Synergistic activity and effectiveness of a double-carbapenem regimen in pandrug-resistant Klebsiella pneumoniae bloodstream infections

Sir, Infections due to carbapenemase-producing Klebsiella pneumoniae (CP-Kp) are associated with a high mortality rate.1,2 Therapeutic options are limited, especially when associated with colistin resistance.3 In this setting, a double-carbapenem regimen has been shown to be effective and safe.4,5 Herein, we evaluated through antibiotic kill studies the in vitro synergistic activity of meropenem plus ertapenem against pandrug-resistant CP-Kp isolated from three patients with bacteraemia who were successfully treated with double-carbapenem therapy. For each patient, informed consent to participate in the study was obtained. An adult patient underwent aortic endoprosthesis placement. One year later, he developed periprosthetic infection that was treated with antimicrobial therapy and prosthesis replacement. During hospitalization, the patient had fever (39°C) and three blood cultures were positive for CP-Kp resistant to colistin (ertapenem, meropenem and colistin MICs of 128, 256 and ≥16 mg/L, respectively). Therapy with 3 g of fosfomycin every 6 h and 50 mg of tigecycline every 12 h was started without response. Therefore, 2 g of meropenem every 8 h plus 1 g of ertapenem every 24 h was given for 21 days with complete recovery. An adult patient underwent aorto-bisiliac graft placement. Four years later, the patient was hospitalized for revascularization of the left lower limb and after 2 days he developed fever (38.5°C). Three blood cultures were positive for CP-Kp resistant to colistin (ertapenem, meropenem and colistin MICs of 256, 256 and ≥16 mg/L, respectively). Meropenem (1 g) every 12 h (adjusted for creatinine clearance) plus 6 mg/kg daptomycin every 24 h was given without any clinical response. Subsequently, therapy was changed to 500 mg of ertapenem every 24 h and 1 g of meropenem every 12 h according to creatinine clearance. The patient became afebrile after 48 h of treatment and blood cultures were sterile. However, he died 2 days later due to acute heart failure. An adult patient was hospitalized because of arterial embolization due to renal haematoma. One day later, the patient had fever (39°C) and 4.5 g of piperacillin/tazobactam every 8 h was started with no clinical response. Blood cultures were positive for CP-Kp resistant to colistin (ertapenem, meropenem and colistin MICs of 256, 128 and ≥16 mg/L, respectively). Meropenem (1 g) every 8 h plus 50 mg of tigecycline every 12 h was given with partial response. Therapy was changed to 2 g of meropenem every 8 h plus 1 g of ertapenem every 24 h and administered for 24 days with complete recovery. Phenotypic analyses showed that the three isolates were all KPC producers, in agreement with a previous report indicating that the circulating strain in our hospital is KPC-3.6,7 The activity of meropenem, alone and plus ertapenem, was investigated by time–kill studies using an initial inoculum of ∼5 × 105 cfu/mL for all isolates. At 2, 4, 6, 8 and 24 h timepoints, the number of cfu was determined. Bactericidal activity was defined as ≥99.9% reduction of the initial bacterial count at each timepoint. Synergy was defined as a ≥100-fold decrease in cfu/mL between the combination and its most active constituent after 24 h. The time–kill analysis showed that ertapenem or meropenem alone exhibited an initial reduction in log cfu/mL followed by a significant regrowth at 24 h in all the patients (Figure 1). When the double-carbapenem combination was assessed, a bactericidal and synergistic activity was achieved at 4, 6 and 8 h and maintained at 24 h at concentrations of meropenem 0.5× MIC plus ertapenem 1× MIC, meropenem 1× MIC plus ertapenem 1× MIC and meropenem 2× MIC plus ertapenem 1× MIC in all the patients (Figure 1). Time–kill studies for ertapenem, meropenem and ertapenem plus meropenem in Patients 1 (a), 2 (b) and 3 (c). MICs of ertapenem and meropenem were determined by broth macrodilution in cation-adjusted Mueller–Hinton broth. The broken horizontal line represents a reduction of 3 log10 cfu/mL compared with the initial bacterial count. GC, growth control; MEM, meropenem; ETP, ertapenem. In the setting of CP-Kp infections, the role of double-carbapenem regimens containing ertapenem has been recently reviewed.8,9 In fact, ertapenem, whose activity is greatly affected by carbapenemases, may act as a suicide substrate, thus leading the other carbapenem (meropenem or doripenem) to exert its antimicrobial activity.4,10 To our knowledge, there are only two reports evaluating the clinical effectiveness of a double-carbapenem regimen. In the first case, a patient with ventilator-associated pneumonia due to CP-Kp was successfully cured with doripenem plus ertapenem and kill studies showed bactericidal activity of this combination.7 The other report concerning three patients successfully treated with a double-carbapenem regimen did not evaluate kill studies.5 In our patients, ertapenem plus meropenem induced both clinical (defervescence in 48 h) and microbiological (absence of growth in blood cultures performed 48 h after therapy) responses. In the in vitro studies, combination treatment exhibited higher bacterial killing than monotherapy, even in the presence of high carbapenem MICs. In all the isolates, the combination treatment maintained a bactericidal effect up to 24 h, thus confirming the clinical efficacy of this regimen. In summary, this report suggests that meropenem plus ertapenem might be considered a promising option in CP-Kp infections, especially in patients for whom colistin treatment is inappropriate due to resistance or toxicity. A prospective evaluation of this therapeutic approach together with systematic in vitro kill studies should be encouraged in order to better define the role of double-carbapenem regimens in the clinical practice. This work was supported by a grant from Sapienza University, Rome (2012). None to declare.