Role of Double-Carbapenem Regimen in the Treatment of Infections due to Carbapenemase Producing Carbapenem-Resistant Enterobacteriaceae: A Single-Center, Observational Study

Abstract

Purpose (i) To compare infections caused by carbapenem-susceptible (CS) and carbapenemase producing carbapenem-resistant Enterobacteriaceae (CP-CRE); (ii) to evaluate the clinical effectiveness of the double-carbapenem (DC) regimen in comparison with the best available treatment (BAT) in infections caused by CP-CRE; and (iii) to determine the exact minimal inhibitory concentrations (MICs) of meropenem/ertapenem (MEM/ETP) and the degree of in vitro ETP+MEM synergism in subjects receiving the DC. Methodology Over a 3-year period (2014-2017), patients with infections due to Enterobacteriaceae were included in a single-center, retrospective, observational study. According to the susceptibility to carbapenems, subjects were divided into CSE and CP-CRE groups. CP-CRE group was further divided into subjects receiving the DC regimen and those treated with other regimens (BAT group). Clinical characteristics and the presence of 5th-day response and 60-day outcome were evaluated for DC and BAT groups. The determination of MEM and ETP actual MICs and the MEM+ETP synergistic activity were performed on strains obtained from subjects receiving the DC regimen. Results A total of 128 patients were included in the study: 55/128 (43%) with infections due to CP-CRE and 73/128 (57%) with infections due to CSE. Among CP-CRE (n=55), 21 subjects (39%) were treated with the DC regimen whereas 34 (61%) received BAT. No differences in terms of severity of infection, presence/absence of concomitant bacteremia, type of infection, and resolution of infection were found; in contrast, DC group tended to have a higher rate of sepsis or septic shock at the onset of infection and a higher rate of 5th-day response. MICs 50/90 were 256/512 and 256/256 μg/mL for MEM and ETP, respectively. Overall, complete in vitro synergism was found in 6/20 strains (30%). Conclusion The DC regimen is a valid and effective therapeutic option in patients with infections due to KPC producing CRE, including those with bacteremic infection and more severe clinical conditions. The clinical effectiveness is maintained even in the presence of extremely high MEM MICs.

Treatment of Infections Due to MDR Gram-Negative Bacteria

“…Although apparently paradoxical, the use of carbapenems in combinations with other agents for the treatment of carbapenem-resistant MDR-GNB was frequent in the past (before the availability of novel BL-BLI). This approach was based on the possibility of achieving sufficient carbapenem concentrations against some resistant organisms with only slightly increased carbapenem MICs, and also because of possible synergistic effects (28–31). According to the results of large observational studies, this approach seemed ultimately favorable for severe CRE infections caused by KPC-producing strains, whereas a recent randomized, controlled trial (RCT) did not find differences in survival between meropenem plus colistin vs. colistin alone for the treatment of severe CRAB infections (10, 11, 32).…”

Ceftolozane/Tazobactam and Ceftazidime/Avibactam for Multidrug-Resistant Gram-Negative Infections in Immunocompetent Patients: A Single-Center Retrospective Study

“…Actual therapeutic strategies are to increase the doses of carbapenem, colistin, and tigecycline or to combine these drugs. Double-carbapenem therapy was adopted as a salvage therapy for critically ill patients with CRE or CPE infections [ 19 , 20 ], but the evidence about this therapeutic option is low [ 21 , 22 ]. Ceftazidime/avibactam and ceftolozane/tazobactam could be useful in the management of carbapenem-sparing programs in settings with a high prevalence of ESBL-producing Enterobacterales and DTR Gram-negative infections.…”

The effect of double-carbapenem therapy on mortality rates and microbiological cure rates in patients diagnosed with carbapenem-resistant Klebsiella pneumoniae infections in comparison to monotherapy and currently used combinations of antibiotics

“…The studies selected for inclusion were assessed for risk of bias and all included studies were determined to have a moderate risk of bias, with the exception of the study conducted by Gutierrez-Gutierrez et al, 2017, (20) (18,19,20,21,22,23,24). Similarly all included studies were determined to have a low risk of bias due to deviations from intended interventions and in bias due to classification of interventions (18,19,20,21,22,23,24). The study conducted by De Pascale et al, 2017 (18) was determined to have a moderate risk of bias due to missing data, all other included studies were determined to have a low risk of bias due to missing data (19,20,21,22,23,24).…”

“…Similarly all included studies were determined to have a low risk of bias due to deviations from intended interventions and in bias due to classification of interventions (18,19,20,21,22,23,24). The study conducted by De Pascale et al, 2017 (18) was determined to have a moderate risk of bias due to missing data, all other included studies were determined to have a low risk of bias due to missing data (19,20,21,22,23,24). In addition, all studies had low risk of bias in both measurements of outcomes and in selection of the reported result (18,19,20,21,22,23,24).…”