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Biomedical subjects

Sujata M Bhavnani

Publications and source records attributed to Sujata M Bhavnani.

At least 19 recordsLinked to original sources
PubMed2006

Isoniazid's bactericidal activity ceases because of the emergence of resistance, not depletion of Mycobacterium tuberculosis in the log phase of growth.

BACKGROUND: It is believed that the cessation of isoniazid's early bactericidal activity during the initial phase of antituberculosis therapy is due to the depletion of Mycobacterium tuberculosis in the exponential phase of growth. We examined the veracity of this cornerstone belief. METHODS: We used an in vitro infection model in which M. tuberculosis was exposed to isoniazid concentration-time profiles encountered in human patients. Experiments were performed to examine the time-related changes in the total bacterial population, the isoniazid-susceptible subpopulation, and the isoniazid-resistant subpopulation. RESULTS: The cessation of microbial kill occurred between days 3 and 4 of isoniazid therapy, as occurs in patients. There were multiple logs of organisms in the exponential phase of growth remaining at the time when bactericidal activity ceased. The isoniazid-susceptible subpopulation was replaced by an isoniazid-resistant subpopulation after 80 h of therapy. The size of the isoniazid-susceptible subpopulation continued to decrease after the total population had ceased to decrease, whereas the resistant subpopulation remained in the exponential phase of growth. Resistance was due to single point mutations in the catalase-peroxidase gene and to reserpine-inhibitable efflux pumps. CONCLUSIONS: The age-old hypothesis that isoniazid's microbial killing of M. tuberculosis during log-phase growth ceases because of the depletion of this bacillary population needs to be modified.

Antitubercular Agents↗
PubMed2006

Pharmacokinetics-pharmacodynamics of antimicrobial therapy: it's not just for mice anymore.

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.

Animals↗
PubMed2006

Pharmacodynamics of cefprozil against Haemophilus influenzae in an in vitro pharmacodynamic model.

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.

Anti-Bacterial Agents↗
PubMed2006

Outcomes evaluation of patients with ESBL- and non-ESBL-producing Escherichia coli and Klebsiella species as defined by CLSI reference methods: report from the SENTRY Antimicrobial Surveillance Program.

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<or=0.008). Among ESBL cases, carbapenem monotherapy and combination therapy were often selected for treatment (32.6% and 13.3%, respectively). Among non-ESBL cases, fluoroquinolones and beta-lactam/beta-lactamase inhibitor combination agents accounted for the highest proportion of treatment regimens (25.0% and 22.5%, respectively), whereas cephalosporin monotherapy and combination therapy were each used as treatment for 10% of cases. Clinical success was similar between patients with ESBL and non-ESBL-producing isolates (83% and 80%, respectively). Although infections arising from E. coli and Klebsiella species are associated with significant mortality, ESBL production alone did not appear to be an independent risk factor for treatment failure.

Adolescent↗
PubMed2006

Comparison of censored regression and standard regression analyses for modeling relationships between antimicrobial susceptibility and patient- and institution-specific variables.

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 < or = 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 < or = 2 mg/liter(L) [2L] or MICs > 2 mg/liter(R) [2R], respectively). Data were fit by CR and SR for which censored MICs were either (i) excluded, (ii) replaced by 2L or 2R, 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 <0.10 log2 (mg/liter) for all parameters for each of the 26 pairs. By SR, these deviations were >0.10 log2 (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 > or = 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.

Anti-Bacterial Agents↗
PubMed2006

Pharmacokinetic-pharmacodynamic relationships describing the efficacy of oritavancin in patients with Staphylococcus aureus bacteremia.

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.

Anti-Bacterial Agents↗
PubMed2005

Relationship between increased levofloxacin use and decreased susceptibility of Streptococcus pneumoniae in the United States.

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, and < or =0.5 to >4 microg/mL, respectively. Variables associated with changes in geometric mean MIC included geographical region (P < 0.0001), 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; P < 0.001 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.

Anti-Bacterial Agents↗
PubMed2005

Assessment of pharmacokinetic-pharmacodynamic target attainment of gemifloxacin against Streptococcus pneumoniae.

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.

Anti-Bacterial Agents↗
PubMed2005

Pharmacokinetics of oritavancin in plasma and skin blister fluid following administration of a 200-milligram dose for 3 days or a single 800-milligram dose.

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 (alpha = 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 microg/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.

Adult↗
PubMed2005

Application of an in vitro infection model and simulation for reevaluation of fluoroquinolone breakpoints for Salmonella enterica serotype typhi.

Salmonella enterica serotype Typhi and nontyphoidal Salmonella remain major causes of morbidity and mortality worldwide. Ampicillin, trimethoprim-sulfamethoxazole, and chloramphenicol no longer provide reliable coverage of Salmonella, and fluoroquinoloes have emerged as first-line treatment options. Due to mounting evidence of decreased in vitro susceptibility and diminished clinical response to fluoroquinolone therapy, it has been suggested that the NCCLS breakpoints for the salmonellae be reevaluated. We utilized an in vitro infection model to determine which pharmacokinetic-pharmacodynamic (PK-PD) measure was most closely linked to fluoroquinolone activity against salmonellae and the magnitude that was predictive of efficacy. Monte Carlo simulation was utilized to determine the probability of attaining potential susceptibility breakpoints for three fluoroquinolones. The free-drug area under the concentration-time curve from 0 to 24 h/MIC ratio was the PK-PD measure most predictive of efficacy, and a ratio of 105 corresponded to 90% of maximal activity. Simulation results suggested susceptible breakpoints of 0.12 microg/ml for ciprofloxacin and gatifloxacin and 0.25 microg/ml for levofloxacin. These proposed breakpoints correspond to the MIC separating the wild-type susceptible organism population from those strains possessing single-step mutations in the quinolone resistance-determining region. These results that integrate PK-PD measures and fluoroquinolone MIC distributions in the genetic context of examined Salmonella isolates clearly demonstrate that the prudent use of a lower susceptibility breakpoint minimizes the probability of clinical failure or delayed response in fluoroquinolone-treated patients.

Anti-Infective Agents↗
PubMed2005

Use of pharmacokinetic-pharmacodynamic target attainment analyses to support phase 2 and 3 dosing strategies for doripenem.

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 microg/ml and that less susceptible strains could be treated with prolonged infusions.

Adolescent↗
PubMed2005

Gemifloxacin for the treatment of respiratory tract infections: in vitro susceptibility, pharmacokinetics and pharmacodynamics, clinical efficacy, and safety.

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.

Anti-Bacterial Agents↗
PubMed2004

Use of pharmacodynamic end points in the evaluation of gatifloxacin for the treatment of acute maxillary sinusitis.

The relationship between drug exposure and the time course of antimicrobial effect at the primary infection site for acute maxillary sinusitis has not previously been explored. This single-center, open-label study quantified the time course of sinus sterilization, described gatifloxacin exposure at the infection site, and posed the hypothesis that the use of continuous and quantitative time-related end points may allow for better characterization of drug effect with fewer patients than traditional clinical trial approaches. Of the 12 enrolled patients, 10 were clinically evaluable, from whom 7 pathogens were isolated: 4 Streptococcus pneumoniae, 2 staphylococci, and 1 Enterobacter aerogenes. The median predicted 24-h area under the curve (AUC) in sinus aspirates and plasma samples was 54.7 mg x h/L and 30.1 mg x h/L, respectively. The median 24-h AUC ratio for sinus aspirates and plasma samples was 1.51 (range, 0.88-2.23). For patients infected with pneumococci, the median time to sinus sterilization was 50 h. The use of quantitative time-related end points may be useful in evaluating the efficacy of antimicrobial agents with fewer patients.

Acute Disease↗
PubMed2004

Pharmacokinetics, safety, and tolerability of ascending single intravenous doses of oritavancin administered to healthy human subjects.

Oritavancin (LY333328 diphosphate) is a novel glycopeptide antimicrobial agent with potent microbiological activity in vitro against Gram-positive bacteria. A single-dose, open-label, noncontrolled, dose-escalation study in 11 healthy human subjects was carried out to evaluate the safety and pharmacokinetics of oritavancin. One subject at each dose level received a single intravenous dose of 0.02, 0.03, 0.05, 0.08, 0.125, 0.20, and 0.325 mg/kg infused over 1 hour and four subjects each received a single-dose of 0.5 mg/kg. Safety and tolerability were evaluated by monitoring adverse events and laboratory parameters. Oritavancin pharmacokinetics were assessed by blood, urine, and fecal sampling. The plasma concentrations of oritavancin after the end of infusion followed a multiexponential decline over a 2-week period. Median (range) C(max) for the 0.5 mg/kg dose group was 6.5 (4.7-7.6) microg/mL. In every subject, plasma concentrations declined to < or =10% of the C(max) within 24 hours. Following a short, constant-rate infusion, the pharmacokinetics of oritavancin were linear across a total dose range from 3.66-44.6 mg. Renal clearance was approximately 0.457 mL/min. The mean (range) plasma terminal half-life of oritavancin was 195.4 (135.8-273.8) hours across all dose levels from 0.05-0.5 mg/kg. Less than 5% and 1% of administered drug were recovered in the urine and feces, respectively, after 7 days. This first time in man evaluation of oritavancin revealed that single doses of oritavancin of up to and including 0.5 mg/kg were safe and well tolerated. Although no clinically relevant changes in renal, hepatic and hematologic indices from baseline were observed, five subjects did manifest asymptomatic and transient elevations of hepatic transaminase concentrations. Because this study was not placebo-controlled and enrolled a small number of subjects, the safety and pharmacokinetic profiles of oritavancin need to be confirmed in additional studies.

Adult↗
PubMed2003

Effect of fluoroquinolone expenditures on susceptibility of Pseudomonas aeruginosa to ciprofloxacin in U.S. hospitals.

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.

Anti-Bacterial Agents↗
PubMed2003

Gatifloxacin and the elderly: pharmacokinetic-pharmacodynamic rationale for a potential age-related dose reduction.

OBJECTIVES: Recently, anecdotal reports via the FDA's MedWatch reporting system have documented rare but serious hyperglycaemia in elderly patients receiving gatifloxacin. One possible factor contributing to these events may be gatifloxacin overexposure, resulting from age-related decreases in renal function in elderly patients predisposed to glycaemic alterations. These analyses examine gatifloxacin exposure in 10 patients with severe hyperglycaemia, provide a pharmacokinetic-pharmacodynamic (PK-PD) rationale for a potential age-related dose reduction to avoid high exposures, and evaluate the likely impact of such a dose reduction on clinical efficacy in this specific patient population. METHODS: First, a previously derived population pharmacokinetic model, with patient demographics, was used to estimate gatifloxacin AUC0-24 following a dosage regimen of 400 mg/24 h in 10 index patients with severe hyperglycaemia. Second, the population pharmacokinetic model and patient demographic data from 2696 patients aged > or =65 years from two New Drug Application (NDA) databases were used to estimate AUC0-24 following dosage regimens for gatifloxacin of 200 and 400 mg/24 h. Finally, Monte Carlo simulation was utilized to assess the probability of achieving PK-PD target exposures against Streptococcus pneumoniae in elderly patients using these regimens. RESULTS: The mean estimated AUC0-24 among severe hyperglycaemia cases was 74 mg.h/L (range 57-100). Gatifloxacin AUC0-24 exposures for the 400 mg regimen were predicted to be higher in patients aged > or =65 years and similar to the severe hyperglycaemia cases. The probability of AUC0-24 > or =60 and > or =70 in patients aged > or =65 years for the 200 mg regimen was 0.03 and <0.01, respectively, versus 0.51 and 0.35 for the 400 mg regimen, respectively. The probability of achieving PK-PD target exposures against S. pneumoniae in patients aged > or =65 years receiving the 200 mg regimen was 0.99. CONCLUSIONS: The probability of a patient aged > or =65 years having an AUC0-24 > or =60-70 mg.h/L is markedly lower following a 200 mg regimen relative to a 400 mg regimen, suggesting a decreased risk of severe hyperglycaemia in a predisposed patient. Moreover, a dose reduction does not appear to significantly modify the likelihood of achieving the PK-PD target of gatifloxacin against S. pneumoniae.

Aged↗
PubMed2003

Relationships between patient- and institution-specific variables and decreased antimicrobial susceptibility of Gram-negative pathogens.

The identification of patients infected with antibiotic-resistant strains of bacteria for inclusion in clinical trials remains a serious challenge for the future development of agents for use against such infections. To identify patient- and institution-specific factors predictive of reduced susceptibility of Enterobacter species, Pseudomonas aeruginosa, and Klebsiella pneumoniae to cefepime, ciprofloxacin, and piperacillin-tazobactam, 5 years (1997-2001) of North American surveillance data were analyzed. The relationship between minimum inhibitory concentration (MIC) values for each organism-agent pair and patient- and institution-specific variables was analyzed using multivariable general linear modeling. The variables most commonly associated with decreases in susceptibility were duration of hospital stay before pathogen isolation, hospital size, primary diagnosis, and medical service. Combinations of these variables were associated with increases in observed MIC90 values of as much as 16-32-fold. Our findings demonstrate a relationship between MIC and certain patient- and institution-specific variables. Such data should be considered in the design of clinical trials directed at the study of resistant pathogens.

Anti-Bacterial Agents↗