Use of High‐Dose 4‐Hour Infusion of Doripenem, in Combination with Fosfomycin, for Treatment of Carbapenem‐ResistantPseudomonas aeruginosaPneumonia

To the Editor—Difficult-to-treat infections caused by carbapenem-resistant Pseudomonas aeruginosa (CRPA) have emerged worldwide [1, 2]. In Thailand, there is an estimated 15% prevalence of CRPA [3]. Treatment strategies using approved antibiotics are essential to optimize the efficacy of treatment of infections due to multidrug-resistant pathogens while pharmaceutical-based drug development is underway [4]. We reported the use of high-dose doripenem, defined as a 4-h infusion of 1 g intravenously every 8 h, in combination with 2 g of fosfomycin intravenously every 8 h for the treatment of CRPA pneumonia. A retrospective study was conducted of patients' medical records for case identification of hospital-acquired pneumonia due to CRPA during the interval from 1 June 2009 through 31 July 2010. A case of hospital-acquired pneumonia was defined by criteria set by the Centers for Diseases Control and Prevention [5]. CRPA was defined as a clinical respiratory specimen of P. aeruginosa resistant to all carbapenems, with an minimum inhibitory concentration (MIC) to doripenem of 4–8 mg/L. Detection of CRPA was performed by basic laboratory standards according to recommendations from the Clinical Laboratory Standard Institute and routinely reported for all P. aeruginosa isolates that were resistant to carbapenems [6]. Eligible subjects were identified by querying the hospital pharmacy database for patient exposure to the high-dose, 4-h infusion of doripenem in combination with fosfomycin for ≥2 days. Medical records were reviewed to confirm the diagnosis of CRPA pneumonia and receipt of dual doripenem and fosfomycin therapy. A standardized data-gathering instrument was completed for each case patient and included demographic characteristics, underlying diseases, regimens of empirical antibiotics, time to initiation of dual doripenem and fosfomycin, clinical outcomes, and/or microbiological outcomes. Clinical outcomes were classified as cure, improvement, failure, or indeterminate with assessment at the time of discontinuation of therapy or at the time of discharge from the hospital, whichever was earlier [7]. Microbiologic outcomes were classified as eradication, presumed eradication, presumed persistence, or indeterminate on the basis of the culture results (if any) of specimens obtained from the original site of infection at any time during therapy [7]. Secondary outcomes included crude mortality and the occurrence of drug-related adverse event(s). During the 14-month study period, 8 patients with hospital-acquired pneumonia met the inclusion criteria, 4 of whom had ventilator-associated pneumonia (Table 1). The median MICs for imipenem, meropenem, and doripenem were >32 mg/L (range, 16 to >32 mg/L), >32 mg/L (range, 16 to >32 mg/L), and 4 mg/L (range, 4–8 mg/L), respectively. All 8 patients were exposed to either imipenem or meropenem prior to receipt of the combination doripenem and fosfomycin therapy, with a switch to the combination regimen within a median of 1 day (range, 1–2 days) after the susceptibility results were available. Six patients (75%) had both favorable clinical outcomes (clinical cure or improvement) and favorable microbiological outcomes. One patient had a favorable microbiological outcome yet died on day 6 of treatment; death was directly related to CRPA, despite a follow-up negative culture (Table 1). The other death occurred on day 5 of treatment in a patient without subsequent culture data, yet the death was likely attributed to CRPA. Six (87%) of the 7 patients who had follow-up microbiological specimens obtained had documented eradication of CRPA. All-cause mortality was 25% (2 of 8 patients), and the 6 survivors tolerated the combination therapy with no significant adverse effects. Demographic and Clinical Characteristics and Outcomes of 8 Patients with Carbapenem-Resistant Pseudomonas aeruginosa Pneumonia Treated with Combination Doripenem-Fosfomycin Therapy A recent report suggests a synergistic effect of combined carbapenem-fosfomycin therapy for ceftazidime-resistant P. aeruginosa [8]. Additional pharmacodynamic data for intravenous doripenem against gram-negative bacteria suggest that a 4-h infusion of 1 g of intravenous doripenem can achieve a 97.2% cumulative fraction of response for P. aeruginosa isolates with doripenem MIC90 of 4 mg/L [9]. This case series is the first to suggest that the combined doripenem and fosfomycin regimen is feasible and effective for the treatment of CRPA with a doripenem MIC of 4–8 mg/L. Additionally, the 4-h infusion of high-dose doripenem was not associated with any adverse drug events, a finding consistent with 1 other report [10]. Future studies are needed to assess the in vitro activity of combination antibiotics, particularly the efficacy and safety associated with 4-h infusions of high-dose doripenem in combination with fosfomycin for the treatment of CRPA. Financial support. This study was supported by Thammasat University Hospital Research Unit. We thank Janssen (Thailand), MSD (Thailand), and Astra Zeneca (Thailand) for their support of the E-test study. Potential conflicts of interest. L.M.M. has served as a consultant to Worldwide Epidemiology Department, GlaxoSmihtKline. A.A.: no conflicts.