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Effectiveness of a Double- Regimen for Infections in Humans Due to Carbapenemase-Producing Pandrug-Resistant

Helen Giamarellou, Lambrini Galani, Fotini Baziaka, Ilias Karaiskos 6th Department of Internal Medicine, Hygeia General Hospital, Athens, Greece

Ertapenem plus or were given in three patients suffering from pandrug-resistant, KPC-2-positive Kleb- siella pneumoniae bacteremia (2 patients) and urinary tract infection (1 patient), respectively. All responded successfully, with- out relapse at follow-up. The results obtained should probably be attributed to ’s increased affinity for the carbapen- emases hindering doripenem/meropenem degradation in the environment of the microorganism.

he worldwide spread of producing carbap- positive blood and urine cultures in which a PDR-CPKP strain, Tenemases, particularly carbapenemase-producing Klebsiella identical with the previous ones as proved by PFGE, was isolated, pneumoniae (CPKP) isolates, is of great concern (1, 2). In Greece, the susceptibilities of which are shown in Table 1. The diagnosis of CPKP is becoming endemic in intensive care units (ICUs), caus- acute bacteremic complicating preexisting bacteri- ing a crude mortality in bacteremic patients of 34.5%, mainly uria was made. He was given 1 g ertapenem every 24 h plus 2 g attributed to the limited choice of effective antimicrobials (3). doripenem every8h(1hafter ertapenem administration) in 4-h , tigecycline, and are the only compounds infusions. The patient became afebrile on the 4th day of therapy, available against extensively drug-resistant (XDR) strains of with negative blood and urine cultures after 48 h of treatment. CPKP, i.e., strains defined as nonsusceptible to at least one agent Therapy continued for 20 days, and the patient was followed up in all but two or fewer antimicrobial categories (4, 5, 6, 7). Unfor- for 10 months without evidence of relapse. tunately, because of its expanding use, the emergence of resistance Case 2. A 42-year-old woman was admitted to the ICU of Hy- to has already been reported (8), whereas clinical experi- geia Hospital in November 2012 because of subarachnoid hemor- ence with fosfomycin is limited (7). In a compassionate attempt to rhage due to a ruptured aneurysm. Endovascular occlusion of the solve the therapeutic problem, the Bulik and Nicolau approach, aneurysm was successfully performed, and subsequently, an in- based on the simultaneous administration of two , dwelling bladder catheter was applied. While the patient was was successfully attempted in three Greek patients (9). To our asymptomatic a week after surgery, a PDR, KPC-2-producing K. knowledge, there are no previously reported cases in humans in pneumoniae strain was isolated in urine cultures at 105 CFU/ml which a double-carbapenem regimen has been administered. (Table 1). Because of urine catheter obstruction, the catheter was Case 1. A 54-year-old man, after an accidental fall that caused urgently replaced. Eighteen hours thereafter, the patient became spinal cord injury, was admitted to an orthopedic hospital in Ath- febrile (39.3°C) and septic. In blood cultures, a CPKP strain iden- ens. He was subjected to posterior spinal fusion plus lumbar lam- tical with the urine isolate was revealed by PFGE. A 14-day course inectomy. The cauda equina injury caused urine retention, and a of 1 g ertapenem every 24 h, followed 1 h later by 1 g meropenem permanent indwelling bladder catheter was necessary. During his every 8 h (reduced dose because of creatinine clearance equal to 30 hospitalization, he spiked high fevers (Ն39°C), and a pandrug- ml/h) in 3-h infusions, was administered. After the 3rd day of resistant (PDR) CPKP strain, i.e., a strain defined as nonsuscep- therapy, the patient became afebrile, with sterile blood and urine tible to all agents in all antimicrobial categories, was isolated from cultures during therapy and after a 3-week follow-up. both blood and urine cultures at Ͼ105 CFU/ml (5). The patient Case 3. A 44-year-old woman was admitted in March 2012 to was transferred to Hygeia Hospital, where blood cultures from a the ICU of Hygeia Hospital because of a car accident. The patient central venous catheter (CVC), blood, and urine were positive for suffered from fractures of the pelvis plus spinal cord injury that the same KPC-2-producing Klebsiella strain shown by PCR and in consequently led to retroperitoneal hematoma complicated with pulsed-field gel electrophoresis (PFGE). A combination of colistin abscesses and cauda equina syndrome. Subsequently, the patient (3 MU every 8 h), doripenem (2 g every 8 h), gentamicin (340 mg underwent many surgical debridements and orthopedic recon- once daily), and fosfomycin (6 g every 6 h) was given without any structions and a permanent indwelling bladder catheter was clinical or bacteriological response. Since the time to positivity was Ͼ2 h for comparing the CVC blood culture to the peripheral, the CVC was removed, and the patient remained afebrile after 24 Received 4 December 2012 Returned for modification 7 January 2013 h. Cultures of the tip of the CVC revealed the same K. pneumoniae Accepted 15 February 2013 strain. The patient was transferred to a rehabilitation center with Published ahead of print 25 February 2013 subsequent negative blood cultures but constantly positive urine Address correspondence to Helen Giamarellou, [email protected]. cultures with the same CPKP strain. Six weeks after his discharge, Copyright © 2013, American Society for Microbiology. All Rights Reserved. he was readmitted to Hygeia Hospital because of high fever doi:10.1128/AAC.02399-12 (Ͼ39°C) and was found to be septic, with normal lung X-rays and

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TABLE 1 Antimicrobial susceptibility patterns of Klebsiella pneumoniae microorganism instead of the copious amounts of KPC that KPC-2-positive isolates would be freely available to degrade doripenem, as happened ini- MICa (mg/liter) for isolates from: tially when the first patient was given only one carbapenem. Blood and urine specimens The three patients described in the present report were excep- from patient: tional, since no that was active in vitro was available. For Urine specimen Antimicrobial 12from patient 3 at least two of them, who were septic and bacteremic, with high Ͼ64 Ͼ64 Ͼ64 MICs of the isolated CPKP strains to all available carbapenems Ͼ64 Ͼ64 Ͼ64 (Ͼ32 mg/liter), the administration of ertapenem plus doripenem Ͼ64 Ͼ64 Ͼ64 or meropenem was a life-saving combination, without any relapse Chloramphenicol Ͼ64 Ͼ64 Ͼ64 at the follow-up. In the 2nd and 3rd patients, instead of dorip- Ͼ Ͼ Ͼ Ciprofloxacin 4 4 4 enem, which was no longer permitted to be given at a high dose Colistin Ͼ16 Ͼ16 Ͼ16 Doripenem Ͼ8 Ͼ8 Ͼ8 (13), 2 g meropenem in 3-h infusions was given based on previous Ertapenem Ͼ8 Ͼ8 Ͼ8 evidence of optimization of the /pharmacody- Fosfomycin Ͼ256 Ͼ1024 128 namics of meropenem by prolonged infusion (10). Gentamicin Ͼ16 (Ͼ256) Ͼ16 (Ͼ256) Ͼ16 (Ͼ256) An alternative explanation for the greater in vivo killing by the Ͼ16 Ͼ16 Ͼ16 Meropenem Ͼ16 (Ͼ32) Ͼ16 (Ͼ32) Ͼ16 (Ͼ32) combination was offered recently, based on the initial reduction in Netilmicin Ͼ32 Ͼ32 32 inoculum density by ertapenem acting as a suicide substrate and Nitrofurantoin Ͼ512 Ͼ512 Ͼ512 thereby permitting doripenem to express its successful activity - Ͼ128 Ͼ128 Ͼ128 against an already reduced, manageable inoculum (11). In order Ͼ Ͼ Tigecycline 8 (12) 8 (12) 4 (4) to support their view, the authors performed further experiments Tobramycin Ͼ16 Ͼ16 Ͼ16 Trimethoprim-sulfamethoxazole Ͼ320 Ͼ320 Ͼ320 in human simulated dosing regimens of ertapenem at 1 g every 24 a All susceptibility tests were performed using the Vitek 2 automated system h administered to immunocompetent mice infected with one of (bioMerieux, Marcy L’ Etoile, France). Susceptibility testing for meropenem, three different CPKP isolates with doripenem MIC values of 8, 32, gentamicin, and tigecycline was also performed with the Etest (bioMerieux, Marcy L’ and Ͼ64 mg/liter. The results were supportive of their theory Etoile, France), and the results are shown in parentheses. without excluding the possibility that some reduction in the bac- terial inoculum by ertapenem contributed to the enhanced effi- cacy of the combination (12). placed. After 5 months of hospitalization in the ICU, the patient The encouraging sustained clinical results obtained in our pa- was transferred to a medical ward. Intermittent catheterization tients, without any adverse effect or toxicity, deserve further elu- was decided, but the patient had bacteriuria with a PDR, KPC-2- cidation regarding the mechanism of the synergism obtained, producing K. pneumoniae strain (Table 1)at105 CFU/ml. Thus, whereas additional clinical experience is required in CPKP infec- efforts to sterilize the urine were considered necessary before the tions, particularly whenever a PDR profile coexists, as in the re- initiation of self-catheterizations to avoid any septic episodes. One ported three cases. gram ertapenem was given every 24 h, followed after1hby2g meropenem every8hin3-hinfusions. Two days later, the urine ACKNOWLEDGMENTS culture was sterile, and the patient was discharged on intermittent All authors report no conflicts of interest. catheterization after a total of 10 days of therapy. After a follow-up There was no financial support for this work. of 6 months, the patient remained asymptomatic, with sterile urine. REFERENCES In the PDR era, the Bulik and Nicolau proposal based on the 1. Nordmann P, Dortet L, Poirel L. 2012. Carbapenem resistance in Entero- administration of double carbapenems for CPKP infections seems bacteriaceae: here is the storm! Trends Mol. Med. 18:263–272. to be a revolutionary approach (9). The investigators combined 2. Cornaglia G, Giamarellou H, Rossolini GM. 2011. Metallo-␤-lactamases: a ertapenem, the carbapenem with the least in vitro activity against last frontier for ␤-lactams? Lancet Infect. Dis. 11:381–393. KPC-positive K. pneumoniae, whose activity is attributed to its 3. 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