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In Vitro Activity of Colistin Or Sulbactam In SOUTHEAST ASIAN J TROP MED PUBLIC HEALTH IN VITRO ACTIVITY OF COLISTIN OR SULBACTAM IN COMBINATION WITH FOSFOMYCIN OR IMIPENEM AGAINST CLINICAL ISOLATES OF CARBAPENEM- RESISTANT ACINETOBACTER BAUMANNII PRODUCING OXA-23 CARBAPENEMASES Wichai Santimaleeworagun1, Payom Wongpoowarak1, Pantip Chayakul2, Sutthiporn Pattharachayakul1, Pimpimon Tansakul3 and Kevin W Garey4 1Department of Clinical Pharmacy, 3Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmaceutical Sciences, 2Department of Medicine, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand; 4Department of Clinical Sciences and Administration, College of Pharmacy, University of Houston, Houston, Texas, USA Abstract. This study investigated the in vitro activity of colistin or sulbactam in combination with fosfomycin or imipenem against eight strains of carbapenem- resistant A. baumannii (CRAB). The eight CRAB clinical isolates were collected from hospitalized patients admitted to Songklanagarind Hospital in southern Thailand during January-December 2008. The isolates were divided into 4 different patterns of clonal relationships using the Repetitive Extragenic Palindromic-Polymerase Chain Reaction method (REP-PCR). The in vitro activity of combination antibacte- rial agents against theses isolates were determined by chequerboard and time-kill methods. All isolates producing OXA-23 carbapenemases were universally sus- ceptible to colistin but intermittently susceptible to other antimicrobial agents. A chequerboard assay showed the synergistic effects of sulbactam plus fosfomycin and colistin plus fosfomycin in 75% and 12.5% of isolates, respectively. Sulbactam 1 at a concentration of 1 x MIC plus fosfomycin at 1 x MIC or at /4 x MIC showed synergism in 75% and 37.5% of clinical isolates, respectively. Bactericidal activity was observed for up to 12 hours of incubation. There was no synergism between colistin and sulbactam, sulbactam and imipenem, and colistin and imipenem, against the tested isolates. Combined use of sulbactam and fosfomycin may pro- vide an alternative therapeutic option for CRAB infections. Key words: Acinetobacter baumannii, carbapenam resistant, colistin, sulbactam, fosfomycin, imipenem, carbapenemase INTRODUCTION negative bacillus, causes nosocomial infections worldwide. In the United Acinetobacter baumannii, a gram- States, Acinetobacter species were ranked Correspondence: Wichai Santimaleeworagun, the second leading cause of mortality Department of Clinical Pharmacy, Faculty of (43.4%) in patients admitted to inten- Pharmaceutical Sciences, Prince of Songkla sive care units (Wisplinghoff et al, 2004). University, Songkhla 90112, Thailand. The National Antimicrobial Resistance Tel: 66 (0) 7442 8222; Fax: 66 (0) 7442 8222 Surveillance Center, Thailand (NARST) E-mail: [email protected] found A. baumannii was the fourth most 890 Vol 42 No. 4 July 2011 IN VITRO ACTIVITY OF ANTIMICROBIAL AGENT COMBINATIONS AGAINST CRAB common clinical pathogen isolated from some GNB, including extended-spectrum specimens studied in 2006 (NARST, b-lactamase-producers (de Cueto et al, 2009). A. baumannii related infections 2006; Falagas et al, 2008a). Falagas et al are associated with adverse outcomes, (2008b) found the MIC of fosfomycin including increased mortality, prolonged against MDR-AB strains ranged from 64 hospitalization, additional hospital costs, to >512 mg/l. In our setting, the MIC50 and reduced patient functional status (Lee and MIC90 of fosfomycin against MDR-AB et al, 2007; Tseng et al, 2007; Young et al, were 64 and 96 mg/l, respectively (Hor- 2007). At Songklanagarind Hospital, a tiwakul et al, 2009). This in vitro activity tertiary care hospital located in southern of fosfomycin against MDR-AB is within Thailand, Jamulitrat et al (2009) found possible therapeutic concentrations (Ban- mortality rates were higher in patients do and Toyoshima, 1984). Since the in vitro with carbapenem-resistant A. baumannii activity of fosfomycin in combination with (CRAB; 52.2%) than carbapenem-sensitive other agents against MDR-AB has not pre- A. baumannii bacteremia (19.9%). At pres- viously been reported, we investigated the ent, the optimum treatment for multi-drug combination of colistin or sulbactam with resistant A. baumannii (MDR-AB) has not fosfomycin or imipenem against in vitro been established. In previous in vitro stud- CRAB infections to evaluate the potential ies, colistin and rifampicin, sulbactam and synergistic or antagonistic effects of these imipenem and rifampicin and imipenem combinations. have been shown to have a synergistic ef- fect on MDR-AB (Song et al, 2007; Tripodi MATHERIALS AND METHODS et al, 2007). However, a synergistic effect with these drug combinations has not Bacterial strains been seen with resistant isolates. All clinical isolates were obtained In Thailand, colistimethate and from inpatients admitted at Songklana- cefoperazone/sulbactam are antimicro- garind Hospital, a university-affiliated bial agents used for treating multi-drug medical school in southern Thailand resistant gram-negative bacterial (GNB) during January-December 2008. CRAB infections, in particular, infections due to was defined as isolates resistant to imi- Pseudomonas aeruginosa and A. bauman- penem. Resistance was defined as a MIC nii. Sulbactam, a b-lactamase inhibitor, is ≥ 16 mg/l according to the Clinical and combined with b-lactam antibiotics (eg, Laboratory Standards Institute (CLSI, ampicillin, cefoperazone) for inhibiting 2009). The clinical isolates of CRAB were b-lactamases, but sulbactam itself also obtained from sterile sites (eg, blood, cere- has activity against A. baumannii (Corbella brospinal fluid, bone marrow, peritoneal et al, 1998). The NARST survey in 2006 fluid, pleural fluid, synovial fluid). Eight (NARST, 2009) found 58% of A. baumannii CRAB specimens were collected; four isolates were susceptible to cefoperazone/ isolates had a MIC against imipenem of sulbactam. In contrast, at our institution 16 mg/l, and the others had a MIC ≥ 32 during 2004-2008, 90% of A. baumannii mg/l. MDR-AB was defined as isolates isolates were sensitive to colistin and cefo- resistant to carbapenem and at least two perazone/sulbactam (unpublished data). antibiotics from the following: piperacil- Fosfomycin has been shown to have ac- lin/tazobactam, ciprofloxacin, amikacin, tivity against gram-positive bacteria and gentamicin, cefoperazone/sulbactam or Vol 42 No. 4 July 2011 891 SOUTHEAST ASIAN J TROP MED PUBLIC HEALTH colistin. All CRAB strains were kept at tant genes, blaIMP-like, blaOXA-23, blaOXA-40, -20ºC until tested. blaOXA-58, blaSIM-1, blaVIM-1 and blaVIM-2, were designed from the nucleotide sequence of Polymerase chain reaction-based DNA each gene retrieved from GenBank. The fingerprint accession numbers of each gene are shown The REP-PCR method was used to in Table 1. Amplification was carried out interpret the clonal relationships of the under the following PCR conditions, 94ºC isolates. In this study, genomic DNA for 5 minutes, followed by 30 cycles of was extracted and the PCR technique first 94ºC for 1 minute then annealing for was used to amplify positions in the 2 minutes. The annealing temperatures REP region. Briefly, selected strains were were optimized for each primer set based cultured in Mueller-Hinton broth (Difco, on the melting temperature of the primer, Detroit, MI) and incubated at 37ºC for 18 followed by 72ºC for 2 minutes and a final hours. The genomic DNA was prepared extension at 72ºC for 10 minutes. The PCR using the DNeasy Qiagen kit (Qiagen, products were evaluated by agarose gel Valencia, CA). The purified DNA was electrophoresis, ligated with the Strata- kept at -20ºC until PCR testing was done. clone PCR cloning kit (Stratagene, La Jolla, The PCR mixture consisted of 1 µl of ge- CA) and transferred to E. coli. The plasmid nomic DNA, 10 mM of each forward and from the overnight E. coli culture was pu- reverse primer (REP-forward: 5’-IIIGC- rified and used for sequencing analysis. GCCGICATCAGGC-3’ and REP-reverse: 5’-ACGTCTTATCAGGCCTAC-3’) (Bou Determination of minimum inhibitory et al, 2000), 0.2 mM of deoxy-nucleotide concentration The MICs of the antimicrobial agents triphosphate and 1.5 mM MgCl2 in 5x GoTaq® buffer. The volume of GoTaq® were determined by the agar dilution polymerase (Promega, Madison, WI) method using Mueller-Hinton agar was 1.25 U. The total volume of the PCR (Difco) plates containing dilutions of the mixture was 50 µl. Thermocycling was antimicrobial agents, according to CLSI carried out with Takara thermocycler dice, protocol (CLSI, 2009). The lowest con- starting with denaturation at 94ºC for 10 centration of an antimicrobial agent that minutes, followed by 30 cycles of 94ºC for inhibited visible growth of the organism 1 minute, 45ºC for 1 minute (annealing was defined as the MIC. The antimicrobial temperature), 72ºC for 2 minutes and a agents used in this study were: fosfomy- final extension at 72ºC for 16 minutes. The cin disodium salt (Sigma Chemical, St PCR products were evaluated by electro- Louis, MO), supplemented with 25 mg/l of phoresis in 1.2% of agarose gel, stained glucose-6-phosphate (G-6-P sodium salt; with ethidium bromide (Invitrogen, Carls- Sigma Chemical), colistin sulfate (Sigma bad, CA). The bands of nucleotides were Chemical), sulbactam (DeF Pharmaceuti- detected by UV transillumination and cal Chemical Service, Shanghai, China), photographed with a camera. An isolate and imipenem (Merck, Rahway, NJ). The was considered a different clone
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