scholarly journals Association between the Presence of Aminoglycoside-Modifying Enzymes andIn VitroActivity of Gentamicin, Tobramycin, Amikacin, and Plazomicin against Klebsiella pneumoniae Carbapenemase- and Extended-Spectrum-β-Lactamase-Producing Enterobacter Species

2016 ◽  
Vol 60 (9) ◽  
pp. 5208-5214 ◽  
Author(s):  
Ghady Haidar ◽  
Ammar Alkroud ◽  
Shaoji Cheng ◽  
Travis M. Churilla ◽  
Bryce M. Churilla ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Treatment Options ◽  
Resistance Mechanisms ◽  
Aminoglycoside Resistance ◽  
Content Type ◽  
Treatment Regimens ◽  
Klebsiella Pneumoniae Carbapenemase ◽  
Research Priority ◽  
Extended Spectrum

ABSTRACTWe compared thein vitroactivities of gentamicin (GEN), tobramycin (TOB), amikacin (AMK), and plazomicin (PLZ) against 13Enterobacterisolates possessing bothKlebsiella pneumoniaecarbapenemase and extended-spectrum β-lactamase (KPC+/ESBL+) with activity against 8 KPC+/ESBL−, 6 KPC−/ESBL+, and 38 KPC−/ESBL− isolates. The rates of resistance to GEN and TOB were higher for KPC+/ESBL+ (100% for both) than for KPC+/ESBL− (25% and 38%, respectively), KPC−/ESBL+ (50% and 17%, respectively), and KPC−/ESBL− (0% and 3%, respectively) isolates. KPC+/ESBL+ isolates were more likely than others to possess an aminoglycoside-modifying enzyme (AME) (100% versus 38%, 67%, and 5%;P= 0.007, 0.06, and <0.0001, respectively) or multiple AMEs (100% versus 13%, 33%, and 0%, respectively;P< 0.01 for all). KPC+/ESBL+ isolates also had a greater number of AMEs (mean of 4.6 versus 1.5, 0.9, and 0.05, respectively;P< 0.01 for all). GEN and TOB MICs were higher against isolates with >1 AME than with ≤1 AME. The presence of at least 2/3 of KPC, SHV, and TEM predicted the presence of AMEs. PLZ MICs against all isolates were ≤4 μg/ml, regardless of KPC/ESBL pattern or the presence of AMEs. In conclusion, GEN and TOB are limited as treatment options against KPC+ and ESBL+Enterobacter. PLZ may represent a valuable addition to the antimicrobial armamentarium. A full understanding of AMEs and other aminoglycoside resistance mechanisms will allow clinicians to incorporate PLZ rationally into treatment regimens. The development of molecular assays that accurately and rapidly predict antimicrobial responses among KPC- and ESBL-producingEnterobacterspp. should be a top research priority.

scholarly journals Combination Regimens for Treatment of Carbapenem-Resistant Klebsiella pneumoniae Bloodstream Infections

2016 ◽  
Vol 60 (6) ◽  
pp. 3601-3607 ◽  
Author(s):  
A. Gomez-Simmonds ◽  
B. Nelson ◽  
D. P. Eiras ◽  
A. Loo ◽  
S. G. Jenkins ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Klebsiella Pneumoniae ◽  
Active Agent ◽  
Bloodstream Infections ◽  
Individual Treatment ◽  
Beta Lactam ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Extended Spectrum

Previous studies reported decreased mortality in patients with carbapenemase-producingKlebsiella pneumoniaebloodstream infections (BSIs) treated with combination therapy but included carbapenem-susceptible and -intermediate isolates, as per revised CLSI breakpoints. Here, we assessed outcomes in patients with BSIs caused by phenotypically carbapenem-resistantK. pneumoniae(CRKP) according to the number ofin vitroactive agents received and whether an extended-spectrum beta-lactam (BL) antibiotic, including meropenem, or an extended-spectrum cephalosporin was administered. We retrospectively reviewed CRKP BSIs at two New York City hospitals from 2006 to 2013, where all isolates had meropenem or imipenem MICs of ≥4 μg/ml. Univariate and multivariable models were created to identify factors associated with mortality. Of 141 CRKP BSI episodes, 23% were treated with a single active agent (SAA), 26% were treated with an SAA plus BL, 28% were treated with multiple active agents (MAA), and 23% were treated with MAA plus BL. Ninety percent of isolates had meropenem MICs of ≥16 μg/ml. Thirty-day mortality was 33% overall and did not significantly differ across the four treatment groups in a multivariable model (P= 0.4); mortality was significantly associated with a Pitt bacteremia score of ≥4 (odds ratio [OR], 7.7; 95% confidence interval [CI], 3.2 to 18.1;P= 0.1), and immunosuppression was protective (OR, 0.4; 95% CI, 0.2 to 1.0;P= 0.04). Individual treatment characteristics were also not significantly associated with outcome, including use of SAAs versus MAA (26% versus 38%,P= 0.1) or BL versus no BL (26% versus 39%,P= 0.1). In summary, in patients with CRKP BSIs caused by isolates with high carbapenem MICs, the role of combination therapy remains unclear, highlighting the need for prospective studies to identify optimal treatment regimens.

scholarly journals Carbapenem-Resistant Klebsiella pneumoniae Strains Exhibit Diversity in Aminoglycoside-Modifying Enzymes, Which Exert Differing Effects on Plazomicin and Other Agents

2014 ◽  
Vol 58 (8) ◽  
pp. 4443-4451 ◽  
Author(s):  
Reem Almaghrabi ◽  
Cornelius J. Clancy ◽  
Yohei Doi ◽  
Binghua Hao ◽  
Liang Chen ◽  
...  
Keyword(s):  
Antimicrobial Resistance ◽  
Klebsiella Pneumoniae ◽  
Bactericidal Activity ◽  
Sequence Type ◽  
Content Type ◽  
Molecular Assays ◽  
Carbapenem Resistant ◽  
Research Priority ◽  
Gentamicin Resistance

ABSTRACTWe measuredin vitroactivity of plazomicin, a next-generation aminoglycoside, and other aminoglycosides against 50 carbapenem-resistantKlebsiella pneumoniaestrains from two centers and correlated the results with the presence of various aminoglycoside-modifying enzymes (AMEs). Ninety-four percent of strains were sequence type 258 (ST258) clones, which exhibited 5ompK36genotypes; 80% and 10% of strains producedKlebsiella pneumoniaecarbapenemase 2 (KPC-2) and KPC-3, respectively. Ninety-eight percent of strains possessed AMEs, including AAC(6′)-Ib (98%), APH(3′)-Ia (56%), AAC(3)-IV (38%), and ANT(2″)-Ia (2%). Gentamicin, tobramycin, and amikacin nonsusceptibility rates were 40, 98, and 16%, respectively. Plazomicin MICs ranged from 0.25 to 1 μg/ml. Tobramycin and plazomicin MICs correlated with gentamicin MICs (r= 0.75 and 0.57, respectively). Plazomicin exerted bactericidal activity against 17% (1× MIC) and 94% (4× MIC) of strains. All strains with AAC(6′)-Ib were tobramycin-resistant; 16% were nonsusceptible to amikacin. AAC(6′)-Ib combined with another AME was associated with higher gentamicin, tobramycin, and plazomicin MICs than AAC(6′)-Ib alone (P= 0.01, 0.0008, and 0.046, respectively). The presence of AAC(3)-IV in a strain was also associated with higher gentamicin, tobramycin, and plazomicin MICs (P= 0.0006,P< 0.0001, andP= 0.01, respectively). The combination of AAC(6′)-Ib and another AME, the presence of AAC(3)-IV, and the presence of APH(3′)-Ia were each associated with gentamicin resistance (P= 0.0002, 0.003, and 0.01, respectively). In conclusion, carbapenem-resistantK. pneumoniaestrains (including ST258 clones) exhibit highly diverse antimicrobial resistance genotypes and phenotypes. Plazomicin may offer a treatment option against strains resistant to other aminoglycosides. The development of molecular assays that predict antimicrobial responses among carbapenem-resistantK. pneumoniaestrains should be a research priority.

scholarly journals Beyond Susceptible and Resistant, Part III: Treatment of Infections due to Gram-Negative Organisms Producing Carbapenemases

2016 ◽  
Vol 21 (2) ◽  
pp. 110-119 ◽  
Author(s):  
Navaneeth Narayanan ◽  
Linda Johnson ◽  
Conan MacDougall
Keyword(s):  
Antimicrobial Agents ◽  
Treatment Options ◽  
Resistance Mechanisms ◽  
Beta Lactam ◽  
Treatment Regimens ◽  
Healthcare Settings ◽  
Gram Negative Organisms ◽  
Few Data ◽  
Almost All

Carbapenemases are enzymes that are capable of inactivating all or almost all beta-lactam antimicrobial agents. These enzymes are frequently coexpressed with other resistance mechanisms to non–beta-lactams, leading to extremely drug-resistant pathogens. Once a curiosity, these enzymes have spread into organisms that are among the most common causes of infection, such as Klebsiella pneumoniae and Escherichia coli. Identification of these organisms has proved challenging for clinical microbiology laboratories, leading to revisions in susceptibility standards for carbapenems. Although currently a rare cause of infection in children, these carbapenem-resistant Enterobacteriaceae (CRE) are becoming endemic in a variety of healthcare settings. Management of infections due to CRE is complicated by a lack of effective treatment options and clinical data on their effectiveness. Treatment of CRE infections in children is particularly challenging because therapeutic options for CRE lack adequate data on dosing and safety in children. Use of unconventional combination treatment regimens, including agents to which the organism is resistant in vitro, may provide some benefit in the treatment of severe CRE infection. Fortunately, several agents with the potential for treatment of CRE infections have been recently approved or are in late clinical development, although few data will be available in the short term to inform use in children.

scholarly journals Assessment of Tedizolid In Vitro Activity and Resistance Mechanisms against a Collection of Enterococcus spp. Causing Invasive Infections, Including Isolates Requiring an Optimized Dosing Strategy for Daptomycin from U.S. and European Medical Centers, 2016 to 2018

2020 ◽  
Vol 64 (4) ◽  
Author(s):  
Cecilia G. Carvalhaes ◽  
Helio S. Sader ◽  
Robert K. Flamm ◽  
Jennifer M. Streit ◽  
Rodrigo E. Mendes
Keyword(s):  
The United States ◽  
Resistance Mechanisms ◽  
Aminoglycoside Resistance ◽  
Content Type ◽  
Medical Centers ◽  
Enterococcus Spp ◽  
Invasive Infections ◽  
Dosing Strategy ◽  
High Level

ABSTRACT High-level aminoglycoside resistance was noted in 30.0% of Enterococcus faecalis and 25.2% of Enterococcus faecium isolates. Only 3.3% and 2.1% of E. faecalis isolates had elevated daptomycin MIC (≥2 mg/liter) and vancomycin resistance, respectively. In contrast, 37.4% to 40.3% of E. faecium isolates exhibited these phenotypes. Tedizolid inhibited 98.9% to 100.0% of enterococci causing serious invasive infections, including resistant subsets. Oxazolidinone resistance was mainly driven by G2576T; however, optrA and poxtA genes were also detected, including poxtA in the United States and Turkey.

scholarly journals Comparative Antibiofilm Efficacy of Meropenem Alone and in Combination with Colistin in an In Vitro Pharmacodynamic Model by Extended-Spectrum-β-Lactamase-Producing Klebsiella pneumoniae

2019 ◽  
Vol 63 (11) ◽  
Author(s):  
Alba Ribera ◽  
Eva Benavent ◽  
Cristina El-Haj ◽  
Joan Gomez-Junyent ◽  
Fe Tubau ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Bactericidal Effect ◽  
Pharmacodynamic Model ◽  
Content Type ◽  
Extended Spectrum

ABSTRACT We compared the efficacies of meropenem alone and in combination with colistin against two strains of extended-spectrum-β-lactamase-producing Klebsiella pneumoniae, using an in vitro pharmacodynamic model that mimicked two different biofilm conditions. Meropenem monotherapy achieved remarkable efficacy (even a bactericidal effect) under all conditions, whereas colistin was almost inactive and resistance emerged. The addition of colistin to meropenem produced no relevant benefits, in contrast to experiences with other microorganisms.

scholarly journals Broad-Spectrum β-Lactam Antibiotics for Treating Experimental Peritonitis in Mice Due to Klebsiella pneumoniae Producing the Carbapenemase OXA-48

2012 ◽  
Vol 56 (5) ◽  
pp. 2759-2760 ◽  
Author(s):  
Olivier Mimoz ◽  
Nicolas Grégoire ◽  
Laurent Poirel ◽  
Manuella Marliat ◽  
William Couet ◽  
...  
Keyword(s):  
Single Dose ◽  
Klebsiella Pneumoniae ◽  
Broad Spectrum ◽  
Content Type ◽  
Extended Spectrum ◽  
Experimental Peritonitis ◽  
Peritonitis Model

ABSTRACTA lethal peritonitis model was induced in mice with aKlebsiella pneumoniaeisolate producing the carbapenemase OXA-48. Administration of a single dose (up to 100 mg/kg) of the antibiotic piperacillin-tazobactam, imipenem-cilastatin, ertapenem, or cefotaxime had little or no impact on lethality. Ceftazidime had the highest efficacyin vivo, which mirrored itsin vitroactivity; this was not the case for carbapenems. Therefore, ceftazidime may be recommended for the treatment of infections due to OXA-48 producers if they do not coproduce an extended-spectrum β-lactamase or a plasmid-mediated AmpC cephalosporinase.

scholarly journals Clofazimine Prevents the Regrowth of Mycobacterium abscessus and Mycobacterium avium Type Strains Exposed to Amikacin and Clarithromycin

2015 ◽  
Vol 60 (2) ◽  
pp. 1097-1105 ◽  
Author(s):  
Beatriz E. Ferro ◽  
Joseph Meletiadis ◽  
Melanie Wattenberg ◽  
Arjan de Jong ◽  
Dick van Soolingen ◽  
...  
Keyword(s):  
Mycobacterium Avium ◽  
Treatment Options ◽  
Mycobacterium Abscessus ◽  
Surface Model ◽  
Target Attainment ◽  
Content Type ◽  
Treatment Regimens ◽  
Combination Regimens ◽  
Type Strains

ABSTRACTMultidrug therapy is a standard practice when treating infections by nontuberculous mycobacteria (NTM), but few treatment options exist. We conducted this study to define the drug-drug interaction between clofazimine and both amikacin and clarithromycin and its contribution to NTM treatment.Mycobacterium abscessusandMycobacterium aviumtype strains were used. Time-kill assays for clofazimine alone and combined with amikacin or clarithromycin were performed at concentrations of 0.25× to 2× MIC. Pharmacodynamic interactions were assessed by response surface model of Bliss independence (RSBI) and isobolographic analysis of Loewe additivity (ISLA), calculating the percentage of statistically significant Bliss interactions and interaction indices (I), respectively. Monte Carlo simulations with predicted human lung concentrations were used to calculate target attainment rates for combination and monotherapy regimens. Clofazimine alone was bacteriostatic for both NTM. Clofazimine-amikacin was synergistic againstM. abscessus(I = 0.41; 95% confidence interval [CI], 0.29 to 0.55) andM. avium(I = 0.027; 95% CI, 0.007 to 0.048). Based on RSBI analysis, synergistic interactions of 28.4 to 29.0% and 23.2 to 56.7% were observed at 1× to 2× MIC and 0.25× to 2× MIC forM. abscessusandM. avium, respectively. Clofazimine-clarithromycin was also synergistic againstM. abscessus(I = 0.53; 95% CI, 0.35 to 0.72) andM. avium(I = 0.16; 95% CI, 0.04 to 0.35), RSBI analysis showed 23.5% and 23.3 to 53.3% at 2× MIC and 0.25× to 0.5× MIC forM. abscessusandM. avium, respectively. Clofazimine prevented the regrowth observed with amikacin or clarithromycin alone. Target attainment rates of combination regimens were >60% higher than those of monotherapy regimens forM. abscessusandM. avium. The combination of clofazimine with amikacin or clarithromycin was synergisticin vitro. This suggests a potential role for clofazimine in treatment regimens that warrants further evaluation.

scholarly journals Spread of ISCR1Elements ContainingblaDHA-1and Multiple Antimicrobial Resistance Genes Leading to Increase of Flomoxef Resistance in Extended-Spectrum-β-Lactamase-Producing Klebsiella pneumoniae

2011 ◽  
Vol 55 (9) ◽  
pp. 4058-4063 ◽  
Author(s):  
Chen-Hsiang Lee ◽  
Jien-Wei Liu ◽  
Chia-Chin Li ◽  
Chun-Chih Chien ◽  
Ya-Fen Tang ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Resistance Genes ◽  
Antimicrobial Agents ◽  
Treatment Options ◽  
Close Monitoring ◽  
Content Type ◽  
Extended Spectrum ◽  
Antimicrobial Resistance Genes ◽  
Multiple Resistance Genes ◽  
Replicon Type

ABSTRACTIncreasing resistance to quinolones, aminoglycosides, and/or cephamycins in extended-spectrum-β-lactamase (ESBL)-producingEnterobacteriaceaeexacerbates the already limited antibiotic treatment options for infections due to these microbes. In this study, the presence of resistance determinants for these antimicrobial agents was examined by PCR among ESBL-producingKlebsiella pneumoniae(ESBL-KP) isolates that caused bacteremia. Pulsed-field gel electrophoresis was used to differentiate the clonal relationship among the isolates studied. Transferability and the location of the resistance genes were analyzed by conjugation experiments, followed by DNA-DNA hybridization. Among the 94 ESBL-KP isolates studied, 20 isolates of flomoxef-resistant ESBL-KP were identified. They all carried a DHA-1 gene and were genetically diverse. CTX-M genes were found in 18 of the isolates. Among these DHA-1/CTX-M-producingK. pneumoniaeisolates, ISCR1was detected in 13 (72%) isolates,qnrgenes (1qnrAand 17qnrBgenes) were detected in 18 (100%),aac(6′)-Ib-crwas detected in 11 (61%), and 16S rRNA methylase (allarmAgenes) was detected in 14 (78%). Four transconjugants were available for further analysis, andqnrB4,aac(6′)-Ib-cr,armA, andblaDHA-1were all identified on these self-transferableblaCTX-M-carrying plasmids. The genetic environments of ISCR1associated witharmA,blaDHA-1, andqnrB4genes in the four transconjugants were identical. Replicon-type analysis revealed a FIIA plasmid among the four self-transferable plasmids, although the other three were nontypeable. The cotransfer of multiple resistance genes with the ISCR1element-carrying plasmids has a clinical impact and warrants close monitoring and further study.

scholarly journals In VitroActivity of Ceftazidime-Avibactam against 338 Molecularly Characterized Gentamicin-Nonsusceptible Gram-Negative Clinical Isolates Obtained from Patients in Canadian Hospitals

2015 ◽  
Vol 59 (6) ◽  
pp. 3623-3626 ◽  
Author(s):  
Andrew J. Denisuik ◽  
James A. Karlowsky ◽  
Tyler Denisuik ◽  
Wright W. Nichols ◽  
Thomas A. Keating ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
16S Rrna ◽  
Klebsiella Pneumoniae ◽  
Gram Negative Bacteria ◽  
Aminoglycoside Resistance ◽  
Single Strain ◽  
Gram Negative ◽  
Content Type ◽  
16S Rrna Methylase

ABSTRACTThe mechanism of aminoglycoside resistance among 338 gentamicin-nonsusceptible Gram-negative bacteria (207Enterobacteriaceaeand 131Pseudomonas aeruginosa) was assessed, and thein vitroactivity of ceftazidime-avibactam against these isolates was determined. Aminoglycoside-modifying enzymes were detected in 91.8% ofEnterobacteriaceaeand 13.7% ofP. aeruginosaisolates. A single strain ofKlebsiella pneumoniaeharbored a 16S rRNA methylase (ArmA). The ceftazidime-avibactam MIC90values were 0.5 μg/ml (MIC, ≤8 μg/ml for 100% of isolates) and 16 μg/ml (MIC, ≤8 μg/ml for 87.8% of isolates) against gentamicin-nonsusceptibleEnterobacteriaceaeandP. aeruginosaisolates, respectively.

scholarly journals Characteristics of Extended-Spectrum β-Lactamase- and Carbapenemase-Producing Enterobacteriaceae Isolates from Rivers and Lakes in Switzerland

2013 ◽  
Vol 79 (9) ◽  
pp. 3021-3026 ◽  
Author(s):  
Katrin Zurfluh ◽  
Herbert Hächler ◽  
Magdalena Nüesch-Inderbinen ◽  
Roger Stephan
Keyword(s):  
Klebsiella Pneumoniae ◽  
Carbapenem Resistance ◽  
Resistance Mechanisms ◽  
Content Type ◽  
Extended Spectrum ◽  
Rivers And Lakes ◽  
Genes Encoding ◽  
River Sample ◽  
Severe Infections ◽  
Enterobacter Amnigenus

ABSTRACTOne of the currently most relevant resistance mechanisms inEnterobacteriaceaeis the production of enzymes that lead to modern expanded-spectrum cephalosporin and even carbapenem resistance, mainly extended-spectrum β-lactamases (ESBLs) and carbapenemases. A worrisome aspect is the spread of ESBL and carbapenemase producers into the environment. The aim of the present study was to assess the occurrence of ESBL- and carbapenemase-producingEnterobacteriaceaeand to further characterize ESBL- and carbapenemase-producingEnterobacteriaceaein rivers and lakes in Switzerland. ESBL-producingEnterobacteriaceaewere detected in 21 (36.2%) of the 58 bodies of water sampled. One river sample tested positive for a carbapenemase-producingKlebsiella pneumoniaesubsp.pneumoniaestrain. Seventy-four individual strains expressing an ESBL phenotype were isolated. Species identification revealed 60Escherichia colistrains, sevenKlebsiella pneumoniaesubsp.pneumoniaestrains, fiveRaoultella planticolastrains, oneEnterobacter cloacaestrain, and oneEnterobacter amnigenusstrain. Three strains were identified as SHV-12 ESBL producers, and 71 strains carried genes encoding CTX-M ESBLs. Of the 71 strains with CTX-M ESBL genes, 8 isolates expressed CTX-M-1, three produced CTX-M-3, 46 produced CTX-M-15, three produced CTX-M-55, one produced CTX-M-79, six produced CTX-M-14, and four produced CTX-M-27. Three of the four CTX-M-27 producers belonged to the multiresistant pandemic sequence typeE. coliB2:ST131 that is strongly associated with potentially severe infections in humans and animals.

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