Comparative in vitro activities of tigecycline and 11 other antimicrobial agents against 215 epidemiologically defined multidrug-resistant Acinetobacter baumannii isolates

Sir, Acinetobacter baumannii is a significant nosocomial pathogen, in particular in ICU patients. Their multidrug resistance, propensity for clonal spread and involvement in hospital outbreaks are a cause of concern. The carbapenems have been relied upon for treating infections caused by multidrug-resistant A. baumannii; however, resistance to this β-lactam class is now a common occurrence. For these pan-resistant A. baumannii isolates, colistin is currently the only remaining treatment option. Alternative treatment strategies are therefore urgently needed. Tigecycline is a novel glycylcycline antibiotic with broad-spectrum activity against many bacterial pathogens, including Acinetobacter spp. This study was performed to compare the in vitro activity of tigecycline with other antimicrobial agents against epidemiologically well-characterized A. baumannii isolates (n = 215) collected in Europe and the United States between 1990 and 2003.1–3 Phenotypic species identification was performed according to the methods of Bouvet and Grimont.4 Isolates growing at 44°C were arbitrarily identified as A. baumannii. To ensure that copy strains were eliminated, strains were selected on the basis of having a unique fingerprint pattern as determined with PFGE. Sporadic strains as well as outbreak-related strains—one strain per given outbreak—were included. MICs were determined by CLSI reference broth microdilution methods.5 Microtitre plates containing dehydrated antibacterial agents were purchased from Merlin Diagnostica (Bornheim, Germany). The antibacterial agents and concentration ranges tested were amikacin, 1–128 mg/L; ampicillin/sulbactam 0.25/0.125–32/16 mg/L; cefepime, 0.25–32 mg/L; colistin, 0.125–16 mg/L; doxycycline, 0.25–32 mg/L; gentamicin, 0.25–32 mg/L; imipenem, 0.25–32 mg/L; levofloxacin, 0.25–32 mg/L; piperacillin, 0.5–64 mg/L; rifampicin, 0.5–32 mg/L; tigecycline, 0.125–16 mg/L and tobramycin, 0.25–32 mg/L. Susceptibility rates were determined using CLSI breakpoints.5 For tigecycline, the US FDA-approved breakpoints of tigecycline against Enterobacteriaceae, i.e. ≤2 mg/L for susceptible isolates and ≥8 mg/L for resistant isolates, were applied. No breakpoint is recommended for rifampicin versus Gram-negative microorganisms by the CLSI. The in vitro activities and MIC distributions of the various antimicrobials against A. baumannii are presented in Table 1. The most active agents were imipenem, colistin and tigecycline with MIC90s of 1, 2 and 4 mg/L, respectively. Moderate activities (MIC90 values ranging between 8 and 32 mg/L) were observed for rifampicin, tobramycin, levofloxacin and doxycycline. Low activities (MIC90s ≥ 64 mg/L) were exerted by ampicillin/sulbactam, cefepime, gentamicin, amikacin and piperacillin. There were seven isolates resistant to imipenem (MICs 16–>32 mg/L; 3.3% of isolates); all but one of these were susceptible to tigecycline with MICs ranging from 0.5 to 2 mg/L, whereas one strain had a tigecycline MIC of 8 mg/L. Six isolates were resistant to colistin (MICs 4–16 mg/L; 2.8% of isolates); none of these was resistant to tigecycline with MICs ranging from ≤0.125 to 4 mg/L. Among the 37 isolates (17.2%) resistant to doxycycline, 25 were still susceptible to tigecycline (MICs ≤0.125–2 mg/L). Conversely, among the 13 isolates (6.0%) resistant to tigecycline, 6 isolates were still susceptible to doxycycline with MICs ranging from 1 to 4 mg/L. MIC distributions of tigecycline and other antimicrobials determined by broth microdilution for 215 A. baumannii isolates MIC50 and MIC90, MICs (mg/L) for 50% and 90% of isolates tested, respectively. Bold figures indicate CLSI breakpoints applied for susceptible isolates. Colistin, levofloxacin, tigecycline (FDA-approved breakpoint): 2 mg/L; doxycycline, gentamicin, imipenem, tobramycin: 4 mg/L; ampicillin/sulbactam, cefepime: 8 mg/L; amikacin, piperacillin: 16 mg/L. aND, not determined, because no breakpoint is recommended for rifampicin versus Gram-negative microorganisms by the CLSI. bMICs of these isolates were greater than or equal to the indicated value. MIC distributions of tigecycline and other antimicrobials determined by broth microdilution for 215 A. baumannii isolates MIC50 and MIC90, MICs (mg/L) for 50% and 90% of isolates tested, respectively. Bold figures indicate CLSI breakpoints applied for susceptible isolates. Colistin, levofloxacin, tigecycline (FDA-approved breakpoint): 2 mg/L; doxycycline, gentamicin, imipenem, tobramycin: 4 mg/L; ampicillin/sulbactam, cefepime: 8 mg/L; amikacin, piperacillin: 16 mg/L. aND, not determined, because no breakpoint is recommended for rifampicin versus Gram-negative microorganisms by the CLSI. bMICs of these isolates were greater than or equal to the indicated value. Resistance to β-lactam antibiotics, aminoglycosides and fluoroquinolones has been a common feature in A. baumannii since the early 1990s, but more recently A. baumannii isolates with resistance to the carbapenems are increasingly reported. Tigecycline is the first glycylcycline and is one of the very few new antimicrobials with activity against Gram-negative bacteria encompassing not only most Enterobacteriaceae, but also—at least in vitro—multiresistant A. baumannii. Tigecycline has a distinct advantage over tetracycline and minocycline in that it evades acquired efflux and target-mediated resistance to classical tetracyclines. Several studies have tested the in vitro activity of tigecycline against A. baumannii and reported good bacteriostatic activity against strains with the wild-type susceptibility profile as well as those resistant to imipenem.6,7 However, clinical experience with this drug as well as with tetracyclines in the treatment of A. baumannii infections is still limited.8,9 Current multicentre studies usually require that isolates are obtained from different patients. However, with highly epidemic microorganisms such as A. baumannii, isolates collected consecutively from different patients may nevertheless be clonally related. Antimicrobial susceptibility testing of isolates with the inclusion of multidrug-resistant epidemic strains tends to overestimate the resistance of these microorganisms. Pachón-Ibánez et al.7 recently reported on the activity of tigecycline against A. baumannii bloodstream isolates. Forty-nine isolates were studied that predominantly represented two major epidemic clones. It is therefore not surprising that 78% of isolates were found to be resistant to imipenem, simply because their strain collection contained a large number of copy strains of an imipenem-resistant outbreak-strain. Conversely, this study design may have led to an overestimate of the activity of tigecycline against A. baumannii because the major epidemic A. baumannii strain may have exhibited a low tigecycline MIC. The strength of the current investigation is that only A. baumannii isolates were included that represented different strain types as assessed by molecular typing. Our data support the findings of Henwood et al.,6 who reported that tigecycline had good in vitro activity (MIC50 and MIC90, 0.5 and 2 mg/L, respectively) against isolates of the A. baumannii complex. Resistance to tigecycline was slightly higher in our study (6% versus 2.7%). Resistance to the carbapenems (3.3%) was still low in our study. The majority of imipenem-resistant isolates were still susceptible to tigecycline which is in keeping with previous reports.7 In conclusion, tigecycline appears to be a promising agent adding to the small armamentarium of antimicrobials that remain active against A. baumannii. Further clinical studies are urgently needed. H. S. has received funds for speaking from Wyeth Pharmaceuticals, Germany. This study was supported by Wyeth Pharmaceuticals, Germany.