Yearly Susceptibility Test Information Collection Research Articles

Steady-state pharmacokinetics and pharmacodynamics of cefepime administered by prolonged infusion in hospitalised patients

The objective of this study was to evaluate the steady-state pharmacokinetics and pharmacodynamics of cefepime administered by prolonged infusion in hospitalised patients requiring antimicrobial therapy. Nine patients received 1 g every 8 h (q8h), infused over 4 h, and steady-state pharmacokinetic parameters were determined by non-compartmental and compartmental methods. Using these pharmacokinetic parameters, 5000-patient Monte Carlo simulations were performed to estimate the pharmacokinetic profiles for six prolonged-infusion dosing regimens. The probability of target attainment (PTA) was calculated at minimum inhibitory concentrations (MICs) ranging from 0.06 μg/mL to 32 μg/mL, and the cumulative fraction of response (CFR) was calculated for six Gram-negative pathogens using MIC data from the Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) (2005–2007, USA). The pharmacodynamic target was free cefepime concentrations remaining above the MIC for 60% of the dosing interval (60% fT > MIC). Mean ± standard deviation maximum and minimum serum concentrations, terminal elimination half-life, elimination rate constant, volume of distribution and systemic clearance of cefepime were 32.5 ± 13.5 μg/mL, 9.5 ± 5.2 μg/mL, 2.4 ± 0.7 h, 0.316 ± 0.116 h −1, 21.3 ± 6.5 L and 6.6 ± 3.6 L/h, respectively. At the susceptibility breakpoint of 8 μg/mL, the PTA was >90% for 1 g and 2 g q8h (4-h infusion) and 1 g and 2 g every 6 h (q6h) (3-h infusion). For Pseudomonas aeruginosa, the CFR was 88.6% for 1 g q8h (4-h infusion) and ≥92.7% for 2 g q8h (4-h infusion) and 1 g and 2 g q6h (3-h infusion). Cefepime 1 g q8h infused over 4 h provides excellent target attainment for susceptible bacterial pathogens with MICs ≤ 8 μg/mL.

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.

Summary trends for the Meropenem Yearly Susceptibility Test Information Collection Program: a 10-year experience in the United States (1999–2008)

The Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) Program was a global, longitudinal antimicrobial resistance surveillance network of more than 100 medical centers worldwide monitoring the susceptibility of meropenem and selected other broad-spectrum comparator agents. In 1999, and from 2000 through 2008, a total of 10 or 15 United States (USA) medical centers each forwarded 200 nonduplicate clinical isolates from serious infections to a central processing laboratory. Over the 10-year period of this surveillance program, the activity of meropenem and an average of 11 other antimicrobial agents were assessed against a total of 27 289 bacterial isolates using Clinical and Laboratory Standards Institute reference methods. Meropenem consistently demonstrated low resistance rates against Enterobacteriaceae species isolates through 2008 and did not exhibit a widespread change in resistance rates over the monitored interval. In fact, the incidence of emerging carbapenemase-producing (KPC-type) Klebsiella spp. showed a decline in 2008 compared to the steeply increasing rates observed from 2004 to 2007. Moreover, the KPC serine carbapenemases have spread to other Enterobacteriaceae species monitored by the MYSTIC Program. Greatest increases in antimicrobial resistance rates were observed for the fluoroquinolones (ciprofloxacin, levofloxacin) among all species monitored by the MYSTIC Program. Current susceptibility rates for meropenem when tested against prevalent pathogens were Pseudomonas aeruginosa (439 strains, 85.4% susceptible), Enterobacteriaceae (1537 strains, 97.3% susceptible), methicillin-susceptible staphylococci (460 strains, 100.0% susceptible), Streptococcus pneumoniae (125 strains, 80.2% at meningitis susceptibility breakpoints), other streptococci (159 strains, 90.0–100.0% susceptible), and Acinetobacter spp. (127 strains, 45.7% susceptible), the widest spectrum among β-lactams tested in 2008 and throughout the last decade. Continued local surveillance of broad-spectrum agents following the completion of the MYSTIC Program (USA) appears critical to detect emerging resistances among pathogens causing the most serious infections requiring carbapenem agents.

Comparative Pharmacodynamics of Intermittent and Prolonged Infusions of Piperacillin/Tazobactam Using Monte Carlo Simulations and Steady-State Pharmacokinetic Data from Hospitalized Patients

Prolonging the infusion of a beta-lactam antibiotic enhances the time in which unbound drug concentrations remain above the minimum inhibitory concentration (fT>MIC). To compare the pharmacodynamics of several dosing regimens of piperacillin/tazobactam administered by intermittent and prolonged infusion using pharmacokinetic data from hospitalized patients. Steady-state pharmacokinetic data were obtained from 13 patients who received piperacillin/tazobactam 4.5 g every 8 hours, infused over 4 hours. Monte Carlo simulations (10,000 pts.) were performed to calculate pharmacodynamic exposures at 50% fT>MIC for 4 intermittent-infusion regimens (3.375 g every 4 and 6 h, 4.5 g every 6 and 8 h) and 4 prolonged-infusion regimens (2.25 g, 3.375 g, 4.5 g, and 6.75 g every 8 h [4-h infusion]) of piperacillin/tazobactam using pharmacokinetic data for piperacillin. Cumulative fraction of response (CFR) was calculated using MIC data for 6 gram-negative pathogens (Meropenem Yearly Susceptibility Test Information Collection, 2004-2007), and probability of target attainment (PTA) was calculated at MICs ranging from 1 microg/mL to 64 microg/mL. The CFR for 3.375 g every 4 hours (intermittent infusion) and 3.375-4.5 g every 8 hours (prolonged infusion) greater than or equal to 90.3% for Escherichia coli, Serratia marcescens, and Citrobacter spp. Increasing the prolonged-infusion dose to 6.75 g improved the CFR to greater than 90% for Enterobacter spp. For every regimen evaluated, the CFR was less than 90% for Klebsiella pneumoniae and Pseudomonas aeruginosa. At an MIC of 16 microg/mL, PTA was greater than 90% for one intermittent-infusion regimen (3.375 g every 4 h) and 3 prolonged-infusion regimens (> or = 3.375 g every 8 h), but no regimen achieved a PTA greater than 90% at an MIC of 64 microg/mL. At doses greater than or equal to 3.375 g every 8 hours, 4-hour infusions of piperacillin/tazobactam achieved excellent target attainment with lower daily doses compared with standard regimens at MICs less than or equal to 16 microg/mL.

Steady-state pharmacokinetics and pharmacodynamics of piperacillin/tazobactam administered by prolonged infusion in hospitalised patients

The objective of this study was to evaluate the steady-state pharmacokinetics and pharmacodynamics of piperacillin/tazobactam, administered by prolonged infusion, in hospitalised patients requiring antimicrobial therapy. Thirteen patients received 4.5 g every 8 h (q8h), infused over 4 h, and pharmacokinetic parameters were determined by non-compartmental methods. Monte Carlo simulations (10 000 patients) were performed to calculate the cumulative fraction of response (CFR) for seven Gram-negative pathogens using minimum inhibitory concentration (MIC) data from the Meropenem Yearly Susceptibility Test Information Collection (2004–2007, USA) as well as the probability of target attainment (PTA) at MICs ranging from 1 μg/mL to 64 μg/mL. The pharmacodynamic target was free piperacillin concentration remaining above the MIC for 50% of the dosing interval. Mean ± standard deviation maximum and minimum serum concentrations, half-life, volume of distribution at steady-state and systemic clearance of piperacillin were 108.2 ± 31.7 μg/mL, 27.6 ± 26.3 μg/mL, 2.1 ± 1.2 h, 22.1 ± 4.0 L and 8.6 ± 3.0 L/h, respectively. The CFR was >90% for Escherichia coli, Serratia marcescens and Citrobacter spp., 88.6% for Enterobacter spp., 87% for Klebsiella pneumoniae, 85.5% for Pseudomonas aeruginosa and 52.8% for Acinetobacter spp. The PTA was 100%, 81.1% and 12.3% at MICs of ≤16 μg/mL, 32 μg/mL and 64 μg/mL, respectively. Piperacillin/tazobactam 4.5 g q8h infused over 4 h provides excellent target attainment for bacterial pathogens with MICs ≤ 16 μg/mL. However, the CFR was <90% for four of the seven Gram-negative pathogens evaluated.

Prevalence and molecular characterization of extended-spectrum β-lactamase-producing Klebsiella pneumoniae in Riyadh, Saudi Arabia

BACKGROUND AND OBJECTIVES:Reports on extended-spectrum β-lactamases (ESBL) production by Enterobacteriaceae, and especially in Klebsiella pneumoniae, are few in Saudi Arabia. Therefore, we determined the prevalence of ESBL in K pneumoniae from Riyadh and characterized the predominant β-lactamase gene in these isolates.METHODS:A total of 400 K pneumoniae samples were isolated from two hospitals in Riyadh during 2007 and screened for production of ESBL using ESBL-E-strips and combined disk methods. PCR assay was used to detect blaTEM, blaSHV, and blaCTX-M genes.RESULTS:Phenotypic characterization identified a high ESBL rate of 55% of K pneumoniae isolates. ESBL-producing K pneumoniae were PCR positive for SHV, TEM and CTX-M β-lactamase genes with prevalences 97.3%, 84.1% and 34.1%, respectively. Within the CTX-M family, two groups of enzymes, CTX-M-1 and CTX-M-9-like genes were found with prevalences of 60% and 40%, respectively.CONCLUSIONS:This study confirms the high rate of ESBL in K pneumoniae clinical isolates in hospitals in Riyadh. This study demonstrates the worldwide spread of blaCTX-M genes. This first report of the presence of the blaCTX-M gene in clincial isolates in Saudi Arabia is evidence of the continuing worldwide spread of this gene.

Comparison of 2002–2006 OPTAMA Programs for US Hospitals: Focus on Gram-Negative Resistance

Resistance among gram-negative bacteria is increasing within the US. To determine pharmacodynamic target attainment rates for 10 antimicrobials against selected gram-negative bacilli and compare these results with previous Optimizing Pharmacodynamic Target Attainment Using the MYSTIC Antibiogram (OPTAMA) assessments. A 5000-patient Monte Carlo simulation using data from population pharmacokinetic studies was employed to estimate the pharmacokinetic profiles for standard and/or prolonged infusion (PI) regimens of cefepime, ceftazidime, ceftriaxone, ciprofloxacin, ertapenem, imipenem, levofloxacin, meropenem, piperacillin-tazobactam, and tigecycline. Minimum inhibitory concentration data were obtained from intensive care units of 15 US hospitals participating in the 2006 MYSTIC (Meropenem Yearly Susceptibility Test Information Collection) study for 640 Escherichia coli, 618 Klebsiella spp., and 606 Pseudomonas aeruginosa isolates. Cumulative fraction of response (CFR) was calculated using pharmacodynamic targets for each antibiotic and compared with results from the 2002 and 2004 OPTAMA studies. Against E. coli, CFRs greater than 92% were maintained for all regimens except the fluoroquinolones (CFR range 69.4-72%), which showed a 7% decrease compared with 2004. The presence of Klebsiella spp. producing KPC-type carbapenemases with associated multidrug resistance resulted in a 7% or greater drop in CFR of standard regimens relative to 2004. Despite these resistant phenotypes, high-dose PI regimens (2 g every 8 hours as 3-hour PI) of cefepime and meropenem achieved CFRs of 97% and 95.8%, respectively. Excluding 3 KPC-harboring hospitals resulted in CFR increases to greater than 98% for carbapenems and cefepime and greater than 88% for all other agents tested, except tigecycline. Against P. aeruginosa, the fluoroquinolones had the lowest CFR (55.8-63.9%), followed by imipenem (74.6-80.4%). The most predictable activity was seen with cefepime 2 g every 12 hours or higher (>90%), ceftazidime 2 g every 8 hours (97.9%), and meropenem 1-2 g every 8 hours (86.7-92.6%). Use of PI for piperacillin-tazobactam and meropenem increased CFRs by 6% and 4%, respectively, over standard infusions. Relative to previous years, an increase in resistance was noted among gram-negative bacilli to common antibiotics, resulting in disproportionate decreases in pharmacodynamic target attainment. The use of PI for beta-lactams may help to overcome these decreases.

MYSTIC Europe 2007: activity of meropenem and other broad-spectrum agents against nosocomial isolates

The Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) Program is a longitudinal antimicrobial surveillance study that has been in existence since 1997 in centers that are actively prescribing meropenem. This report examines the results from the study in Europe in 2007. A total of 5208 isolates were examined for activity (MIC) of meropenem and other broad-spectrum antibacterial comparators. Cumulative susceptibility rates using Clinical and Laboratory Standards Institute criteria against all methicillin-susceptible staphylococci were imipenem (97.7%) > meropenem (97.3%) > piperacillin/tazobactam (96.2%) > tobramycin (94.2%) > gentamicin (92.0%) > ciprofloxacin (84.0%) > ceftazidime (39.8%). Against all species of Enterobacteriaceae, the rates were meropenem (99.4%) > imipenem (98.3%) > tobramycin (92.0%) > gentamicin (89.5%) > ceftazidime (86.2%) > piperacillin/tazobactam (85.5%) > ciprofloxacin (84.2%). Meropenem was most effective against the nonfermenters, although multidrug-resistant Acinetobacter spp. and imipenem-resistant Pseudomonas aeruginosa strains were reported. The continued need for surveillance studies such as MYSTIC is exemplified, and results from these types of surveillance can, hopefully, help in the correct choice of empiric therapy.

Steady‐State Pharmacokinetics and Pharmacodynamics of Meropenem in Hospitalized Patients

To evaluate the steady-state pharmacokinetics and pharmacodynamics of meropenem 500 mg every 6, 8, and 12 hours, based on renal function, in hospitalized patients. Prospective, open-label, steady-state pharmacokinetic study. One tertiary care medical center and one community hospital. Twenty adult patients (12 men, 8 women) with suspected or documented bacterial infections requiring antimicrobial therapy. Patients received 30-minute infusions of meropenem 500 mg every 6 hours (group 1), every 8 hours (group 2), or every 12 hours (group 3) based on estimated creatinine clearances greater than 60, 40-60, or 10-39 ml/minute, respectively. Serial blood samples were collected after 2 or more days of therapy. Meropenem concentrations were determined by high-performance liquid chromatography, and pharmacokinetic data were analyzed by noncompartmental methods. Monte Carlo simulations (10,000 patients) were performed to calculate the cumulative fraction of response (CFR) for a percentage of the dosing interval that free drug concentrations remain above the minimum inhibitory concentration (fT>MIC) of 40% by using pharmacokinetic data for each group and MIC data for seven gram-negative pathogens from the Meropenem Yearly Susceptibility Test Information Collection (MYSTIC, 2004-2005) database. Maximum and minimum serum concentrations (mean +/- SD) were 29.2+/-9.8 and 2.4+/-1.1 microg/ml, 33.2+/-8.5 and 3.8+/-2.7 microg/ml, and 33.5+/-4.7 and 4.9+/-1.6 microg/ml for groups 1, 2, and 3, respectively. The half-life values were 2.5+/-0.9, 3.4+/-1.3, and 6.1+/-1.4 hours, and the values for volume of distribution at steady state were 29.3+/-8.7, 23.8+/-8.1, and 28.7+/-8.6 L for groups 1, 2, and 3, respectively. For all three groups, the CFR was greater than 90% for the enteric pathogens and Pseudomonas aeruginosa and 82.4-85.2% for Acinetobacter species. Pharmacodynamic analyses suggest that regimens of meropenem 500 mg every 6, 8, or 12 hours, adjusted for renal function, are acceptable for treatment of infections caused by enteric gram-negative pathogens and P. aeruginosa. However, more aggressive dosing or alternative dosing strategies may be necessary for Acinetobacter species.

Comparative activity of meropenem in US medical centers (2007): initiating the 2nd decade of MYSTIC program surveillance

Since 1997, the Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) Program has monitored the antimicrobial activity of broad-spectrum agents against pathogens from hospitalized patients. In the United States, 2894 isolates were submitted in 2007 from 15 sites, including 1392 Enterobacteriaceae, 643 nonfermentative Gram-negative bacilli, and 829 Gram-positive cocci. All isolates were tested by broth microdilution methods. Meropenem (MIC 90 range, 0.12–2 μg/mL) exhibited the lowest resistance rates (1.9–2.4%) against Enterobacteriaceae, and fluoroquinolones had the highest rates of resistance (17.3–18.3%). KPC carbapenemases, usually found in Klebsiella pneumoniae, were also detected in Citrobacter freundii, Enterobacter spp., and Escherichia coli. Confirmed extended-spectrum β-lactamase–producing isolate rates for E. coli, Klebsiella spp., and Proteus mirabilis isolates were 6.0%, 12.0%, and 0.0%, respectively. Meropenem remained active against Gram-positive pathogens such as staphylococci (methicillin-susceptible; MIC 90, 0.12–0.25 μg/mL), Streptococcus pneumoniae (MIC 90, 0.5 μg/mL), and β-hemolytic and viridans group streptococci (MIC 90 range, 0.06–0.25 μg/mL). These US MYSTIC Program results demonstrate the continued emergence of novel β-lactamases and multidrug-resistant bacterial phenotypes necessitating monitoring of carbapenem activities against Enterobacteriaceae species as well as nonfermentative bacilli.

Antimicrobial breakpoints for Gram-negative aerobic bacteria based on pharmacokinetic–pharmacodynamic models with Monte Carlo simulation

This study describes a comprehensive programme designed to develop pharmacokinetic-pharmacodynamic (PK-PD) breakpoints for numerous antimicrobial classes against key gram-negative aerobic bacteria. A 10,000 subject Monte Carlo simulation was constructed for 13 antimicrobials (21 dosing regimens). Published pharmacokinetic data and protein binding were varied according to log-normal and uniform distributions. MICs were fixed at single values from 0.03 to 64 mg/L. The PK-PD susceptible breakpoint was defined as the MIC at which the probability of target attainment was > or = 90%. PK-PD, CLSI and European Committee on Antimicrobial Susceptibility Testing breakpoints were applied to MICs from the 2005 worldwide Meropenem Yearly Susceptibility Test Information Collection database to evaluate the impact of breakpoint discrepancies. PK-PD breakpoints were within one dilution of the CLSI and European breakpoints for all antimicrobials tested--with a few exceptions. When discrepancies were noted, the PK-PD breakpoint was lower than the CLSI breakpoint [ceftriaxone (0.5 versus 8 mg/L), ertapenem (0.25 versus 2 mg/L), ciprofloxacin (0.125 versus 1 mg/L) and levofloxacin (0.25-0.5 versus 2 mg/L)] and higher than the European breakpoint [ceftazidime (4-8 versus 1 mg/L), aztreonam (4-8 versus 1 mg/L), although ciprofloxacin was an exception to this pattern (0.125 versus 0.5-1 mg/L)]. For Enterobacteriaceae, breakpoint discrepancies resulted in modest (< or = 10%) differences in the percentages susceptible. In contrast, large (> 15%) discrepancies were noted for Pseudomonas aeruginosa and Acinetobacter baumannii. Breakpoint agreement exists for imipenem, meropenem and the aminoglycosides. In contrast, discrepancies exist for piperacillin/tazobactam, cephalosporins, ertapenem, aztreonam and the fluoroquinolones. These discrepancies are most pronounced for P. aeruginosa and A. baumannii.

Trends in antimicrobial susceptibility of Gram-negative isolates from a paediatric intensive care unit in Warsaw: results from the MYSTIC programme (1997-2007)

The Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) programme is a longitudinal global surveillance study to monitor in vitro data on microbial susceptibility in centres that prescribe meropenem. This overview provides data on the susceptibility of Gram-negative bacteria (n = 1300) isolated from clinical specimens of children hospitalized in a paediatric intensive care unit (ICU) during 1997-2007. MICs of meropenem and eight other antibiotics were determined using the CLSI agar dilution method. Meropenem, imipenem and ciprofloxacin were most active (>90% susceptibility) against the tested isolates. A greater proportion of Pseudomonas aeruginosa isolates was susceptible to meropenem compared with imipenem. Antibiotic susceptibility of Enterobacteriaceae and Acinetobacter baumannii showed an increase in 2007. Only susceptibility of P. aeruginosa to ceftazidime and cefepime increased. The incidence of extended-spectrum beta-lactamase (ESBL) producers among Enterobacteriaceae isolates decreased from 37% in 1997 to 21.8% in 2007, and AmpC beta-lactamase producers decreased from 24.6% to 5.7%. Consumption of cephalosporins remained the same and piperacillin/tazobactam increased 3-fold. During 11 years, despite an increase in carbapenem consumption, meropenem and imipenem have retained excellent activity against the majority of isolates studied. The comparison of antibiotic susceptibility of Gram-negative isolates in 1997 and 2007 showed a trend of increase, and the number of beta-lactamase-producing isolates among Enterobacteriaceae showed a trend of decrease possibly related to changes in antibiotic policy.

Susceptibility of Bacterial Isolates From Turkey - A Report From the Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) Program

The study monitored the susceptibility of nosocomial pathogens to meropenem and comparator antimicrobial agents isolated as part of the Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) Program from Turkish university hospitals. In terms of minimum inhibitory concentration 90% (MIC90) values, meropenem was two- and eight-fold more active than imipenem against Escherichia coli and Klebsiella pneumoniae, respectively. 40.5% of K. pneumoniae, 23.1% of Klebsiella oxytoca and 15.3% of E. coli isolates were extended-spectrum β-lactamase (ESBL) producers. Piperacillin/tazobactam was the most active agent against isolates of Pseudomonas aeruginosa, followed by meropenem and imipenem. Against Acinetobacter baumannii isolates, meropenem and imipenem were the most active agents. Continued surveillance by the MYSTIC Program appears to be prudent to help focus on effective empiric treatment regimens.

Meropenem activity against European isolates: report on the MYSTIC (Meropenem Yearly Susceptibility Test Information Collection) 2006 results

The MYSTIC (Meropenem Yearly Susceptibility Test Information Collection) Program is a longitudinal antimicrobial surveillance study that has been in place since 1997 in centers that are actively prescribing meropenem. This report examines the activity of meropenem and other broad-spectrum antibacterial comparators against the 7124 isolates submitted by 40 European centers during 2006 and compares the results with those obtained in 2002. Cumulative susceptibility rates against all methicillin-susceptible staphylococci were amikacin (99.2%) > meropenem and imipenem (98.1%) > piperacillin + tazobactam (96.6%) > gentamicin (91.8%) > tobramycin (91.1%) > ciprofloxacin (83.1%) > ceftazidime (59.7%). Against all species of Enterobacteriaceae, the rates were meropenem (98.9%) > imipenem (97.9%) > amikacin (97.1%) > gentamicin (91.0%) > piperacillin + tazobactam (83.4%) > ceftazidime (82.3%) > ciprofloxacin (82.2%) > tobramycin (75.1%). The carbapenems were also the most effective class against nonfermenters, although there are increasing numbers of multidrug-resistant (MDR)- Acinetobacter spp. being reported. Overall meropenem is still retaining excellent activity against the majority of isolates studied. The continued need for surveillance studies such as MYSTIC in order that correct clinical decisions concerning antibiotic selection are made is once again demonstrated.

Antibiotic resistance surveillance over a 4-year period (2000–2003) in Turkey: results of the MYSTIC Program

The Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) Program is a global study that provides antimicrobial susceptibility data in centers prescribing meropenem. The activity of meropenem and 7 broad-spectrum antimicrobials have been examined against 5208 bacterial isolates from 9 Turkish centers between 2000 and 2003. Cumulative susceptibility rates against all species of Enterobacteriaceae combined were ranked as follows: meropenem (99.3%), imipenem (97.6%), cefepime (80.0%), piperacillin–tazobactam (73.6%), ceftazidime (70.3%), ciprofloxacin (70.1%), cefotaxime (66.9%), and tobramycin (67.2%). The production of extended-spectrum β-lactamases (ESBLs) was detected in 48.7% of Klebsiella pneumoniae and in 19.5% of Escherichia coli isolates. Of ESBL producing K. pneumoniae isolates, 75.7% were resistant to tobramycin, 40.3% to ciprofloxacin, and 48.3% to piperacillin–tazobactam. Only piperacillin/tazobactam and carbapenems were active against more than 50% of Pseudomonas aeruginosa at the National Committee for Clinical Laboratory Standards-susceptible breakpoint, and the carbapenems were the most active compounds against Acinetobacter spp. These data confirm the continued potency of meropenem against Enterobacteriaceae in units where it is actively being prescribed.

Pharmacodynamics of ceftazidime and meropenem in cerebrospinal fluid: results of population pharmacokinetic modelling and Monte Carlo simulation

Ceftazidime and meropenem are frequently used in the empirical treatment of hospital-acquired cerebrospinal fluid (CSF) infections. Although their dispositions in CSF have been described, the ability of these agents to achieve critical pharmacodynamic targets against the array of nosocomial CSF Gram-negative bacteria encountered in practice has not been reported. Serum and CSF pharmacokinetic data were obtained from hospital patients with external ventricular drains and who received ceftazidime or meropenem. Concentration-time profiles in serum and CSF were modelled using a three-compartment model with zero-order infusion and first-order elimination and transfer. The model parameters were identified using population pharmacokinetic analysis [Big Non-Parametric Adaptive Grid (BigNPAG)]. A Monte Carlo simulation (9999 subjects) estimated the probability of target attainment (PTA) for total drug CSF concentrations at 50% and 100% T(>MIC) for ceftazidime 2 g intravenously every 8 h and meropenem 2 g intravenously every 8 h. The Gram-negative infection isolates of the seven most prevalent Gram-negative bacilli from the Meropenem Yearly Susceptibility Test Information Collection Program were used as a measure of contemporary MIC distribution. Post-Bayesian measures of bias and precision, observed-predicted plots and R(2) values were highly acceptable for both drugs. Although the PTA in CSF was approximately one dilution higher for ceftazidime compared with meropenem at a given MIC value, the cumulative fraction of response (CFR) in CSF against all Gram-negatives was markedly higher for meropenem when compared with ceftazidime secondary to the higher occurrence of lower MIC values for meropenem. Both agents had a low CFR against Pseudomonas aeruginosa. The pharmacodynamics of meropenem was superior to that of ceftazidime against Gram-negative pathogens in the CSF.

Activity of meropenem as serine carbapenemases evolve in US Medical Centers: monitoring report from the MYSTIC Program (2006)

The Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) Surveillance Program was designed to monitor the antimicrobial potency and spectrum of meropenem, and selected broad-spectrum comparison agents against pathogens from hospitalized patients. In the 2006 (year 8 of the study) United States sample, a total of 2841 isolates (94.7% compliance) including 641 Escherichia coli, 619 Klebsiella spp., 606 Pseudomonas aeruginosa, 456 oxacillin-susceptible Staphylococcus aureus, 300 streptococci, 149 Enterococcus faecalis, and 70 Gram-positive anaerobic organisms were tested by reference broth microdilution or agar dilution susceptibility methods. The carbapenems, especially meropenem, consistently demonstrated the lowest resistance rates against Enterobacteriaceae strains, and the fluoroquinolones had the highest and increasing resistance rates. The presence of qnr-mediated fluoroquinolone resistance was investigated using polymerase chain reaction methods but was only observed at very low levels (2.1%) and was not clonally associated. Confirmed extended-spectrum β-lactamase rates for E. coli and Klebsiella spp. were only 4.8% and 5.0%, respectively, with mobile AmpC (CMY-2 and FOX-5) enzymes shown in 13 additional Enterobacteriaceae isolates. Clonally related KPC-type serine carbapenemase production (57 strains, 9.5%) was observed at a rate 2-fold greater than the prior year among Klebsiella spp. isolates, primarily from 1 geographic region (Middle Atlantic States). These MYSTIC Program (2006) results demonstrate the continued need to monitor the carbapenem class potency and spectrum of activity against Enterobacteriaceae as well as P. aeruginosa because of the documented presence of serine carbapenemases and rare incidence of metallo-β-lactamases that may further compromise their activity and that of other β-lactam agents.

Integrating Susceptibility Data from Two Surveillance Programs with Unique Methodological Techniques: The Antibiogram Resistance Method or Isolate-Based Resistance Monitoring (ARMOR) Study Group

Background Antimicrobial resistance can be tracked by several methods. The optimal application of surveillance strategies is an integral part in curbing the resistance epidemic. Objectives The Antimicrobial Resistance Management (ARM) and Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) programs are ongoing antibiotic surveillance studies with different methodologies. Our aim was to compare susceptibility data generated by each program to determine if the two methods produce similar results. Methods ARM is a Web-based, antibiogram-driven surveillance system, whereas MYSTIC tests individual bacterial isolates in accordance with Clinical Laboratory Standards Institute methods. We compared national susceptibility rates during 1999 to 2004 from ARM and MYSTIC for Escherichia coli and Klebsiella pneumoniae. Results E. coli susceptibility was greater than 90% for all agents evaluated except ciprofloxacin and levofloxacin. Susceptibility rates in ARM and MYSTIC were similar (within 5%), with the exception of levofloxacin — for which susceptibility was reported as 92.3% in ARM and 83% in MYSTIC ( P &lt; 0.0001). Amikacin, cefepime, ceftriaxone, imipenem, and meropenem were identified by both surveillance programs as the most active agents against E. coli and K. pneumoniae. Both systems detected increasing fluoroquinolone resistance ( P &lt; 0.0001) and relatively stable activity among other agents tested. For K. pneumoniae, all agents displayed resistance rates less than 10%. Susceptibility rates in ARM and MYSTIC were remarkably similar. The largest difference was 2.9% for piperacillin/tazobactam (92.8% in ARM vs 95.7% in MYSTIC, P &lt; 0.0001). Regionally, nonsusceptibility to E. coli and K. pneumoniae was similar, though for some comparisons MYSTIC reported higher rates of nonsusceptibility in the Northeast, Northwest, and South Central. Conclusion Surveillance of antibiotic activity patterns can be performed confidently with either method discussed above. Attempts should be made to integrate results from different surveillance programs to optimize surveillance.

Reevaluation of current susceptibility breakpoints for Gram-negative rods based on pharmacodynamic assessment

Although pharmacodynamic (PD) modeling is now being considered for decision support for susceptibility breakpoint determination against Gram-negative bacteria, these PD-derived breakpoints should be verified using a clinically applicable population of organisms. In this analysis, a 5000-patient Monte Carlo simulation was used to determine PD breakpoints, the highest 2-fold MIC in which the probability of bactericidal target attainment (PTA) remained ≥90%. Percent susceptibilities for 639 Pseudomonas aeruginosa, 103 Acinetobacter baumannii, 705 Escherichia coli, and 418 Klebsiella spp. collected during the 2004 Meropenem Yearly Susceptibility Test Information Collection surveillance study were then defined according to the PD-derived breakpoint (% S PD) and compared with the current Clinical Laboratory Standards Institute (CLSI)-defined breakpoints (% S CLSI). % S PD and % S CLSI were compared with the bactericidal PTA for each pathogen population to determine the degree of agreement. Resulting PD breakpoints were drug and dose dependent; moreover, values were commonly 2 to 4 MIC dilutions lower than CLSI breakpoints. Overall, % S PD more closely agreed with the PTA for the tested β-lactam and fluoroquinolone dosing regimens. In contrast, % S CLSI overestimated PTA for many dosing regimens, especially against Pseudomonas: piperacillin/tazobactam 4.5 g qid (+9.7%), ciprofloxacin 0.4 g bid (+13.7%) and 0.4 g tid (+9.3%), and levofloxacin 0.5 g every 24 h (+22.4%) and 0.75 g every 24 h (+9.9%). Differences were most pronounced against the nonfermenting Gram-negative bacteria and were not observed among the Enterobacteriaceae. As a result, a new method of breakpoint classification is proposed, which is dosing regimen and pathogen specific, and is designed to denote isolates as susceptible only if target bactericidal exposures are achievable with the dosing regimen selected.

Pharmacodynamic Target Attainment of Six β‐Lactams and Two Fluoroquinolones Against Pseudomonas aeruginosa, Acinetobacter baumannii, Escherichia coli, and Klebsiella Species Collected from United States Intensive Care Units in 2004

To determine the likelihood that antibiotic regimens achieve bactericidal pharmacodynamic exposures against common nosocomial pathogens. Pharmacodynamic Monte Carlo simulation model. Microbiologic data generated from isolates from the 14 centers in the United States in the 2004 Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) surveillance study. Five thousand simulated patients with infection. Pharmacokinetic profiles of the patients were simulated to determine the bactericidal cumulative fraction of response (CFR) for commonly used intravenous regimens of cefepime, ceftazidime, ceftriaxone, ciprofloxacin, imipenem, levofloxacin, meropenem, and piperacillin-tazobactam against Pseudomonas aeruginosa, Acinetobacter baumannii, Escherichia coli, and Klebsiella species. Ciprofloxacin and levofloxacin had CFRs among the lowest of all drugs against all pathogens, especially P. aeruginosa (40.4-65.5%) and A. baumannii (43.6-48.2%). The low CFR of about 78% against E. coli with these two agents was of particular concern. Among the beta-lactams, only high-dose cefepime and ceftazidime regimens achieved CFRs of greater than 90% against P. aeruginosa, followed by cefepime 2 g every 12 hours and the carbapenems (86.3-89.7%). No regimen achieved an optimum CFR for A. baumannii. All beta-lactam regimens achieved a greater-than-90% likelihood of having bactericidal CFRs against Enterobacteriaceae. Because of the continual evolution of resistance among gram-negative bacteria in the United States, reevaluation of optimum dosing strategies for beta-lactam and fluoroquinolone antibiotics is necessary.