Search

Objectives: The emergence of polymyxin resistance threatens to leave clinicians with few options for combatting drug-resistant Acinetobacter baumannii . The objectives of the current investigation were to define the in vitro emergence of polymyxin resistance and identify a combination regimen capable of eradicating A. baumannii with no apparent drug susceptibilities., Methods: Two clonally related, paired, A. baumannii isolates collected from a critically ill patient who developed colistin resistance while receiving colistin methanesulfonate in a clinical population pharmacokinetic study were evaluated: an A. baumannii isolate collected before (03-149.1, polymyxin-susceptible, MIC 0.5 mg/L) and an isolate collected after (03-149.2, polymyxin-resistant, MIC 32 mg/L, carbapenem-resistant, ampicillin/sulbactam-resistant). Using the patient's unique pharmacokinetics, the patient's actual regimen received in the clinic was recreated in a hollow-fibre infection model (HFIM) to track the emergence of polymyxin resistance against 03-149.1. A subsequent HFIM challenged the pan-resistant 03-149.2 isolate against polymyxin B, meropenem and ampicillin/sulbactam alone and in two-drug and three-drug combinations., Results: Despite achieving colistin steady-state targets of an AUC 0-24 >60 mg·h/L and C avg of >2.5 mg/L, colistin population analysis profiles confirmed the clinical development of polymyxin resistance. During the simulation of the patient's colistin regimen in the HFIM, no killing was achieved in the HFIM and amplification of polymyxin resistance was observed by 96 h. Against the polymyxin-resistant isolate, the triple combination of polymyxin B, meropenem and ampicillin/sulbactam eradicated the A. baumannii by 96 h in the HFIM, whereas monotherapies and double combinations resulted in regrowth., Conclusions: To combat polymyxin-resistant A. baumannii , the triple combination of polymyxin B, meropenem and ampicillin/sulbactam holds great promise., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Carbapenem antibiotics are considered the treatment of choice for serious extended-spectrum beta-lactamase (ESBL)-producing Gram-negative bacteria (GNB) infections. The study objectives were to evaluate efficacy and safety of de-escalation therapy to ertapenem for treatment of infections caused by extended-spectrum-β-lactamase-producing Enterobacteriaceae., Methods: We conducted a randomized controlled trial of adult patients with documented ESBL-producing Enterobacteriaceae infections who had received any group 2 carbapenem for less than 96 h. In the intervention group, the previously-prescribed group 2 carbapenem was de-escalated to ertapenem. In the control group, the group 2 carbapenem was continued., Results: During June 2011-December 2014, 32 patients were randomized to the de-escalation group and 34 to the control group. Most common sites of infection were urinary tract infection (42%). Characteristics of both groups were comparable. By using a 15% predefined margin, ertapenem was non-inferior to control group regarding the clinical cure rate (%Δ = 14.0 [95% confidence interval: -2.4 to 31.1]), the microbiological eradication rate (%Δ = 4.1 [-5.0 to 13.4]), and the superimposed infection rate (%Δ = -16.5 [-38.4 to 5.3]). Patients in the de-escalation group had a significantly lower 28-day mortality rate (9.4% vs. 29.4%; P = .05), a significantly shorter median length of stay (16.5 days [4.0-73.25] vs. 20.0 days [1.0-112.25]; P = .04), and a significantly lower defined daily dose of carbapenem use (12.9 ± 8.9 vs. 18.4 ± 12.6; P = .05)., Conclusions: Ertapenem could be safely used as de-escalation therapy for ESBL-producing Enterobacteriaceae infections, once the susceptibility profiles are known. Future studies are needed to investigate ertapenem efficacy against ESBL-producing Enterobacteriaceae pneumonia to determine its applicability in life-threatening conditions., Trial Registration: ClinicalTrials.gov identifier: NCT01297842 . Registered on 14 February 2011. First patient enrolled on 27 June 2011.

The objective of this study was to determine the comparative pharmacodynamics of four different carbapenems in combination with polymyxin B (PMB) against carbapenem-resistant Acinetobacter baumannii isolates using time-kill experiments at two different inocula. Two A. baumannii strains (03-149-1 and N16870) with carbapenem minimum inhibitory concentrations (MICs) ranging from 8 to 64 mg/L were investigated in 48-h time-kill experiments using starting inocula of 10 6  CFU/mL and 10 8  CFU/mL. Concentration arrays of ertapenem, doripenem, meropenem and imipenem at 0.25×, 0.5×, 1×, 1.5× and 2× published maximum serum concentration (C max ) values (C max concentrations of 12, 21, 48 and 60 mg/L, respectively) were investigated in the presence of 1.5 mg/L PMB. Use of carbapenems without PMB resulted in drastic re-growth. All carbapenem combinations were able to achieve a ≥3 log 10 CFU/mL reduction by 4 h against both strains at 10 6  CFU/mL, whereas maximum reductions against strain 03-149-1 at 10 8  CFU/mL were 1.0, 3.2, 2.2 and 3.3 log 10 CFU/mL for ertapenem, doripenem, meropenem and imipenem, respectively. None of the combinations were capable of reducing 10 8  CFU/mL of N16870 by ≥2 log 10 CFU/mL. Ertapenem combinations consistently displayed the least activity, whereas doripenem, meropenem and imipenem combinations had similar activities that were poorly predicted by carbapenem MICs. As doripenem, meropenem, or imipenem displayed similar pharmacodyanmics in combination, the decision of which carbapenem to use in combination with PMB may be based on toxicodynamic profiles if drastic discordance in MICs is not present., Competing Interests: Conflicts of Interest: None declared., (Copyright © 2016. Published by Elsevier B.V.)

Objective: To determine in vitro and in vivo activity of tebipenem against ESBL-producing E. coli., Material and Method: Minimum inhibitory concentration (MIC) of tebipenem against 100 clinical isolates of ESBL-producing E. coli was performed by broth micro-dilution technique. Blood and urine samples from 10 healthy male subjects before and after receiving 300 mg of tebipenem pivoxil 3 times a day for 2 consecutive days were determined for inhibitory and bactericidal titers against a clinical urinary isolate of ESBL-producing E. coli by disk diffusion method and broth micro- dilution method., Results: MIC50 and MC90 of tebipenem against ESBL-producing E. coli were both 0.06 mg/L with MIC range from ≤ 0.06 to 0.25 mg/L. The inhibition zones were observed around the disks inoculated with serum samples and urine samples collected from all study subjects after receiving tebipenem pivoxil for at least 1 hour and 5 hours, respectively. The inhibitory titer of 1:160 and bactericidal titer of 1:160 of serum samples were observed for at least one hour after ingestion of tebipenem pivoxil. Inhibitory titer of 1:640 and bactericidal titer of 1:640 of urine samples were observed after at least 14 hours after ingestion of tebipenem pivoxil. No subjects experienced side effects related to receiving tebipenem pivoxil., Conclusion: Tebipenem is very active against ESBL-producing E. coli. Oral administration of tebipenem pivoxil 300 mg 3 times a day for two days was well tolerated, safe and induced high inhibitory and bactericidal activity in serum and urine. Tebipenem pivoxil could be an oral agent for effective therapy of ESBL-producing E. coli infections.

In this surveillance study, we identified the genotypes, carbapenem resistance determinants, and structural variations of AbaR-type resistance islands among carbapenem-resistant Acinetobacter baumannii (CRAB) isolates from nine Asian locales. Clonal complex 92 (CC92), corresponding to global clone 2 (GC2), was the most prevalent in most Asian locales (83/108 isolates; 76.9%). CC108, or GC1, was a predominant clone in India. OXA-23 oxacillinase was detected in CRAB isolates from most Asian locales except Taiwan. blaOXA-24 was found in CRAB isolates from Taiwan. AbaR4-type resistance islands, which were divided into six subtypes, were identified in most CRAB isolates investigated. Five isolates from India, Malaysia, Singapore, and Hong Kong contained AbaR3-type resistance islands. Of these, three isolates harbored both AbaR3- and AbaR4-type resistance islands simultaneously. In this study, GC2 was revealed as a prevalent clone in most Asian locales, with the AbaR4-type resistance island predominant, with diverse variants. The significance of this study lies in identifying the spread of global clones of carbapenem-resistant A. baumannii in Asia.

Background: Increased infection caused by multidrug resistant (MDR) Pseudomonas aeruginosa has raised awareness of the resistance situation worldwide. Carbapenem resistance among MDR (CR-MDR) P. aeruginosa has become a serious life-threatening problem due to the limited therapeutic options. Therefore, the objectives of this study were to determine the prevalence, the antibiotic susceptibility patterns and the relatedness of CR-MDR P. aeruginosa in tertiary hospitals across Thailand., Methods: MDR P. aeruginosa from eight tertiary hospitals across Thailand were collected from 2007-2009. Susceptibility of P. aeruginosa clinical isolates was determined according to the Clinical and Laboratory Standards Institute guideline. Selected CR-MDR P. aeruginosa isolates were genetically analyzed by pulsed-field gel electrophoresis., Results: About 261 clinical isolates were identified as MDR P. aeruginosa and approximately 71.65% were found to be CR-MDR P. aeruginosa. The result showed that the meropenem resistance rate was the highest reaching over 50% in every hospitals. Additionally, the type of hospitals was a major factor affecting the resistance rate, as demonstrated by significantly higher CR-MDR rates among university and regional hospitals. The fingerprinting map identified 107 clones with at least 95% similarity. Only 4 clones were detected in more than one hospital., Conclusions: Although the antibiotic resistance rate was high, the spreading of CR-MDR was found locally. Specific strains of CR-MDR did not commonly spread from one hospital to another. Importantly, clonal dissemination ratio indicated limited intra-hospital transmission in Thailand.

This study reports for the first time the AbaR4-type resistance island with the bla(OXA-23) gene in two carbapenem-resistant A. nosocomialis isolates from South Korea and Thailand.

The MIC(50) and MIC(90) values of doripenem, determined by Etest, for 110 isolates of Burkholderia pseudomallei were 0.5 and 0.75 microg/ml, respectively. There were significant correlations between MICs determined by Etest and MICs determined by agar dilution, MICs determined by Etest and inhibition zone size, and MICs determined by agar dilution and inhibition zone size.

A cross-sectional study was conducted from August to September, 2003 to determine the prevalence and risk factors in acquiring extended-spectrum beta-lactamase (ESBL) producing gram-negative bacilli (GNB) in patients admitted to Siriraj Hospital and the outcomes of these infections. Of 346 isolates of gram-negative bacteria in 249 patients, 102 isolates from 87 patients were colonization only, but 244 isolates from 162 patients were infections. The common GNB were Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii and Enterobacter cloacae. The overall prevalence of ESBL producers was 30.1%. K. pneumoniae had a very high prevalence of ESBL producers (56.9%). The urinary tract was the most common site for ESBL- producing GNB infections. Nosocomial infections, duration from admission to infection, peripheral line, urinary catheterization, nasogastric tube insertion and previous use of beta-lactams, cephalosporins and fluoroquinolones were associated with acquiring ESBL-producing GNB infections. ESBL-producing GNB were significantly more resistant to antimicrobial agents. More than 80% of ESBL-producing GNB were susceptible to carbapenems. Mortality in patients infected with ESBL-producing GNB (41.3%) was significantly higher than those infected with non- ESBL-producing GNB (19.8%).