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Extensively drug‐resistant carbapenemase‐producing Enterobacteriaceae: an emerging challenge for clinicians and healthcare systems

2015; Wiley; Volume: 277; Issue: 5 Linguagem: Inglês

10.1111/joim.12350

1365-2796

Gian María Rossolini,

Infections and bacterial resistance

The global dissemination of carbapenem-resistant Enterobacteriaceae showing extensively drug-resistant (XDR) phenotypes is one of the most worrying aspects of the ongoing 'antibiotic resistance crisis', in which antibiotics are progressively losing their efficacy due to the relentless increase in antibiotic resistance and the concomitant lag in the discovery and development of new antibiotics 1. As elegantly reviewed by Tängdén and Giske 2, the global dissemination of carbapenem-resistant Enterobacteriaceae is mostly due to strains of Klebsiella pneumoniae and less frequently of other species producing various types of acquired carbapenemases. By contrast, strains with other carbapenem-resistance mechanisms (such as decreased outer membrane permeability and overproduction of expended-spectrum or AmpC-type β-lactamases) overall exhibit a lower potential for dissemination and have therefore remained in the backstage. In fact, some lineages of carbapenemase-producing Enterobacteriaceae (CPE), such as K. pneumoniae of clonal complex (CC) 258 producing KPC-type carbapenemases, have proved extremely successful at spreading within healthcare settings, leading to rapid dissemination in some areas and even globally 2. In addition to the propensity for rapid diffusion, CPE represent a major challenge for both clinicians and healthcare systems as a result of two other features: (i) their XDR phenotypes, including most of the agents available for treatment of enterobacterial infections, and (ii) the potential for causing infections associated with high mortality rates 2, 3. Indeed, mortality can be particularly high amongst immunocompromised patients such as allogeneic stem cell transplant recipients, in whom infection-related mortality rates above 60% have been observed 4. It is difficult to treat infections caused by CPE because of the inadequacy of antimicrobial options. Colistin, tigecycline, fosfomycin and some aminoglycosides are amongst the few agents that usually retain activity against these pathogens, which in addition to carbapenemases invariably possess several resistance determinants yielding complex XDR phenotypes. The minimal inhibitory concentration (MIC) of carbapenems may vary depending on the species, the type of carbapenemase, the level of expression and the presence of additional resistance mechanisms (such as outer membrane permeability defects). In some cases, MICs are higher than the resistance break points, whereas in others they remain in the intermediate or even in the susceptible range and the strain will be reported as susceptible according to current interpretive guidelines 2. The available evidence, derived from retrospective observational studies, consistently points to the superiority of combination therapy versus monotherapy for treatment of severe CPE infections and also supports the inclusion of carbapenems in combination regimens, especially if the bacterial isolate exhibits relatively low carbapenem MICs 2, 5, 6. On the other hand, carbapenem-sparing regimens have been advocated for treating patients without comorbidities to reduce the selective pressure generated by carbapenem overuse 7. Although there is now reasonable consensus that combination therapy is superior to monotherapy, the nature of the most appropriate combination regimens remains controversial and selection based on the results of in vitro susceptibility testing and on the site of infection is usually advocated 8. In this context, clinicians should also be aware that, with CPE, different in vitro testing systems may yield different results for carbapenem MICs 9, 10, and accuracy problems may be encountered when testing susceptibility to tigecycline and gentamicin with automated systems or gradient diffusion systems that are often used in the clinical microbiology laboratory 11, 12. Therefore, for CPE infections, it is always advisable to ascertain the susceptibility testing methodology used by the referral laboratory, and in some cases, confirmatory susceptibility testing by reference broth microdilution for CPE isolates should be requested. Moreover, this issue may complicate the interpretation of data from retrospective observational studies. Finally, it should be noted that, in current anti-CPE combination regimens, drugs are often administered at increased dosages compared to those reported in the respective labels (e.g. colistin at 9–10 million units daily divided into two or three doses or tigecycline at 75–100 mg every 12 h) 2, usually resulting in off-label prescriptions. As noted by Tängdén and Giske 2, colistin is a backbone agent in the anti-CPE combination regimens. However, colistin-resistant CPE (mostly K. pneumoniae) have increasingly been reported 13-16 and, in some areas, have rapidly reached alarming proportions. In Italy, a country affected since 2010 by a CPE epidemic mostly sustained by KPC-type carbapenemase-producing K. pneumoniae (KPC-Kp) strains, a rapid nationwide dissemination of colistin-resistant KPC-Kp strains has been observed recently, with overall resistance rates higher than 40% 17. The emergence and dissemination of colistin resistance amongst CPE further narrows the repertoire of treatment options for these pathogens and is clearly a matter of major concern. In such cases, combinations with fosfomycin could be an option 2, but clinical experience is still limited. On the other hand, combination of colistin with rifampicin was shown to exert a synergistic effect against colistin-resistant strains of KPC-Kp in vitro 18, but clinical studies are required to determine the potential significance of this observation for treatment of infections caused by colistin-resistant CPE. Finally, a double-carbapenem regimen (meropenem or doripenem plus ertapenem) was reported to be successful in a few cases of infections caused by colistin-resistant CPE 19, 20, but even this approach will require further validation in larger clinical studies. Given the shortage of treatment options and the potential for dissemination of CPE, surveillance and infection control are of paramount importance to limit dissemination at the local, national and international levels 2. Surveillance and infection control should target not only CPE infections but also colonized subjects, who represent the major source of CPE dissemination within healthcare settings and of cross-border transfer of CPE strains from countries in which these pathogens are endemic 21. In fact, as members of the family Enterobacteriaceae, CPE are likely to colonize the intestinal tract and, possibly, other sites (upper respiratory tract, urinary tract and skin). Colonization by CPE can last for months 22 and represents a risk factor for subsequent infection. In a large follow-up study, an overall infection rate of 9% was observed amongst colonized patients, with risk factors for subsequent infection in these patients including intensive care unit stay, central venous catheter use, antibiotic exposure and diabetes mellitus 23. The risk of infection appears to be particularly high in some patient groups: in stem cell transplant recipients, the rates of infection were found to be 26% and 39%, respectively, amongst previously colonized patients undergoing autologous or allogeneic transplantation 4. Oral administration of nonabsorbable antibiotics active against CPE (e.g. gentamicin and colistin) for intestinal decolonization therapy has been evaluated in several studies 24-26. This approach was found to be effective in a number of cases, although decolonization was sometimes transient and the success was inversely associated with concomitant administration of systemic antimicrobial chemotherapy. Based on this finding, and due to concerns about the risk of further resistance selection against potentially useful agents, this practice remains controversial and should be considered experimental and only suitable for particular at-risk patient groups. The global dissemination of XDR strains of CPE is a major challenge for clinicians and healthcare systems and has been recognized as a public health issue. New antibiotics active against CPE are a major unmet clinical need, and research in this area has been revamped in recent years. A number of novel antibiotics with anti-CPE activity are currently in clinical development, including: (i) plazomicin, an aminoglycoside with good activity against many CPE (but not against strains that also produce 16S ribosomal methylases); (ii) combinations of beta-lactams with new beta-lactamase inhibitors, such as avibactam, relebactam or RPX7009, which are active against some carbapenemases (but not against metallo-beta-lactamases) and can restore the activity of the companion beta-lactams (ceftazidime, atreonam or carbapenems); and (iii) eravacycline, a fluorocycline that is active against many CPE (but not against Proteus and Serratia species) 1, 2. However, the expected timeframe for introduction of these novel antibiotics in clinical practice remains relatively long, and none will completely cover the diverse spectrum of CPE that is spreading in the clinical setting 2. Moreover, the clinical development of the new anti-CPE drugs is being challenged by the difficulties in designing clinical trials suitable to assess their efficacy. In this scenario, proactive surveillance, infection control and antimicrobial stewardship programmes remain the only affordable options to control CPE dissemination. Integrated strategies based on these options have proved successful 27 and should be actively pursued at the local, national and international levels to control further dissemination of CPE. The author wishes to acknowledge the support for experimental work on CPE carried out at the University of Siena by a grant from the FP7 project EvoTAR (no. HEALTH-F3-2011-2011-282004). G.M.R. has served on scientific advisory boards for Astra-Zeneca, Cubist, Achaogen, Rempex, Angelini ACRAF, Durata, Menarini and Biotest and has received speaker honoraria from Pfizer, Novartis, Astra-Zeneca, Basilea and Angelini ACRAF and research grants from Pfizer, Astra-Zeneca, Cubist, VenatorX, Biotest, bioMérieux and Becton-Dickinson.