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...

Several investigators have suggested that the 24-h area under the concentration-time curve (AUC)/MIC ratio (AUC/MIC24 or AUIC24) can be used to make comparisons of antimicrobial activity between fluoroquinolone antibiotics. Limited data exist regarding the generic predictive ability of AUC/MIC24 for the antimicrobial effects of fluoroquinolones. The purposes of the present investigation were to determine if the AUC/MIC24 can be used as a generic outcome predictor of fluoroquinolone antibacterial activity and to determine if a similar AUC/MIC24 breakpoint can be established for different fluoroquinolones. Using an in vitro pharmacodynamic model, 29 duplicate concentration time-kill curve experiments simulated AUC/MIC24s ranging from 52 to 508 SIT-1.h (inverse serum inhibitory titer integrated over time) with ciprofloxacin or ofloxacin against three strains of Pseudomonas aeruginosa. Each 24-h experiment was performed in cation-supplemented Mueller-Hinton broth with a starting inoculum of 10(6) CFU/ml. At timed intervals cation-supplemented Mueller-Hinton broth samples were collected for CFU and fluoroquinolone concentration determinations. Transformation of bacterial counts into the cumulative bacterial effect parameter of the 24-h area under the effect curve (AUEC24) was performed for each concentration time-kill curve. Multivariate regression analysis was used to compare pharmacodynamic predictors (AUC/MIC24, 24-h AUC, peak concentration [Cmax] to MIC ratios [Cmax:MIC], etc.) with ln AUEC24. To identify threshold breakpoint AUC/MIC24s, AUEC24s were stratified by the magnitude of AUC/MIC24 into subgroups, which were analyzed for differences in antibacterial effect. The Kruskal-Wallis test and subsequent Tukey's multiple comparison test were used to determine which AUC/MIC subgroups were significantly different. Multiple regression analysis revealed that only AUC/MIC24 (r2 = 0.65) and MIC (r2 = 0.03) were significantly correlated with antibacterial effect. At similar AUC/MIC24s, yet different MICs, Cmaxs, or elimination half-lives, the AUEC24s were similar for both fluoroquinolones. The relationship between AUC/MIC24 and ln AUEC24 was best described by a sigmoidal maximal antimicrobial effect (Emax) model (r2 = 0.72; Emax = 9.1; AUC/MIC50 = 119 SIT-1.h; S = 2.01 [S is an exponent that reflects the degree of sigmoidicity]). Ciprofloxacin-bacteria AUC/MIC24 values of < 100 SIT-1.h were significantly different (P < 0.05) from the AUC/MIC24 values of > 100 SIT-1.h. An ofloxacin AUC/MIC24 of > 100 SIT-1.h and an AUC/MIC24 of < 100 SIT-1.h exhibited a trend toward a significant difference (P > 0.05 but < 0.1). The inverse relationship between drug exposure and MIC increase postexposure was described by a sigmoidal fixed Emax model (AUC/MIC24, r2 = 0.40; AUC/MIC50 = 95 SIT-1.h; S = 1.97; Cmax:MIC, r2 = 0.41; Cmax:MIC50 = 7.3; S = 2.01). These data suggest that AUC/MIC24 may be the most descriptive measurement of fluoroquinolone antimicrobial activity against P. aeruginosa, that ofloxacin and ciprofloxacin have similar AUC/MIC24 threshold breakpoints at approximately 100 SIT-1.h, that the concentration-dependent selection of resistant organisms may parallel the threshold breakpoint of the antimicrobial effect, and that AUC/MIC24 generically describes the antibacterial effects of different fluoroquinolones.

Peritoneal dialysate fluid (PDF) is a bacteriostatic medium that compromises the antibacterial activity of cell wall-active agents. By use of an in vitro static model, methicillin-resistant Staphylococcus aureus (MRSA), methicillin-susceptible S. aureus (MSSA), methicillin-susceptible Staphylococcus epidermidis (MSSE), and Streptococcus sanguis were exposed to daptomycin at concentrations of 10, 30, and 100 mg/liter, cefazolin at 125 mg/liter, and vancomycin at 25 mg/liter in cation-adjusted Mueller-Hinton Broth or Todd Hewitt Broth (for S. sanguis) and PDF at pHs of 5.5 and 7.4. The pH had no effect on antibacterial activity. Neither cefazolin nor vancomycin produced a bactericidal or a bacteriostatic effect versus MRSA, MSSA, MSSE, or S. sanguis in PDF, while all concentrations of daptomycin were bactericidal against all organisms in PDF. Daptomycin did not exhibit concentration-dependent activity in PDF. Daptomycin appears to be a promising agent for use in peritoneal dialysis-associated peritonitis, producing bacterial kill to a greater extent and at a higher rate than cefazolin or vancomycin in PDF.Roughly 15% (ϳ20,000 to 30,000) of patients with end stage renal disease (ESRD) in the United States are managed with peritoneal dialysis (PD). This number is increasing by nearly 6,000 patients per year and is expected to increase even further in the face of increased economic pressure due to the lower cost of PD relative to hemodialysis (ϳ$32,000 versus $44,000/ year) (18). Moreover, PD allows greater patient freedom and spares the body from large hemodynamic fluctuations when compared with hemodialysis (18).The problem with PD has been, and continues to be, PDassociated peritonitis (PDAP). PDAP accounts for approximately 30 to 40% of all patient transfers to hemodialysis, represents the leading cause for hospitalization among patients on PD, and imposes a significant burden of morbidity and mortality (5, 6). Furthermore, several investigative groups have provided evidence suggesting that repeated or severe episodes of peritonitis may cause the peritoneal membrane to become unsuitable for dialysis, leading to technique failure, requiring either transfer to hemodialysis or transplantation to maintain life (4,7,13,14).The pathogens most commonly associated with peritonitis are gram positive. Approximately 28 to 32% of infections are caused by Staphylococcus epidermidis, 23 to 26% are caused by Staphylococcus aureus, and 20% are caused by other grampositive species (5). Present empirical therapy for peritonitis typically includes administration of a cephalosporin, usually cefazolin, mixed in the peritoneal dialysate fluid (PDF). Vancomycin is used in the setting of known or suspected betalactam resistance (8). However, the bacteriostatic nature of PDF may compromise the antibacterial activity of such cell wall-active agents (2, 10-12, 15, 19, 21).Daptomycin is a novel cyclic lipopeptide antibiotic with rapid, bactericidal activity against gram-positive pathogens (16). Daptomycin is under clinical investigation for...

No abstract

This investigation explored pharmacodynamic characteristics of fluoroquinolones against Bacteroides thetaiotamicron and the potential for development of resistance. An in vitro model was used to generate kill curves with three fluoroquinolones at various area under the concentration-time curve (AUC)/MIC ratios. Concentration-independent killing was observed. Increases in MICs were noted following exposure to fluoroquinolones at AUC/MIC ratios of 6 to 14.We have previously reported fluoroquinolone resistance in clinical and ATCC strains of Bacteroides fragilis while conducting experiments with fluoroquinolones in an in vitro pharmacodynamic model (8; M. L.