Combination testing of multidrug-resistant cystic fibrosis isolates of Pseudomonas aeruginosa: use of a new parameter, the susceptible breakpoint index

Milne, K.; Gould, Ian M.

doi:10.1093/jac/dkp384

Cited by 42 publications

(36 citation statements)

References 16 publications

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“…The selection of empirical therapy for the treatment of multidrug-resistant organisms which infect the respiratory tract of individuals with CF is not an easy task. CFASS takes into account the MICs of the antimicrobials, current antimicrobial therapy, and antimicrobial allergy or intolerance (if known) when selecting combinations for testing and uses the recently described SBPI to aid ranking of the combination results in the order of their in vitro effectiveness (19).…”

Section: Discussionmentioning

confidence: 99%

“…Confirmation of isolate identification was performed as previously described (19). MIC testing was performed on Mueller-Hinton agar (MHA) using Etest methodology according to the instructions of the manufacturers (AB Biodisk, Solna, Sweden, and bioMérieux, Basingstoke, United Kingdom) The antimicrobials tested were amikacin, gentamicin, netilmicin (testing discontinued 2006), tobramycin, ciprofloxacin, levofloxacin, aztreonam, ceftazidime, piperacillin (testing discontinued 2003), piperacillin-tazobactam, imipenem, meropenem, colistin, ticarcillin/clavulanate, ampicillin/sulbactam, chloramphenicol, minocycline, doxycycline (testing introduced October 2003), co-rimoxazole, and rifampin.…”

Section: Methodsmentioning

confidence: 99%

“…It therefore follows that the greater the SBPI value, the more effective that combination is in vitro (19).…”

Section: Sbpimentioning

confidence: 99%

“…The isolates which are identified at a local level by the referring centers are typically referred when the isolates are multidrug resistant or there are problems locally with identifying suitable treatment regimens. Etest methodology was used to facilitate the MIC and combination testing of the isolates, and the fractional inhibitory concentration index (FICI) and the susceptible breakpoint index (SBPI) were used to aid interpretation of the combination testing results (19).…”

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confidence: 99%

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Combination Antimicrobial Susceptibility Testing of Multidrug-Resistant Stenotrophomonas maltophilia from Cystic Fibrosis Patients

Milne

Gould

2012

Antimicrob Agents Chemother

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Stenotrophomonas maltophilia is increasingly being isolated from the respiratory tract of individuals with cystic fibrosis, and, because of its multidrug-resistant nature, the selection of suitable treatment regimens can be problematical. Etest methodology was used to facilitate MIC and antimicrobial combination testing on 80 isolates of S. maltophilia cultured from the respiratory tract of Scottish individuals with cystic fibrosis between 2001 and 2010. The overall rate of susceptibility for the 1,410 MIC tests was 23.1%, and resistance was 68.9%. The most active antimicrobials were minocycline, co-trimoxazole, and doxycycline, with 92.4%, 87.3%, and 58.8% of isolates being susceptible, respectively. Of the 517 combinations, 13.2% were synergistic, with the most synergistic being ticarcillin/clavulanate plus aztreonam (91.7% synergistic), ticarcillin/clavulanate plus colistin (40%), and ticarcillin/clavulanate plus levofloxacin (19.4%). Colistin plus tobramycin was the only antagonistic combination (0.2%). By the median susceptible breakpoint index, the most active combinations were minocycline plus co-trimoxazole (median index, 20), minocycline plus piperacillin-tazobactam (median, 20), and co-trimoxazole plus ceftazidime (median, 16.5). The increasing problem of multidrug resistance in organisms recovered from the respiratory tracts of individuals with cystic fibrosis is not going to go away. Current susceptibility testing methods do not address the slow-growing organisms associated with chronic infection, and interpretive standards are based on achievable blood levels of antimicrobials. Addressing these issues specifically for organisms recovered from the respiratory tracts of individuals with cystic fibrosis should lead to better therapeutic outcomes and improved wellbeing of individuals with cystic fibrosis.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…It therefore follows that the greater the SBPI value, the more effective that combination is in vitro (19).…”

Section: Sbpimentioning

confidence: 99%

mentioning

confidence: 99%

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Combination Antimicrobial Susceptibility Testing of Multidrug-Resistant Stenotrophomonas maltophilia from Cystic Fibrosis Patients

Milne

Gould

2012

Antimicrob Agents Chemother

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“…Plates were read after 24 h of incubation at 37°C. Synergy between TGC and COL was quantified by calculation of the fractional inhibitory concentration index (FICI) and the susceptibility breakpoint index (SBPI) (21,22). A FICI of Յ0.5 was defined as synergy, a FICI of 0.5 to Յ4.0 as indifferent or additive, and values of Ն4.0 as antagonistic.…”

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In Vitro and In Vivo Activities of Tigecycline-Colistin Combination Therapies against Carbapenem-Resistant Enterobacteriaceae

Betts

Phee

Hornsey

et al. 2014

Antimicrob Agents Chemother

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We assessed the activity of tigecycline (TGC) combined with colistin (COL) against carbapenem-resistant enterobacteria. Synergy occurred in vitro against the majority of isolates, with the exception of Serratia marcescens. In a simple animal model (Galleria mellonella), TGC-COL was superior (P < 0.01) in treating Escherichia coli, Klebsiella pneumoniae, and Enterobacter infections, including those with TGC-COL resistance. Clinical studies are needed to determine whether TGC-COL regimens may be a viable option. Resistance to antimicrobial agents is an ongoing problem that consistently undermines our ability to treat bacterial infections (1). The emergence of multidrug-resistant (MDR) Enterobacteriaceae producing extended-spectrum ␤-lactamases (ESBLs) has led to the increased use of carbapenems. Carbapenem resistance in Enterobacteriaceae (CRE) may be mediated by mutations affecting membrane permeability (porin loss), overexpression of intrinsic ␤-lactamases (AmpC), and/or broad-spectrum resistance-nodulation-division (RND)-type efflux pumps (2) but also via the acquisition of carbapenem-hydrolyzing enzymes, including members of the KPC, IMP, VIM, OXA-48, and NDM families (3, 4). Although CRE strains are often reported to be susceptible to polymyxins (polymyxin B, colistin) and tigecycline (TGC) (5-7), there are concerns with the use of these drugs for treatment with debate over how to safely dose colistin (COL) (8) and warnings over the efficacy of TGC in the treatment of bloodstream and other serious infections (9). Rapid emergence of resistance has also been documented with these two agents if either one is used alone in the treatment of MDR Gram-negative infections (10). Due to the lack of alternatives, clinicians are increasingly using antimicrobials in combination. The mechanism of action of COL is not entirely clear, although it has been previously shown to disrupt the integrity of the Gram-negative outer membrane (11), thereby increasing its permeability by drugs that are typically excluded (12). This may improve the activity of a number of antibiotics which would otherwise have little effect (13). This approach is validated by reports of better clinical outcomes with unorthodox therapies for an increasing range of carbapenem-resistant bacteria (14-16). In this study, we assessed the activity of TGC in combination with COL against a range of CRE both in vitro and in vivo by using standard checkerboard and time-kill assays and a simple invertebrate model (Galleria mellonella) of infection and therapeutics (17-19) (we do acknowledge that currently the G. mellonella model lacks the required validation with regard to comparability with human therapy).Enterobacteriaceae isolates used in this study (n ϭ 18) consisted of susceptible type strains and clinical isolates exhibiting resistance to ␤-lactams (including carbapenems), TGC, or COL (Table 1). MICs of TGC and COL were determined by Etest (bioMérieux, France), and mechanisms of resistance were confirmed by genetic and phenotypic tests as previously described...

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Drug–Drug Combinations

Turnidge

2013

Fundamentals of Antimicrobial Pharmacokinetics and Pharmacodynamics

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Antimicrobial combination therapy has a long history. The potential for synergy between two antimicrobial agents has been sought using in vitro techniques such as disk approximation, checkerboard titration, in vitro killing experiments with fi xed drug concentrations, through the use of in vitro pharmacodynamic models, through animal models, and through retrospective and prospective clinical studies. The most widely examined combinations are those that include aminoglycosides, especially for the treatment of serious Pseudomonas aeruginosa infections, and for the management of enterococcal and staphylococcal endocarditis. The in vitro and animal studies of P. aeruginosa support the concept that combinations of aminoglycosides with β-lactams improve effi cacy and outcomes. Some models suggest that the mechanism of improved effi cacy relates less to synergy and more the prevention of the selection of aminoglycoside-resistant mutants. However, human clinical studies to date have failed to demonstrate convincingly that there are better outcomes with combination therapy in terms of effi cacy or the prevention of resistance emergence. For endocarditis, there has been strong evidence accumulated for combination therapy enterococcal endocarditis using in vitro and animal models, although there are no randomised clinical data to confi rm these. Data supporting the use of combination in staphylococcal therapy has been less robust, and Panton-valentine leukocidin producing S. aureusCell-wall active agent + clindamycin or linezolid the role of combination treatment for this indication is now in question. Ultimately, an in vitro or animal model of the pharmacodynamic interaction of drug classes that can be shown to predict clinical outcomes is still required. Such a model does not currently exist.

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Combination testing of multidrug-resistant cystic fibrosis isolates of Pseudomonas aeruginosa: use of a new parameter, the susceptible breakpoint index

Abstract: The Etest is a useful tool for determining MICs and testing antimicrobial combinations. The SBPI is more discriminatory than the FICI, allowing easy ranking of the combinations, and is likely to have clinical relevance.

Cited by 42 publications

References 16 publications

Combination Antimicrobial Susceptibility Testing of Multidrug-Resistant Stenotrophomonas maltophilia from Cystic Fibrosis Patients

Combination Antimicrobial Susceptibility Testing of Multidrug-Resistant Stenotrophomonas maltophilia from Cystic Fibrosis Patients

In Vitro and In Vivo Activities of Tigecycline-Colistin Combination Therapies against Carbapenem-Resistant Enterobacteriaceae

Drug–Drug Combinations

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