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...

Antibiotic pharmacodynamics is an evolving science that focuses on the relationship between drug concentration and pharmacologic effect, which is an antibiotic-induced bacterial death that also can manifest as an adverse drug reaction. The pharmacologic action of antibiotics usually can be described as concentration dependent or independent, although such classifications are highly reliant on the specific antibiotic and bacterial pathogen being studied. Quantitative pharmacodynamic parameters, such as ratio of the area under the concentration-time curve during a 24-hour dosing period to minimum inhibitory concentration (AUC0-24:MIC), ratio of maximum serum antibiotic concentration to MIC (Cmax:MIC), and duration of time that antibiotic concentrations exceed MIC (T>MIC), have been proposed as likely predictors of clinical and microbiologic success or failure for different pairings of antibiotic and bacteria. Thus far, most pharmacodynamic data reported have focused on fluoroquinolones, but work has been conducted on vancomycin, beta-lactams, macrolides, aminoglycosides, and other antibiotics. Despite the development of a number of different pharmacodynamic modeling systems, remarkable agreement exists between in vitro, animal, and limited human data. Although still somewhat premature and requiring additional clinical validation, antibiotic pharmacodynamics will likely advance on four fronts: the science should prove to be extremely useful and represent a cost-effective and efficient method to help develop new antibiotics; formulary committees will likely use pharmacodynamic parameters to assist in differentiating antibiotics of the same chemical class in making antibiotic formulary selections; pharmacodynamic principles will likely be used to design optimal antibiotic strategies for patients with severe infections; and limited data to date suggest that the application of pharmacodynamic concepts may limit or prevent the development of antibiotic resistance. The study of antibiotic pharmacodynamics appears to hold great promise and will likely become a routine part of our daily clinical practices.

BACKGROUND: In 2008, specialty medications accounted for 15.1% of total pharmacy benefit medication spending, and per member expenditures have increased by 11.1% annually from 2004 to 2008 within a commercially insured population of 8 million members. Insurers face increasing pressure to control specialty medication expenditures and to rely on increasing member cost share through creation of a fourth copayment tier within the incentive-based formulary pharmacy benefit system. Data are needed on the influence that member out-of-pocket (OOP) expense may have on prescription abandonment (defined as the patient never actually taking possession of the medication despite evidence of a written prescription generated by a prescriber).

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