Minocycline; Pilot Projects; Prospective Studies; Risk Factors; Tigecycline; Time Factors; Treatment Outcome

Tigecycline is one of the few therapeutic options for treating infections caused by some multi-drug resistant pathogens, such as Klebsiella pneumoniae. However, tigecycline-resistant K. pneumoniae has been discovered recently in China. From 2009 to 2013, nine tigecycline-resistant K. pneumoniae isolates were identified in our hospital. Six of nine strains were identified before using tigecycline. To investigate the efflux-mediated resistance mechanisms of K. pneumoniae, the expression of efflux pump genes (acrA, acrB, tolC, oqxA and oqxB) and pump regulators (acrR, marA, soxS, rarA, rob and ramA) were examined by real-time RT-PCR. Molecular typing of the tigecycline resistant strains was performed. ST11 was the predominant clone of K. pneumoniae strains, while ST1414 and ST1415 were novel STs. Efflux pump inhibitor (EPI)-carbonyl cyanide chlorophenylhydrazone (CCCP) was able to reverse the resistance patterns of 5 resistant K. pneumoniae strains. In comparison with strain A111, a tigecycline-susceptible strain (negative control), we found that the expression levels of efflux pump genes and pump regulators were higher in a majority of resistant strains. Higher expression levels of regulators rarA (2.41-fold, 9.55-fold, 28.44-fold and 18.31-fold, respectively) and pump gene oqxB (3.87-fold, 31.96-fold, 50.61-fold and 29.45-fold, respectively) were observed in four tigecycline resistant strains (A363, A361, A368, A373, respectively). Increased expression of acrB was associated with ramA and marA expression. To our knowledge, studies on tigecycline resistance mechanism in K. pneumoniae are limited especially in China. In our study, we found that both efflux pump AcrAB-TolC and OqxAB contributed to tigecycline resistance in K. pneumoniae isolates.

Topics: Anti-Bacterial Agents; Bacterial Proteins; China; Genes, MDR; Humans; Klebsiella Infections; Klebsiella pneumoniae; Membrane Transport Proteins; Microbial Sensitivity Tests; Minocycline; Tetracycline Resistance; Tigecycline

Colistin, tigecycline, levofloxacin, tobramycin, and rifampin alone and in combination with doripenem were investigated for their in vitro activities and postantibiotic effects (PAEs) on Klebsiella pneumoniae. The in vitro activities of tested antibiotics in combination with doripenem were determined using a microbroth checkerboard technique. To determine the PAEs, K. pneumoniae strains in the logarithmic phase of growth were exposed for 1 h to antibiotics, alone and in combination. Recovery periods of test cultures were evaluated using viable counting after centrifugation. Colistin, tobramycin, and levofloxacin produced strong PAEs ranging from 2.71 to 4.23 h, from 1.31 to 3.82 h, and from 1.35 to 4.72, respectively, in a concentration-dependent manner. Tigecycline and rifampin displayed modest PAEs ranging from 1.18 h to 1.55 h and 0.92 to 1.19, respectively. Because it is a beta-lactam, PAEs were not exactly induced by doripenem (ranging from 0.10 to 0.18 h). In combination, doripenem scarcely changed the duration of PAE of each tested antibiotic alone. The findings of this study may have important implications for the timing of doses during K. pneumoniae therapy with tested antibiotics.

Topics: Carbapenems; Colistin; Doripenem; Dose-Response Relationship, Drug; Drug Combinations; Humans; Intensive Care Units; Klebsiella Infections; Klebsiella pneumoniae; Levofloxacin; Minocycline; Rifampin; Tigecycline; Tobramycin

In this study, the characteristics of carbapenem-resistant Enterobacteriaceae (CRE) isolates from Korea was investigated. A total of 22 CRE isolates were investigated, and most were identified as Klebsiella pneumoniae (16 isolates). In vitro antimicrobial susceptibility testing, multilocus sequence typing, and pulsed-field gel electrophoresis were performed. Extended-spectrum β-lactamase (ESBL) and carbapenemase genes were detected using gene amplification and sequencing. Efflux pump activity and inactivating mutations in OmpK35/36 were also investigated. Among 22 CRE isolates, only 5 produced metallo-β-lactamases (3 NDM-1, one VIM-2 and one IMP-1). Four and 2 K. pneumoniae and Serratia marcescens isolates showed resistance to polymyxins, respectively, and 2 CRE isolates (1 K. pneumoniae and C. freundii) were resistant to tigecycline. The prevalent carbapenem resistance mechanism found in K. pneumoniae might be porin defects. The most prevalent clone of carbapenem-resistant K. pneumoniae was ST11 (56.3%), which is the most frequently identified clone among ESBL-producing K. pneumoniae isolates from Korea. Three NDM-1-producing K. pneumoniae isolates belonged to a single clone (ST340) despite their different antimicrobial susceptibilities. In the present study, the clonal dissemination of carbapenem-resistant K. pneumoniae isolates (ST11) and NDM-1-producing K. pneumoniae isolates (ST340) was determined. Polymyxin- and tigecycline-resistant CRE isolates were also identified, which limits treatment options for infections causes by these organisms.

Topics: Anti-Bacterial Agents; Bacterial Proteins; beta-Lactam Resistance; beta-Lactamases; Carbapenems; Electrophoresis, Gel, Pulsed-Field; Humans; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Minocycline; Multilocus Sequence Typing; Mutation; Polymyxins; Porins; Republic of Korea; Tigecycline

Carbapenem resistance due to OXA-48 enzymes in Klebsiella pneumoniae is increasing particularly in the Middle Eastern and European regions. Treatment options are limited. The aim of this study was to evaluate the in vitro synergistic activity of fosfomycin in combination with imipenem, meropenem, colistin and tigecycline against OXA-48 producing K. pneumoniae strains. Twelve carbapenem-resistant OXA-48 producing K. pneumoniae isolates were enrolled in this study. Synergistic activity of fosfomycin combined with imipenem, meropenem, colistin, and tigecycline was assessed by chequerboard method. The combination of fosfomycin was synergistic with imipenem, meropenem and tigecycline with the ratios of 42%, 33%, and 33%, respectively. Whilst the combination of fosfomycin with colistin was fully antagonistic against all of the strains, there was no statistically significant difference between the in vitro synergistic activities of fosfomycin in combination with imipenem, meropenem and tigecycline combinations (P > 0.05). Fosfomycin in combination with other agents can be preferred against multidrug resistant K. pneumoniae strains.

Topics: Anti-Bacterial Agents; beta-Lactam Resistance; beta-Lactamases; Colistin; Disk Diffusion Antimicrobial Tests; Drug Synergism; Fosfomycin; Humans; Imipenem; Klebsiella Infections; Klebsiella pneumoniae; Meropenem; Minocycline; Molecular Typing; Real-Time Polymerase Chain Reaction; Thienamycins; Tigecycline

We performed a nested case-control study (ratio of 1:4) on the emergence of tigecycline-resistant multidrug-resistant Klebsiella pneumoniae (TR-MDRKP) isolates among patients who initially presented with a tigecycline-susceptible MDRKP isolate. Out of 260 patients, 24 (9%) had a subsequent clinical culture positive for a TR-MDRKP isolate within the 90-day follow-up period. On logistic regression analyses, receipt of tigecycline (adjusted odds ratio [OR], 5.06; 95% confidence interval [CI], 1.80 to 14.23; P = 0.002) was the only independent predictor of subsequent isolation of a TR strain.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Case-Control Studies; Drug Resistance, Multiple, Bacterial; Female; Follow-Up Studies; Humans; Klebsiella Infections; Klebsiella pneumoniae; Logistic Models; Male; Microbial Sensitivity Tests; Middle Aged; Minocycline; Tigecycline; Time Factors

The efficacies of tigecycline and ceftazidime against fatal pneumonia in rats caused by an extended-spectrum β-lactamase (ESBL)-positive Klebsiella pneumoniae strain or its wild-type (WT) progenitor were compared. Ceftazidime at 12.5 or 50 mg/kg of body weight twice daily (b.i.d.) was effective (50% or 100% rat survival) in pneumonia caused by the WT isolate but unsuccessful (100% rat mortality) in pneumonia caused by the ESBL-positive variant. In contrast, tigecycline at 6.25, 12.5, or 25 mg/kg b.i.d. showed dosage-dependent efficacy up to 100% rat survival irrespective of the ESBL character of the infecting organism.

Topics: Animals; Anti-Bacterial Agents; Area Under Curve; beta-Lactamases; Ceftazidime; Dose-Response Relationship, Drug; Klebsiella Infections; Klebsiella pneumoniae; Lung; Male; Microbial Sensitivity Tests; Minocycline; Pneumonia, Bacterial; Rats; Survival Analysis; Tigecycline

A carbapenem-sparing regimen of tigecycline plus gentamicin or colistin was effective for treating 24 of 26 (92%) Klebsiella pneumoniae carbapenemase-producing K. pneumoniae infectious episodes in 22 polytrauma intensive care unit patients without comorbidities. The 30-day crude mortality rate was 14%. Regimens were considered appropriate in 12% of episodes according to the Vitek 2 System and in 100% based on E-test.

Topics: Adult; Aged; Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Carbapenems; Colistin; Drug Therapy, Combination; Female; Gentamicins; Humans; Intensive Care Units; Klebsiella Infections; Klebsiella pneumoniae; Male; Middle Aged; Minocycline; Retrospective Studies; Tigecycline; Treatment Outcome

To investigate the trend of tigecycline susceptibility and mechanisms behind tigecycline non-susceptibility in Klebsiella pneumoniae and Escherichia coli isolates causing neonatal septicaemia (2007-10).. MICs of tigecycline for the isolates were determined. The isolates were evaluated for β-lactamases and carbapenemases. Molecular typing of the tigecycline-resistant isolates was performed. Expression of efflux pump genes (acrA, acrB and tolC) and regulators (soxS and ramA) was examined by real-time RT-PCR and western blotting. Sequencing of the ramA and ramR genes was carried out to identify mutations within these genes.. Tigecycline susceptibility was evaluated in all K. pneumoniae (n = 57) and E. coli (n = 19) blood isolates. The prevalence of extended-spectrum β-lactamase (ESBL)-producing organisms was high, but tigecycline non-susceptibility remained low in these isolates. Though MIC values of tigecycline remained in the susceptible range, there was a 2-fold increase in the value of MIC90 from 2007 to 2010. Over the 4 year period K. pneumoniae showed higher MIC values of tigecycline in comparison with E. coli. Tigecycline non-susceptibility was not observed among carbapenem-resistant isolates. Only two ESBL-producing clonally distinct K. pneumoniae isolates showed tigecycline resistance with overexpression of ramA and the AcrAB-TolC pump. No mutations were present within the ramA and ramR genes that might enhance the expression of the pump.. The study showed for the first time the trend of tigecycline susceptibility in E. coli and K. pneumoniae causing neonatal septicaemia. Tigecycline still has potent antimicrobial effects against most ESBL- or carbapenemase-producing K. pneumoniae and E. coli, but the increasing MIC values make it essential to be vigilant.

Topics: Anti-Bacterial Agents; beta-Lactamases; Blotting, Western; Drug Resistance, Bacterial; Escherichia coli; Escherichia coli Infections; Gene Expression Profiling; Humans; Infant, Newborn; Klebsiella Infections; Klebsiella pneumoniae; Membrane Transport Proteins; Microbial Sensitivity Tests; Minocycline; Molecular Typing; Mutant Proteins; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Sepsis; Sequence Analysis, DNA; Tigecycline

Nine isolates of Klebsiella pneumoniae were isolated from a renal transplant patient suffering from recurrent urosepsis over a period of 4 months. Imipenem resistance was detected after imipenem-ertapenem therapy. When treatment was switched to tigecycline the K. pneumoniae developed resistance to tigecycline (MIC = 8 mg/L). The nine isolates were tested by determination of agar dilution MICs, phenotypic carbapenemase, extended-spectrum beta-lactamases and metallo-beta-lactamase (MBL) testing and pulsed-field gel electrophoresis. Polymerase chain reaction and sequencing analysis were employed for identification of bla genes and mapping of the integron carrying the MBL gene. The nine isolates were clonally related and all produced the SHV-12 enzyme. Five MBL-producing isolates showed imipenem MICs ranging from 2 to 64 mg/L and all were detected by testing with imipenem and EDTA. The five isolates harboured the bla(VIM-1) gene. Three isolates showed increased tigecycline MICs (4-8 mg/L). Serial blood cultures obtained on the same day resulted in a VIM-positive/tigecycline-susceptible and a VIM-negative/tigecycline-resistant K. pneumoniae isolate. No isolate developed concurrent imipenem and tigecycline resistance. The patient had a persistent urinary tract infection and recurrent bacteraemia caused by a mixed population of Klebesiella pneumoniae isolates adapting to the selective pressure of antimicrobial therapy at the time. The present study is a worrisome example of what could happen when an immunocompromised host is subjected to the pressures of antimicrobial therapy. In addition, we report the first treatment-emergent MIC increase of tigecycline from 0.5 to 8 mg/L in K. pneumoniae.

Topics: Aged; Anti-Bacterial Agents; Bacterial Proteins; Base Sequence; beta-Lactamases; Carbapenems; Chromosome Mapping; Cross Infection; Drug Resistance, Multiple, Bacterial; Humans; Kidney Transplantation; Klebsiella Infections; Klebsiella pneumoniae; Male; Microbial Sensitivity Tests; Minocycline; Sequence Analysis, DNA; Tigecycline; Urinary Tract Infections

Topics: Adult; Anti-Bacterial Agents; beta-Lactamases; Colistin; Drug Resistance, Multiple, Bacterial; Female; Humans; India; Klebsiella Infections; Klebsiella pneumoniae; Male; Mauritius; Microbial Sensitivity Tests; Minocycline; Multilocus Sequence Typing; Phylogeography; Tigecycline

Although resistance to tigecycline has been reported in surveillance studies, very few reports have described the emergence of resistance in vivo. We report two cases of patients with infections due to SHV-12-producing Klebsiella pneumoniae and K. pneumoniae carbapenemase-3 (KPC-3)-producing Escherichia coli, which developed tigecycline resistance in vivo after treatment. The reported limited experience underlines the risk of occurrence of a tigecycline MIC increase under treatment pressure.

Topics: Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Drug Resistance, Multiple, Bacterial; Escherichia coli; Escherichia coli Infections; Humans; Klebsiella Infections; Klebsiella pneumoniae; Male; Microbial Sensitivity Tests; Middle Aged; Minocycline; Tigecycline

Infections produced by multidrug-resistant pathogens represent a therapeutic challenge because of the few therapeutic options available. Tigecycline is a relatively new antibiotic, with a wide spectrum of activity including some of these resistant bacteria. In adults is prescribed for the treatment of some infections caused by carbapenem resistant K. pneumoniae, however it has not been approved in children because of potential adverse effects in the dental enamel.. Case series study. Medical records were reviewed in all children from 0 to 14 years of age that received tigecycline between January of 2008 and March of 2010.. 9 patients received Tigecycline mainly for treatment of peritonitis, bacteremia, pneumonia and sepsis caused by carbapenem resistant K. pneumoniae. A dose of 1 mg/kg q 12 hours was administered to all patients. No adverse events were reported and a total of 6 patients had complete resolution of the infection.. Tigecycline could be considered a therapeutic option for treating infections produced by multidrug-resistant pathogens in children. The use in children is still compassionate and in this series of cases Tigecycline was well tolerated and safe.

Topics: Anti-Bacterial Agents; beta-Lactam Resistance; Carbapenems; Child, Preschool; Compassionate Use Trials; Fatal Outcome; Female; Humans; Infant; Klebsiella Infections; Klebsiella pneumoniae; Male; Minocycline; Retrospective Studies; Tigecycline

Carbapenem-resistant Klebsiella pneumoniae (CR-Kp) is an emerging multidrug-resistant nosocomial pathogen. This is a retrospective chart review describing the outcomes and treatment of 60 cases of CR-Kp bloodstream infections. All CR-Kp isolated from blood cultures were identified retrospectively from the microbiology laboratory from January 2007 to May 2009. Clinical information was collected from the electronic medical record. Patients with 14-day hospital mortality were compared to those who survived 14 days. The all-cause in-hospital and 14-day mortality for all 60 CR-Kp bloodstream infections were 58.3% and 41.7%, respectively. In this collection, 98% of tested isolates were susceptible in vitro to tigecycline compared to 86% to colistimethate, 45% to amikacin, and 22% to gentamicin. Nine patients died before cultures were finalized and received no therapy active against CR-Kp. In the remaining 51 patients, those who survived to day 14 (n = 35) were compared to nonsurvivors at day 14 (n=16). These patients were characterized by both chronic disease and acute illness. The 90-day readmission rate for hospital survivors was 72%. Time to active therapy was not significantly different between survivors and nonsurvivors, and hospital mortality was also similar regardless of therapy chosen. Pitt bacteremia score was the only significant factor associated with mortality in Cox regression analysis. In summary, CR-Kp bloodstream infections occur in patients who are chronically and acutely ill. They are associated with high 14-day mortality and poor outcomes regardless of tigecycline or other treatment regimens selected.

Topics: Adult; Aged; Anti-Bacterial Agents; Bacteremia; Carbapenems; Colistin; Drug Resistance, Multiple, Bacterial; Female; Humans; Klebsiella Infections; Klebsiella pneumoniae; Male; Middle Aged; Minocycline; Prognosis; Retrospective Studies; Tigecycline; Treatment Outcome

Tigecycline resistance has been attributed to ramA overexpression and subsequent acrA upregulation. The ramA locus, originally identified in Klebsiella pneumoniae, has homologues in Enterobacter and Salmonella spp. In this study, we identify in silico that the ramR binding site is also present in Citrobacter spp. and that Enterobacter, Citrobacter and Klebsiella spp. share key regulatory elements in the control of the romA-ramA locus. RACE (rapid amplification of cDNA ends) mapping indicated that there are two promoters from which romA-ramA expression can be regulated in K. pneumoniae. Correspondingly, electrophoretic binding studies clearly showed that purified RamA and RamR proteins bind to both of these promoters. Hence, there appear to be two RamR binding sites within the Klebsiella romA-ramA locus. Like MarA, RamA binds the promoter region, implying that it might be subject to autoregulation. We have identified changes within ramR in geographically distinct clinical isolates of K. pneumoniae. Intriguingly, levels of romA and ramA expression were not uniformly affected by changes within the ramR gene, thereby supporting the dual promoter finding. Furthermore, a subset of strains sustained no changes within the ramR gene but which still overexpressed the romA-ramA genes, strongly suggesting that a secondary regulator may control ramA expression.

Topics: Anti-Bacterial Agents; Bacterial Proteins; Base Sequence; Binding Sites; Drug Resistance, Bacterial; Gene Expression Regulation, Bacterial; Genes, Bacterial; Humans; Klebsiella Infections; Klebsiella pneumoniae; Membrane Transport Proteins; Microbial Sensitivity Tests; Minocycline; Molecular Sequence Data; Reverse Transcriptase Polymerase Chain Reaction; Tigecycline

Topics: Bacteremia; beta-Lactamases; Calciphylaxis; Coinfection; Colistin; Drug Resistance, Bacterial; Escherichia coli; Escherichia coli Infections; Humans; Klebsiella Infections; Klebsiella pneumoniae; Middle Aged; Minocycline; Tigecycline

Knowledge of the etiology of pyogenic liver and pancreatic abscesses is an important factor in determining the success of combined surgical and antibiotic treatment. Literature shows geographical variations in the prevalence and distribution of causative organisms, and the spread of Klebsiella pneumoniae carbapenemase-producing bacteria is an emerging cause of abdominal infections.. We herein describe two cases of intra-abdominal abscesses due to monomicrobial infection by Klebsiella pneumoniae Sequence Type 258 producing K. pneumoniae carbapenemase 3 (KPC-Kp). In case 1, a 50-year-old HIV-negative Italian woman with chronic pancreatitis showed infection of a pancreatic pseudocystic lesion caused by KPC-Kp. In case 2, a 64-year-old HIV-negative Italian woman with pancreatic neoplasm and liver metastases developed a liver abscess due to KPC after surgery. Both women were admitted to our hospital but to different surgical units. The clonal relationship between the two isolates was investigated by pulsed-field gel electrophoresis (PFGE). In case 2, the patient was already colonized at admission and inter-hospital transmission of the pathogen was presumed. A long-term combination regimen of colistin with tigecycline and percutaneous drainage resulted in full recovery and clearance of the multidrug-resistant (MDR) pathogen.. Timely microbiological diagnosis, the combined use of new and old antibiotics and radiological intervention appeared to be valuable in managing these serious conditions. The emergence and dissemination of MDR organisms is posing an increasing challenge for physicians to develop new therapeutic strategies and control and prevention frameworks.

Topics: Abdominal Abscess; Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Colistin; Drug Resistance, Multiple, Bacterial; Electrophoresis, Gel, Pulsed-Field; Female; Humans; Klebsiella Infections; Klebsiella pneumoniae; Liver Neoplasms; Middle Aged; Minocycline; Pancreatic Neoplasms; Pancreatitis, Chronic; Tigecycline

Carbapenem-resistant Klebsiella pneumoniae (CRKP) is an increasingly common cause of health care-associated urinary tract infections. Antimicrobials with in vitro activity against CRKP are typically limited to polymyxins, tigecycline, and often, aminoglycosides. We conducted a retrospective cohort study of cases of CRKP bacteriuria at New York-Presbyterian Hospital from January 2005 through June 2010 to compare microbiologic clearance rates based on the use of polymyxin B, tigecycline, or an aminoglycoside. We constructed three active antimicrobial cohorts based on the active agent used and an untreated cohort of cases that did not receive antimicrobial therapy with Gram-negative activity. Microbiologic clearance was defined as having a follow-up urine culture that did not yield CRKP. Cases without an appropriate follow-up culture or that received multiple active agents or less than 3 days of the active agent were excluded. Eighty-seven cases were included in the active antimicrobial cohorts, and 69 were included in the untreated cohort. The microbiologic clearance rate was 88% in the aminoglycoside cohort (n = 41), compared to 64% in the polymyxin B (P = 0.02; n = 25), 43% in the tigecycline (P < 0.001; n = 21), and 36% in the untreated (P < 0.001; n = 69) cohorts. Using multivariate analysis, the odds of clearance were lower for the polymyxin B (odds ratio [OR], 0.10; P = 0.003), tigecycline (OR, 0.08; P = 0.001), and untreated (OR, 0.14; P = 0.003) cohorts than for the aminoglycoside cohort. Treatment with an aminoglycoside, when active in vitro, was associated with a significantly higher rate of microbiologic clearance of CRKP bacteriuria than treatment with either polymyxin B or tigecycline.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Aminoglycosides; Anti-Bacterial Agents; Carbapenems; Cohort Studies; Drug Resistance, Bacterial; Female; Humans; Klebsiella Infections; Klebsiella pneumoniae; Male; Microbial Sensitivity Tests; Middle Aged; Minocycline; Polymyxin B; Retrospective Studies; Tigecycline; Treatment Outcome; Urinary Tract Infections; Urine; Young Adult

In vitro activity of fosfomycin was evaluated against 68 bla(KPC)-possessing Klebsiella pneumoniae (KpKPC) isolates, including 23 tigecycline- and/or colistin-nonsusceptible strains. By agar dilution, 93% of the overall KpKPC were susceptible (MIC(50/90) of 16/64 microg/ml, respectively). The subgroup of 23 tigecycline- and/or colistin-nonsusceptible strains showed susceptibility rates of 87% (MIC(50/90) of 32/128 microg/ml, respectively). Notably, 5 out of 6 extremely drug-resistant (tigecycline and colistin nonsusceptible) KpKPC were susceptible to fosfomycin. Compared to agar dilution, disk diffusion was more accurate than Etest.

Topics: Anti-Bacterial Agents; beta-Lactamases; Colistin; Drug Resistance, Bacterial; Fosfomycin; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Minocycline; Phenotype; Tigecycline

Five Klebsiella pneumoniae isolates with reduced susceptibility to tigecycline (MIC, 2 microg/ml) were analyzed. A gene homologous to ramR of Salmonella enterica was identified in Klebsiella pneumoniae. Sequencing of ramR in the nonsusceptible Klebsiella strains revealed deletions, insertions, and point mutations. Transformation of mutants with wild-type ramR genes, but not with mutant ramR genes, restored susceptibility to tigecycline and repressed overexpression of ramA and acrB. Thus, this study reveals a molecular mechanism for tigecycline resistance in Klebsiella pneumoniae.

Topics: Anti-Bacterial Agents; Bacterial Proteins; Base Sequence; DNA Mutational Analysis; DNA Primers; DNA, Bacterial; Drug Resistance, Bacterial; Gene Expression; Genes, Bacterial; Humans; In Vitro Techniques; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Minocycline; Mutation; Reverse Transcriptase Polymerase Chain Reaction; Tigecycline

Tigecycline is a new glycylcycline with broad-spectrum activity. Among these new agents, tigecycline is unique in generally having good activity against Gram-negative bacteria. Tigecycline has been approved for the treatment of complicated intra-abdominal infections and complicated skin and skin structure infections. Tigecycline had good activity against most ESBL-producing Enterobacteriaceae and may be a therapeutic alternative to carbapenems in some infections caused by ESBL-producing isolates, many of which are also multiresistant to quinolones, aminoglycosides, and classical tetracyclines.. One hundred and eight clinical isolates of Klebsiella spp. (64 K. pneumoniae and 44 K. oxytoca) were included. The susceptibility to selected antibiotics was tested by the disk-diffusion method. Tigecycline's MIC was determined by the Etest.. Of all the analyzed Klebsiella spp. strains, 31 (28.7%) produced ESBLs. Most of the Klebsiella spp. strains were susceptible to imipenem (100%), tigecycline (92.5%), and the combination of piperacilline and tazobactam (80.6%). Tigecycline exhibited high activity against Klebsiella strains, with MICs ranging from 0.19 to 4 microg/ml.. Tigecycline demonstrated excellent inhibitory activity against the analyzed strains. These data suggest that tigecycline, with an expanded broad-spectrum antimicrobial activity, may be an effective therapeutic option for the treatment of serious infections caused by Klebsiella strains.

Topics: Anti-Bacterial Agents; beta-Lactamases; Cross Infection; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; Enterobacteriaceae; Humans; Klebsiella; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Minocycline; Tigecycline

The spread of antimicrobial resistance among members of the Enterobacteriaceae is a significant clinical threat. We report the treatment of pan-resistant Klebsiella pneumoniae bacteraemia with combination tigecycline and colistin in a 49-year-old male and review available therapeutic options. Despite a poor prognosis, the patient recovered, but remains colonized with the pan-resistant isolate.

Topics: Animals; Anti-Bacterial Agents; Bacteremia; Colistin; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Humans; Klebsiella Infections; Klebsiella pneumoniae; Male; Microbial Sensitivity Tests; Middle Aged; Minocycline; Pneumonia, Bacterial; Tigecycline

Optimal antimicrobial therapy for infections due to ertapenem-resistant Enterobacteriaceae remains undetermined. In this study, a diabetic patient with recurrent pyomyositis and osteomyelitis caused by extended-spectrum β-lactamase (ESBL)-producing Klebsiella pneumoniae developed ertapenem resistance after imipenem/cilastatin treatment, which was a currently recommended therapy. He was finally treated successfully using tigecycline. Ertapenem resistance was in part explained by the production of SHV-type ESBL and the absence of an outer membrane protein, OmpK36. Our observation suggests that tigecycline may be an alternative for invasive infections caused by ESBL-producing Enterobacteriaceae with decreased susceptibility to carbapenem.

Topics: Anti-Bacterial Agents; beta-Lactams; Diabetes Complications; Ertapenem; Humans; Klebsiella Infections; Klebsiella pneumoniae; Male; Middle Aged; Minocycline; Osteomyelitis; Pyomyositis; Recurrence; Salvage Therapy; Tigecycline; Treatment Outcome

This observational retrospective study aims to present early experience with tigecycline (TIG) in the treatment of infections due to multi-drug resistant (MDR) microorganisms.. Adult patients included, received TIG for >5 days either as monotherapy (M group) or as presumed active monotherapy (PAM group). In the PAM group, all co-administered antimicrobial(s) were resistant in vitro against the targeted pathogen(s) or had been clinically and microbiologically failing after >or=5 days of therapy despite in vitro susceptibility.. Forty-five patients (35 in ICU) were treated for 28 Acinetobacter baumannii and 23 Klebsiella pneumoniae infections [21 ventilator-associated and healthcare-acquired pneumonia (VAP/HCAP), 10 bloodstream infections (BSI) and 14 surgical infections (SI)]. Successful overall clinical outcome was 80%, i.e. 81.8% in M group, 78.3% in PAM group, 90.5% in VAP/HCAP, 80% in BSI, 64.3% in SI and 85% in the cases with septic shock. Superinfections from Enterobacteriaceae inherently resistant to tigecycline occurred in 31.8% of M and 13% of PAM group (p<0.001).. TIG represents a promising option in infections from MDR pathogens, however, further clinical experience is required.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Adult; Aged; Analysis of Variance; Anti-Bacterial Agents; Bacteremia; Chi-Square Distribution; Cross Infection; Drug Resistance, Multiple, Bacterial; Female; Gram-Negative Bacterial Infections; Humans; Klebsiella Infections; Klebsiella pneumoniae; Logistic Models; Male; Microbial Sensitivity Tests; Middle Aged; Minocycline; Pneumonia, Ventilator-Associated; Retrospective Studies; Shock, Septic; Surgical Wound Infection; Tigecycline

Tigecycline is a glycylcycline with activity against Enterobacteriaceae, including multidrug-resistant isolates of Klebsiella pneumoniae and Escherichia coli producing extended-spectrum beta-lactamase (ESBL) and carbapenemases. Herein, we used an in vivo murine thigh model to characterize the pharmacodynamic profile of tigecycline against genotypically and phenotypically diverse K. pneumoniae and E. coli isolates. Doses of 3.125 to 300 mg/kg, divided 1 to 6 times daily, were administered subcutaneously against six (two nonresistant, one carbapenemase, and three ESBL producing) K. pneumoniae strains and five (two nonresistant and three ESBL producing) E. coli strains. The phenotypic profile (reported tigecycline MIC) for all isolates ranged from 0.125 to 2 microg/ml. Mean correlation coefficients of free (f) drug exposures (percentage of the dosing interval that free drug concentration remained above the MIC [fT>MIC], the ratio of the free drug area under the concentration-time curve/MIC [fAUC/MIC], and the ratio of maximum concentration of free drug in serum/MIC) for all 11 isolates were 0.595, 0.969, and 0.897, respectively. The fAUC/MIC was the pharmacodynamic parameter that best described the efficacy of tigecycline against both E. coli and K. pneumoniae. Interestingly, reductions in the number of CFU were noted even though doses achieved an fT>MIC of 0%. With respect to fAUC/MIC in the neutropenic model, the cumulative 80% and 50% effective pharmacodynamic indexes (EI(80) and EI(50)) for all 11 isolates were 8.4 and 4.7, respectively. An experiment in nonneutropenic mice infected with an ESBL-producing E. coli and K. pneumoniae isolate resulted in the lowest tigecycline fAUC/MIC EI(80) and EI(50) values at 1.8 and 1.0 for E. coli and 1.7 and 1.6 for K. pneumoniae. While the phenotypic profile of tigecycline appeared to drive efficacy irrespective of ESBL or carbapenemase production, the presence of a competent immune system markedly reduced this required exposure.

Topics: Animals; Anti-Bacterial Agents; Escherichia coli; Escherichia coli Infections; Female; Klebsiella Infections; Klebsiella pneumoniae; Mice; Minocycline; Tigecycline

Topics: Acinetobacter baumannii; Acinetobacter Infections; Anti-Bacterial Agents; Drug Resistance, Multiple, Bacterial; Humans; Klebsiella Infections; Klebsiella pneumoniae; Minocycline; Sepsis; Serum; Tigecycline; Urinary Tract Infections; Urine

Nosocomial isolates of Klebsiella pneumoniae resistant to all commonly used antimicrobial agents have emerged in many regions of the world. It is unknown if efflux systems contribute to the multidrug resistance phenotype.. The expression of genes encoding the efflux pump AcrAB and the global regulators MarA, SoxS and RamA were examined and correlated with antimicrobial resistance.. Twenty isolates belonged to the two important clones representing KPC-possessing strains endemic to our region. Virtually all of these isolates had negligible or absent expression of the genes, and resistance to fluoroquinolones and aminoglycosides could be explained by alternative mechanisms. All of these isolates were susceptible to tigecycline. A group of 14 heterogeneous isolates was also examined. There was a correlation between expression of marA with expression of soxS. Only expression of soxS was significantly correlated with expression of acrB. With a background substitution in GyrA, increased expression of acrB and marA appeared to contribute to fluoroquinolone resistance in some isolates. A correlation was noted between expression of soxS and ramA (but not marA and acrB) and tigecycline MICs. Following in vitro exposure to tigecycline, resistance occurred in association with a marked increase in marA and acrB expression in isolates lacking expression of soxS and ramA.. While laboratory-derived tigecycline resistance was associated with increased acrB expression, the variation in tigecycline MICs in clinical isolates was associated only with selected regulator genes. It appears that other mechanisms beyond activation of the acrAB system mediate tigecycline resistance.

Topics: Anti-Bacterial Agents; Bacterial Proteins; Drug Resistance, Bacterial; Endemic Diseases; Gene Expression; Gene Expression Profiling; Humans; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Minocycline; New York City; Tigecycline

Topics: Anti-Bacterial Agents; Bacterial Proteins; beta-Lactam Resistance; beta-Lactamases; beta-Lactams; Carbapenems; Colombia; Drug Resistance, Bacterial; Greece; Humans; Israel; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Minocycline; Population Surveillance; Puerto Rico; Tigecycline

Topics: Anti-Bacterial Agents; Drug Resistance, Multiple, Bacterial; Humans; Klebsiella Infections; Klebsiella pneumoniae; Male; Mediastinitis; Middle Aged; Minocycline; Tigecycline; Treatment Outcome

We report the use of tigecycline, firstly with colistin and finally alone, in a patient with a persistent breakthrough bacteremia due to a Klebsiella pneumoniae isolate harboring a metallo-beta-lactamase (VIM-1) and an extended-spectrum beta-lactamase (SHV-12). Time-kill studies demonstrated that the combination of both compounds was synergistic along the first 12 h, suppressing the regrowth observed after 3 to 6 h when colistin was tested alone.

Topics: Aged; Anti-Bacterial Agents; Bacteremia; beta-Lactamases; Colistin; Drug Synergism; Drug Therapy, Combination; Humans; Klebsiella Infections; Klebsiella pneumoniae; Male; Microbial Sensitivity Tests; Microbial Viability; Minocycline; Tigecycline

Tigecycline showed excellent in vitro activity against 50 clinical isolates of Klebsiella pneumoniae producing extended-spectrum beta-lactamases, plasmid-mediated AmpC-type beta-lactamases, or both. This activity was not affected by porin loss. Porin loss, however, did affect the activity of imipenem against strains that expressed both types of enzymes.

Topics: Anti-Bacterial Agents; beta-Lactamases; Imipenem; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Minocycline; Plasmids; Porins; Tigecycline

Strains of Klebsiella pneumoniae that produce one of three possible carbapenemases--KPC--have recently been identified with increasing frequency among isolates recovered from patients residing along the East Coast of the United States, particularly within the New York City metropolitan region. These strains have exhibited resistance to multiple antibiotic classes, including carbapenem agents. We report a case of nosocomial pneumonia and empyema caused by a KPC-producing isolate of K. pneumoniae at a large midwestern U.S. tertiary care facility in which the patient was treated with tigecycline. Although the pneumonia was treated successfully, the empyema recurred in association with a treatment-emergent tigecycline minimum inhibitory concentration (MIC) increase from 0.75 to 2 microg/ml. Clinicians should be aware of the potential occurrence of this treatment-emergent MIC increase, especially in the setting of sustained tigecycline therapy. In addition, the emergence of carbapenem-resistant Enterobacteriaceae reinforces the importance of antibiotic stewardship and strict infection control practices.

Topics: Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Cross Infection; Drug Resistance, Multiple, Bacterial; Empyema; Female; Humans; Klebsiella Infections; Klebsiella pneumoniae; Middle Aged; Minocycline; Pneumonia, Bacterial; Tigecycline

Topics: Drug Resistance, Bacterial; Drug Resistance, Multiple; Enterobacter aerogenes; Enterobacteriaceae Infections; Humans; Klebsiella Infections; Klebsiella pneumoniae; Male; Minocycline; Tigecycline; Urinary Tract Infections