Our aim was to identify treatment regimens for infections caused by carbapenem-resistant gram-negative bacteria in our hospital. In this study, a total of 44 patients who infected with carbapenem-resistant gram-negative were found in 65,000 inpatients over a 2-year period, indicative of a very low infectious rate. Furthermore, monotherapy (trimethoprim/sulfamethoxazole, amikacin, meropenem, and doxycycline) was an effective antibiotic regimen for the treatment of CRKP infection; monotherapy of moxifloxacin, piperacillin/tazobactam, cefepime, and ceftazidime was the preferred antibiotic choice for CRPA infection; and cefoperazone/sulbactam monotherapy or tigecycline combination therapy could effectively treat CRAB infections.
Carbapenem is the treatment option for patients who develop serious infections with MDR, XDR, and PDR gram-negative bacilli, but unfortunately the resistance to carbapenem significantly compromises this treatment choice [11]. Consequently, carbapenem resistance among gram-negative bacteria is disseminating worldwide, which poses a serious threat to current medical practices. Similar to previous reports [12, 13], CRAB isolates in our study were XDR strains, showing susceptibility to only one and/or two antibiotics in vitro. Unlike previous reports [12, 13], CRKP and CRPA isolates in our study were MDR, indicative of a better antibiotic choice in vitro.
In fact, the antibiotic susceptibility determined by in vitro culture does not always correlate with the success of clinical therapy in vivo [11]. Exact antibiotic doses and bacterial inocula can be easily assessed on agar plates, but this may not be replicated in patients. As a result, despite many in vitro studies of bacterial infection, the findings do not always translate into successful treatment in clinical studies. In this study, we observed that the implementation of antibiotic regimens in CRKP and CRPA-infected patients were consistent with in vitro activity. However, a minor difference was found in CRAB-infected patients. Of the 29 patients with CRAB, resistance to empirical antibiotics piperacillin/tazobactam (2/2, 100%) and imipenem/cilastatin (1/1, 100%) was shown in vitro but patients effectively recovered, and in 20 cases resistance to cefoperazone/sulbactam was shown but clinical efficacy was evident for most patients. This discrepancy maybe attributed to the different environments in vivo and in vitro, the minimum inhibitory concentrations, as well as the clinical efficacy of the cefoperazone/sulbactam combination [14, 15].
Current guidance for the treatment of carbapenem-resistant gram-negative bacterial infections relies on antibiotic therapy based on polymyxins (including colistin or polymyxin B), aminoglycosides, and tigecycline [16, 17]. Emerging retrospective clinical studies show that antibiotic options have not yet been fully standardized, and that treatments may need to be individualized to control carbapenem-resistant pathogens depending on different regions [1]. Papst et al. showed that in Israel, monotherapy was the preferred choice for treating CRPA and CRAB infections, whereas in all other countries, combination therapy with two drugs was standard [11]. Ceftazidime/avibactam was commonly used for the treatment of CRKP-infected patients in the USA, whereas ceftolozane/tazobactam was often used in Spain, Italy, France, and the USA [11]. Chen et al. reported that both monotherapy of colistin and combination therapy of colistin and carbapenem showed high cure rates of CRAB and CRKP [18]. Our study showed that our hospital’s antibiotic treatment strategies, which included monotherapy of trimethoprim/sulfamethoxazole, amikacin, meropenem, and/or doxycycline therapy for CRKP, monotherapy of moxifloxacin, piperacillin/tazobactam, cefepime, and/or ceftazidime for CRKP, and monotherapy of cefoperazone/sulbactam or combination therapy with cefoperazone/sulbactam and tigecycline for CRAB, according to standard guidance, led to a high cure rate.
Carbapenem resistance mechanisms are most commonly associated with carbapenemase production, porin loss, drug efflux, and target alteration [19]. In China, KPC-2 and NDM gene were identified as the main resistance mechanism of CRKP to carbapenem [20, 21]. Han et al reported that the carbapenemase gene among CRKP were KPC-2 (64.6%, 457/709), NDM (21.1%, 150/709) and OXA-232 (9.3%, 66/709), while only 9 strains were positive for multiple carbapenemases [21]. Additionally, carbapenem-resistance gene OXA-23 played a critical role in carbapenem-resistance of CRAB [22], and metallo-β-lactamase IMP-45 may contribute to CRPA resistance to carbapenem [23, 24].
In summary, our study collates the successful treatment regimens for infections caused by carbapenem-resistant gram-negative bacteria in our hospital. In the future, it will be of great interest to elucidate the molecular mechanisms of carbapenem resistance. It will also be important to further identify optimal antibiotic treatment strategies through a multi-centre study involving a greater number of patients in Shanghai.