Mutant Prevention Concentrations of Levofloxacin Alone and in Combination with Azithromycin, Ceftazidime, Colistin (Polymyxin E), Meropenem, Piperacillin-Tazobactam, and Tobramycin against Pseudomonas aeruginosa

Abstract

The mutant prevention concentrations (MPCs) of levofloxacin alone and in combination with ceftazidime, colistin (polymyxin E), meropenem, piperacillin-tazobactam, and tobramycin were established against Pseudomonas aeruginosa. Antibiotic combinations using levofloxacin with any antibiotic with individual activity against P. aeruginosa resulted in synergistic lowering (an at-least-fourfold reduction) of the isolate's MPC.With a limited pool of available antibiotics capable of treating Pseudomonas aeruginosa infections, the suppression of the further emergence of resistance is important. Fluoroquinolones, such as ciprofloxacin and levofloxacin, are routinely used to treat patients with P. aeruginosa infections. Fluoroquinolone resistance can be selected for upon exposure to the fluoroquinolones, leading to dramatic increases in MICs and subsequent treatment failure (3, 4).The manipulation of fluoroquinolone-dosing strategies has been suggested as a way to limit the selection for fluoroquinolone-resistant mutants and preserve this antimicrobial class (1-3, 9, 11). A range of fluoroquinolone concentrations, known as the mutant selection window (MSW), exists in which point mutations are more likely to be selected for. The MSW is bound by the MIC at its lower end and the organism's mutant prevention concentration (MPC) at its upper end. The MPC is the drug concentration required to prevent the emergence of all single-step-mutation, fluoroquinolone-resistant mutants in a population of approximately 10 10 bacterial cells (2, 11). If fluoroquinolone-dosing strategies maintain concentrations above the MPC for a long enough duration, a reduced risk of selecting for single-step-mutation, resistant mutants may result.The addition of a second antibiotic to a fluoroquinolone treatment regime has been shown to lower an organism's MPC (1, 2, 11). In order to survive treatment with two antimicrobials, an organism has to develop spontaneous mutations causing resistance to both drugs, assuming that the two antimicrobials act via different modes of action and that the organism is initially susceptible to both agents (1, 2, 11).We examined this dual-drug MPC hypothesis by determining the MPCs of levofloxacin alone and in combination with other drugs against P. aeruginosa. Additionally, MPCs for the nonfluoroquinolone antimicrobials were established individually to examine whether any MPC changes observed with the dualdrug therapy were due to synergistic (an at-least-fourfold reduction) or additive (a less-than-fourfold reduction) effects. The working hypothesis was that two antimicrobials that possessed different mechanisms of action and that both displayed individual activity against P. aeruginosa would display a reduced MPC in combination relative to the individual antimicrobial MPCs.The P. aeruginosa isolates (46139, 49674, and 36375) were collected as part of the North American Urinary Tract Infection Collaborative Alliance (10). The identity of each isolate was confirmed by the central reference laboratory (Health Sciences Centr...

Comparative study of the mutant prevention concentrations of vancomycin alone and in combination with levofloxacin, rifampicin and fosfomycin against methicillin-resistant Staphylococcus epidermidis

“…Surprisingly, vancomycin in combination with rifampicin (2 or 4 mg ml À1 ) or levofloxacin (2 mg ml À1 ) did not lead to significant lowering of the isolates' vancomycin MPCs in general. According to Zhanel et al 32 and Firsov et al, 33 the MPC of an antibiotic could not be lowered when combined with a partner at a relatively lower concentration. Likewise, the failure of vancomycin MPCs to be significantly lowered when combined with levofloxacin or rifampicin might also result from the lower concentrations of levofloxacin and rifampicin used in combination (levofloxacin and rifampicin are both concentrationdependent antibiotics).…”

Comparative Study of the Mutant Prevention Concentrations of Sulfamethoxazole-Trimethoprim Alone and in Combination with Levofloxacin against <i>Stenotrophomonas maltophilia</i>

“…So narrowing the MSW through combination therapy is a good way. Zhanel et al [25] and Cai et al [11] showed that combination of LVX with colistin is more efficient than colistin alone at preventing selection of colistin resistance in Pseudomonas aeruginosa. Mohammed et al exhibited LVX in combination with Ceftazidime can result in a synergistic action in sensitive isolates of Pseudomonas aeruginosa [26].…”

Alternativas terapêuticas para o tratamento de infecções por Pseudomonas aeruginosa multirresistentes endêmicas no Brasil.

“…Pseudomonas aeruginosa, uma opção a se apresentar diante dessa problemática, é o estudo de combinações de antimicrobianos em busca de efeitos sinérgicos (Bouza, Muñoz, 2000;Choi et al, 2004;Davies, Davies, 2010;Lyczak et al, 2002;Tripodi et al, 2007;Zhanel et al, 2006). Pseudomonas aeruginosa MR é de difícil tratamento e, aliado a dificuldade no desenvolvimento de novas drogas (o que ocasiona um temor de um possível regresso à era pré-antibiótica), os resultados sinérgicos obtidos apresentam uma opção de tratamento às infecções ocasionadas por esse microrganismo (Levin, Oliveira, 2008;Paterson, Lipman, 2007;Tillotson, 2008).…”

“…Uma opção para esse quadro seria o uso combinado de antimicrobianos para obtenção de um efeito sinérgico (Rodloff et al, 2006;Tripodi et al, 2007;Zhanel et al, 2006). …”

“…Um estudo de Rahal et al (1998) Devido à resistência aos carbapenêmicos e a dificuldade no desenvolvimento de novas drogas (Tillotson, 2008), muitos autores têm previsto um retorno à era pré-antibiótica, postulando a volta de antibióticos abdicados atualmente (Levin, Oliveira, 2008;Paterson, Lipman, 2007;Schurek et al, 2009;Theuretzbacher, 2012;Timurkaynak et al, 2006), porém, uma alternativa mais sustentável é o estudo de combinações de antibióticos que alcancem efeitos sinérgicos (Choi et al, 2004;Tripodi et al, 2007;Zhanel et al, 2006 (Bouza, Muñoz, 2000).…”