scholarly journals Comparative Effectiveness of Aminoglycosides, Polymyxin B, and Tigecycline for Clearance of Carbapenem-Resistant Klebsiella pneumoniae from Urine

2011 ◽  
Vol 55 (12) ◽  
pp. 5893-5899 ◽  
Author(s):  
Michael J. Satlin ◽  
Christine J. Kubin ◽  
Jill S. Blumenthal ◽  
Andrew B. Cohen ◽  
E. Yoko Furuya ◽  
...  

ABSTRACTCarbapenem-resistantKlebsiella pneumoniae(CRKP) is an increasingly common cause of health care-associated urinary tract infections. Antimicrobials within vitroactivity 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 activein vitro, was associated with a significantly higher rate of microbiologic clearance of CRKP bacteriuria than treatment with either polymyxin B or tigecycline.

2016 ◽  
Vol 60 (6) ◽  
pp. 3601-3607 ◽  
Author(s):  
A. Gomez-Simmonds ◽  
B. Nelson ◽  
D. P. Eiras ◽  
A. Loo ◽  
S. G. Jenkins ◽  
...  

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.


2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S285-S285 ◽  
Author(s):  
Mohamad Yasmin ◽  
Steven Marshall ◽  
Michael Jacobs ◽  
Daniel D Rhoads ◽  
Laura J Rojas ◽  
...  

Abstract Background Vaborbactam is a cyclic boronic acid β-lactamase inhibitor (BLI) developed to potently inhibit Ambler class A&C enzymes, including KPC carbapenemases. Metallo-β-lactamases (MBL) and some Class D oxacillinases (OXA) are not inactivated by vaborbactam. Meropenem-vaborbactam (MV) was recently approved for the treatment of carbapenem-resistant Enterobacteriaceae complicated urinary tract infections. Recent studies have identified outer membrane porin (Ompk35 and -36) mutations in Klebsiella pneumoniae (KP) as a mechanism of decreased susceptibility to MV. We evaluated the activity of MV against a historical cohort of KP clinical isolates with these porin gene mutations. Methods WGS of carbapenem-resistant KP clinical isolates was performed and those harboring mutations in Ompk35 or Ompk36 were selected for testing. Strain KP ATCC BAA-1705 was used as a positive control. Meropenem and MV minimum inhibitory concentrations (MIC) were determined by broth microdilution (BMD) in custom 96-well plates (ThermoFisher Scientific) with a constant 8 µg/mL vaborbactam concentration. The MIC of ceftazidime–avibactam (CZA) was determined by standard BMD reference methods and interpreted according to CLSI criteria. Results A total of 105 KP isolates with either partial or complete mutations in outer membrane porin genes were included in the analysis. All isolates were resistant to Meropenem. The median MV MIC was 0.03 µg/mL (range, 0.015 to >16 µg/mL). Eleven isolates (10.4%) were resistant to MV. Sixteen additional isolates (16.1%) demonstrated higher than expected MV MICs ranging from 1 to 4 µg/mL. Only 1/11 resistant isolates harbored a gene for MBL production. Gene mutations in blaKPC were not detected. See Table 1 for characteristics of resistant isolates. Conclusion Resistance and decreased susceptibility to MV is demonstrated in a historical cohort of KP clinical isolates dating back to 2013. WGS reliably identifies porin variants secondary to gene mutations in Ompk35 and Ompk36 as the underlying mechanism of decreased susceptibility. CZA appears to retain activity against these isolates. Caution should be exercised regarding the empiric use of MV against increasingly resistant KP as a result of non-β-lactamase-mediated mechanisms. Disclosures All authors: No reported disclosures.


2020 ◽  
Vol 64 (5) ◽  
Author(s):  
Michael R. Jacobs ◽  
Caryn E. Good ◽  
Andrea M. Hujer ◽  
Ayman M. Abdelhamed ◽  
Daniel D. Rhoads ◽  
...  

ABSTRACT Plazomicin was tested against 697 recently acquired carbapenem-resistant Klebsiella pneumoniae isolates from the Great Lakes region of the United States. Plazomicin MIC50 and MIC90 values were 0.25 and 1 mg/liter, respectively; 680 isolates (97.6%) were susceptible (MICs of ≤2 mg/liter), 9 (1.3%) intermediate (MICs of 4 mg/liter), and 8 (1.1%) resistant (MICs of >32 mg/liter). Resistance was associated with rmtF-, rmtB-, or armA-encoded 16S rRNA methyltransferases in all except 1 isolate.


2017 ◽  
Vol 62 (2) ◽  
Author(s):  
Yawei Zhang ◽  
Qi Wang ◽  
Yuyao Yin ◽  
Hongbin Chen ◽  
Longyang Jin ◽  
...  

ABSTRACT Carbapenem-resistant Enterobacteriaceae (CRE) infection is highly endemic in China, but estimates of the infection burden are lacking. We established the incidence of CRE infection from a multicenter study that covered 25 tertiary hospitals in 14 provinces. CRE cases defined as carbapenem-nonsusceptible Citrobacter freundii, Escherichia coli, Enterobacter cloacae, or Klebsiella pneumoniae infections during January to December 2015 were collected and reviewed from medical records. Antimicrobial susceptibility testing and carbapenemase gene identification were performed. Among 664 CRE cases, most were caused by K. pneumoniae (73.9%), followed by E. coli (16.6%) and E. cloacae (7.1%). The overall CRE infection incidence per 10,000 discharges was 4.0 and differed significantly by region, with the highest in Jiangsu (14.97) and the lowest in Qinghai (0.34). Underlying comorbidities were found in 83.8% of patients; the median patient age was 62 years (range, 45 to 74 years), and 450 (67.8%) patients were male. Lower respiratory tract infections (65.4%) were the most common, followed by urinary tract infection (16.6%), intra-abdominal infection (7.7%), and bacteremia (7.7%). The overall hospital mortality rate was 33.5%. All isolates showed nonsusceptibility to carbapenems and cephalosporins. The susceptibility rate of polymyxin B was >90%. Tigecycline demonstrated a higher susceptibility rate against E. coli than against K. pneumoniae (90.9% versus 40.2%). Of 155 clinical isolates analyzed, 89% produced carbapenemases, with a majority of isolates producing KPC (50%) or NDM (33.5%)-type beta-lactamases among K. pneumoniae and E. coli. The incidence of CRE infection in China was 4.0 per 10,000 discharges. The patient-based disease burden in tertiary hospitals in China is severe, suggesting an urgent need to enhance infection control.


2013 ◽  
Vol 57 (3) ◽  
pp. 1542-1545 ◽  
Author(s):  
Liang Chen ◽  
Kalyan D. Chavda ◽  
Roberto G. Melano ◽  
Michael R. Jacobs ◽  
Michael H. Levi ◽  
...  

ABSTRACTWe report the nucleotide sequence of a novelblaKPC-2-harboring IncFIIK1plasmid, pBK32179, isolated from a carbapenem-resistantKlebsiella pneumoniaeST258 strain from a New York City patient. pBK32179 is 165 kb long, consists of a large backbone of pKPN3-like plasmid, and carries an 18.5-kbblaKPC-2-containing element that is highly similar to plasmid pKpQIL. pBK32179-like plasmids were identified in 8.3% of strains in a collection of 96K. pneumoniaeisolates from hospitals in the New York City area.


2011 ◽  
Vol 55 (10) ◽  
pp. 4742-4747 ◽  
Author(s):  
Laura García-Sureda ◽  
Antonio Doménech-Sánchez ◽  
Mariette Barbier ◽  
Carlos Juan ◽  
Joan Gascó ◽  
...  

ABSTRACTClinical isolates ofKlebsiella pneumoniaeresistant to carbapenems are being isolated with increasing frequency. Loss of the expression of the major nonspecific porins OmpK35/36 is a frequent feature in these isolates. In this study, we looked for porins that could compensate for the loss of the major porins in carbapenem-resistant organisms. Comparison of the outer membrane proteins from twoK. pneumoniaeclinical isogenic isolates that are susceptible (KpCS-1) and resistant (KpCR-1) to carbapenems revealed the absence of OmpK35/36 and the presence of a new 26-kDa protein in the resistant isolate. An identical result was obtained when another pair of isogenic isolates that are homoresistant (Kpn-3) and heteroresistant (Kpn-17) to carbapenems were compared. Mass spectrometry and DNA sequencing analysis demonstrated that this new protein, designated OmpK26, is a small monomeric oligogalacturonate-specific porin that belongs to the KdgM family of porins. Insertion-duplication mutagenesis of the OmpK26 coding gene,yjhA, in the carbapenem-resistant, porin-deficient isolate KpCR-1 caused the expression of OmpK36 and the reversion to the carbapenem-susceptible phenotype, suggesting that OmpK26 is indispensable for KpCR-1 to lose OmpK36 and become resistant to these antibiotics. Moreover, loss of the major porin and expression of OmpK26 reducedin vitrofitness and attenuated virulence in a murine model of acute systemic infection. Altogether, these results indicate that expression of the oligogalacturonate-specific porin OmpK26 compensates for the absence of OmpK35/36 and allows carbapenem resistance inK. pneumoniaebut cannot restore the fitness of the microorganism.


2014 ◽  
Vol 58 (8) ◽  
pp. 4443-4451 ◽  
Author(s):  
Reem Almaghrabi ◽  
Cornelius J. Clancy ◽  
Yohei Doi ◽  
Binghua Hao ◽  
Liang Chen ◽  
...  

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.


2016 ◽  
Vol 60 (8) ◽  
pp. 4717-4721 ◽  
Author(s):  
Yaakov Dickstein ◽  
Yuval Geffen ◽  
Steen Andreassen ◽  
Leonard Leibovici ◽  
Mical Paul

ABSTRACTTo improve antibiotic prescribing, we sought to establish the probability of a resistant organism in urine culture given a previous resistant culture in a setting endemic for multidrug-resistant (MDR) organisms. We performed a retrospective analysis of inpatients with paired positive urine cultures. We focused on ciprofloxacin-resistant (cipror) Gram-negative bacteria, extended-spectrum-beta-lactamase (ESBL)-producingEnterobacteriaceae, carbapenem-resistantEnterobacteriaceae(CRE), and carbapenem-resistant nonfermenters (CRNF). Comparisons were made between the frequency of each resistance phenotype following a previous culture with the same phenotype and the overall frequency of that phenotype, and odds ratios (ORs) were calculated. We performed a regression to assess the effects of other variables on the likelihood of a repeat resistant culture. A total of 4,409 patients (52.5% women; median age, 70 years) with 19,546 paired positive urine cultures were analyzed. The frequencies of ciprorbacteria, ESBL-producingEnterobacteriaceae, CRE, and CRNF among all cultures were 47.7%, 30.6%, 1.7%, and 2.6%, respectively. ORs for repeated resistance phenotypes were 1.87, 3.19, 48.25, and 19.02 for ciprorbacteria, ESBL-producingEnterobacteriaceae, CRE, and CRNF, respectively (P< 0.001 for all). At 1 month, the frequencies of repeated resistance phenotypes were 77.4%, 66.4%, 57.1%, and 33.3% for ciprorbacteria, ESBL-producingEnterobacteriaceae, CRE, and CRNF, respectively. Increasing time between cultures and the presence of an intervening nonresistant culture significantly reduced the chances of a repeat resistant culture. Associations were statistically significant over the duration of follow-up (60 months) for CRE and for up to 6 months for all other pathogens. Knowledge of microbiology results in the six preceding months may assist with antibiotic stewardship and improve the appropriateness of empirical treatment for urinary tract infections (UTIs).


2014 ◽  
Vol 59 (1) ◽  
pp. 553-557 ◽  
Author(s):  
Kyle D. Brizendine ◽  
Sandra S. Richter ◽  
Eric D. Cober ◽  
David van Duin

ABSTRACTCarbapenem-resistantKlebsiella pneumoniae(CRKP) is an emerging pathogen with a devastating impact on organ transplant recipients (OTRs). Data describing urinary tract infections (UTIs) due to CRKP, compared to extended-spectrum β-lactamase (ESBL)-producing and susceptibleK. pneumoniae, are lacking. We conducted a retrospective cohort study comparing OTRs with a first episode of UTI due to CRKP, ESBL-producingK. pneumoniae, or susceptibleK. pneumoniae. We identified 108 individuals; 22 (20%) had UTIs due to CRKP, 22 (20%) due to ESBL-producingK. pneumoniae, and 64 (60%) due to susceptibleK. pneumoniae. Compared to susceptibleK. pneumoniae(27%), patients with UTIs due to CRKP or ESBL-producingK. pneumoniaewere more likely to have a ≥24-hour stay in the intensive care unit (ICU) before or after development of the UTI (64% and 77%, respectively;P< 0.001). Among 105/108 hospitalized patients (97%), the median lengths of stay prior to UTI with CRKP or ESBL-producingK. pneumoniae(7 and 8 days, respectively) were significantly longer than that for susceptibleK. pneumoniae(1 day;P< 0.001). Clinical failure was observed for 8 patients (36%) with CRKP, 4 (18%) with ESBL-producingK. pneumoniae, and 9 (14%) with susceptibleK. pneumoniae(P= 0.073). Microbiological failure was seen for 10 patients (45%) with CRKP, compared with 2 (9%) with ESBL-producingK. pneumoniaeand 2 (3%) with susceptibleK. pneumoniae(P< 0.001). In multivariable logistic regression analyses, CRKP was associated with greater odds of microbiological failure (versus ESBL-producingK. pneumoniae: odds ratio [OR], 9.36, 95% confidence interval [CI], 1.94 to 72.1; versus susceptibleK. pneumoniae: OR, 31.4, 95% CI, 5.91 to 264). In conclusion, CRKP is associated with ICU admission, long length of stay, and microbiological failure among OTRs with UTIs. Greater numbers are needed to determine risk factors for infection and differences in meaningful endpoints associated with carbapenem resistance.


mSphere ◽  
2021 ◽  
Vol 6 (2) ◽  
Author(s):  
Kasturi Banerjee ◽  
Michael P. Motley ◽  
Elizabeth Diago-Navarro ◽  
Bettina C. Fries

ABSTRACT Capsular polysaccharide (CPS) heterogeneity within carbapenem-resistant Klebsiella pneumoniae (CR-Kp) strain sequence type 258 (ST258) must be considered when developing CPS-based vaccines. Here, we sought to characterize CPS-specific antibody responses elicited by CR-Kp-infected patients. Plasma and bacterial isolates were collected from 33 hospital patients with positive CR-Kp cultures. Isolate capsules were typed by wzi sequencing. Reactivity and measures of efficacy of patient antibodies were studied against 3 prevalent CR-Kp CPS types (wzi29, wzi154, and wzi50). High IgG titers against wzi154 and wzi50 CPS were documented in 79% of infected patients. Patient-derived (PD) IgGs agglutinated CR-Kp and limited growth better than naive IgG and promoted phagocytosis of strains across the serotype isolated from their donors. Additionally, poly-IgG from wzi50 and wzi154 patients promoted phagocytosis of nonconcordant CR-Kp serotypes. Such effects were lost when poly-IgG was depleted of CPS-specific IgG. Additionally, mice infected with wzi50, wzi154, and wzi29 CR-Kp strains preopsonized with wzi50 patient-derived IgG exhibited lower lung CFU than controls. Depletion of wzi50 antibodies (Abs) reversed this effect in wzi50 and wzi154 infections, whereas wzi154 Ab depletion reduced poly-IgG efficacy against wzi29 CR-Kp. We are the first to report cross-reactive properties of CPS-specific Abs from CR-Kp patients through both in vitro and in vivo models. IMPORTANCE Carbapenem-resistant Klebsiella pneumoniae is a rapidly emerging public health threat that can cause fatal infections in up to 50% of affected patients. Due to its resistance to nearly all antimicrobials, development of alternate therapies like antibodies and vaccines is urgently needed. Capsular polysaccharides constitute important targets, as they are crucial for Klebsiella pneumoniae pathogenesis. Capsular polysaccharides are very diverse and, therefore, studying the host’s capsule-type specific antibodies is crucial to develop effective anti-CPS immunotherapies. In this study, we are the first to characterize humoral responses in infected patients against carbapenem-resistant Klebsiella pneumoniae expressing different wzi capsule types. This study is the first to report the efficacy of cross-reactive properties of CPS-specific Abs in both in vitro and in vivo models.


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