Search

Fosfomycin, a phosphonic class antibiotic with a broad spectrum of antibacterial activity, has been used outside the United States since the early 1970s for the treatment of a variety of infections. In the United States, an oral (tromethamine salt) formulation is used for uncomplicated urinary tract infections. Recently, there has been interest in the use of an intravenous solution (ZTI-01) for the treatment of a broad range of infections associated with multidrug-resistant bacteria. In this era of multidrug-resistant bacteria with few treatment options, it is critical to understand the pharmacokinetic-pharmacodynamic (PK-PD) determinants for fosfomycin efficacy. Since such data are limited, a one-compartment in vitro infection model was used to determine the PK-PD index associated with efficacy and the magnitude of this measure necessary for various levels of effect. One challenge isolate ( Escherichia coli ATCC 25922, for which the fosfomycin agar MIC is 0.5 mg/liter and the broth microdilution MIC is 1 mg/liter) was evaluated in the dose fractionation studies, and two additional clinical E. coli isolates were evaluated in the dose-ranging studies. Mutation frequency studies indicated the presence of an inherently fosfomycin resistant E. coli subpopulation (agar MIC = 32 to 64 mg/liter) within the standard starting inoculum of a susceptibility test. Due to the presence of this resistant subpopulation, we identified the percentage of the dosing interval that drug concentrations were above the inherent resistance inhibitory concentration found at baseline to be the PK-PD index associated with efficacy ( r 2 = 0.777). The magnitudes of this PK-PD index associated with net bacterial stasis and 1- and 2-log 10 CFU/ml reductions from baseline at 24 h were 11.9, 20.9, and 32.8, respectively. These data provide useful information for modernizing and optimizing ZTI-01 dosing regimens for further study.

A doripenem population pharmacokinetic model and Monte Carlo simulations were utilized for dose regimen decision support for future clinical development. Simulation results predict that 500 mg of doripenem administered over 1 h every 8 h would be effective against bacterial strains with MICs less than 2 μg/ml and that less susceptible strains could be treated with prolonged infusions.

The treatment of community-acquired respiratory tract infections has been complicated by the emergence of multidrug-resistant Streptococcus pneumoniae . Although traditionally rare, a growing concern for fluoroquinolone-resistant pneumococci has surfaced. More pharmacodynamically potent antimicrobial agents are clearly needed, as the use of such agents may further optimize clinical and microbiological outcomes for patients and slow the emergence of fluoroquinolone resistance. For fluoroquinolones, the ratio of the 24-h area under the concentration–time curve of the agent to the minimum inhibitory concentration of the agent against the pathogen for the fraction of unbound drug is the major pharmacokinetic–pharmacodynamic (PK–PD) measure correlating with efficacy in nonclinical models and infected patients. A 2500-patient Monte Carlo simulation, utilizing a patient–population pharmacokinetic model derived from phase 3 registration trials and the minimum inhibitory concentration distribution for gemifloxacin against 3117 clinical strains of S. pneumoniae , was carried out to estimate the probability of gemifloxacin attaining exposures associated with efficacy. The overall probability PK–PD target attainment for gemifloxacin was greater than 0.99. Gemifloxacin is among the most pharmacodynamically potent fluoroquinolones and is more potent than ciprofloxacin, ofloxacin, and levofloxacin. Preferential use of pharmacodynamically potent agents over other alternatives may lead to improved clinical outcomes and decreased selection of fluoroquinolone-resistant pneumococci.

Oritavancin is a novel glycopeptide currently being developed for the treatment of complicated skin and skin structure infections (cSSSI), including those caused by multidrug resistant gram-positive pathogens. The disposition of oritavancin in skin structures was investigated using a cantharide-induced blister fluid model. Seventeen healthy male subjects received oritavancin, but only 16 subjects were evaluated after one subject discontinued study drug. Each subject (eight per dose group) received 200 mg of oritavancin once a day for 3 days (group A) or 800 mg as one single dose (group B). Group A plasma samples and exudates from blister fluid were collected on days 3, 4, 7, 9, and 12 and on days 3, 4, 7, and 9, respectively. Group B samples and exudates were collected on days 1, 2, 5, 7, and 10 and on days 1, 2, 5, and 7, respectively. Drug concentrations were determined using a liquid chromatography-tandem mass spectrometry assay and, subsequently, pharmacokinetic analysis was performed. Differences between treatment groups in ratios for area under the concentration-time curve for blister fluid and plasma (AUC blister fluid /AUC plasma ratios) were evaluated using a t test (α = 0.05). Mean maximum concentration of drug in plasma or blister fluid was approximately 8-fold and 11-fold higher in plasma than in blister fluid following the 200- or 800-mg doses of oritavancin, respectively. Mean AUC blister fluid /AUC plasma ratios at 24 h were 0.190 (standard deviation [SD], 0.052) and 0.182 (SD, 0.062) for groups A and B, respectively ( P = 0.791). To place these results in a clinical context, mean drug concentrations in blister fluid exceed the oritavancin MIC at which 90% of strains are inhibited of Staphylococcus aureus (2 μg/ml) by approximately 2- to 5.5-fold at 12 h and 1.5- to 3-fold at 24 h following administration of both dosing regimens. These results support the potential use of oritavancin for the treatment of cSSSI.

Increasing reports of fluoroquinolone-non-susceptible Streptococcus pneumoniae are of clinical concern. We examined the relationship between outpatient fluoroquinolone use and susceptibility of community-acquired S. pneumoniae isolates. Using multivariable general linear modeling, US SENTRY Antimicrobial Surveillance Program and Intercontinental Medical Statistics data (1997-2002) were analyzed to determine the influence of selected patient-, institution-, and geographic region-specific factors, including local fluoroquinolone usage, on the minimum inhibitory concentration (MIC) of levofloxacin against S. pneumoniae. Levofloxacin MIC50, MIC90, and MIC range (n = 384 from 26 hospitals) were 1, 1, andor =0.5 to4 microg/mL, respectively. Variables associated with changes in geometric mean MIC included geographical region (P0.0001), medical service (P = 0.0002), study year (P = 0.0006), primary diagnosis group (P = 0.02), and 2 interactions (duration of hospital stay before isolate collection by bed capacity, P = 0.06, and levofloxacin use by geographical region, P = 0.08; P0.001 when study year was removed from the model). MIC increased with levofloxacin use across all geographical regions, with increases of 54% and 126% in the southwest and west, respectively. In contrast to other fluoroquinolones, increased levofloxacin use, along with other variables, was associated with decreased pneumococcal susceptibility. Given the US environment of increasing pneumococcal resistance, these data may be useful in better understanding factors related to emergence of fluoroquinolone resistance.

Echinocandins exhibit concentration-dependent effects on Candida species, and preclinical studies support the administration of large, infrequent doses. The current report examines the pharmacokinetics/pharmacodynamics of two multicenter, randomized trials of micafungin dosing regimens that differed in both dose level and dosing interval. Analysis demonstrates the clinical relevance of the dose level and area under the concentration-time curve (AUC). Better, although not statistically significant ( P = 0.056), outcomes were seen with higher maximum concentrations of drug in serum ( C max ) and large, infrequent doses. The results support further clinical investigation of novel micafungin dosing regimens with large doses but less than daily administration. (These studies have been registered at ClinicalTrials.gov under registration no. NCT00666185 and NCT00665639.)

The effect of fluoroquinolone use on the susceptibility of Pseudomonas aeruginosa to fluoroquinolones in U.S. hospitals was studied. Benchmarking surveys were sent annually to pharmacists practicing in U.S. hospitals from 1993 to 1999. Data collected included hospital characteristics, antimicrobial expenditures and use, antimicrobial stewardship activities, and bacterial susceptibilities. Antimicrobial expenditures were normalized for the number of occupied beds (OBs) per year. General linear modeling and repeated-measures mixed-effects modeling were used to determine factors predictive of P. aeruginosa susceptibility to fluoroquinolones. A total of 174 hospitals provided data for fluoroquinolone expenditures and susceptibility of P. aeruginosa; the median number of years of data was 3 (range, 1-6), representing 416 hospital years. Community hospitals contributed a majority of the data. Median fluoroquinolone expenditures increased gradually from $230 per OB in 1993 to $400 per OB in 1998. A 55% increase to $620 per OB occurred in 1999, largely because of increased spending on levofloxacin. Susceptibility to ciprofloxacin was commonly used to assess fluoroquinolone susceptibility. The median susceptibility of P. aeruginosa to ciprofloxacin decreased from 84% to 71%. Increasing expenditures for ofloxacin and levofloxacin, but not ciprofloxacin, were associated with decreasing P. aeruginosa susceptibility to ciprofloxacin. In the final multivariable model, each study year after 1993 and every increase in ofloxacin expenditure of $100 per OB were associated with decreases in P. aeruginosa susceptibility. Data from a benchmarking survey of U.S. hospitals for 1993-1999 revealed increases in levofloxacin expenditures, total fluoroquinolone expenditures, expenditures for nonfluoroquinolone antipseudomonal antimicrobials, and total antimicrobial expenditures in 1999. Increases in expenditures for levofloxacin and ofloxacin were associated with a significant decrease in P. aeruginosa susceptibility to ciprofloxacin.

An understanding of fundamental PK-PD principles forms the basis for the rational use of antimicrobial agents. For quinolones, the fAUC24:MIC ratio is predictive of efficacy in animal and in vitro infection models, and in infected patients. The magnitude of the fAUC24:MIC ratio predictive of efficacy in animal and in vitro infection models has been shown to be concordant with those obtained from human data. By accounting for PK and microbiologic variability together with PK-PD targets associated with efficacy or resistance suppression by Monte Carlo simulation, it is possible to discriminate between therapeutic regimens and select those regimens likely to be of greater benefit to patients. The maturation of antimicrobial PK-PD as a scientific discipline continues to accelerate and currently impacts clinical practice, drug development, and regulatory decision making.

The frequency of resistance to β-lactams among nosocomial isolates has been increasing due to extended-spectrum β-lactamase (ESBL)-producing enteric bacilli. Although clinical outcome data are desirable, assessment of clinical efficacy has been limited due to the lack of a statistically meaningful number of well-documented cases. Since time above the MIC ( T >MIC) is the pharmacokinetic-pharmacodynamic (PK-PD) measure that best correlates with in vivo activity of β-lactams, a stochastic model was used to predict the probability of PK-PD target attainment ranging from 30 (P30) to 70% (P70) T >MIC, for standard dosing regimens of both piperacillin-tazobactam and cefepime against Escherichia coli and Klebsiella pneumoniae ESBL phenotypes. The P70/30 T >MIC for cefepime at 2 g every 12 h against E. coli and K. pneumoniae was 0.99/1.0 and 0.96/1.0 and for a regimen of 1 g every 12 h was 0.96/1.0 and 0.93/0.99, respectively. For piperacillin-tazobactam at 3.375 g every 4 h against E. coli and K. pneumoniae , the P70/30 T >MIC was 0.77/0.96 and 0.48/0.77 and for a regimen of 3.375 g every 6 h was 0.28/0.91 and 0.16/0.69, respectively. These data suggest that the probability of achieving T >MIC target attainment rates is generally higher with cefepime than with piperacillin-tazobactam for present-day ESBL-producing strains when one uses contemporary dosing regimens.

Background The relationship between antimicrobial activity and exposure relative to MIC is typically evaluated using one of three PK-PD indices, AUC:MIC ratio, Cmax:MIC ratio, and %T>MIC. However, under certain circumstances, none of these PK-PD indices may be the most optimal. These include when the fitted Hill functions for each of the PK-PD indices do not allow for sufficient discrimination, the variability about the fitted functions is wide, and/or the pattern of dose fractionation data is non-informative. Relationships fit using the traditional PK-PD indices may be suboptimal for drugs which exhibit extreme PK characteristics such as abnormally short or long half-lives. As described herein, we explored the use of a fourth PK-PD index for such instances, AUC/τ:MIC ratio (τ = dosing interval). Methods Previously-described ceftolozane dose-fractionation data from a study using a neutropenic murine thigh-infection model were evaluated [AAC 2013; 57(4):1577–82]. In this prior study, mice were infected with E. coli ATCC 25922 (MIC = 0.5 mg/L) or K. pneumoniae ATCC 43816 (MIC = 1.4 mg/L). Ceftolozane doses ranged from 1.56 to 1600 mg/kg/24h given q3h, q6h, q12h, or q24h. Relationships between log10 colony forming units (CFU) at 24 hours and AUC:MIC ratio, Cmax:MIC ratio, %T>MIC, and AUC/τ:MIC ratio were evaluated by pathogen and pooled using Hill-type models and non-linear least squares regression. Results For evaluations of data by pathogen, AUC/τ:MIC ratio best described changes in log10 CFU at 24 hours. The coefficients of determination (r2) for these pathogens were improved by 0.20 and 0.11, respectively, relative to the highest r2 achieved using any of the traditional PK-PD indices. Similar results were observed when the data were evaluated using a pooled approach (Figure 1). Conclusion AUC/τ:MIC ratio may be useful to evaluate drugs demonstrating the extremes of PK. Accordingly, this PK-PD index best described ceftolozane PK-PD, an agent with a very short murine plasma half-life ( Disclosures All authors: No reported disclosures.

Background While many have advocated for the use of EDSS to enhance patient care, EDSS that incorporates PK-PD, the science behind antimicrobial stewardship, has thus far been an unattainable goal. Herein, we describe the use of such a technology and clinicians’ therapy decisions when treating patients with pneumonia. Methods Data for patients with pneumonia entered into EDSS over a 20-month period that were evaluated included: 1) patient demographics, creatinine clearance, and pneumonia severity score; 2) pneumonia type; 3) pathogen; 4) clinician-selected antimicrobials; 5) EDSS-presented regimens; and 6) clinician-reported outcomes. Clinicians were provided probabilities of attaining PK-PD targets associated with efficacy for both clinician-selected and EDSS-presented regimens. A regimen with a probability of PK-PD target attainment ≥90% was considered PK-PD optimized. Results Data for 126 cases were available. The median (min, max) age and creatinine clearance were 56.5 (18, >90) years and 72.5 (2.5, 193.3) mL/minute/1.73 m2, respectively. Pneumonia types included community-acquired (39%), healthcare-associated (30%), ventilator-associated (18%), and hospital-acquired (13%). CURB-65 pneumonia scoring was used in 66% of cases with a median (min, max) score of 3 (0, 5). The most common pathogens were P. Aeruginosa (32%), MRSA (15%), and S. pneumoniae (14%). Multi-drug-resistant pathogens comprised 15% of all pathogens. PK-PD optimized regimens were selected in only 65% of cases despite such a regimen being presented in 91% of cases. For those cases in which outcome data were available (n = 36), 81% of patients were considered improved at 48 hours while only 64% were deemed clinically improved or a success at the final outcome assessment on Days 7–10. Among those cases for whom PK-PD optimized and non-optimized regimens were selected (64 and 36%, respectively), 78 and 62% of patients had successful clinical outcomes on Days 7–10, respectively. Conclusion Given that patients with pneumonia represent a vulnerable population and that options for therapy can be limited, selection of optimal early therapy is crucial. PK-PD integrated EDSS presents clinicians the opportunity to optimize therapy and improve outcomes for patients with pneumonia. Disclosures S. M. Bhavnani, ICPD Technologies: Shareholder, stock options. C. M. Rubino, ICPD Technologies: Shareholder, stock options. P. G. Ambrose, ICPD Technologies: Shareholder, stock options.

Background The increasing prevalence of resistant Candida species has led to renewed interest in evaluating the utility of echinocandins. PK-PD target attainment analyses are increasingly used to inform decisions about susceptibility breakpoints. We carried out such analyses to evaluate anidulafungin, micafungin, and caspofungin Clinical and Laboratory Standards Institute (CLSI) susceptibility breakpoints for C. Albicans, C. glabrata, and C. parapsilosis. Methods Monte Carlo simulations (n = 2000) were conducted using published population PK models [J Clin Pharmacol 2004; 44:590–598, ICAAC 2008; Abstr A-011, AAC 2013; 57:1664–1671]. The following labeled intravenous dosing regimens for the treatment of candidemia were evaluated: anidulafungin 200 mg followed by 100 mg daily, micafungin 100 mg daily, and caspofungin 70 mg followed by 50 mg daily. Day 1 free-drug plasma AUC values were calculated for simulated patients after administration of each agent. Free-drug plasma AUC:MIC ratio targets associated with 1-log10 CFU reductions from baseline of C. Albicans and C. glabrata for anidulafungin, micafungin, and caspofungin, derived from neutropenic murine disseminated candidiasis models, were used [AAC 2007; 52:539–550, AAC 2010; 54:2497–2506]. Similar such targets for C. parapsilosis were utilized to evaluate caspofungin and micafungin. Percent probabilities of PK-PD target attainment were computed by MIC. The results were evaluated in the context of MIC distributions for each pathogen from a collection of isolates obtained worldwide from 2014 to 2015 [ECCMID 2017; Abstr P1748]. Results Among the CLSI susceptibility breakpoints evaluated, only one was supported by the analysis results shown in Figure 1 (caspofungin vs. C. glabrata), and only one other susceptibility breakpoint was within one dilution of the highest MIC at which the percent probability of PK-PD target attainment was ≥90% (anidulafungin vs. C. glabrata). All other susceptibility breakpoints were ≥2 dilutions above this MIC. Conclusion These results demonstrate the need to re-evaluate the echinocandin susceptibility breakpoints for Candida spp. Establishing appropriate susceptibility breakpoints will ensure appropriate prescribing and optimal patient outcomes. Disclosures All authors: No reported disclosures.

Background Debates over the safety and efficacy of vancomycin have plagued clinical practice for more than half a century. A recent paradigm shift has occurred as the science of PK-PD has encouraged the use of optimized regimens which achieve targeted exposures. However, change is slow and we suspect prescribing habits may not be in line with this consensus approach. Herein, using data from electronic decision support software (EDSS), we describe clinicians’ vancomycin prescribing habits. Methods Data obtained over a 20-month period from an EDSS included: 1) clinician demographics; 2) patient demographics; 3) clinician-selected antimicrobials; and 4) EDSS suggested PK-PD optimized antimicrobial regimens. A vancomycin regimen was considered to be PK-PD optimized if the EDSS provided percent probability of PK-PD target attainment (PTA) was ≥90%. Results Data for 87 clinicians and 104 vancomycin-treated cases were available. Of all clinicians, 62% were clinical pharmacists, 38% were physicians, with close to half of being ID specialists. Of all the clinicians, 55% had ≥10 years of clinical experience. Of the 104 cases, the median (min, max) patient age, weight and creatinine clearance were 43.5 (23, >90) years, 81.6 (47.6, 170.6) kg, and 100.2 (7.3, 188.1) mL/min/1.73 m2, respectively. For 61.5% of selected vancomycin regimens, PTA were ≥90%. The distribution of PTA for the remaining 38.5% of cases is shown in Figure 1. Among these 38.5%, an alternative optimized regimen was presented 97.5% of the time. Further evaluation of clinician demographics among cases with a PK-PD optimized regimen demonstrated that 61% had ≥ 10 years clinical experience while only 44% of those who did not chose a PK-PD-optimized regimen had the same experience. While the majority of clinicians in both the optimized and non-optimized groups were clinical pharmacists, ID physicians represented 55% of all physicians who chose a non-optimized vancomycin regimen. Conclusion Data obtained from an EDSS demonstrated that clinicians who chose a non-optimized vancomycin regimen had less experience than those who chose an optimized regimen. Data suggest that education for optimizing vancomycin dosing using PK-PD is needed as part of antimicrobial stewardship training initiatives. Disclosures S. M. Bhavnani, ICPD Technologies: Shareholder, stock options. C. M. Rubino, ICPD Technologies: Shareholder, stock options. P. G. Ambrose, ICPD Technologies: Shareholder, stock options.

BC-3781, a pleuromutilin antimicrobial agent, is being developed for the treatment of patients with acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia. Data from a phase 2 study of patients with ABSSSI were used to refine a previous population pharmacokinetic (PK) model and explore potential predictors of PK variability. The previously derived population PK model based on data from three phase 1 studies was applied to sparse sampling data from a phase 2 ABSSSI study and modified as necessary. Covariate analyses were conducted to identify descriptors (e.g., body size, renal function, age) associated with interindividual variability in PK. All population PK analyses were conducted by using Monte Carlo parametric expectation maximization implemented in S-ADAPT 1.5.6. The population PK data set contained 1,167 concentrations from 129 patients; 95% of the patients had 5 or more PK samples (median, 11). The previous population PK model (three-compartment model with first-order elimination and nonlinear protein binding) provided an acceptable and unbiased fit to the data from the 129 patients. Population PK parameters were estimated with acceptable precision; individual clearance values were particularly well estimated (median individual precision of 9.15%). Graphical covariate evaluations showed no relationships between PK and age or renal function but modest relationships between body size and clearance and volume of distribution, which were not statistically significant when included in the population PK model. This population PK model will be useful for subsequent PK-pharmacodynamic analyses and simulations conducted to support phase 3 dose selection. (This study has been registered at ClinicalTrials.gov under registration no. NCT01119105.)

The influence of using ofloxacin in place of ciprofloxacin on hospital fluoroquinolone expenditures, total antimicrobial expenditures, and susceptibility of Pseudomonas aeruginosa to fluoroquinolones was studied. Hospitals with fluoroquinolone expenditures of at least $1 per occupied bed per year were administered annual surveys covering the years 1993 through 1996. The two most recent consecutive years of data were compared among hospitals that used ciprofloxacin as their primary fluoroquinolone during both years (group 1), hospitals whose ofloxacin purchases increased from accounting foror =25% of total fluoroquinolone expenditures during year 1 to accounting for25% during year 2 (group 2), and hospitals whose ofloxacin purchases accounted for at least 25% of total fluoroquinolone expenditures for both years (group 3). A total of 109 hospitals were included in the study. Most hospitals spent more on fluoroquinolones and total antimicrobials in year 2 than year 1. Group 3 hospitals had a significant increase in expenditures for fluoroquinolones and non-fluoroquinolone antipseudomonal antimicrobials. Group 2 hospitals did not realize antimicrobial cost savings and had higher rates of Pseudomonas aeruginosa resistance than hospitals that used ciprofloxacin. Whether a hospital changed its pattern of ciprofloxacin and ofloxacin purchasing was not significantly associated with expenditures for fluoroquinolones, nonfluoroquinolone antimicrobial agents, or all antimicrobials. Susceptibility of P. aeruginosa to ciprofloxacin was lower in hospitals with greater proportions of ofloxacin use. Individual hospital, ciprofloxacin expenditures, and study year were found to be predictive of P. aeruginosa susceptibility to ciprofloxacin among all pooled hospitals.

We report on 28 patients who underwent voriconazole monitoring because of disease progression or toxicity. A relationship ( P < 0.025) between disease progression and drug concentration was detected. Favorable responses were observed in 10/10 patients with concentrations above 2.05 μg/ml, while disease progressed in 44% ( n = 18) of patients with concentrations below 2.05 μg/ml.

Pharmacokinetic-pharmacodynamic (PK-PD) analyses for efficacy using phase III trial data from patients treated with a ceftaroline fosamil dosing regimen of 600 mg intravenously (i.v.) every 12 h (q12h) for 5 to 7 days for community-acquired bacterial pneumonia (CABP) were conducted. High clinical and microbiological success rates (84.7 and 86.3%, respectively) and percentages of time during the dosing interval that free-drug steady-state concentrations remained above the MIC ( f % T >MIC) (98.4% had f % T >MIC values of ≥63.3) were observed among 124 microbiologically evaluable patients. As a result, significant PK-PD relationships could not be identified. These data provide support for the use of a ceftaroline fosamil dosing regimen of 600 mg i.v. q12h to treat patients with CABP.

Ceftaroline, the active form of ceftaroline fosamil, is a broad-spectrum cephalosporin antibiotic. A population pharmacokinetic (PPK) model for ceftaroline was developed in NONMEM® using data from 185 healthy subjects and 92 patients with acute bacterial skin and skin structure infection (ABSSSI). Data from 128 patients with community-acquired bacterial pneumonia (CABP) were used for external model validation. Healthy subjects received 50-2,000 mg ceftaroline fosamil via intravenous (IV) infusion over 1 hour or intramuscular (IM) injection q12h or q24h. ABSSSI and CABP patients received 600 mg of ceftaroline fosamil IV over 1 hour q12h. A three-compartment model with zero-order IV or parallel first-order IM input and first-order elimination described ceftaroline fosamil PK. A two-compartment model with first-order conversion of prodrug to ceftaroline and parallel linear and saturable elimination described ceftaroline PK. Creatinine clearance was the primary determinant of ceftaroline exposure. Good agreement between the observed data and both population (r(2) = 0.93) and individual post-hoc (r(2) = 0.98) predictions suggests the PPK model can adequately approximate ceftaroline PK using covariate information. Such a PPK model can evaluate dose adjustments for patients with renal impairment and generate ceftaroline exposures for use in pharmacokinetic-pharmacodynamic assessments of efficacy in patients with ABSSSI or CABP.

Ceftaroline, the active form of ceftaroline fosamil, is a broad-spectrum cephalosporin antibiotic. A population pharmacokinetic (PPK) model for ceftaroline was developed in NONMEM® using data from 185 healthy subjects and 92 patients with acute bacterial skin and skin structure infection (ABSSSI). Data from 128 patients with community-acquired bacterial pneumonia (CABP) were used for external model validation. Healthy subjects received 50-2,000 mg ceftaroline fosamil via intravenous (IV) infusion over 1 hour or intramuscular (IM) injection q12h or q24h. ABSSSI and CABP patients received 600 mg of ceftaroline fosamil IV over 1 hour q12h. A three-compartment model with zero-order IV or parallel first-order IM input and first-order elimination described ceftaroline fosamil PK. A two-compartment model with first-order conversion of prodrug to ceftaroline and parallel linear and saturable elimination described ceftaroline PK. Creatinine clearance was the primary determinant of ceftaroline exposure. Good agreement between the observed data and both population (r(2) = 0.93) and individual post-hoc (r(2) = 0.98) predictions suggests the PPK model can adequately approximate ceftaroline PK using covariate information. Such a PPK model can evaluate dose adjustments for patients with renal impairment and generate ceftaroline exposures for use in pharmacokinetic-pharmacodynamic assessments of efficacy in patients with ABSSSI or CABP.

In an era of rapidly emerging antimicrobial-resistant bacteria, it is critical to understand the importance of the relationships among drug exposure, duration of therapy, and selection of drug resistance. Herein we describe the results of studies designed to determine the ceftolozane-tazobactam exposure necessary to prevent the amplification of drug-resistant bacterial subpopulations in a hollow-fiber infection model. The challenge isolate was a CTX-M-15-producing Escherichia coli isolate genetically engineered to transcribe a moderate level of bla CTX-M-15 . This organism's bla CTX-M-15 transcription level was confirmed by relative quantitative reverse transcription-PCR (qRT-PCR), β-lactamase hydrolytic assays, and a ceftolozane MIC value of 16 mg/liter. In these studies, the experimental duration (10 days), ceftolozane-tazobactam dose ratio (2:1), and dosing interval (every 8 h) were selected to approximate those expected to be used clinically. The ceftolozane-tazobactam doses studied ranged from 125-62.5 to 1,500-750 mg. Negative- and positive-control arms included no treatment and piperacillin-tazobactam at 4.5 g every 6 h, respectively. An inverted-U-shaped function best described the relationship between bacterial drug resistance amplification and drug exposure. The least- and most-intensive ceftolozane-tazobactam dosing regimens, i.e., 125-62.5, 750-375, 1,000-500, and 1,500-750 mg, did not amplify drug resistance, while drug resistance amplification was observed with intermediate-intensity dosing regimens (250-125 and 500-250 mg). For the intermediate-intensity ceftolozane-tazobactam dosing regimens, the drug-resistant subpopulation became the dominant population by days 4 to 6. The more-intensive ceftolozane-tazobactam dosing regimens (750-375, 1,000-500, and 1,500-750 mg) not only prevented drug resistance amplification but also virtually sterilized the model system. These data support the selection of ceftolozane-tazobactam dosing regimens that minimize the potential for on-therapy drug resistance amplification.

Given the limited understanding about pharmacokinetic-pharmacodynamic (PK-PD) determinants of oseltamivir efficacy, data from two phase 2 influenza virus inoculation studies were evaluated. Healthy volunteers in studies 1 and 2 were experimentally infected with influenza A/Texas (the concentration of neuraminidase inhibitor which reduced neuraminidase activity by 50% [IC 50 ] = 0.18 nM) or B/Yamagata (IC 50 = 16.76 nM), respectively. In study 1, 80 subjects received 20, 100, or 200 mg of oral oseltamivir twice daily (BID), 200 mg oseltamivir once daily, or placebo for 5 days. In study 2, 60 subjects received 75 or 150 mg of oral oseltamivir BID or placebo for 5 days. Oseltamivir carboxylate (OC) (active metabolite) PK was evaluated using individual PK data and a population PK model to derive individual values for area under the concentration-time curve from 0 to 24 h (AUC 0–24 ), minimum concentration of OC in plasma ( C min ), and maximum concentration of OC in plasma ( C max ). Exposure-response relationships were evaluated for continuous (area under composite symptom score curve [AUCSC], area under the viral titer curve, and peak viral titer) and time-to-event (alleviation of composite symptom scores and cessation of viral shedding) efficacy endpoints. Univariable analyses suggested the existence of intuitive and highly statistically significant relationships between OC AUC 0–24 evaluated as a 3-group variable and AUCSC, time to alleviation of composite symptom scores, and time to cessation of viral shedding. The upper OC AUC 0–24 threshold (∼14,000 ng · h/ml) was similar among these endpoints. Multivariable analyses failed to demonstrate the influence of study/strain on efficacy endpoints. These results provide the first demonstration of exposure-response relationships for efficacy for oseltamivir against influenza and suggest that OC exposures beyond those achieved with the approved oseltamivir dosing regimen will provide enhanced efficacy. The clinical applicability of these observations requires further investigation.

Tuberculous meningitis (TBM) is the most lethal form of tuberculosis, and new treatments that improve outcomes are required. We randomly assigned adults with TBM to treatment with standard antituberculosis treatment alone or in combination with ciprofloxacin (750 mg/12 h), levofloxacin (500 mg/12 h), or gatifloxacin (400 mg/24 h) for the first 60 days of therapy. Fluoroquinolone concentrations were measured with plasma and cerebrospinal fluid (CSF) specimens taken at predetermined, randomly assigned times throughout treatment. We aimed to describe the pharmacokinetics of each fluoroquinolone during TBM treatment and evaluate the relationship between drug exposure and clinical response over 270 days of therapy (Controlled Trials number ISRCTN07062956). Sixty-one patients with TBM were randomly assigned to treatment with no fluoroquinolone ( n = 15), ciprofloxacin ( n = 16), levofloxacin ( n = 15), or gatifloxacin ( n = 15). Cerebrospinal fluid penetration, measured by the ratio of the plasma area under the concentration-time curve from 0 to 24 h (AUC 0–24 ) to the cerebrospinal fluid AUC 0–24 , was greater for levofloxacin (median, 0.74; range, 0.58 to 1.03) than for gatifloxacin (median, 0.48; range, 0.47 to 0.50) or ciprofloxacin (median, 0.26; range, 0.11 to 0.77). Univariable and multivariable analyses of fluoroquinolone exposure against a range of different treatment responses revealed worse outcomes among patients with lower and higher plasma and CSF exposures than for patients with intermediate exposures (a U-shaped exposure-response). TBM patients most likely to benefit from fluoroquinolone therapy were identified, along with exposure-response relationships associated with improved outcomes. Fluoroquinolones add antituberculosis activity to the standard treatment regimen, but to improve outcomes of TBM, they must be started early, before the onset of coma.

Perhaps the most crucial step in the clinical development of an antimicrobial agent is the selection of a dosing regimen. Such decisions impact not only the success of a program but also the well being of individual patients, the emergence of resistance, and society as a whole. For fusidic acid, the selection of a dosing regimen for the treatment of patients with acute bacterial skin and skin-structure infection (ABSSSI) was based on the integration of knowledge gained from human population pharmacokinetic, in vitro infection, and mathematical models. The overarching goal of these studies was to identify a dosing regimen that would maximize the probabilities of positive clinical outcomes and limit the emergence of bacterial resistance during therapy. Novel dosing regimens identified included 1500 mg twice daily on day 1 followed by 600 mg twice daily for 10-14 days, a regimen that was subsequently found to be effective in a phase 2 clinical study of patients with ABSSSI. Herein, we review the data supporting the use of this novel fusidic acid dosing regimen, which will undergo further clinical evaluation in phase 3 clinical trials.

The pharmacokinetics-pharmacodynamics (PK-PD) of fusidic acid were investigated against methicillin-resistant Staphylococcus aureus (MRSA) and Streptococcus pyogenes using in vitro infection models. Front-loaded and non-front-loaded fusidic acid dosing regimens were evaluated over 48 h using a 1-compartment infection model and over 240 h using a hollow fiber infection model (HFIM). All dosing regimens demonstrated initial decreases in bacterial density against both isolates in both in vitro models. A mechanism-based PK-PD model was developed to describe the effect of the concentration-time course of fusidic acid on the time course of MRSA in the in vitro infection model. With the use of this model and Monte Carlo simulation to evaluate the effect of different dosing regimens against MRSA, front-loaded [≥ 1200 mg every 12 h (Q12) × 2 doses followed by ≥ 600 mg Q12 h] compared to non-front-loaded (600 mg Q12 h) dosing regimens demonstrated better activity. HFIM data confirmed the effect of the front-loaded dosing regimens over 48 h and also demonstrated the suppression of growth of the total population and resistant subpopulations for MRSA over 96 and 120 h, respectively, associated with these dosing regimens.

Echinocandins have become a first-line therapy for invasive candidiasis (IC). Using phase 3 trial data for patients with IC, pharmacokinetic-pharmacodynamic (PK-PD) relationships for efficacy for micafungin were examined. Micafungin exposures were estimated using a population pharmacokinetic model, and univariable and multivariable logistic regressions were used to identify factors associated with outcome, including the micafungin area under the concentration-time curve (AUC)/MIC ratio. Monte Carlo simulation was used to evaluate the probability of achieving AUC/MIC ratios associated with efficacy. Mycological and clinical success rates for evaluable cases were 89.4 and 90.9, respectively. MIC 50 s and MIC 90 s for Candida species inhibition were 0.008 and 0.5 mg/liter, respectively. The median AUC/MIC ratio was 15,511 (range, 41.28 to 98,716). Univariable analyses revealed a significant relationship between the AUC/MIC ratio and mycological response, with the worst response being among patients with lower (≤3,000) AUC/MIC ratios ( P = 0.005). For patients with Candida parapsilosis , AUC/MIC ratios of ≥285 were predictive of a higher mycological response ( P = 0.11). Multivariable logistic regression demonstrated the AUC/MIC ratio, APACHE II score, and history of corticosteroid use to be significant independent predictors of a favorable response. PK-PD target attainment analyses suggested that 76.7% and 100% of patients would achieve an AUC/MIC ratio of ≥3,000 for an MIC of 0.03 mg/liter and an AUC/MIC ratio of ≥285 for an MIC of C. parapsilosis than other Candida species suggests consideration of species-specific echinocandin susceptibility breakpoints and values that are lower than those currently approved by regulatory agencies.

When faced with a neonate, infant, or child with a suspected infection, the clinician must select a specific antimicrobial at a specific dose for a specific duration to treat that infection. Many issues require careful consideration, and include knowledge of the suspected pathogens and their susceptibility to the antimicrobials under consideration, the pharmacokinetic (PK) characteristics of the antimicrobials, and the clinician’s assessment of the need to achieve a cure for that particular patient (Table 1). PK and pharmacodynamics (PD) principles together with Monte Carlo simulation can assist the clinician in selecting the appropriate antimicrobial and dosing regimen. Recent advances in our understanding of antimicrobial PK and PD have lead to important insights in the parameters associated with a successful outcome, and in ways to minimize both drug toxicity and the development of antimicrobial resistance.

Tigecycline is a new-generation of tetracycline (glycylcyclines) and is active in vitro against bacteria that possess any of the classical genes that confer tetracycline resistance through ribosomal protection or efflux pumps. Herein, tigecycline disposition in patients with community- or hospital-acquired pneumonia was described using a population pharmacokinetic model. Additionally, the influence of covariates, such as body surface area, severity of illness, and clinical laboratory measures, on tigecycline disposition was evaluated. An intravenous loading dose of 100 mg was followed by 50 mg of tigecycline every 12 h. The final population pharmacokinetic model was a two-compartment model with linear elimination and with a relationship between tigecycline clearance and body surface area and creatinine clearance. The model was parameterized using total clearance (CL), the volume of the central compartment, distributional clearance from the central to the peripheral compartment, and volumes of distribution at steady state. Relationships between body surface area and creatinine clearance were identified as significant predictors of interindividual variability on CL. This model will serve as the basis for estimating tigecycline exposure for pharmacokinetic-pharmacodynamic analyses for efficacy and safety among patients with community- or hospital-acquired pneumonia.

Our thesis is a simple one: although a drug can fail in an individual patient for many reasons, appropriately sized and conducted drug-development programs often fail because of insensitive, uninformative end points, and/or poor a priori regimen decisions. The difficulty in successfully developing antimicrobial agents at present is often exacerbated by company decision-makers who are either uninformed or disregard the difference between empirical-based (ie, akin to playing pin-the-tail on the donkey) and quantitative model-based development plans. Frequently, the focus is on Gantt charts (project event schedules) and the on-time submission of a New Drug Application to a regulatory body, such as the US Food and Drug Administration. Such misplaced focus has led and will continue to lead to a number of problems, including program failure or, even worse, regulatory approval of an inappropriate dosing regimen with associated negative safety and efficacy sequelae. We believe that the goal of drug development is not a New Drug Application submitted on time but, rather, an approved, differentiated, safe, and effective new medicine. Here, we focus on the pharmacokinetic-pharmacodynamic data needed to guide dosing regimen decisions for patients with hospital-acquired bacterial pneumonia or ventilator-associated bacterial pneumonia. Early consideration of these data in development programs will reduce risk not only to sponsors but also, most importantly, to the patients enrolled in the clinical trials.

Oritavancin is a novel glycopeptide antimicrobial agent with potent in vitro activity against a wide variety of gram-positive bacteria, including multidrug-resistant strains of staphylococci and enterococci. A population pharmacokinetic model was developed to describe the disposition of oritavancin with data from a pooled population of phase 1 healthy subjects and phase 2 and 3 patients with complicated skin and skin structure infections or Staphylococcus aureus bacteremia. In addition, the potential influence of factors such as the subject's age, gender, and clinical laboratory measures on oritavancin disposition was evaluated. Oritavancin was administered as both single- and multiple-dose intravenous (i.v.) infusions in fixed doses ranging from 100 to 800 mg or weight-based doses ranging from 0.02 to 10 mg/kg of body weight, with infusion durations ranging from 0.13 to 6.5 h across all studies. The most robust fit to the data ( n = 6,290 oritavancin plasma concentrations from 560 subjects) was obtained using a three-compartment model with zero-order i.v. infusion and first-order elimination. The model was parameterized using total clearance (CL), volume of central compartment (Vc), distributional clearances from the central to both the first and second peripheral compartments, and volumes of distribution for both the first and second peripheral compartments. Weight and study phase (phase 1 versus phase 2/3) were identified as significant predictors of the interindividual variability in CL, while body surface area and age were significant for Vc. These results suggest that dose modification may be warranted in patients weighing >110 kg. However, the mild nature of the observed relationships for Vc suggest that dosing adjustments are not necessary for elderly patients.

The pharmacokinetics and pharmacodynamics of a novel liposomal amikacin for inhalation were evaluated in cystic fibrosis patients with chronic pseudomonas infection. Twenty-four patients from two studies received 500 mg of liposomal amikacin by inhalation once daily for 14 days. Serum, sputum, and 24-h urine samples were collected on days 1 and 14 of therapy; pulmonary function tests (PFT) and sputum for quantitative microbiology were assessed at baseline and serially for 14 days. Relationships between amikacin exposure in serum and sputum and absolute change in PFT endpoints and log10CFU ofPseudomonas aeruginosafrom baseline on days 7 and 14 of therapy were assessed. On days 7 and 14, absolute change from baseline in forced expiratory volume in 1 s (FEV1), percent predicted forced expiratory volume in 1 s (FEV1% predicted), and forced expiratory flow between 25 and 75% of forced vital capacity (FEF25-75%) increased by 0.24 (P= 0.002) and 0.13 (P= 0.10) liters, 7.49 (P< 0.001) and 4.38 (P= 0.03), and 0.49 (P< 0.001) and 0.42 (P= 0.02) liters/s, respectively. In addition, relative change from baseline in FEV1% predicted was 10.8% (P< 0.001) and 5.62% (P= 0.073) on days 7 and 14, respectively. While significant relationships between absolute change in PFT endpoints and the ratio of serum or sputum area under the concentration-time curve to the MIC (AUC/MIC) were not observed, relationships between change in log10CFU and serum AUC/MIC ratio and change in log10CFU and absolute changes in all PFT endpoints were significant. Together, these findings likely represent drug effect and warrant the further development of liposomal amikacin for inhalation.

Hospitalized neonates are exposed to antibiotic-resistant bacterial pathogens and develop nosocomial infections. Limited data are available regarding the neonatal pharmacokinetics of meropenem, a broad spectrum carbapenem antibiotic.Neonates2 months of age received a single dose of meropenem at 10 or 20 mg/kg. Meropenem serum concentrations were measured at specified times during the 24 hours postinfusion. Population pharmacokinetics (PPK) were evaluated using NONMEM. Using Monte Carlo simulation (MCS), the probability of pharmacokinetic-pharmacodynamic target attainment was evaluated by computer modeling from predictions extrapolated from PPK data, using "virtual" dosing regimens of 10, 20, and 40 mg/kg administered every 8 or 12 hours against community- and hospital-acquired pathogens.Thirty-seven neonates were enrolled, 22 were born at36 weeks (range, 23-41 weeks) gestational age. Meropenem clearance was greater in neonates with older chronologic ages and in those born at later gestational ages. Serum creatinine and postconceptional age (PCA) were the best overall predictors of meropenem elimination: CL (L/h/kg) = 0.041 + 0.040/SCr + 0.003 x (PCA-35). MCS demonstrated that in infants during the first 2 weeks of life, a dosage of 20 mg/kg/dose every 8 hours achieved the desired PD target in 95% of preterm neonates and 91% of term neonates against Pseudomonas aeruginosa isolated from patients managed in adult and pediatric intensive care units in the United States.MCS based on PPK determinations demonstrated that a meropenem dose of 20 mg/kg every 8 hours should provide adequate therapy for most nosocomial Gram-negative pathogens.

Recent studies of nonneutropenic patients with candidemia or candidiasis suggest that fluconazole pharmacodynamic parameters correlate with clinical outcomes; however, additional data of correlation to mortality in patients with candidemia would be valuable. We assessed the impact of MICs for Candida , fluconazole pharmacodynamics, and patient characteristics on all-cause mortality with use of a prospective cohort of 96 hospitalized patients with candidemia. Among 84 patients for whom Candida isolates were available for testing, the most frequent Candida species isolated were Candida albicans (44%), followed by Candida parapsilosis (20.2%), and Candida glabrata (20.2%). Fluconazole resistance (MIC of ≥64 μg/ml) was present in 7 (8.3%) to 10 (11.9%) of 84 isolates, depending on the MIC endpoint determination method (50% or 80% inhibition read at 24 or 48 h). Overall mortality occurred in 27 (28.1%) of 96 patients, and nonsurvivors were more likely to have fluconazole-resistant isolates (25% versus 6.7%; P = 0.02). Multivariable analysis demonstrated an association between fluconazole resistance and mortality, but it did not reach statistical significance (odds ratio, 5.3; 95% confidence interval, 0.8 to 33.4; P = 0.08). By pharmacodynamic analysis, a fluconazole area under the concentration-time curve/MIC of P ≤ 0.09). These data support previous findings of an antifungal exposure-response relationship to mortality in patients with candidemia. In addition, similar MICs were obtained using a 24- or 48-h MIC endpoint determination, thus providing the opportunity to assess earlier the impact of isolate susceptibility on therapy.

Exposure-response analyses were performed using data from 89 patients (10 clinical trials) with Streptococcus pneumoniae community-acquired pneumonia who received quinolones. Relationships between the free-drug AUC/MIC ratio and clinical and microbiologic response were identified. Such data may be useful to establish prior expectations for the no-treatment effect when conducting noninferiority clinical trials.

Correctly determined susceptibility breakpoints are important to both the individual patient and to society at large. A previously derived patient population pharmacokinetic model and Monte Carlo simulation (9999 patients) were used to create a likelihood distribution of tigecycline exposure, as measured by the area under the concentration-time curve at 24 h (AUC(24)). Each resultant AUC(24) value was paired with a clinically relevant fixed MIC value ranging from 0.12 to 2 mg/L. For each AUC(24)-MIC pair, the probability of microbiologic response was calculated using an exposure-response relationship, which was derived from patients with complicated skin and skin structure infections that involved Staphylococcus aureus or streptococci or both. The median probability of microbiologic success was 94% or greater for MIC values up to and including 0.25 mg/L. The median probability of microbiologic success was 66% or less for MIC values of 0.5 mg/L or greater. These data support a susceptibility breakpoint of 0.25 mg/L for S. aureus and streptococci.

Pirfenidone is a small, synthetic molecule under investigation for treatment of idiopathic pulmonary fibrosis. In an open-label, single-dose crossover study, the pharmacokinetics (PK) of pirfenidone were investigated with or without food and antacids in healthy adult volunteers. Concentrations of pirfenidone and its metabolites in plasma and urine were determined by liquid chromatography with tandem mass spectrometry, and candidate pharmacokinetic models were fit to plasma data using weighted, non-linear regression. The effect of food and antacids on pirfenidone exposure was evaluated by determining 'equivalence' using FDA guidelines. Adverse events were recorded by site personnel and classified by investigators on the basis of severity and relationship to study drug. Sixteen subjects yielded 64 pharmacokinetic profiles. The best fit was achieved using a five-compartment, linear model with an allowance for direct conversion to the primary metabolite (5-carboxy-pirfenidone). Coadministration with food decreased the rate and, to a lesser degree, the extent of pirfenidone absorption of absorption. Analysis of adverse events revealed a correlation between pirfenidone C(max) and the risk of gastrointestinal (GI) adverse events, suggesting that food may reduce the risk of certain adverse events associated with pirfenidone. Administration of pirfenidone with food has a modest effect on overall exposure but results in lower peak concentrations, which may improve tolerability.

The objective of these analyses was to assess the penetration of tigecycline into colon wall tissue and epithelial lining fluid (ELF). The analyses included data from subjects without infection (phase 1) and patients with intra-abdominal infections (phase 2/3). Steady-state serum samples were collected from all subjects/patients ( n = 577), while colon wall specimens ( n = 23) and ELF specimens ( n = 30) were obtained from subjects without infection. Tissue and serum data were simultaneously comodeled by using the BigNPAG program, and a four-compartment, open model with zero-order intravenous input and first-order elimination was employed. To examine the full range of tissue penetration and the associated probabilities of occurrence, a 9,999-subject Monte Carlo simulation was performed with two outputs, one for ELF penetration and one for colon wall tissue penetration. Data were well fit using models described above, with all r 2 values above 0.95. For subjects without infection, the median (5th and 95th percentiles) colon wall and ELF penetration ratios were 1.73 (0.160 and 199) and 1.15 (0.561 and 5.23), respectively. Simulation results predict that tissue penetration varies considerably and likely explain unexpected clinical outcomes for those patients infected with strains at margins of the MIC distribution.

Sinusitis remains 1 of the most common reasons for antimicrobial prescriptions in the United States, with health care costs approaching $4 billion annually. We utilized the serial sinus aspirate sampling (SSAS) technique to obtain daily specimens to evaluate the time course of drug effect in patients with acute maxillary sinusitis. Eighteen patients with a radiologically confirmed acute maxillary sinusitis were enrolled into a study evaluating the relationship between levofloxacin exposure and the time course of antimicrobial effect using SSAS. SSAS was performed daily during therapy for bacteriologic evaluation. Six steady-state levofloxacin concentrations were obtained. Levofloxacin plasma and sinus aspirate concentrations were modeled using Monte Carlo Parametric Expectation Maximization algorithm implemented in S-ADAPT 1.53. Endpoints evaluated included time to resolution of signs and symptoms and time to sinus sterilization. Among the 18 enrolled patients, 15 were clinically evaluable. From these, 1 Streptococcus pneumoniae , 3 Haemophilus influenzae , 1 Moraxella catarrhalis , 1 Corynebacterium spp., and 1 coagulase-negative Staphylococcus organisms were isolated, with the latter 2 organisms being likely contaminants. For the pathogens, levofloxacin MIC values ranged from 0.03 to 2 mg/L. All pathogens were eradicated by the 4th day of therapy. The median and mean time to sinus sterilization (pathogens only) was 1 and 1.4 days, respectively. The median time to resolution of each sign and symptom ranged from 1.5 to 12–19 days, with the 83% of total signs and symptoms resolved by the end of therapy (day 5). The mean plasma area under the concentration-time curve (AUC) (mg ∙ h/L) was 100.1 ( n = 14, %CV = 27). Plasma AUC/MIC ratios ranged from 33.9 to 1696 for isolated pathogens. In this pilot SSAS study, levofloxacin rapidly eradicated isolated pathogens from the maxillary sinus.

Since the advent of the modern era of antimicrobial chemotherapy in the 1930s, animal infection models have allowed for the in vivo evaluation of antimicrobial agents for the treatment of experimentally induced infection. Today, animal pharmacokinetic-pharmacodynamic (PK-PD) infection models serve as a cornerstone of the preclinical assessment process for antibacterial agents and dose and dosing interval selection, as decision support for setting in vitro susceptibility breakpoints, and, finally, for the evaluation of the meaning of in vitro resistance. Over the past 15 years, considerable PK-PD data have been derived from infected patients for many classes of antimicrobial agents. These data provide the opportunity to confirm knowledge gained from animal PK-PD infection models.

An in vitro pharmacodynamic model was used to determine the pharmacokinetic–pharmacodynamic (PK–PD) measure and magnitude most strongly related to cefprozil activity against Haemophilus influenzae . Using 3 clinical isolates of H. influenzae , a series of dose-fractionation studies were conducted, simulating cefprozil pediatric pharmacokinetics. The studies were designed to deliver a range of free cefprozil AUC 24 given once daily, twice daily, and by continuous infusion (CI). Drug effect, characterized by computing the log 10 ratio of the area under the 24-h bacterial colony-forming unit (CFU) (AUC CFU ) curve to drug-free control, was fit to a Hill-type model for 3 PK–PD measures of activity: AUC 24 /MIC, C max /MIC, and %T > MIC. Once daily regimens provided much less activity than twice daily or CI regimens. AUC 24 /MIC and %T > MIC characterized the data well, whereas C max /MIC did not. Based on the PK–PD model results, for cefprozil twice daily, 50% and 80% of maximum drug effect ( E max ) was achieved at a %T > MIC of approximately 52% and 75%, respectively. A 2-log 10 reduction in log 10 ratio would require free drug %T > MIC of 58% or AUC 24 /MIC of 86. Bacteriostasis was achieved at a %T > MIC and an AUC 24 /MIC of approximately 25% and 30%, respectively. An in vitro pharmacodynamic model was able to characterize the PK–PD of cefprozil against H. influenzae . Consistent with limited clinical data, a minimum %T > MIC of 40% to 50% would be suggested to achieve in vivo activity in otitis media, with maximal activity at approximately 70%T > MIC.

Bloodstream infections due to antimicrobial-resistant Staphylococcus aureus occur with increasing frequency and represent an important cause of morbidity and mortality. To date, the evaluation of pharmacokinetic-pharmacodynamic relationships for efficacy among patients with bacteremia has been limited. The objectives of these analyses were to evaluate relationships between microbiological and clinical responses for patients with S. aureus bacteremia and exposures for oritavancin, a novel bactericidal glycopeptide in development. Bayesian oritavancin exposure predictions, following treatment with 5, 6.5, 8, or 10 mg/kg of body weight/day, were derived using a validated population pharmacokinetic model for 55 patients with S. aureus bacteremia. Using classification and regression tree analysis, a breakpoint of the percentage of the dosing interval duration for which free-drug concentrations were above the MIC (free-drug % time > MIC) of 22% was identified for microbiological response; the probabilities of success greater than or equal to and less than this value were 93% and 76%, respectively. Using logistic regression, a relationship was found between microbiological response and free-drug % time > MIC (odds ratio = 4.42, P = 0.09, and odds ratio = 8.84, P = 0.05, when one patient, a medical outlier, was excluded). A similar relationship was found for clinical response. These results will be valuable in supporting dose selection of oritavancin for patients with S. aureus bacteremia.

In order to identify patients likely to be infected with resistant bacterial pathogens, analytic methods such as standard regression (SR) may be applied to surveillance data to determine patient- and institution-specific factors predictive of an increased MIC. However, the censored nature of MIC data (e.g., MIC ≤ 0.5 mg/liter or MIC > 8 mg/liter) imposes certain limitations on the use of SR. In order to investigate the nature of these limitations, simulations were performed to compare a regression tailored for censored data (censored regression [CR]) and one tailored for an SR. By using a model relating piperacillin-tazobactam MICs against Enterobacter spp. to patient age and hospital bed capacity, 200 simulations of 500 isolates were performed. Various MIC censoring patterns were imposed by using 26 left- or right-censored ( L , R ) pairs (i.e., MICs ≤ 2 mg/liter L [2 L ] or MICs > 2 mg/liter R [2 R ], respectively). Data were fit by CR and SR for which censored MICs were either (i) excluded, (ii) replaced by 2 L or 2 R , or (iii) replaced by 2 L − 1 or 2 R + 1 . Total censoring for the 26 pairs ranged from 7 to 86%. By CR, deviations of average parameter estimates from the true parameter values were 2 (mg/liter) for all parameters for each of the 26 pairs. By SR, these deviations were >0.10 log 2 (mg/liter) for at least 18 of the 26 pairs for all but one parameter. Two-standard-error confidence intervals for individual parameters contained as little as 0% of cases for all SR approaches but ≥91.5% of cases for the CR approach. When censored MIC data are modeled, CR may reduce or eliminate biased parameter estimates obtained by SR.

As extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae continue to emerge worldwide, selection of empiric treatment modalities is an increasing challenge. Data describing the clinical outcomes associated with different treatment regimens have been limited. Using data from centers with confirmed ESBL- and non-ESBL-producing Escherichia coli and Klebsiella species isolates in North America, Latin America, and Europe, potential risk factors for the occurrence of invasive ESBL- and non-ESBL-producing Enterobacteriaceae infections and factors associated with clinical outcome were evaluated. Of the 175 cases considered evaluable, 77% were ESBL-producing organisms. Underlying comorbidities and potential risk factors were generally similar between ESBL and non-ESBL cases with a statistically greater proportion of ESBL cases requiring gastrostomy or jejunostomy tubes, ventilatory assistance, or care in the intensive care unit before culture (P

Gemifloxacin is a synthetic fluoroquinolone antimicrobial agent exhibiting potent activity against most gram-negative and gram-positive organisms, such as the important community-acquired respiratory pathogens Streptococcus pneumoniae (including multidrug-resistant S. pneumoniae), Haemophilus influenzae , and Moraxella catarrhalis . The agent's mechanism of action involves dual targeting of two essential bacterial enzymes: DNA gyrase and topoisomerase IV. Gemifloxacin was approved by the Food and Drug Administration in April 2003 for treatment of community-acquired pneumonia and acute bacterial exacerbation of chronic bronchitis. The drug has an oral bioavailability of approximately 71%. Approximately 20-35% of gemifloxacin is excreted unchanged in the urine after 24 hours. The elimination half-life of gemifloxacin is 6-8 hours in patients with normal renal function, supporting once-daily dosing. The 24-hour free-drug area under the plasma concentration-time curve:minimum inhibitory concentration ratio (fAUC(0-24):MIC) associated with efficacy, based on results from in vitro and animal models of infection, is approximately 30. With a mean fAUC(0-24) of approximately 3 microg*hour/ml (35% of total AUC(0-24) of 8.4) and a median S. pneumoniae MIC for 90% of tested strains of 0.03, a fAUC(0-24):MIC ratio of 100 would be expected after standard dosing (320 mg once/day). In clinical studies involving both hospitalized and outpatient populations, gemifloxacin has been highly effective in the treatment of community-acquired pneumonia and acute exacerbation of chronic bronchitis. Clinical success rates ranged from 93.9-95.9% in patients with community-acquired pneumonia and 96.1-97.5% in those with acute exacerbation of chronic bronchitis. Gemifloxacin is well tolerated; the frequency of adverse events with this agent is low. Most adverse events are mild-to-moderate in severity, with diarrhea (< 4%), nausea and rash (< 3%), and headache (< 2%) most commonly reported. Drug interactions with gemifloxacin are not common, although absorption is greatly reduced when given with divalent and trivalent cation-containing compounds, such as antacids. Due to its potent activity against many common gram-positive and gram-negative respiratory pathogens, its proven clinical efficacy, and its favorable safety profile, gemifloxacin is a highly effective empiric treatment for community-acquired lower respiratory tract infections.