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Biomedical subjects

David P Nicolau

Publications and source records attributed to David P Nicolau.

At least 19 recordsLinked to original sources
PubMed2007

Is all free time above the minimum inhibitory concentration the same: implications for beta-lactam in vivo modelling.

Previously, ertapenem 50 mg/kg every 6h given subcutaneously to mice achieved a similar 24-h cumulative free time above the minimum inhibitory concentration (fT>MIC) to 1g every 24h in humans. However, this simplified regimen (SR) does not provide a superimposable concentration-time profile to that observed in humans, thus allowing concentrations to fluctuate above and below the minimum inhibitory concentration (MIC) throughout the 24-h period. Herein, we compared a complex regimen (CR; 9 various mg/kg doses over 24 h) providing a near superimposable concentration-time profile with the SR to determine implications on bacterial kill against eight extended-spectrum beta-lactamase (ESBL)-producing isolates over a wide MIC range. The CR resulted in a similar (+/-5%) 24-h cumulative fT>MIC to ertapenem 1 g every 24h in humans over an MIC range of 0.032 mg/L to 16 mg/L. Similar bacterial kill was observed with both regimens against all eight ESBL-producing isolates examined. In mouse models, it appears that the 24-h cumulative fT>MIC and not the distribution of the fT>MIC over 24 h drives efficacy.

Animals↗
PubMed2006

Cefepime pharmacodynamics in patients with extended spectrum beta-lactamase (ESBL) and non-ESBL infections.

OBJECTIVE: This study was designed to compare cefepime exposures with microbiological outcomes in ESBL and non-ESBL infections and determine the pharmacodynamic profiles associated with successful outcome. METHODS: Cefepime pharmacodynamic exposures of unbound drug [time above MIC (fT>MIC), minimal concentration over MIC (fC(min)/MIC), and area under the curve over MIC (fAUC/MIC)] for 18 patients with ESBL and non-ESBL infections were determined by using a published population pharmacokinetic model. Classification and regression tree analysis was used to identify pharmacodynamic breakpoints that predicted eradication. A 5000-patient Monte Carlo Simulation was conducted to estimate the probability of target attainment for the goal pharmacodynamic exposures. RESULTS: Eradication was 80% when fT>MIC was 50% compared with 0% when T>MIC was less than 50% (p<0.05). The median fC(min)/MIC ratio for ESBL group was statistically lower than that for the non-ESBL group (1.54 versus 138, p<0.001). Regardless of ESBL production, all pathogens were eradicated when fC(min)/MIC>7.6 and only 33.3% were eradicated when fC(min)/MIC< or =7.6 (p<0.05). Pharmacodynamic exposures of 50% fT>MIC and fAUC/MIC>1654 were also predictive of eradication. While conventional dosage regimens of 2g q 12h and q 8h failed to achieve adequate target attainment, 4 g continuous infusion and 2g q 6-8h prolonged infusion could attain more than 90% of target attainment at the MIC of 2 microg/ml for the breakpoint of fCmin/MIC=7.6. CONCLUSION: Microbiological eradication in patients receiving cefepime was best predicted by fCmin/MIC ratio greater than 7.6 regardless of the presence of an ESBL. Continuous or prolonged infusion regimens provided the greatest probability of attaining this exposure.

Aged↗
PubMed2006

Impact of extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella species on clinical outcomes and hospital costs: a matched cohort study.

OBJECTIVES: To evaluate the economic and clinical impact of infection with extended-spectrum beta -lactamase (ESBL)-producing Escherichia coli and Klebsiella species (ESBL-EK). DESIGN: A matched-cohort analysis of the cost of illness. SETTING: An 810-bed, urban, community hospital in Hartford, Connecticut. PATIENTS: Twenty-one case patients infected with ESBL-EK at a site other than the urinary tract were matched with 21 control subjects infected with a non-ESBL-producing organism on the basis of pathogen species, age, anatomic site of infection, hospitalization in the intensive care unit (ICU) during the time of infection, date of hospitalization, and initial antibiotics received. RESULTS: Mean infection-related costs per patient were significantly greater for case patients than for control patients ($41,353 vs $24,902; P=.034). Infection-related length of stay was the main driver of cost, which was prolonged for case patients, compared with control patients (21 vs 11 days; mean difference, 9.7 days [95% confidence interval {CI}, 3.2-14.6 days]; P=.006). The additional cost attributed to the presence of an ESBL-EK infection was $16,450 per patient (95% CI, $965-$31,937). Case patients were more likely than control patients to have clinical failure (P=.027), and the rate of treatment success for case patients whose initial treatment involved antibiotics other than carbapenems was lower than that for their matched control patients (39% vs 83%; P=.013). Treatment was successful in patients for whom initial treatment was with a carbapenem, regardless of the ESBL status of the pathogen. CONCLUSION: The cost of non-urinary tract infections caused by ESBL-EK was 1.7 times the cost of non-urinary tract infections caused by non-ESBL producers. Prompt recognition and appropriate antimicrobial selection may minimize this ESBL-related impact on hospital costs.

Adolescent↗
PubMed2006

Peritoneal fluid penetration of tigecycline.

OBJECTIVE: To describe the peritoneal fluid penetration of tigecycline. CASE SUMMARY: A 33-year-old critically ill man who had undergone orthotopic liver and cadaveric renal transplant presented with sepsis. The patient required empiric antimicrobial coverage, continuous veno-venous hemofiltration, prolonged mechanical ventilation, tracheostomy placement, and maintenance immunosuppressive therapy. After multiple infections with multi-drug resistant pathogens, the patient developed vancomycin-resistant Enterococcus faecium peritonitis. Tigecycline 50 mg was administered every 12 hours, and ascites fluid drug concentrations were obtained. Drug concentrations in the peritoneal fluid were determined by high-performance liquid chromatography and revealed a tigecycline concentration of 0.074 microg/mL. Despite aggressive measures, the patient's condition continued to decline; he died 2 weeks after tigecycline initiation. DISCUSSION: As of October 3, 2006, these are the first data to describe tigecycline peritoneal fluid penetration. Tigecycline was aggressively administered at twice the recommended dosage for overt liver failure in light of the severity of this patient's condition. A tigecycline peritoneal fluid concentration of 44-54% of serum concentration was calculated based on the patient's peritoneal fluid drug concentration and previously published serum concentrations from a similar population. CONCLUSIONS: Peritoneal penetration of tigecycline was approximately 50% in this critically ill patient. Establishment of site-specific breakpoints for tigecycline may be necessary. Future studies will need to evaluate the penetration of tigecycline into peritoneal fluid and other tissues.

Adult↗
PubMed2006

Randomized, open-label, comparative study of piperacillin-tazobactam administered by continuous infusion versus intermittent infusion for treatment of hospitalized patients with complicated intra-abdominal infection.

The purpose of this randomized, multicenter, open-label study was to compare the continuous infusion of piperacillin-tazobactam with the standard intermittent infusion in 262 hospitalized patients with complicated intra-abdominal infections. Within 1 day of surgical intervention, eligible patients were randomized (1:1) to piperacillin-tazobactam 12 g/1.5 g administered continuously over 24 h or 3 g/0.375 g administered over 30 min intermittently every 6 h for 4 to 14 days. The demographics of the patients in the groups were similar, with a median APACHE II score of 7 and a median length of hospitalization of 7 days. Among 167 clinically evaluable patients, 86.4% and 88.4% of the patients treated with the continuous infusion and the intermittent infusion, respectively, were clinically cured or improved at the test-of-cure visit (P = 0.817). Bacteriological success was observed in 83.9% and 87.9% of patients (P = 0.597) in the two groups, respectively, and no differences in bacteriological response by pathogen were noted. Defervesence and white blood cell count normalization occurred in the majority of patients within 3 days and were similar between patients receiving the continuous infusion and those receiving the intermittent infusion. Drug-related adverse events were generally mild and were reported in similar numbers of patients in each arm of the trial. The results of this study support continuous infusion as a safe and reasonable alternate mode of administration of piperacillin-tazobactam for the treatment of complicated intra-abdominal infection.

APACHE↗
PubMed2006

Comparative in vivo efficacy of meropenem, imipenem, and cefepime against Pseudomonas aeruginosa expressing MexA-MexB-OprM efflux pumps.

To identify the optimal pharmacodynamic exposures of meropenem, imipenem, and cefepime, and the emergence of resistance in vivo for Pseudomonas aeruginosa overexpressing MexA-MexB-OprM efflux pumps, we used the murine thigh model. Mice were challenged with P. aeruginosa isolates: PAO1 (K767 wild type), K767+ (MexA-MexB-OprM efflux mutant), and DeltaK767 (knockout strain). Efficacy (Delta log colony-forming unit [CFU]) was determined at various exposures of %T > MIC at both standard (10(5) CFU/thigh) and high (10(7) CFU/thigh) inoculums. At 10(5) CFU/thigh, meropenem and imipenem produced a maximal activity against PAO1 (-2.82, -1.88) and K767+ (-2.24, -2.68) at 40%T > MIC; cefepime at 70%T > MIC produced a comparable kill (-2.74 and -2.19, respectively). Similar magnitudes of kill were observed at the 10(7) inocula. Except for DeltaK767 with cefepime, no development of resistance emerged at various %T > MIC. All agents exhibited reduced activity against DeltaK767. DeltaK767 cefepime-resistant strains were isolated up to 100%T > MIC. The overexpression of MexA-MexB-OprM efflux pumps did not result in the loss of efficacy of the antibiotics tested regardless of the amount of bacterial inocula; however, their presence also did not lead to increased selection for resistance. The effects of efflux mechanisms on beta-lactam agents in vivo warrant further research.

Animals↗
PubMed2006

Pharmacodynamic profiling of imipenem, meropenem and ertapenem against clinical isolates of extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella spp. from Brazil.

The pharmacodynamic potency of imipenem, meropenem and ertapenem against extended-spectrum beta-lactamase (ESBL)-producing isolates was investigated. Minimal inhibitory concentration (MIC) determination, confirmation of ESBLs by Etest and the disk approximation test were performed for 133 ESBL-producing isolates of Escherichia coli and Klebsiella spp. Pharmacodynamic exposure, measured as percent of the dosing interval during which free drug was above the MIC (% fT>MIC), was modelled via a 5000-subject Monte Carlo simulation. Bactericidal cumulative fraction of response (CFR), defined as 40% fT>MIC, was calculated against each bacterial population. All agents achieved high bactericidal CFR against all ESBL isolates as a group, but ertapenem (96.26%) was slightly less effective than imipenem (99.96%) and meropenem (99.90%) (P<0.05). Similar results were observed against Klebsiella spp. only (P<0.05). Against E. coli, CFRs were close to 100%. Ertapenem is probably an effective agent against ESBL-producing bacteria, although its ability to achieve bactericidal pharmacodynamic exposures will depend on the bacterial susceptibility.

Brazil↗
PubMed2006

Evaluation of bacterial kill when modelling the bronchopulmonary pharmacokinetic profile of moxifloxacin and levofloxacin against parC-containing isolates of Streptococcus pneumoniae.

OBJECTIVES: The increasingly recognized prevalence of first-step parC mutants in Streptococcus pneumoniae and the development of de novo resistance while on fluoroquinolone therapy are of concern. Previous work by our group demonstrated the ability of moxifloxacin, but not levofloxacin, to eradicate parC mutants. The objective of this experiment was to determine whether these fluoroquinolone antibiotics provided equivalent bacterial kill when similar AUC/MICs were examined. METHODS: An in vitro pharmacodynamic model was used to simulate the epithelial lining fluid (ELF) concentrations following oral administration of levofloxacin 500 mg once daily and moxifloxacin 400 mg once daily in older adults. In addition, a range of AUC/MICs were also modelled, including levofloxacin 750 mg once daily. Five different S. pneumoniae containing first-step parC mutations and one isolate without mutations were tested for 48 h and time-kill curves were constructed. Samples at 0, 24 and 48 h were collected for phenotypic and genotypic profiling. HPLC was used to verify that target exposures were achieved. RESULTS: The isolate without a parC mutation displayed a 4 log reduction in cfu after treatment with levofloxacin 500 mg and did not select for resistance. In all five isolates containing first-step parC mutations, resistance emerged within 48 h with a > or =16-fold increase in MIC and the acquisition of a gyrA mutant. Increasing the exposure of levofloxacin to approximately 750 mg dose still led to > or =16-fold increase in MIC at 48 h in two of the four isolates containing parC mutations. On the other hand, moxifloxacin 400 mg sustained bacterial killing against the two isolates tested without the selection of resistant mutants. It appears that the critical AUC/MIC necessary to prevent the acquisition of resistance for levofloxacin is 200 and approximately 400 for moxifloxacin. CONCLUSIONS: Due to suboptimal exposures, once-daily oral regimens of levofloxacin at both 500 and 750 mg inconsistently led to bactericidal activity and the frequent acquisition of a second-step gyrA mutation in S. pneumoniae isolates already containing a first-step parC mutation. Conversely, once-daily moxifloxacin 400 mg provides exposures that vastly exceed the apparent efficacy breakpoint and did not select for second-step mutants until exposures were decreased 4-fold. As a result of these data and the emerging literature involving mutations in the pneumococcus, caution should be exercised when the respiratory fluoroquinolones are used to treat patients infected with S. pneumoniae suspected of having parC mutations.

Adult↗
PubMed2006

Comparison of probability of target attainment calculated by Monte Carlo simulation with meropenem clinical and microbiological response for the treatment of complicated skin and skin structure infections.

Monte Carlo simulation is often used to predict the cumulative fraction of response (CFR) for antibiotics, but the relevance of these predictions to outcomes in humans has not been well studied. We compared the CFR for meropenem 500 mg every 8h against pathogens causing complicated skin and skin structure infections from a randomised, multicentre clinical trial with clinical response (CR) and microbiological response (MR). A population pharmacokinetic model was utilised to estimate pharmacokinetic parameters for 96 clinically evaluable patients with pathogen and minimum inhibitory concentration (MIC) data available. A 1000-subject Monte Carlo simulation was performed to estimate bacteriostatic (20% of time serum concentration above the MIC (T>MIC)) and bactericidal (40% T>MIC) exposures for comparison. Only the bactericidal CFR versus the CR was not statistically different (92% CR versus 91.9% CFR; 95% confidence interval of the difference, -7.7% to 4.2%), whilst bacteriostatic CFRs overestimated actual CR and MR. This study demonstrates that the use of Monte Carlo simulation to predict the CR of meropenem in complicated skin and skin structures is accurate.

Anti-Infective Agents↗
PubMed2006

Optimising antibiotic dosing regimens based on pharmacodynamic target attainment against Pseudomonas aeruginosa collected in Hungarian hospitals.

Owing to increasing resistance rates in Europe, pharmacodynamic analyses were proposed to determine optimal empirical antibiotic therapy against Pseudomonas aeruginosa isolated in Hungary. Minimum inhibitory concentrations for 180 non-duplicate P. aeruginosa collected from 14 hospitals in Hungary were determined by Etest methodology. A 5000-subject Monte Carlo simulation was performed to calculate the bactericidal cumulative fraction of response (CFR) for standard dosing regimens of cefepime, ceftazidime, ciprofloxacin, imipenem, meropenem and piperacillin/tazobactam. In the case of poor CFR, alternative dosage regimens were simulated for selected agents by increasing the infusion time, dose and frequency. Owing to high resistance rates in Hungary, no regimen achieved >90% CFR. CFRs for standard dosing regimens were: meropenem 1g every 8h (q8h), 77.1%; ceftazidime 2g q8h, 75.3%; imipenem 0.5 g every 6h (q6h), 71.7%; and piperacillin/tazobactam 4.5 g and 3.375 g q6h, 72.4% and 71.0%, respectively. Ciprofloxacin achieved significantly lower bactericidal CFRs than any beta-lactam. Prolonged infusion regimens improved the CFR for cefepime, imipenem, meropenem and piperacillin/tazobactam. Overall, the highest CFR (88.1%) was achieved by a 3-h infusion of meropenem 2g q8h. Given the poor CFR predicted with standard dosage regimens against these isolates, it seems prudent to consider alternative dosage strategies such as increasing doses, frequencies or infusion times as well as combination therapy when empirically treating infections caused by P. aeruginosa in Hungary.

Anti-Bacterial Agents↗
PubMed2006

Serum bactericidal activities of high-dose daptomycin with and without coadministration of gentamicin against isolates of Staphylococcus aureus and Enterococcus species.

The purpose of this experiment was to evaluate the pharmacokinetics and serum bactericidal titers (SBTs) of daptomycin alone and in combination with gentamicin against strains of Staphylococcus aureus and enterococci to determine if there might be any benefit to the addition of the aminoglycoside. A multiple-dose, randomized crossover study was performed in 11 healthy volunteers to evaluate the steady-state pharmacokinetic profile of 6 mg/kg of body weight daptomycin once daily with or without 1 mg/kg gentamicin every 8 h. SBTs were determined against clinical isolates of nosocomial (MRSA 494) and community-acquired (CA-MRSA 44) methicillin-resistant S. aureus, vancomycin-susceptible Enterococcus faecalis (VSEF 49452), vancomycin-resistant Enterococcus faecium (VREF 80), and quality control strains of methicillin-susceptible S. aureus (ATCC 29213) and vancomycin-susceptible E. faecalis (ATCC 29212). Enhancement of bactericidal activity was evaluated by calculating and comparing the areas under the bactericidal curve (AUBC) for each dosing regimen against each isolate. The area under the concentration-time curve from 0 to 24 h and clearance for daptomycin alone were 645 +/- 91 microg.h/ml and 9.47 +/- 1.4 mg/h/kg, respectively, compared with 642 +/- 69 microg.h/ml and 9.45 +/- 1.0 mg/h/kg for daptomycin plus gentamicin. Daptomycin alone displayed sustained bactericidal activity against five of the six isolates over the entire 24-h dosing interval; bactericidal activity was maintained for 8 h against VREF 80. Mean AUBCs for daptomycin alone ranged from 935 to 1,263 and 36 to 238 against staphylococcal and enterococcal isolates, respectively, compared with 902 to 972 and 34 to 213 against staphylococci and enterococci when coadministered with gentamicin. The results of this study suggest that the addition of gentamicin does not alter the pharmacokinetic profile or enhance the bactericidal activity of daptomycin against staphylococcal or enterococcal isolates.

Adolescent↗
PubMed2006

Tissue penetration of telavancin after intravenous administration in healthy subjects.

The pharmacokinetic disposition of telavancin administered 7.5 mg/kg of body weight every 24 h was determined in plasma and skin blister fluid. The mean penetration of telavancin into blister fluid was 40%. This study reveals that adequate concentrations are achieved in both plasma and blister fluid for pathogens frequently implicated in skin and soft tissue infections.

Adult↗
PubMed2006

Population pharmacokinetics and pharmacodynamics of meropenem in pediatric patients.

Meropenem is a highly potent carbapenem antibiotic against gram-positive and gram-negative bacteria. Meropenem plasma concentration data from 99 pediatric patients (aged 0.08-17.3 years) were used to develop a population pharmacokinetic model. Pharmacokinetic analysis was performed using NONMEM with exponential interindividual variability and combinational residual error model. A 2-compartment model was found to fit the data best. Creatinine clearance and body weight were the most significant covariates explaining variabilities in meropenem pharmacokinetics among pediatric patients. The validated final model was used to predict meropenem plasma concentrations in 37 pediatric meningitis patients, receiving 40 mg/kg meropenem, who had minimum inhibitory concentration values of the causative pathogens and outcome available. Since the causative pathogens in all patients were eradicated, no break points for required exposure could be found. The microbiological outcomes indicate that the current clinical dosage regimen provides sufficient drug exposure to eradicate the pathogens commonly involved in pediatric meningitis.

Adolescent↗
PubMed2006

Population pharmacokinetic analysis and dosing regimen optimization of meropenem in adult patients.

The objectives of this study were to develop a meropenem population pharmacokinetic model using patient data and use it to explore alternative dosage regimens that could optimize the currently used dosing regimen to achieve higher likelihood of pharmacodynamic exposure against pathogenic bacteria. We gathered concentration data from 79 patients (ages 18-93 years) who received meropenem 0.5, 1, or 2 g over 0.5- or 3-hour infusion every 8 hours. Meropenem population pharmacokinetic analysis was performed using the NONMEM program. A 2-compartment model fit the data best. Creatinine clearance, age, and body weight were the most significant covariates to affect meropenem pharmacokinetics. Monte Carlo simulation was applied to mimic the concentration-time profiles while 1 g meropenem was administrated via infusion over 0.5, 1, 2, and 3 hours. The 3-hour prolonged infusion improved the likelihood of obtaining both bacteriostatic and bactericidal exposures most notably at the current susceptibility breakpoints.

Abdominal Abscess↗
PubMed2006

Resource utilization of adults admitted to a large urban hospital with community-acquired pneumonia caused by Streptococcus pneumoniae.

OBJECTIVE: To determine if penicillin-nonsusceptible Streptococcus pneumoniae, among other variables, was significantly associated with greater hospital costs among patients with community-acquired pneumonia (CAP). DESIGN: Retrospective, cohort study. SETTING: Eight hundred ten-bed, urban, private, teaching hospital. PATIENTS: Adult patients admitted between 1999 and 2003 with CAP caused by S pneumoniae. INTERVENTION: Clinical criteria and costs (inflated to 2004 dollars) were collected from the medical charts and detailed hospital bills for each individual patient. Costs were compared according to classification by penicillin susceptibility. Multivariate linear regression was utilized to determine variables independently associated with increased hospital costs and length of stay. RESULTS: Of 168 patients included, 44 patients (26%) had CAP caused by penicillin-nonsusceptible S pneumoniae. Median total hospital costs were 8,654 dollars (25th to 75th percentile, 5,457 dollars to 16,027 dollars), with no difference between susceptible and nonsusceptible groups. Bed costs accounted for 55.6% of total costs, followed by laboratory (9.9%) and pharmacy (9.8%) costs. Regression analyses determined that ICU admission (p < 0.001), unexplained delays in discharge (p = 0.001), and neoplasm (p < 0.04) were independently predictive of both total hospital costs (adjusted r2 = 0.46) and increasing length of stay (adjusted r2 = 0.30). Hospital mortality, bacteremia, and congestive heart failure were also associated with at least one of the dependent variables. CONCLUSION: In the current era in which more potent antibiotics are empirically utilized to treat CAP, it does not appear that a simple classification of penicillin nonsusceptibility complicates the economic impact of S pneumoniae infection. Focused efforts to reduce length of stay, including minimizing prolonged and unnecessary observation of patients, should have the most profound effect on reducing total costs.

Adult↗
PubMed2006

Update on daptomycin: the first approved lipopeptide antibiotic.

Daptomycin, the first approved member of the lipopeptide antibiotic class, exhibits potent bactericidal in vitro activity against most Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus species and penicillin-resistant Streptococcus species. Since its approval in 2003 for the treatment of complicated skin and skin structure infections, several review articles have summarised daptomycin's mechanism of action, pharmacokinetics, pharmacodynamics, clinical trials and safety profiles. The objective of this paper is to summarise past information with a focus on the latest susceptibility data of isolates collected worldwide, new pharmacodynamic studies, clinical data regarding bacteraemia/endocarditis and postmarketing surveillance in the treatment of skin and skin-structure infections.

Animals↗