Synergistic Activity of Colistin and Ceftazidime against Multiantibiotic-Resistant Pseudomonas aeruginosa in an In Vitro Pharmacodynamic Model

Abstract

Despite the marketing of a series of new antibiotics for antibiotic-resistant gram-positive bacteria, no new agents for multiple-antibiotic-resistant gram-negative infections will be available for quite some time. Clinicians will need to find more effective ways to utilize available agents. Colistin is an older but novel antibiotic that fell into disfavor with clinicians some time ago yet still retains a very favorable antibacterial spectrum, especially for Pseudomonas and Acinetobacter spp. Time-kill curves for two strains of multiantibiotic-resistant Pseudomonas aeruginosa were generated after exposure to colistin alone or in combination with ceftazidime or ciprofloxacin in an in vitro pharmacodynamic model. MICs of colistin, ceftazidime, ciprofloxacin, piperacillintazobactam, imipenem, and tobramycin were 0.125, >32, >4, >128/4, 16, and >16 mg/liter, respectively. Colistin showed rapid, apparently concentration-dependent bactericidal activity at concentrations between 3 and 200 mg/liter. We were unable to detect increased colistin activity at concentrations above 18 mg/liter due to extremely rapid killing. The combination of colistin and ceftazidime was synergistic (defined as at least a 2-log 10 drop in CFU per milliliter from the count obtained with the more active agent) at 24 h. Adding ciprofloxacin to colistin did not enhance antibiotic activity. These data suggest that the antibacterial effect of colistin combined with ceftazidime can be maximized at a peak concentration of <18 mg/liter.The polypeptide antibiotics of the polymyxin class, including polymyxin E (colistin), were first made available for clinical use in the late 1950s and early 1960s. These agents are rapidly bactericidal against many gram-negative bacteria (13). Colistin is available clinically with sulfomethylated amino groups, thought to minimize pain at injection sites as well as having other side effects (2). Studies have found the sulfomethylated derivates to have one-half to one-eighth the activity of the parent compound (8, 13), though the activity of the derivatives may change with time secondary to in vivo hydrolysis and it is not clear which moiety possesses the majority of clinical activity (1, 2). The MIC of the sulfomethyl colistin at which 90% of isolates are inhibited for 94 Pseudomonas aeruginosa isolates was found to be 4 mg/liter, with a range of 0.5 to 32 mg/liter (4).Perhaps as a result of concerns about toxicity, the parenteral use of colistin has been rather limited. Colistin is thought to be nephro-and neurotoxic, though clinical trials involving this agent have not been in universal agreement on the rate of toxicity. (3, 12). The toxicity of colistin was thought to be dose dependent (9), though recent data from a pharmacokinetic study of colistin in 31 cystic fibrosis patients found no relationship between any adverse effects and concentration in plasma (15).Resistance to beta-lactams, quinolones, and aminoglycosides in P. aeruginosa continues to increase. As no novel agents have been introduced to combat these mult...

Polymyxins Revisited

“…Numerous studies have been performed in recent years using a pharmacodynamic model or standard time-kill studies of the effect of polymyxin B or colistin against strains of P. aeruginosa (19,59,67,93,107,166), A. baumannii (60,88,106,136,160,170), and K. pneumoniae (20). Nearly all studies demonstrated that the polymyxins produce concentration-dependent killing, with an initial kill followed by regrowth.…”

Post-antibiotic effect of colistin, alone and in combination with amikacin, on Pseudomonas aeruginosa strains isolated from cystic fibrosis patients

“…20 There are few experimental and clinical studies in the literature regarding combinations of colistin with other antibiotics, such as beta-lactams, rifampin, amikacin, trimethoprim-sulfomethoxazole and ciprofloxacin, against multidrug-resistant Gram-negative bacteria. 13,[21][22][23][24] In a recent study, we have shown the existence of in-vitro synergy between colistin methanesulfonate and amikacin in 12% of 50 P. aeruginosa strains isolated from CF patients. 25 In the present study, synergistic interactions were seen in two of seven clinical strains.…”

“…13 Lung tissue penetration of colistin following i.v. infusion is unknown, and pharmacokinetic studies have been reported recently.…”

In vitro activity of colistin against nonfermentative gram-negative bacilli Kolistinin non-fermentatifgram-negatif bakterilere in-vitro etkinliğinin değerlendirilmesi

“…Besides colistin alone, antibiotic combinations including colistin will be a new therapeutic option for the treatment of multidrug-resistant strains, if in-vitro data correlate well with clinical studies (1,5,12). Again, determining a standardized breakpoint is important for interpretation of these synergy studies.…”