Klebsiella Pneumoniae Carbapenemase-producing K. Pneumoniae Strains Research Articles

Pharmacokinetic/pharmacodynamic modelling to evaluate the efficacy of various dosing regimens of ceftazidime/avibactam in patients with pneumonia caused by Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae: a multicentre study in northern China

The objective of this study was to evaluate the efficacy of different dosing regimens of ceftazidime/avibactam (CZA) in patients with Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (KPC-Kp) pulmonary infections. A total of 70 KPC-Kp strains were isolated from sputum and bronchoalveolar lavage samples of patients with pulmonary infections in three hospitals in northern China from April 2015 to October 2015. Monte Carlo simulation (MCS) was performed using population pharmacokinetic parameters of CZA combined with the minimum inhibitory concentration (MIC) distributions gained from antimicrobial susceptibility testing to predict the efficacy of different dosing regimens. Various CZA dosing regimens were modelled using MCS. The in vitro study showed potent activity of CZA against KPC-Kp strains with MIC50/90 values of 1/2 mg/L, with a susceptibility rate of 95.7%. The values of cumulative fraction of response (CFR) for bactericidal (50%fT>5×MIC) target were as follows: for patients with creatinine clearance (CLCr) >51 mL/min, the CFR was 96.01% for 2.5 g CZA every 12 h (q12h) and 97.14% for 2.5 g CZA every 8 h (q8h); and for patients with moderate renal impairment (CLCr >30 to ≤50 mL/min), the CFR was 95.75% for 1.25 g CZA q12h and 97.09% for 1.25 g CZA q8h. This study indicated that the recommended dose of CZA can provide adequate pharmacodynamic exposure for treating KPC-Kp pneumonia.

Prevalence and mechanisms of fosfomycin resistance among KPC-producing Klebsiella pneumoniae clinical isolates in China

The threat of antibiotic resistance has increased dramatically in recent years. Fosfomycin, an old antibiotic agent, has been re-introduced to fight infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (KPC-KP). However, the trend of fosfomycin resistance among KPC-KP strains is increasing. In this study, 80 KPC-KP clinical isolates were collected from three teaching hospitals during 2014-2017 in China and were subjected to whole-genome sequencing (WGS). The fosfomycin resistance phenotype and resistance mechanisms were investigated by antimicrobial susceptibility testing and carbon source growth test, respectively. Among all KPC-KP strains, 80.0% (64/80) were resistant to fosfomycin and 36.3% (29/80) were positive for the mobile fosfomycin resistance gene fosA3. Among the 63 strains that were unable to grow in M9 basic medium with glycerol-3-phosphate (G3P) as the sole carbon source (mediated by mutation of the target gene glpT), there was no significant difference regarding the MIC distribution of fosfomycin between fosA3-positive and fosA3-negative strains (P=0.577). Among the 50 strains that were negative for fosA3 but positive for fosA, the fosfomycin MICs of strains unable to grow in M9 basic medium with G3P as the sole carbon source were significantly higher (P < 0.001) than in strains that were able to grow in M9 basic medium with G3P as the sole carbon source. Our findings indicate that fosfomycin resistance among KPC-KP in China is an emerging problem and the two major mechanisms of resistance identified were plasmid-mediated fosfomycin resistance gene fosA3 and mutation of the target gene glpT.

Bloodstream infection caused by KPC-producing Klebsiella pneumoniae resistant to ceftazidime/avibactam: epidemiology and genomic characterization

ObjectivesThe aim of this study was to evaluate the incidence of ceftazidime/avibactam resistance among Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae (KPC-Kp) strains isolated from patients with bloodstream infection. MethodsWe collected 120 carbapenemase producing Enterobacteriaceae (CPE) strains from unique patients hospitalized in two Italian hospitals between January 2018 to February 2019. Strains were phenotypically characterized for the type of carbapenemase production and susceptibility to ceftazidime/avibactam. Ceftazidime/avibactam-resistant strains were characterized by whole-genome sequencing. ResultsDuring the study period, we characterized 105 (87.5%) KPC producers among a total of 120 CPE strains. Ceftazidime/avibactam resistance was found in three KPC-Kp strains isolated from patients with no history of previous ceftazidime/avibactam-based treatment. Of note, two out of three ceftazidime–avibactam-resistant KPC-Kp were also resistant to meropenem/vaborbactam. Genomic characterization showed that a ceftazidime/avibactam-resistant KPC-Kp harboured a mixed population with D179Y mutated KPC-2, while the other two ceftazidime–avibactam-resistant KPC-Kp possessed non-functional ompK35-ompK37 and mutated ompK36 porins associated with higher copy number of blaKPC gene. ConclusionsOur results showed that incidence of ceftazidime/avibactam resistance emerged in KCP-Kp strains independently from previous antimicrobial exposure. Resistance to ceftazidime/avibactam was associated with mutations within the blaKPC gene or porin deficiency associated with higher blaKPC copy number and is also related to the meropenem/vaborbactam resistance.

Is meropenem MIC increase against KPC-producing Klebsiella pneumoniae correlated with increased resistance rates against other antimicrobials with Gram-negative activity?

The aim of this study was to assess the minimum inhibitory concentration (MIC) distribution for meropenem and other antimicrobials with Gram-negative activity against Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (KPC-Kp) clinical isolates collected at a tertiary hospital in Italy between 2013-2016. The antimicrobial susceptibility of KPC-Kp strains was tested by the broth microdilution method using customised 96-well plates and the results were interpreted according to European Committee on Antimicrobial Susceptibility Testing (EUCAST) recommendations. Among 169 consecutive KPC-Kp clinical isolates, 45 (26.6%) were susceptible to meropenem (MIC≤2mg/L). Among the 124 meropenem-resistant isolates, 73 (58.9%) had a meropenem MIC between 16-64mg/L. The overall resistance rate for the other antimicrobials tested was very high both for ciprofloxacin and levofloxacin (99.0%), was moderate for amikacin (37.4%) and was low for gentamicin (11.2%), colistin (8.2%) and tigecycline (7.7%). Aminoglycosides had a dichotomous behaviour in relation to meropenem MIC increase. The resistance rate for gentamicin remained <20% across all meropenem MICs; conversely, that for amikacin increased from <20% in the presence of meropenem MIC≤8mg/L up to ca. 80% in the presence of meropenem MIC≥64mg/L. Resistance rates for tigecycline and colistin remained <20% in the presence of meropenem MICs up to 64mg/L. The overall susceptibility rates of antimicrobials with Gram-negative activity may vary greatly among KPC-Kp clinical isolates. A tight relationship between meropenem MIC increase and the resistance rate for amikacin was documented.

Nosocomial transmission of carbapenem-resistant Klebsiella pneumoniae in an Italian university hospital: a molecular epidemiological study

To describe the phenotypic and genotypic profiles of Klebsiella pneumoniae carbapenemase-producing K.pneumoniae (KPC-Kp) strains isolated from patients with invasive infections at an Italian university hospital in order to assess the epidemiological trend. An observational prospective study was undertaken at the University Hospital of Sassari, Italy to detect KPC-Kp strains in patients with invasive bacteraemia. Isolates were identified phenotypically; carbapenemase production was assessed using phenotypic and genotypic methods. Sequencing of blaKPC genes, pulsed-field gel electrophoresis and multi-locus sequence typing were performed. During the period 2015-2017, 46 cases of invasive infection with K.pneumoniae were recorded. Two-thirds (67.4%) of the patients were male, and the mean age was 69.4 years. Most patients had at least one comorbidity (56.5%) and/or had been hospitalized previously (70.5%), 81.8% had current or recent medical device use, and 85.4% had recent antibiotic exposure. The mortality rate was 52.3%. A multi-drug-resistant pattern (including carbapenems, fluoroquinolones, third-/fourth-generation cephalosporins) was shown for all K.pneumoniae isolates. KPC-3 and -2 were produced by all strains. The most common sequence types were 512 (91.3%) and 101 (8.7%), grouped into three clusters (A, A1 and B). A high incidence of KPC-Kp in patients with invasive infections was recorded at an Italian university hospital compared with the incidence measured before 2015. This study confirmed the importance of the KPC-3 carbapenemase variant, as reported by other Italian studies. High mortality and comorbidity rates appear to be associated with KPC-Kp infection.

Predictors of outcome in ICU patients with septic shock caused by Klebsiella pneumoniae carbapenemase–producing K. pneumoniae

The aim of this study was to identify factors associated with mortality in intensive care unit patients with Klebsiella pneumoniae carbapenemase–producing K. pneumoniae (KPC-Kp) septic shock. A retrospective analysis of intensive care unit patients with KPC-Kp infection and septic shock observed in a large teaching hospital from November 2010 to December 2014 was performed. A total of 111 patients were included in the study. The most frequent source of infection was unknown-focus bacteraemia in 53 patients (47.7%). The rate of resistance to colistin was 51.3%; 30-day mortality was reported for 44 patients (39.6%). Surviving patients were more frequently treated with an initial therapy (within 24 hours) including two or more antibiotics displaying in vitro activity against the isolated KPC-Kp strain (41.8 vs. 18.1%, p 0.01) and were also more likely to receive a definitive therapy including two or more in vitro active antibiotics (85.1 vs. 15.9%, p <0.001). Cox regression analysis revealed that a colistin-containing antibiotic regimen (hazard ratio (HR) 0.21, confidence interval (CI) 95% 0.05–0.72, p <0.001), use of two or more in vitro active antibiotics as definite therapy (HR 0.08, CI 95% 0.02–0.21, p <0.001) and control of removable source of infection (HR 0.14, CI 95% 0.04–0.25, p <0.001) were associated with favourable outcome; colistin resistance (HR 8.09, CI 95% 3.14–11.23, p 0.001) and intra-abdominal source of infection (HR 2.92, CI 95% 2.11–4.12, p 0.002) were associated with death. In conclusion, use of a definitive therapy with at least two antibiotics displaying in vitro activity against the KPC-Kp isolates was the most important determinant of favourable outcome, whilst isolation of colistin-resistant strains was associated with death in septic patients with KPC-Kp infection.

Coincidental detection of the first outbreak of carbapenemase-producing Klebsiella pneumoniae colonisation in a primary care hospital, Finland, 2013.

In Finland, occurrence of Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (KPC-KP) has previously been sporadic and related to travel. We describe the first outbreak of colonisation with KPC-KP strain ST512; it affected nine patients in a 137-bed primary care hospital. The index case was detected by chance when a non-prescribed urine culture was taken from an asymptomatic patient with suprapubic urinary catheter in June 2013. Thereafter, all patients on the 38-bed ward were screened until two screening rounds were negative and extensive control measures were performed. Eight additional KPC-KP-carriers were found, and the highest prevalence of carriers on the ward was nine of 38. All other patients hospitalised on the outbreak ward between 1 May and 10 June and 101 former roommates of KPC-KP carriers since January had negative screening results. Two screening rounds on the hospital's other wards were negative. No link to travel abroad was detected. Compared with non-carriers, but without statistical significance, KPC-KP carriers were older (83 vs 76 years) and had more often received antimicrobial treatment within the three months before screening (9/9 vs 90/133). No clinical infections occurred during the six-month follow-up. Early detection, prompt control measures and repetitive screening were crucial in controlling the outbreak.

Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae at a single institution: insights into endemicity from whole-genome sequencing.

The global emergence of Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (KPC-Kp) multilocus sequence type ST258 is widely recognized. Less is known about the molecular and epidemiological details of non-ST258 K. pneumoniae in the setting of an outbreak mediated by an endemic plasmid. We describe the interplay of blaKPC plasmids and K. pneumoniae strains and their relationship to the location of acquisition in a U.S. health care institution. Whole-genome sequencing (WGS) analysis was applied to KPC-Kp clinical isolates collected from a single institution over 5 years following the introduction of blaKPC in August 2007, as well as two plasmid transformants. KPC-Kp from 37 patients yielded 16 distinct sequence types (STs). Two novel conjugative blaKPC plasmids (pKPC_UVA01 and pKPC_UVA02), carried by the hospital index case, accounted for the presence of blaKPC in 21/37 (57%) subsequent cases. Thirteen (35%) isolates represented an emergent lineage, ST941, which contained pKPC_UVA01 in 5/13 (38%) and pKPC_UVA02 in 6/13 (46%) cases. Seven (19%) isolates were the epidemic KPC-Kp strain, ST258, mostly imported from elsewhere and not carrying pKPC_UVA01 or pKPC_UVA02. Using WGS-based analysis of clinical isolates and plasmid transformants, we demonstrate the unexpected dispersal of blaKPC to many non-ST258 lineages in a hospital through spread of at least two novel blaKPC plasmids. In contrast, ST258 KPC-Kp was imported into the institution on numerous occasions, with other blaKPC plasmid vectors and without sustained transmission. Instead, a newly recognized KPC-Kp strain, ST941, became associated with both novel blaKPC plasmids and spread locally, making it a future candidate for clinical persistence and dissemination.

Emergence of KPC-producing Klebsiella pneumoniae in Uruguay: infection control and molecular characterization.

We describe the first outbreak of Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (KPC-KP), the infection control measures adopted and the shift in resistance patterns of isolates during antibiotic treatment. The ST258 KPC-KP strain exhibited a multiresistant antibiotic phenotype including co-resistance to gentamycin, colistin and tigecycline intermediate susceptibility. Isolates before and after treatment had different behaviour concerning their antibiotic susceptibility and the population analysis profile study. A progressive increase in the aminoglycosides (acquiring amicacin resistance) and β-lactam MICs, and a decreased susceptibility to fosfomycin was observed throughout the administration of combined antimicrobial regimens including meropenem. A high meropenem resistance KPC-KP homogeneous population (MIC 256 Jg/mL), could arise from the meropenem heterogeneous low-level resistance KPC-KP population (MIC 8 Jg/mL), by the selective pressure of the prolonged meropenem therapy. The kpc gene was inserted in a Tn4401 isoform a, and no transconjugants were detected. The core measures adopted were successful to prevent evolution towards resistance dissemination.

Epidemic of Klebsiella pneumoniae ST11 Clone Coproducing KPC-2 and 16S rRNA Methylase RmtB in a Chinese University Hospital

BackgroundEmergence of rmtB-positive Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae (KPC-KP) poses a great threat to antimicrobial treatment options.MethodsFrom January 2010 to December 2010, non-duplicate KPC-KP isolates from our hospital were screened for rmtB and multiple other resistance determinants with PCR. Subsequent studies included MIC determination, PFGE, and multilocus sequence typing. Records from patients with KPC-KP isolated were retrospectively reviewed. Comparisons of molecular and clinical characteristics between rmtB-positive and rmtB–negative isolates were systematically performed, as well as the environmental colonization study in ICU wards.ResultsA total of 84 KPC-KP strains were collected, including 48 rmtB-positive KPC-KP (RPKP) and 36 rmtB-negative KPC-KP (RNKP) isolates. All KPC-KP isolates were multidrug resistant, with colistin and tigecycline being the most active agents. Compared with RNKP, RPKP displayed a much severer resistance phenotype. Susceptibility rates for amikacin (0% for RPKP versus 88.9% for RNKP, p < 0.01), fosfomycin (8.5% for RPKP versus 88.9% for RNKP, p < 0.01), and minocycline (6.7% for RPKP versus 52.8% for RNKP, p < 0.01), were all significantly lower in RPKP strains. Isolates belonging to PFGE pulsetype A and sequence type 11 were predominant in both groups, including 39 (81.3%) RPKP and 22 (61.1%) RNKP isolates. Nevertheless, RNKP showed more complex genetic backgrounds compared with RPKP. Diverse clinical characteristics were found in both cohorts, however, no significant differences were observed between RPKP and RNKP patients.ConclusionsRPKP strains have spread widely and gradually replaced RNKP in our hospital. They seemed to show much severer resistance phenotypes compared with RNKP and had a bigger dissemination potential. Prudent use of available active agents combined with good control practices is therefore mandatory.