Summary: The spread of Enterobacteriaceae, primarily Klebsiella pneumoniae, producing KPC, VIM, IMP, and NDM carbapenemases, is causing an unprecedented public health crisis. Carbapenemase-producing enterobacteria (CPE) infect mainly hospitalized patients but also have been spreading in long-term care facilities. Given their multidrug resistance, therapeutic options are limited and, as discussed here, should be reevaluated and optimized. Based on susceptibility data, colistin and tigecycline are commonly used to treat CPE infections. Nevertheless, a review of the literature revealed high failure rates in cases of monotherapy with these drugs, whilst monotherapy with either a carbapenem or an aminoglycoside appeared to be more effective. Combination therapies not including carbapenems were comparable to aminoglycoside and carbapenem monotherapies. Higher success rates have been achieved with carbapenem-containing combinations. Pharmacodynamic simulations and experimental infections indicate that modification of the current patterns of carbapenem use against CPE warrants further attention. Epidemiological data, though fragmentary in many countries, indicate CPE foci and transmission routes, to some extent, whilst also underlining the lack of international collaborative systems that could react promptly and effectively. Fortunately, there are sound studies showing successful containment of CPE by bundles of measures, among which the most important are active surveillance cultures, separation of carriers, and assignment of dedicated nursing staff.

Carbapenemases in Klebsiella pneumoniae and Other Enterobacteriaceae: an Evolving Crisis of Global Dimensions

Multilocus sequence typing reveals that many bacterial species have a clonal structure and that some clones are widespread. This underlying phylogeny was not revealed by pulsed-field gel electrophoresis, a method better suited to short-term outbreak investigation. Some global clones are multiresistant and it is easy to assume that these have disseminated from single foci. Such conclusions need caution, however, unless there is a clear epidemiological trail, as with KPC carbapenemase-positive Klebsiella pneumoniae ST258 from Greece to northwest Europe. Elsewhere, established clones may have repeatedly and independently acquired resistance. Thus, the global ST131 Escherichia coli clone most often has CTX-M-15 extended-spectrum β-lactamase (ESBL), but also occurs without ESBLs and as a host of many other ESBL types. We explore this interaction of clone and resistance for E. coli, K. pneumoniae, Acinetobacter baumannii- a species where three global lineages dominate--and Pseudomonas aeruginosa, which shows clonal diversity, but includes the relatively 'tight' serotype O12/Burst Group 4 cluster that has proved adept at acquiring resistances--from PSE-1 to VIM-1 β-lactamases--for over 20 years. In summary, 'high-risk clones' play a major role in the spread of resistance, with the risk lying in their tenacity--deriving from poorly understood survival traits--and a flexible ability to accumulate and switch resistance, rather than to constant resistance batteries.

Multiresistant Gram-negative bacteria: the role of high-risk clones in the dissemination of antibiotic resistance

Klebsiella pneumoniae producing Klebsiella pneumoniae carbapenemase (KPC) has been associated with serious infections and high mortality. The optimal antimicrobial therapy for infection due to KPC-producing K. pneumoniae is not well established. We conducted a retrospective cohort study to evaluate the clinical outcome of patients with bacteremia caused by KPC-producing K. pneumoniae. A total of 41 unique patients with blood cultures growing KPC-producing K. pneumoniae were identified at two medical centers in the United States. Most of the infections were hospital acquired (32; 78%), while the rest of the cases were health care associated (9; 22%). The overall 28-day crude mortality rate was 39.0% (16/41). In the multivariate analysis, definitive therapy with a combination regimen was independently associated with survival (odds ratio, 0.07 [95% confidence interval, 0.009 to 0.71], P = 0.02). The 28-day mortality was 13.3% in the combination therapy group compared with 57.8% in the monotherapy group (P = 0.01). The most commonly used combinations were colistin-polymyxin B or tigecycline combined with a carbapenem. The mortality in this group was 12.5% (1/8). Despite in vitro susceptibility, patients who received monotherapy with colistin-polymyxin B or tigecycline had a higher mortality of 66.7% (8/12). The use of combination therapy for definitive therapy appears to be associated with improved survival in bacteremia due to KPC-producing K. pneumoniae.

https://aac.asm.org/content/aac/56/4/2108.full.pdf

Treatment Outcome of Bacteremia due to KPC-Producing Klebsiella pneumoniae: Superiority of Combination Antimicrobial Regimens

https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(14)61924-8/pdf

Predictors of mortality in patients with bloodstream infections caused by KPC-producing Klebsiella pneumoniae and impact of appropriate antimicrobial treatment.

Carbapenem-resistant members of the family Enterobacteriaceae have spread across the world and within the United States (2, 5, 15). In the United States, carbapenem-resistant Klebsiella pneumoniae constitutes 92% of all carbapenem-resistant Enterobacteriaceae and carbapenemase production mediated by blaKPC is the most prevalent mechanism conferring resistance to carbapenems (5). Carbapenem-resistant Enterobacteriaceae are coresistant to almost all classes of antimicrobials (29), and infections are associated with extremely high rates of morbidity and mortality and high costs (30). Colistimethate sodium, i.e., colistin, is one of the few remaining therapeutic options available to treat infections due to carbapenem-resistant Enterobacteriaceae. Despite the toxicity of this relatively old agent, colistin is frequently used to treat infections due to carbapenem-resistant Enterobacteriaceae because (i) therapeutic alternatives are not yet available and (ii) colistin has a long history and track record in the treatment of invasive infections due to Gram-negative bacilli (28, 31, 35). In most cases, colistin is the last viable effective option for the treatment of invasive bloodstream infections due to carbapenem-resistant Enterobacteriaceae.

In the past few years, there have been sporadic reports of colistin-resistant, carbapenem-resistant Enterobacteriaceae cases from various parts of the world, e.g., Greece (2, 37), Israel (28), South Korea (32), and Singapore (33). In Athens, Greece, an outbreak during the years 2004 and 2005 involving 13 patients in a single hospital unit was reported (2). Colistin-resistant, carbapenem-resistant Enterobacteriaceae cases have never been reported from the United States. There have been case reports of polymyxin B-resistant, carbapenem-resistant Enterobacteriaceae from the New York City area (usually, resistance to polymyxin B confers resistance to polymyxin E, i.e., colistin, and vice versa), but these events remain sporadic and rare, with no outbreaks reported thus far (4, 8, 17). The mechanism(s) of colistin resistance in carbapenem-resistant Enterobacteriaceae is not yet known. The genetic basis of colistin resistance in Acinetobacter baumannii is being investigated (1, 13, 18), but it remains unclear whether the same mechanism(s) is associated with colistin resistance in carbapenem-resistant Enterobacteriaceae. Additionally, the microbiological definitions of colistin resistance are also not well established, as formal Clinical and Laboratory Standards Institute (CLSI) criteria and breakpoints have not been established (7). Lastly, the clinical significance of colistin resistance remains to be defined.

We describe here the first cluster, as far as we know, of colistin-resistant, carbapenem-resistant K. pneumoniae in the United States, which involved two hospitals and a long-term acute-care (LTAC) facility, in the summer of 2009. The epidemiologic and molecular outbreak investigations that followed are detailed.

Outbreak of Colistin-Resistant, Carbapenem-Resistant Klebsiella pneumoniae in Metropolitan Detroit, Michigan

A matched 1:3 case-control study investigated factors predicting colistin-resistant versus colistin-susceptible KPC-producing Klebsiella pneumoniae acquisition and its impact on patient outcomes. Case patients were more often admitted from other institutions (P = 0.019) and had longer therapy with β-lactam/β-lactamase inhibitors (P = 0.002) and higher overall mortality (P = 0.05). All 52 study isolates were clonally related, suggesting horizontal dissemination. None of these parameters independently predicted colistin resistance, which probably occurred in a susceptible KPC-KP strain that was subsequently disseminated horizontally.

Risk Factors and Outcomes Associated with Acquisition of Colistin-Resistant KPC-Producing Klebsiella pneumoniae: a Matched Case-Control Study

The aim of this study was to investigate the effect of the implementation of an antibiotic stewardship program (ASP) on antibiotic consumption in our 428-bed hospital. The Infection Control Committee implemented an ASP beginning in January 2016, aiming to reduce inappropriate antibiotic use through improved prescribing practices. The ASP included both pre-authorization and prospective audit and feedback strategies. We collected pharmacy and hospital data for the years 2015 (pre-intervention) and 2016 (post-intervention). Consumption data were expressed as daily defined doses (DDDs) per 100 patient-days (PD) and the significance of the differences between 2015 and 2016 was assessed by paired t-test. Antibiotic resistance rates for the most important hospital pathogens were monitored for 2015–2016. The ASP effectively reduced consumption of most antimicrobials; total antibiotic use decreased by 16.7% (from 104.3 in 2015 to 86.9 DDDs/100 patient-days in 2016, p < 0.001) owing to reduction of 19.1% for non-restricted and 13.8% for restricted antibiotics. Important restricted antimicrobials, such as colistin, carbapenems, quinolones and tigecycline showed significantly decreased usage post-intervention. Significant changes in the resistance rates were not observed, except a decreasing trend for colistin and tigecycline (Acinetobacter baumannii and Klebsiella pneumoniae) and also vancomycin (enterococci). The ASP was successful in terms of reducing the antibiotic consumption for the first year of its implementation. Interestingly, antimicrobials requiring pre-authorization exhibited a lower reduction than other antibiotics. Potential effects of the ASP in reducing resistance rates remain to be shown.

First-year results of an antibiotic stewardship program in a Greek tertiary care hospital

This study aimed to investigate the effects of a 4-year antibiotic stewardship program (ASP) in a tertiary hospital. We monitored data for 2015 (pre-intervention) and 2016-2019 (post-intervention) about antibiotic consumption (DDD/100 bed days), Clostridioides difficile infections (CDIs), resistance rates, length of stay (LOS), and annual antibiotic costs. Significant reductions were observed for total antibiotics/colistin/carbapenems/quinolones/tigecycline consumption and resistance rates of Pseudomonas aeruginosa, Klebsiella pneumoniae, and vancomycin-resistant enterococci. Considerable reductions occurred for LOS (4.18 [2015]/3.0 [2019] days), CDIs (1.47 [2015]/0.86 [2019] per 1000 patients), antibiotic cost/patient (39.45€ [2015]/23.69€ [2019]). The ASP was successful in reducing antibiotic consumption, antibiotic costs, length of hospital stay, and CDIs.

Georgios Chrysos

Papers

Risk Factors and Outcomes Associated with Acquisition of Colistin-Resistant KPC-Producing Klebsiella pneumoniae: a Matched Case-Control Study

First-year results of an antibiotic stewardship program in a Greek tertiary care hospital

Impact of a 4-year antimicrobial stewardship program implemented in a Greek tertiary hospital