Optimizing pharmacodynamic target attainment using the MYSTIC antibiogram: data collected in North America in 2002

The OPTAMA Program is intended to examine typical antimicrobial regimens used in the treatment of common nosocomial pathogens and the likelihood of these regimens attaining appropriate pharmacodynamic exposure in different parts of the world. A 5,000-subject Monte Carlo simulation was used to estimate pharmacodynamic target attainment for meropenem, imipenem, ceftazidime, cefepime, piperacillin-tazobactam, and ciprofloxacin against Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa. Standard dosing regimens from North America were used. Pharmacokinetic parameter variability was derived from existing healthy volunteer data, and MIC data came from the 2002 MYSTIC Program. Ciprofloxacin displayed the lowest target attainment against all bacterial species (41 to 46% for A. baumannii, 53 to 59% for P. aeruginosa, and 80 to 85% for the Enterobacteriaceae). Increasing the dose to 400 mg every 8 h did not significantly increase target attainment against nonfermenters. Piperacillin-tazobactam target attainments were similar to that of ceftazidime against all pathogens. Higher doses of both compounds were needed to achieve better target attainments against P. aeruginosa. Overall, meropenem, imipenem, and cefepime attained the highest probabilities of attainment against the Enterobacteriaceae (99 to 100%). The carbapenems appear to be the most useful agents against A. baumannii (88 to 92%), and these agents, along with higher doses of any of the beta-lactams, would be the most appropriate choices for empirical therapy for P. aeruginosa infection. Given the lack of agreement between percent susceptibility and probability of target attainment for certain antimicrobial regimens, a methodology employing stochastic pharmacodynamic analyses may be a more useful tool for differentiating the most-optimal compounds and dosing regimens in the clinical setting of initial empirical therapy.     

Empiric therapy for secondary peritonitis: a pharmacodynamic analysis of cefepime, ceftazidime, ceftriaxone, imipenem, levofloxacin, piperacillin/tazobactam, and tigecycline using Monte Carlo simulation

BACKGROUND: Inappropriate antibiotic therapy (ie, the selection of an empiric agent without activity against the responsible pathogen) of secondary peritonitis may result in poor patient outcomes. The selection of an appropriate agent can be challenging because of the emerging resistance of target organisms to commonly prescribed antibiotics. OBJECTIVE: The aim of this study was to perform a pharmacodynamic analysis, using recent global surveillance data, of commonly prescribed antibiotic agents and a newer agent, tigecycline, indicated in 2005 for the treatment of complicated intra-abdominal infections, to determine their probability for achieving microbiologic success against aerobic bacteria associated with secondary peritonitis. METHODS: A 2-compartment model was constructed using pharmacokinetic data from critically ill patients and global surveillance data on MIC distributions for microorganisms encountered in secondary peritonitis. A Monte Carlo simulation of the modeled data was performed to determine drug-appropriate pharmacodynamic end points, including free-drug time above the MIC, steady-state concentration above the MIC, and AUC/MIC ratios. A cumulative fraction of response (CFR) against aerobic bacteria involved in secondary peritonitis was calculated for cefepime, ceftazidime, ceftriaxone, imipenem, levofloxacin, pip eracillin/tazobactam, and tigecycline. A CFR > or =90% was considered microbiologic success. The following treatment regimens, administered as 30-minute N infusions, were examined: cefepime 1 and 2 g q12h, ceftazidime 1 and 2 g q8h, ceftriaxone 1 and 2 g q24h, imipenem 500 mg q6h, levofloxacin 750 mg q24h, pip eracillin/tazobactam 3.375 g q6h, and tigecycline 50 mg q12h, after a loading dose of 100 mg. RESULTS: A CFR > or =90% against nonenterococcal bacteria was predicted for imipenem 500 mg q6h (96.8%), cefepime 2 and 1 g q12h (95.3% and 92.4%, respectively), ceftazidime 2 g q8h (94.2%), and piperacillin/tazobactam 3.375 g q6h (91.2%). A CFR of 84.5% was predicted for tigecycline 50 mg q12h. Ceftriaxone and levofloxacin were predicted to have a CFR <80%. When enterococci were included in the model, the predicted CFRs for imipenem, piperacillin/tazobactam, and tigecycline were 93.4%, 88.4%, and 86.7%, respectively. CONCLUSIONS:: MIC distribution and pathogen prevalence strongly influence the likelihood of microbiological success in secondary peritonitis; therefore, decisions regarding empiric therapy should consider local epidemiology. Using current global data, the following regimens are adequate choices if Enterococcus is not targeted: Combination therapy (with metronidazole) using cefepime 1 g or 2 g q12h, or ceftazidime 2 g q8h; or monotherapy with imipenem 500 mg q6h or piperacillin-tazobactam 3.375 g q6h. When Enterococcus is included in the epidemiologic mix, imipenem, piperacillin/tazobactam, and tigecycline all appear to be viable monotherapeutic choices.     

The OPTAMA programme: utilizing MYSTIC (2002) to predict critical pharmacodynamic target attainment against nosocomial pathogens in Europe

OBJECTIVES: The Optimising Pharmacodynamic Target Attainment using the MYSTIC (Meropenem Yearly Susceptibility Test Information Collection) Antibiogram (OPTAMA) programme identifies antibiotic regimens with the highest probability of attaining critical pharmacodynamic targets, accounting for the inherent variability in pharmacokinetics, dosages and MIC distributions. METHODS: European MIC data were obtained from the MYSTIC programme. Pharmacodynamic target attainment was calculated by Monte Carlo simulation for meropenem, imipenem, ceftazidime, cefepime, piperacillin/tazobactam and ciprofloxacin against Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa. RESULTS: Significant differences in probability of target attainment were found, with Northern Europe demonstrating the highest probabilities of target attainment and Eastern Europe the lowest. The carbapenems had the highest target attainments and susceptibility levels across all regions and pathogens. The cephalosporins demonstrated high target attainments and susceptibility results against E. coli and K. pneumoniae in Northern and Southern Europe. Piperacillin/tazobactam and ciprofloxacin had the lowest levels for both parameters in all regions. Desirable target attainment was not achieved (except for carbapenems in Northern Europe) for A. baumannii and P. aeruginosa; thus, combination therapy may be appropriate empirical therapy for these pathogens in Southern and Eastern Europe. The closest correlations between target attainment and susceptibility were for meropenem 1 g every 8 h, imipenem 0.5 g every 6 h and ceftazidime 1 g every 8 h. CONCLUSIONS: The study highlighted significant overestimations between the probability of target attainment and the reported percentage susceptibility, particularly for piperacillin/tazobactam and ciprofloxacin. The approach of the OPTAMA programme provides a novel tool which complements susceptibility data to help in the selection of appropriate empirical antibiotic therapy.     

Pharmacodynamic comparisons of antimicrobials against nosocomial isolates of escherichia coli, klebsiella pneumoniae, acinetobacter baumannii and pseudomonas aeruginosa from the MYSTIC surveillance program: the OPTAMA Program, South America 2002

The OPTAMA (Optimizing Pharmacodynamic Target Attainment using the MYSTIC [Meropenem Yearly Susceptibility Test Information Collection] Antibiogram) Program provides insight into the appropriate antibiotic options for empiric therapy for common nosocomial pathogens. In this report, South America is represented by Brazil, Colombia, Peru, and Venezuela. A 5000-subject Monte Carlo Simulation estimated pharmacodynamic target attainment for meropenem, imipenem, ceftazidime, cefepime, piperacillin/tazobactam, and ciprofloxacin against Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa. Pharmacokinetic parameter variability was derived from existing healthy volunteer data, and minimum inhibitory concentration (MIC) data came from the 2002 MYSTIC program. Piperacillin/tazobactam and ciprofloxacin displayed the lowest target attainment against all bacterial species (14% to 24% for A. baumannii, 26% to 37% for P. aeruginosa, and 48% to 66% for the Enterobacteriaceae). Overall, the carbapenems had the highest probabilities of attainment against the Enterobacteriaceae (98% to 100%) and A. baumannii (73% to 74%), whereas cefepime obtained the greatest target attainment against P. aeruginosa (65%). Because no single regimen had high target attainment against A. baumannii and P. aeruginosa, the use of combination therapy to treat these pathogens in South America may be justified. Because of the lack of agreement with percent susceptibility for certain antimicrobial regimens, the use of pharmacodynamic target attainment may be a more accurate predictor of microbiologic success.     

Use of Monte Carlo simulation to assess the pharmacodynamics of beta-lactams against Pseudomonas aeruginosa infections in children: a report from the OPTAMA program

BACKGROUND: Assessing the likelihood of achieving bactericidal pharmacodynamic exposures against Pseudomonas aeruginosa with intravenous antimicrobial regimens would provide insights into the selection of empiric therapy in the pediatric population. OBJECTIVE: The objective of this study was to use pharmacodynamic modeling to determine the likelihood of various pediatric antibiotic regimens achieving bactericidal exposures against P aeruginosa in children. METHODS: Minimum inhibitory concentrations (MICs) were determined for meropenem (20 and 40 mg/kg q8h), imipenem (15 and 25 mg/kg q6h), ceftazidime (50 mg/kg q8h), cefepime (50 mg/kg q8h), and piperacillin/tazobactam (75 mg/kg q6h) against P aeruginosa isolates from 2 pediatric institutions. A 5000-patient Monte Carlo simulation was performed to predict attainment of pharmacodynamic targets against P aeruginosa for each of these regimens in a population of 10-year-olds. Optimal regimens were defined as those that had a > or =90% likelihood of attaining target exposures. RESULTS: At institution 1, high-dose imipenem, high-dose meropenem, and ceftazidime achieved bactericidal pharmacodynamic exposures (likelihood of target attainment: 94%, 92%, and 92%, respectively). No other regimen was associated with a high probability of attaining bactericidal exposure (low-dose imipenem, 87%; cefepime, 85%; low-dose meropenem, 84%; piperacillin/tazobactam, 60%). At institution 2, no regimen was associated with a high likelihood of attaining bactericidal exposure; the calculated probabilities were cefepime, 78%; ceftazidime, 65%; high-dose meropenem, 58%; high-dose imipenem, 57%; low-dose imipenem, 54%; low-dose meropenem, 47%; and piperacillin/tazobactam, 47%. A lack of agreement between attainment of bactericidal exposures and percent susceptibility was apparent for many of the regimens. CONCLUSIONS: Few regimens demonstrated a high likelihood of achieving bactericidal exposures against P aeruginosa at these institutions. Importantly, percent susceptibility overestimated attainment of the bactericidal target for some regimens, suggesting that further study is necessary in pediatric patients. The findings of this study highlight differences in target attainment and MIC distributions between institutions, emphasizing the importance of using institution-specific data when selecting empiric antimicrobial therapy.     

In vitro activity and beta-lactamase stability of FK-037, a parenteral cephalosporin.

The in vitro activity of FK-037, 5-amino-2-[[(6R, 7R)-7-[[(Z)-2-(2-amino-4-thiazolyl)-2- methoxyimino) acetyl] amino]-2-carboxy-8-oxo-5-thia-1- azabicyclo[4.2.0]oct-2-en-3-yl]methyl]-1-(2-hydroxyethyl)-1H-pyrazoli um hydroxide, inner salt, sulfate (1:1), a new parenteral cephem, was compared with those of cefepime, ceftazidime, imipenem, and ciprofloxacin. FK-037 inhibited methicillin-susceptible staphylocci at < or = 4 micrograms/ml. Of 98 isolates of homogenous methicillin-resistant Staphylococcus aureus, 55 (56.1%) were inhibited by 8 micrograms of FK-037 per ml, compared to 3.1% for cefepime. Imipenem was the most active beta-lactam tested against staphylococci. The MIC of FK-037 for 90% of the strains tested (MIC90) was 0.06 micrograms/ml for hemolytic streptococci, Streptococcus pneumoniae, viridans group streptococci, and Streptococcus bovis. The MIC90 for many of the members of the family Enterobacteriaceae was 1 microgram/ml, similar to that of cefepime and lower than those of ceftazidime and imipenem. The MIC90 for Klebsiella pneumoniae and Enterobacter cloacae was 8 micrograms/ml, similar to that for cefepime, but all isolates were inhibited by 2 micrograms of imipenem per ml. K. pneumoniae isolates with cefotaxime and ceftazidime MICs of > 32 micrograms/ml with Bush type 2b' beta-lactamases were inhibited by 4 micrograms of FK-037 per ml. E. cloacae, Citrobacter freundii, and S. aureus stably resistant to FK-037 could be selected by repeated transfer in the presence of FK-037. The FK-037 MIC90 for Pseudomonas aeruginosa was 4 microgram/ml, compared to 32 microgram/ml for cefepime and ceftazidime and 8 microgram/ml for imipenem. Xanthomonas maltophilia, Pseudomonas cepacia, Acinetobacter anitratus, and Bacteroides species were resistant to FK-037 (MIC, more than or equal 32 microgram/ml). MBCs were identical to or within twofold of the MICs except for a 32-fold greater MBC for P. aeruginosa. Inoculum size and acid environment did not lower the activity of FK-037. FK-037 was not appreciably hydrolyzed by Bush group 1, 2a, 2b, and 2e beta-lactamases but was hydrolyzed by 2b' and 2d enzymes at rates comparable to that of ceftazidime. Nonetheless, FK-037 inhibited bacteria possessing TEM-3, -5, and -7 and SHV -5 at less than or equal 8 microgram/ml. Overall, FK-037 has lower MICs against staphylococci and P. aeruginosa than the currently available iminomethoxy aminothiazolyl cephalosporins and has activity against members of the family Enterobacteriaceae comparable to that of cefepime.     

Pharmacodynamics of antimicrobials for the empirical treatment of nosocomial pneumonia: a report from the OPTAMA Program

OBJECTIVE: To compare the probability of achieving specific pharmacodynamic exposures of commonly used intravenous antibiotics for the empirical treatment of nosocomial pneumonia against those pathogens most commonly implicated in the disease. DESIGN: Ten thousand-subject Monte Carlo simulation. SETTING: Research center. SUBJECT: None. INTERVENTIONS: Pharmacodynamic analysis was conducted for the following antimicrobials at standard doses: meropenem, imipenem-cilastatin, ceftazidime, cefepime, piperacillin/tazobactam, and ciprofloxacin. Prevalence of causative pathogens was based on the 2000 SENTRY Antimicrobial Surveillance Study, and minimum inhibitory concentration (MIC) values were obtained using the 2003 US MYSTIC database. The probabilities of each drug and dosing regimen in achieving pharmacodynamic targets were calculated. Bactericidal targets were defined as 40% T>MIC for the carbapenems, 50% T>MIC for other beta-lactams, and an area under the curve (AUC)/MIC ratio of 125 for ciprofloxacin. A sensitivity analysis was performed using two alternate models to determine the impact of varying pathogen prevalence on target attainment. MEASUREMENTS AND MAIN RESULTS: Meropenem and imipenem provided high probabilities of achieving their bactericidal target of 40% T>MIC, with target attainments of 98% for all regimens. At the bactericidal end point of 50% T>MIC, cefepime 2 g every 8 hrs displayed the highest target attainment at 99.9%, followed by cefepime 2 g every 12 hrs, ceftazidime 2 g every 8 hrs, piperacillin/tazobactam 4.5 g every 6 hrs and 3.375 g every 6 hrs, cefepime 1 g every 12 hrs, and ceftazidime 1 g every 8 hrs with target attainments of 95.0%, 92.5%, 92.3%, 91.3%, 90.3%, and 67.9%, respectively. Ciprofloxacin presented the lowest probability of achieving its bactericidal target of an AUC/MIC ratio of 125, with target attainments of 54.7% and 12.0% when given as 400 mg every 8 hrs and 400 mg every 12 hrs, respectively. CONCLUSIONS: Meropenem, imipenem, cefepime, ceftazidime (2 g every 8 hrs), and piperacillin/tazobactam have high probabilities of achieving adequate pharmacodynamic exposures when given for the empirical treatment of nosocomial pneumonia in the absence of methicillin-resistant S. aureus. Ceftazidime 1g every 8 hrs and ciprofloxacin produce low target attainment rates and will not likely result in high clinical success rates when given as monotherapy.     

Contemporary in vitro synergy rates for aztreonam combined with newer fluoroquinolones and beta-lactams tested against gram-negative bacilli

Aztreonam has been commonly used in various combinations to enhance antimicrobial spectrum of co-drugs and produce potential synergistic activity. Although well studied in vitro over 10 years ago, aztreonam combination testing has been poorly documented with newer or commonly used agents against contemporary isolates. All MIC tests (alone or in combination) used in this experiment were reference broth microdilution methods in checkerboard tray designs. Aztreonam was combined with ciprofloxacin, gatifloxacin, levofloxacin, cefepime, ceftazidime and imipenem at clinically relevant concentrations. Interaction categories were defined by established criteria. Forty strains each of Pseudomonas aeruginosa and Enterobacteriaceae (12 species; aztreonam MIC, 1-16 microg/ml) were tested for each antimicrobial combination (480 total determinations). No antagonism or indeterminate interactions were identified. The overall rates of synergy or partial synergy for aztreonam with fluoroquinolone combinations was 63.4% versus P. aeruginosa, greatest for aztreonam with gatifloxacin (67.5%). Interaction categories varied greatly among aztreonam with beta-lactam combinations. Aztreonam with ceftazidime or cefepime versus P. aeruginosa had 75.0 - 85.0% partial or complete synergy rates, but aztreonam with imipenem showed dominant indifference (65.0%). In contrast, aztreonam with imipenem was more likely to exhibit synergy (32.5%) when tested against Enterobacteriaceae. Aztreonam, often used as an aminoglycoside substitute in antimicrobial combinations, continues to demonstrate enhanced, but variable drug activity interactions for contemporary antimicrobial combinations when tested against recent (2002) clinical isolates.     

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.     

In vitro and in vivo antibacterial activities of BO-2727, a new carbapenem.

BO-2727, a new injectable carbapenem, was evaluated for its in vitro and in vivo antibacterial activities in comparison with those of biapenem, meropenem, imipenem, cefpirome, and ceftazidime. BO-2727 had activity comparable to that of imipenem against methicillin-susceptible staphylococci and streptococci, with MICs at which 90% of strains tested (MIC90s) are inhibited being equal to 0.5 microgram/ml or less. Against methicillin-resistant staphylococci, BO-2727 was the most active among the antibiotics tested, with MIC90s ranging from 4 to 8 micrograms/ml. BO-2727 was highly active against members of the family Enterobacteriaceae, Haemophilus influenzae, and Moraxella catarrhalis, with MIC90s ranging from 0.006 to 2 micrograms/ml. BO-2727 was also highly active against Pseudomonas aeruginosa (imipenem-susceptible strains), for which the MIC90 was 2 micrograms/ml, which was lower than those of imipenem, cefpirome, and ceftazidime and comparable to those of biapenem and meropenem. Differences in activity between BO-2727 and the other carbapenems against imipenem-resistant P. aeruginosa were particularly striking (MIC90, 8 micrograms/ml). Furthermore, BO-2727 displayed a high degree of activity against many of the ceftazidime-, ciprofloxacin-, and/or gentamicin-resistant isolates of P. aeruginosa. The in vivo efficacy of BO-2727 against experimental septicemia caused by gram-positive and gram-negative bacteria, including methicillin-resistant Staphylococcus aureus and imipenem-resistant P. aeruginosa, reflected its potent in vitro activity and high levels in plasma.     

Simulation of antibiotic pharmacodynamic exposure for the empiric treatment of nosocomial bloodstream infections: a report from the OPTAMA program

OBJECTIVE: We developed a model to predict the pharmacodynamic exposure of antibiotics against bacteria commonly implicated in nosocomial bloodstream infections to determine which dosage regimens would provide the greatest likelihood of obtaining a bactericidal effect. METHODS: Pharmacodynamic exposures were simulated for 5000 subjects receiving standard doses of ceftazidime, cefepime, piperacillin/tazobactam, meropenem, imipenem, or ciprofloxacin. Exposures were indexed to the MICs of bacteria weighted by their prevalence in causing nosocomial bloodstream infections, derived from 2002 SENTRY data. Enterococci were excluded. MIC data were derived from the 2003 Meropenem Yearly Surveillance Test Information Collection resistance study. The probabilities of achieving bactericidal exposures (ie, target attainment) for each antibiotic regimen were compared. The effect of increasing prevalence of methicillin-resistant Staphylococcus aureus (MRSA) on attainment of bactericidal targets was tested. RESULTS: All dosage regimens except ciprofloxacin and ceftazidime 1 g q8h achieved >90% likelihood of bactericidal exposure. The rank order of target attainment was as follows: imipenem 500 mg q6h, 100.0%; imipenem 1 g q8h, 99.9%; cefepime 2 g q12h, 99.4%; meropenem 1 g q8h, 98.4%; cefepime 1 g q12h, 98.2%; piperacillin/tazobactam 3.375 g q6h, 97.9%; piperacillin/tazobactam 4.5 gq8h, 95.0%; ceftazidime 2 g q8h, 94.2%; ceftazidime 1 g q8h, 71.7%; ciprofloxacin 400 mg q8h, 63.3%; and ciprofloxacin 400 mg q12h,63.0%. Target attainments dropped to <90% for all agents when MRSA was modeled at > or =10% prevalence. CONCLUSIONS: The results of this model analysis suggest that standard doses of the carbapenems, piperacillin/tazobactam, and cefepime, and higher doses of ceftazidime, may provide optimal likelihood of achieving bactericidal exposure against pathogens implicated in nosocomial bloodstream infections, excluding MRSA and enterococci. When MRSA rates are > or =10%, therapy with an antibiotic that has activity against this phenotype should be empirically initiated.     

In vitro activities of cefepime alone and with amikacin against aminoglycoside-resistant gram-negative bacteria.

The in vitro activity of cefepime was compared with those of ceftazidime, cefotaxime, and cefpirome against aminoglycoside-resistant gram-negative bacteria. Cefepime was the most active cephalosporin, with a MIC for 90% of strains tested for all non-Pseudomonas aeruginosa species of less than or equal to 4 micrograms/ml. No cefepime resistance was encountered among members of the family Enterobacteriaceae. Of the 40 aminoglycoside-resistant P. aeruginosa isolates, 15% were resistant to cefepime, compared with 18% for ceftazidime, 30% for cefpirome, and 35% for cefotaxime. Synergism between cefepime and amikacin was observed and occurred most frequently in P. aeruginosa strains resistant to cefepime but susceptible to amikacin. In no case did cefepime and amikacin exhibit antagonism against P. aeruginosa.     

In vitro activity of ceftazidime and ceftriaxone

The in vitro susceptibility of 230 clinical isolates, including 55 anaerobic bacteria, was tested with ceftazidime, ceftriaxone, cefotaxime, cefoperazone, moxalactam, cefamandole, cefoxitin, and ticarcillin. Ceftazidime was the most active drug against Pseudomonas aeruginosa and Acinetobacter sp. Against Enterobacteriaceae, ceftazidime and ceftriaxone were similar to cefotaxime, moxalactam, and cefoperazone and more active than cefamandole, cefoxitin, and ticarcillin. Cefoxitin and moxalactam were significantly more active against Bacteroides fragilis than were the other beta-lactam drugs. Against Staphylococcus aureus, ceftriaxone showed moderate activity, while ceftazidime was relatively inactive. These results indicate a potential role for ceftazidime and ceftriaxone against infections involving facultative and aerobic gram-negative bacilli.     

Probability of pharmacodynamic target attainment with standard and prolonged-infusion antibiotic regimens for empiric therapy in adults with hospital-acquired pneumonia

Background: The pharmacodynamic characteristics of antibiotics should be considered when choosing empiric dosage regimens for the treatment of pneumonia.Objective: This study compared the probabilities of achieving requisite pharmacodynamic exposure (ie, f T > MIC, AUC/MIC) for antibiotics given for the empiric treatment of hospital-acquired pneumonia (HAP) as recommended by the 2005 guidelines of the American Thoracic Society and the Infectious Diseases Society of America.Methods: In a 5000-patient Monte Carlo simulation, pharmacodynamic analyses were performed for standard doses of cefepime, ceftazidime, ceftriaxone, ciprofloxacin, ertapenem, imipenem, levofloxacin, meropenem, and piperacillin/tazobactam. Prolonged 3-hour infusion regimens were also evaluated for anti-pseudomonal β-lactams. MIC data were incorporated from the 2007 Meropenem Yearly Susceptibility Test Information Collection, a national surveillance study. The weighted cumulative fraction of response (wCFR) against common pneumonia pathogens was determined for each regimen. A second scenario was conducted by altering the pathogen prevalence to assess wCFR for late-onset pneumonia (ie, HAP in patients with prolonged mechanical ventilation). Optimal wCFR was defined a priori as ≥90%.Results: Among the 0.5-hour infusions, cefepime, ceftazidime, and meropenem had the highest wCFRs (≥90%) against pathogens that cause HAP (cefepime, 1 g q8h, 92.8%; 2 g q8h, 97.2%; 2 g q12h, 94.3%; ceftazidime, 2 g q8h, 93.2%; meropenem, 1 g q8h, 90.9%; 2 g q8h, 93.9%). Imipenem (500 mg q6h, 85.5%; 1 g q8h, 88.1%) and piperacillin/tazobactam (4.5 g q6h, 80.5%) as 0.5-hour infusions were nearly optimal, whereas ceftriaxone, ertapenem, and the fluoroquinolones had the lowest wCFR values. All regimens showed lower wCFRs for late-onset pneumonia than for HAP. Optimal wCFRs were found only with prolonged (3-hour) infusions of 2 g q8h for ceftazidime (94.5%) and meropenem (90.1%), whereas cefepime 2 g q8h achieved optimal wCFR with both a 0.5-hour infusion (93.1%) and a 3-hour infusion (95.3%).Conclusions: Results of this model suggest that standard doses of most antipseudomonal β-lactams (cefepime, ceftazidime, and meropenem) had high probabilities of achieving optimal pharmacodynamic exposure as empiric therapy for HAP, whereas the low probabilities predicted from ceftriaxone, ertapenem, and the fluoroquinolones suggest that these agents would be inappropriate as monotherapy. For late-onset HAP, prolonged infusions of cefepime, ceftazidime, and meropenem offered the highest probabilities of achieving bactericidal exposure.     

Ro 17-2301: in vitro comparison with aztreonam, imipenem, ceftazidime, cefotaxime and netilmicin

The in vitro activity of the novel monobactam antibiotic, Ro 17-2301 has been compared with those of aztreonam, imipenem, ceftazidime, cefotaxime and netilmicin. A total of 438 clinical isolates of aerobic gram-negative rods were employed and an agar dilution method was used for measurement of MIC. Ro 17-2301 was highly active against a wide variety of Enterobacteriaceae species (MIC range less than or equal to 0.03-8, MIC50 less than or equal to 0.03, MIC90 0.06 mg/l). The activity of aztreonam parallelled that of Ro 17-2301 although the latter seemed to have more uniformly high activity against Klebsiella sp. The other agents showed generally high activity against Enterobacteriaceae except netilmicin against Providencia stuartii (MIC50 4, MIC90 greater than or equal to 16 mg/l). Activity against Pseudomonas aeruginosa. was more variable. Ro 17-2301 and aztreonam were moderately active (MIC50 2, MIC90 8 and 16 mg/l, respectively). Imipenem was the most active agent against Acinetobacter, whereas Ro 17-2301 was moderately active. In conclusion, Ro 17-2301 shows impressive activity against Enterobacteriaceae and moderate activity against Acinetobacter and P. aeruginosa. Ro 17-2301 may well prove to be a useful agent in the treatment of gram-negative infections.     

Geographic variations in activity of broad-spectrum beta-lactams against Pseudomonas aeruginosa: summary of the worldwide SENTRY Antimicrobial Surveillance Program (1997-2000)

With reports of increasing resistance to antimicrobial agents among Pseudomonas aeruginosa clinical isolates worldwide, the activities of cefepime and eight other broad-spectrum beta-lactams against 6969 isolates collected during 1997-2000 from the four regions of the SENTRY Antimicrobial Surveillance Program. P. aeruginosa isolates were tested by the reference broth microdilution method against nine beta-lactam antimicrobial agents (aztreonam, cefepime, ceftazidime, imipenem, meropenem, piperacillin +/- tazobactam, ticarcillin +/- clavulanate), three aminoglycosides (amikacin, gentamicin, tobramycin), and two fluoroquinolones (ciprofloxacin, levofloxacin). The strains were contributed by more than 100 medical centers. National Committee for Clinical Laboratory Standards criteria were used to identify susceptible and resistant isolates. P. aeruginosa strains from Latin America were generally the most resistant to all classes of antimicrobials, compared with strains from other regions. The beta-lactams exhibited a wide range of potency, with carbapenems most active (meropenem, 80-91% susceptible; imipenem, 76-88% susceptible). Piperacillin/tazobactam was the most active penicillin (77-80% susceptible), and cefepime (67-83% susceptible) had an average 2% (range, 0.7-3.5%) greater susceptibility rate than ceftazidime (66-80% susceptible) across all regions. The rank order of beta-lactam activity according to percent resistant isolates in North American P. aeruginosa strains was: meropenem (4.8% resistant) > cefepime (6.8%) > imipenem (8.6%) > piperacillin/tazobactam (10.3%) > piperacillin (12.9%). Only 2.3% and 6.5% of isolates were resistant to amikacin or tobramycin, respectively, and nearly 16% of P. aeruginosa strains were resistant to ciprofloxacin. Compared with other geographic regions, strains of P. aeruginosa remain most susceptible in North America. In all regions, aminoglycosides in combination with carbapenems, cefepime, or piperacillin/tazobactam would provide more potential antipseudomonal activity than fluoroquinolone combinations for wide-spectrum empiric regimens.     

Pharmacodynamics of ceftazidime administered as continuous infusion or intermittent bolus alone and in combination with single daily-dose amikacin against Pseudomonas aeruginosa in an in vitro infection model.

We compared the pharmacodynamics and killing activity of ceftazidime, administered by continuous infusion and intermittent bolus, against Pseudomonas aeruginosa ATCC 27853 and ceftazidime-resistant P. aeruginosa 27853CR with and without a single daily dose of amikacin in an in vitro infection model over a 48-h period. Resistance to ceftazidime was selected for by serial passage of P. aeruginosa onto agar containing increasing concentrations of ceftazidime. Human pharmacokinetics and dosages were simulated as follows: half-life, 2 h; intermittent-bolus ceftazidime, 2 g every 8 h (q8h) and q12h; continuous infusion, 2-g loading dose and maintenance infusions of 5, 10, and 20 micrograms/ml; amikacin, 15 mg/kg q24h. There was no significant difference in time to 99.9% killing between any of the monotherapy regimens or between any combination regimen against ceftazidime-susceptible P. aeruginosa. Continuous infusions of 10 and 20 micrograms/ml killed as effectively as an intermittent bolus of 2 g q12h and q8h, respectively. Continuous infusion of 20 micrograms/ml and an intermittent bolus of 2 g q8h were the only regimens which prevented organism regrowth at 48 h, while a continuous infusion of 5 micrograms/ml resulted in the most regrowth. All of the combination regimens exhibited a synergistic response, with rapid killing of ceftazidime-susceptible P. aeruginosa and no regrowth. Against ceftazidime-resistant P. aeruginosa, none of the ceftazidime monotherapy regimens achieved 99.9% killing. The combination regimens exhibited the same rapid killing of the resistant strain as occurred with the susceptible strain; however, regrowth occurred with all regimens. The combination regimens of continuous infusion of 20 micrograms/ml plus amikacin and intermittent bolus q8h or q12h plus amikacin continued to be synergistic. Overall, continuous infusion monotherapy with ceftazidime at concentrations 4 to 5 and 10 to 15 times the MIC was as effective as an intermittent bolus of 2 g q12h (10 to 15 times the MIC) and q8h (25 to 35 times the MIC), respectively, against ceftazidime-susceptible P. aeruginosa. Combination therapy with amikacin plus ceftazidime, either intermittently q8h or by continuous infusion of 20 micrograms/ml, appeared to be effective and exhibited synergism against ceftazidime-resistant P. aeruginosa.     

Evaluation of Several Dosing Regimens of Cefepime, with Various Simulations of Renal Function, against Clinical Isolates of Pseudomonas aeruginosa in a Pharmacodynamic Infection Model

The objectives of this study were as follows: (i) to examine the killing activity of 2-g doses of cefepime against two clinical isolates (mucoid and nonmucoid) of Pseudomonas aeruginosa in a pharmacodynamic in vitro infection model, (ii) to compare the percentage of time above the MIC (T > MIC) for each of the regimens against P. aeruginosa, and (iii) to evaluate the area under the bactericidal curve for each regimen. Cefepime was administered at intervals of 8, 12, and 24 h with and without tobramycin, and two different levels of renal function were simulated: normal (creatinine clearance [CL_CR] = 90 ml/min) and decreased (CR_CL = 60 ml/min). Also, the killing activity of cefepime with and without tobramycin was compared to the killing activity of ceftazidime (2 g every 8 h) with and without tobramycin. The T > MIC was 100% in the central chamber except for the regimen in which cefepime was administered every 12 h and the CL_CR was 90 ml/min, which provided concentrations above the MIC for 92% of the dosing interval against the C31 (mucoid; MIC of cefepime, 4 μg/ml) isolate and for 75% of the interval against the C34 (nonmucoid; MIC of cefepime, 8 μg/ml) isolate. All cefepime and ceftazidime monotherapy simulations resulted in 99.9% killing of the nonmucoid isolate within 4 to 8 h and within 4 to 6 h, respectively. Against the mucoid isolate, 99.9% killing was achieved only with combination therapy. The results of this study indicate that cefepime dosed at 2 g every 12 h under conditions of normal renal function and every 24 h with decreased creatinine clearance (60 ml/min) is effective both as monotherapy and in combination therapy against a nonmucoid strain of P. aeruginosa. With cefepime MICs of 4 and 8 μg/ml, the single-agent regimens provided T > MIC values in the central chamber for 92 and ≥75% of the dosing interval against the mucoid and nonmucoid isolates, respectively. Cefepime dosed at 2 g every 12 h, with a creatinine clearance of 90 ml/min, and every 24 h, with a creatinine clearance of 60 ml/min, resulted in killing activity equivalent to that of ceftazidime dosed at 2 g every 8 h. None of the monotherapies provided adequate killing of the mucoid strain of P. aeruginosa despite drug concentrations being above the MIC for ≥92% of all dosing intervals. Finally, combination therapy with tobramycin and either cefepime or ceftazidime enhanced the killing of both the mucoid and nonmucoid P. aeruginosa isolates.     

Evaluation of the in vitro antimicrobial activity of cefepime compared to other broad-spectrum beta-lactams tested against recent clinical isolates from 10 Chinese hospitals. Chinese Antimicrobial Resistance Study Group

A surveillance study was initiated in China in 1998 in which 10 medical centers participated. The susceptibility profiles of 996 commonly occurring pathogens belonging to 10 different species groups were tested by the Etest (AB BIODISK, Solna, Sweden) against six broad-spectrum beta-lactam antimicrobial agents (cefepime, ceftazidime, ceftriaxone, imipenem, cefoperazone/sulbactam and piperacillin or oxacillin). Quality control was closely monitored and cefepime- and/or imipenem-resistant Enterobacteriaceae were referred to the reference laboratory (University of Iowa College of Medicine, Iowa City, IA) for confirmation. The isolates of Citrobacter spp. and Enterobacter spp. were generally inhibited by imipenem (100% susceptible) and cefepime (89-94%), but were more resistant to the other drugs tested (< or = 74% susceptible). The indole-positive Proteus spp. and Serratia spp. isolates were > 94% susceptible to all tested beta-lactams except piperacillin. Organisms capable of producing extended spectrum beta-lactamases (ESBLs), which included Klebsiella spp. and Escherichia coli, were most susceptible to imipenem (100%) and cefepime (> 90%). Among the non-enteric Gram-negative bacilli, all drugs were marginally active against Pseudomonas aeruginosa (MIC90s, 32-> 256 ug/mL) and the Acinetobacter spp. were rather resistant to all the compounds, except imipenem (96% susceptible). All strains of Staphylococcus spp. were susceptible to the tested antimicrobials except for ceftazidime, which had a low potency (MIC90, 12-16 micrograms/mL) against Chinese isolates with MICs that fell into the intermediate category. Cefepime, the fourth-generation cephalosporin, showed a very broad spectrum of activity against Gram-negative pathogens as well as oxacillin-susceptible Staphylococcus spp. that was comparable with imipenem (widest spectrum) and superior to the other tested beta-lactams overall. Continued monitoring of clinical strains in China seems necessary to guide chemotherapy.     

In vitro evaluation of cefepime and other broad-spectrum beta-lactams in Taiwan medical centers. The Taiwan Antimicrobial Resistance Study Group

The rates of resistance to commonly used antimicrobial agents have been documented to be at alarmingly high levels in Taiwan for both Gram-positive and Gram-negative species. This study was conducted to assess the current resistance patterns in six medical centers strictly controlled using a common MIC methodology and quality assurance measures. Cefepime, a new clinically introduced broad-spectrum "fourth-generation" cephalosporin, was compared to other members in this class including ceftazidime, cefpirome, ceftriaxone, piperacillin/tazobactam, and imipenem. These antimicrobials were tested against ten species groups of common clinical isolates of Enterobacteriaceae, non-enteric Gram-negative bacilli, and oxacillin-susceptible Staphylococcus spp. The results confirmed that extended spectrum beta-lactamase (ESBL) production in Klebsiella spp. (21.7%) and Escherichia coli (16.7%) was common in all medical centers surveyed. Cefepime was more active against these two species as well as against Amp C producing species, indole-positive Proteae, and Acinetobacter species. The activity of cefepime was comparable although slightly less than that of ceftazidime against Serratia spp. and Pseudomonas aeruginosa strains. All or nearly all staphylococci isolates were susceptible to the beta-lactam antimicrobial agents, except for ceftazidime. Overall, these antimicrobial agents had descending spectrums of activity as follows: imipenem > cefepime > cefpirome > piperacillin/tazobactam > ceftazidime > ceftriaxone for the 550 isolates tested. Cefepime seems to be an important broad-spectrum beta-lactam that can be used with confidence against many important pathogens in Taiwan, including those harboring resistance mechanisms. A continued surveillance program seems prudent for this geographic area.