Abstract
The Clinical and Laboratory Standards Institute (CLSI) lowered the MIC breakpoints for meropenem and imipenem from 4 mg/liter to 1 mg/liter for Enterobacteriaceae in 2010. The breakpoint change improves the probability of pharmacodynamic target attainment and eliminates the need for microbiology labs to perform confirmatory testing for Klebsiella pneumoniae carbapenemase (KPC) production or other beta-lactamases that hydrolyze carbapenems. However, there are limited data evaluating clinical outcomes of the affected breakpoints, and it is unknown if patients infected with Enterobacteriaceae with reduced susceptibility are more likely to have poor outcomes when treated with a carbapenem. We conducted a single-center retrospective matched-cohort analysis in adult patients with Enterobacteriaceae infections treated with meropenem, imipenem, or doripenem. Patients with Enterobacteriaceae infection with a carbapenem MIC of 2 to 8 mg/liter were matched based on pathogen, source of infection, comorbidities, and disease severity (1:1 ratio) to those with a carbapenem MIC of ≤1 mg/liter. A total of 36 patients were included in the study. The group with carbapenem MICs of 2 to 8 mg/liter had a significantly higher 30-day mortality than the group with carbapenem MICs of ≤1 mg/liter (38.9% compared to 5.6%, P = 0.04). Total hospital length of stay (LOS) and intensive care unit (ICU) LOS were longer in the group with MICs of 2 to 8 mg/liter than in the group with MICs of ≤1 mg/liter (57.6 days compared to 34.4 days [P = 0.06] and 56.6 days compared to 21.7 days [P < 0.01], respectively). Patients infected with Enterobacteriaceae with a carbapenem MIC of 2, 4, or 8 mg/liter had higher mortality rates and longer ICU LOS than matched cohorts with carbapenem MICs of ≤1 mg/liter, which supports CLSI's recommendation to lower susceptibility breakpoints for carbapenems.
INTRODUCTION
The number of Gram-negative bacteria exhibiting multidrug resistance is increasing (1). Perhaps most concerning is the development of multiple resistance mechanisms to potent broad-spectrum antibiotics such as carbapenems. The threat of carbapenem-resistant Enterobacteriaceae (CRE) has become reality due to the spread of Klebsiella pneumoniae carbapenemases (KPC), leaving clinicians with a paucity of active antimicrobial treatment options (1–4).
To aid clinicians in the appropriate selection of antimicrobial therapy, MICs are established by various regulatory agencies as a standard for interpreting the susceptibility of an organism to a particular antibiotic. Existing evidence suggests that MICs are important predictors of patient outcomes when assessing effective antimicrobial therapy for various infections (5, 6). Pharmacodynamic targets may remain similar irrespective of the production of any specific mechanism of resistance by a particular organism; this appears to be true with Enterobacteriaceae and extended-spectrum-beta-lactamase (ESBL) production (7–9). Thus, although genetic resistance mechanisms can be quite complex, well-established MIC values and susceptibility breakpoints can equip clinicians with enough data to employ effective antimicrobial therapy. Currently, susceptibility breakpoints of carbapenems against Enterobacteriaceae are different among the Clinical and Laboratory Standards Institute (CLSI), Food and Drug Administration (FDA), and European Committee on Antimicrobial Susceptibility Testing (EUCAST) (6, 10), which may cause confusion regarding the role of carbapenem therapy (Table 1).
TABLE 1.
Susceptibility breakpoints of meropenem against Enterobacteriaceae by organization
| Organization | Breakpoint (mg/liter) |
||
|---|---|---|---|
| Sensitive | Intermediate | Resistant | |
| Food and Drug Administration | ≤4 | 8 | ≥16 |
| Clinical and Laboratory Standards Institute | ≤1 | 2 | ≥4 |
| European Committee on Antimicrobial Susceptibility Testing | ≤2 | 4–8 | >8 |
Mathematical models predicting suboptimal pharmacodynamic target attainment with use of standard carbapenem dosing strategies exist for isolates with higher MICs. This contributed to the decision to lower the CLSI susceptibility breakpoint for carbapenems against Enterobacteriaceae from ≤4 mg/liter to ≤1 mg/liter. Additionally, lowering the breakpoint would eliminate the need for microbiology labs to perform more cumbersome confirmatory resistance testing for KPC (6, 11, 12). There is a limited amount of data evaluating clinical outcomes with the use of carbapenems for treatment of Enterobacteriaceae infection with MICs of 2 to 8 mg/liter. The primary goal of this study was to determine if a difference in clinical outcomes existed between patients treated with a carbapenem for Enterobacteriaceae infections with MICs of ≤1 mg/liter and MICs of 2 to 8 mg/liter.
MATERIALS AND METHODS
This study was a single-center retrospective matched-cohort analysis conducted at the University of Michigan Hospitals and Health Centers and approved by the Institutional Review Board. The hospital is a 930-bed university-affiliated tertiary medical center. Patients admitted between 1 January 2009 and 1 August 2013 with a positive culture for Klebsiella, Citrobacter, Escherichia, Enterobacter, Proteus, or Serratia were screened for inclusion. Adult patients (≥18 years of age) treated with ≥48 h of imipenem, meropenem, or doripenem were included. Patients were excluded if they were treated with ertapenem, transferred from an outside hospital with incomplete records, deemed by the attending physician to be colonized with Enterobacteriaceae, or infected with isolates with carbapenem MICs of ≥16 mg/liter.
Patients infected with Enterobacteriaceae with carbapenem MICs of 2 to 8 mg/liter were matched at a 1:1 ratio to those with carbapenem MICs of ≤1 mg/liter. Matching was based on age ± 10 years, Charlson comorbidity index score ± 3, source of infection, pathogen, and intensive care unit (ICU) status at the time of positive culture. Patient demographics, microbiologic data (causative organism, source of infection, antibiotic susceptibilities), antibiotic therapy, length of hospitalization, hospital readmission, and mortality were collected for each patient by using inpatient electronic medical records. Concomitant antibiotics were evaluated and defined as any antimicrobial agent with Gram-negative activity. Organism susceptibilities were tested with Vitek 2 or Etest (bioMérieux, Durham, NC).
The primary endpoint of this analysis was 30-day all-cause mortality from the first day of positive culture. Secondary outcomes included total hospital length of stay (LOS), length of ICU stay, and hospital readmission within 30 days of discharge. All baseline demographics and clinical outcomes were compared between patients infected with an organism with carbapenem MICs of ≤1 mg/liter and those with carbapenem MICs of 2, 4, and 8 mg/liter. All statistical analyses were performed using SPSS software, version 20.0 (SPSS, Inc., Chicago, IL). Demographic data were analyzed using appropriate descriptive statistics. Categorical data were analyzed by a 2-tailed Student t test, and dichotomous data were analyzed by Fisher's exact test. Additionally, survival was analyzed by the Kaplan-Meier method with 2-sided log rank statistics. A P value of ≤0.05 was considered statistically significant.
RESULTS
A total of 36 patients were included in the study: 18 patients in the group with carbapenem MICs of ≤1 mg/liter and 18 patients in the group with carbapenem MICs of 2 to 8 mg/liter. Baseline demographics were similar between the groups (Table 2), and the majority of patients in both groups presented with elevated Charlson comorbidity index scores (6.1 and 6.6, P = 0.54), were admitted to the ICU during their hospitalization (72.2% and 61.1%, P = 0.72), and received infectious diseases consultation (88.9% and 88.9%, P > 0.99). Approximately two-thirds of pathogens came from high-risk sources (blood, respiratory, or intra-abdominal), and Klebsiella species and Escherichia coli were the most common pathogens, accounting for 72.2% of infections. Meropenem therapy was prescribed for 16/18 (88.9%) patients in both groups, and the mean duration of therapy was similar between groups (11 ± 8.5 days and 11 ± 9.4 days, P > 0.99). In patients with normal renal function (creatinine clearance of >50 ml/min) and severe infections, imipenem was dosed at 1,000 mg every 6 h, meropenem was dosed at either 1,000 mg every 8 h or 500 mg every 6 h, and doripenem was dosed 500 mg every 8 h. Appropriate adjustments were made for impaired renal function, and any deviations from recommended guideline dosing captured in this patient sample were likely at random. Concomitant Gram-negative therapy was common among groups (50% in the group with MICs of ≤1 mg/liter compared to 77.8% in the group with MICs of 2 to 8 mg/liter, P = 0.16). Amikacin, colistin, and tigecycline were commonly used with the carbapenem in the high-MIC group. In the cohort with MICs of 2 to 8 mg/liter, 55.6% of patients had an MIC of 2 mg/liter, 27.8% had an MIC of 4 mg/liter, and 16.7% had an MIC of 8 mg/liter.
TABLE 2.
Baseline demographics and characteristics stratified by carbapenem MIC
| Demographic or characteristic | Value |
P value | |
|---|---|---|---|
| MIC of ≤1 mg/liter (n = 18 patients) | MIC of 2–8 mg/liter (n = 18 patients) | ||
| Mean age ± SD (yrs) | 59 ± 13.6 | 61 ± 13.0 | 0.65 |
| No. (%) of males | 12 (66.7) | 7 (38.9) | 0.18 |
| Mean Charlson comorbidity index ± SD | 6.6 ± 2.2 | 6.1 ± 2.6 | 0.54 |
| No. (%) of patients with comorbidities | |||
| Chronic cardiovascular disease | 14 (77.8) | 14 (77.8) | >0.99 |
| Chronic lung disease | 6 (33.3) | 5 (27.8) | >0/99 |
| Central nervous system disease | 1 (5.6) | 3 (16.7) | 0/60 |
| Chronic renal disease | 4 (22.2) | 6 (33.3) | 0.71 |
| Chronic liver disease | 3 (16.7) | 3 (16.7) | >0.99 |
| Diabetes | 10 (55.6) | 8 (44.4) | 0.74 |
| Malignancy | 3 (16.7) | 4 (22.2) | >0.99 |
| Solid organ transplant | 4 (22.2) | 4 (22.2) | >0.99 |
| Bone marrow transplant | 0 | 1 (5.6) | >0.99 |
| Autoimmune disease | 0 | 2 (11.1) | 0.49 |
| No. (%) of patients with ICU admission | 13 (72.2) | 11 (61.1) | 0.72 |
| No. (%) of patients with infectious disease consultation | 16 (88.9) | 16 (88.9) | >0.99 |
| No. (%) of patients with infection by organism | |||
| Klebsiella | 9 (50.0) | 9 (50.0) | >0.99 |
| Escherichia | 4 (22.2) | 4 (22.2) | >0.99 |
| Citrobacter | 2 (11.1) | 2 (11.1) | >0.99 |
| Serratia | 2 (11.1) | 2 (11.1) | >0.99 |
| Enterobacter | 1 (5.6) | 1 (5.6) | >0.99 |
| Polymicrobial | 10 (55.6) | 6 (33.3) | 0.31 |
| No. (%) of patients by culture sources | |||
| Blood | 3 (16.7) | 3 (16.7) | >0.99 |
| Respiratory | 6 (33.3) | 6 (33.3) | >0.99 |
| Intra-abdominal | 3 (16.7) | 3 (16.7) | >0.99 |
| Urinary | 4 (22.2) | 4 (22.2) | >0.99 |
| Wound | 2 (11.1) | 2 (11.1) | >0.99 |
| No. (%) of patients with MIC of: | |||
| ≤1 mg/liter | 18 (100.0) | 0 | NAb |
| 2 mg/liter | 0 | 10 (55.6) | NA |
| 4 mg/liter | 0 | 5 (27.8) | NA |
| 8 mg/liter | 0 | 3 (16.7) | NA |
| No. (%) of patients with carbapenem use | |||
| Meropenem | 16 (88.9) | 16 (88.9) | >0.99 |
| Imipenem | 1 (5.6) | 2 (11.1) | >0.99 |
| Doripenem | 1 (5.6) | 0 | >0.99 |
| Mean duration of therapy ± SD (days) | 11 ± 8.5 | 11 ± 9.4 | >0.99 |
| No. (%) of patients on concomitant antibioticsa | 9 (50.0) | 14 (77.8) | 0.16 |
| One additional agent | 7 (38.9) | 8 (44.4) | 0.74 |
| Two additional agents | 2 (11.1) | 6 (33.3) | 0.23 |
Agent used to double-cover Gram-negative organism.
NA, not applicable.
Patients in the group with carbapenem MICs of 2, 4, and 8 mg/liter had significantly higher 30-day mortality than those in the group with carbapenem MICs of ≤1 mg/liter (38.9% compared to 5.6%, P = 0.04) (Table 3). Similar mortality rates were noted for MICs of 2, 4, and 8 mg/liter, at 40%, 40%, and 33%, respectively. Furthermore, the high-MIC group was associated with decreased overall survival by Kaplan-Meier log rank test (P = 0.01; Fig. 1). Total hospital LOS was numerically longer (57.6 days compared to 34.4 days, P = 0.06) and ICU LOS was significantly longer (56.6 days compared to 21.7 days, P < 0.01) in the group with MICs of 2 to 8 mg/liter than in the group with MICs of ≤1 mg/liter. Hospital readmission rates were similar between groups (27.3% and 17.6%, P = 0.65).
TABLE 3.
Clinical outcomes stratified by carbapenem MIC
| Outcome | Value |
P value | |
|---|---|---|---|
| MIC of ≤1 mg/liter | MIC of 2–8 mg/liter | ||
| No. of patients with 30-day mortality/total number of patients (%) | 1/18 (5.6) | 7/18 (38.9) | 0.04 |
| Mean total hospital length of stay ± SD, in days | 34.4 ± 25 | 57.6 ± 45 | 0.06 |
| Mean ICU length of stay ± SD, in days | 21.7 ± 19 | 56.6 ± 44 | <0.01 |
| No. of patients with 30-day hospital readmission/total number of patients (%) | 3/17 (17.6) | 3/11 (27.3) | 0.65 |
FIG 1.
Kaplan-Meier cumulative survival analysis: MICs of ≤1 mg/liter compared to MICs of 2 to 8 mg/liter.
DISCUSSION
To our knowledge, the results presented here represent the largest analysis of clinical outcomes associated with infections caused by Enterobacteriaceae stratified by carbapenem MIC. With the matched-cohort study design, we detected a statistically significant higher mortality rate and longer ICU LOS as well as numerically longer total hospital LOS and 30-day hospital readmission in the high-MIC group than in the low-MIC group. The results of this study, and various other studies assessing patient outcomes based upon MIC, illustrate the need to continuously reassess preestablished susceptibility breakpoints.
Bhat and colleagues (13) evaluated outcomes of patients with Gram-negative bacteremia treated with cefepime stratified by MIC. A classification and regression tree (CART) analysis conducted in their study revealed that a cefepime MIC of ≥8 mg/liter was associated with increased mortality (58.4% compared to 21.4%, P = 0.001), despite the fact that an MIC of 8 mg/liter was considered susceptible at the time of the study (13). Tam and colleagues (14) evaluated outcomes in patients with Pseudomonas aeruginosa bacteremia with reduced susceptibility (defined as an MIC of 32 to 64 mg/liter) to piperacillin-tazobactam, and the susceptibility breakpoint was ≤64 mg/liter at the time of the study. Among patients with a Pseudomonas bloodstream infection, a higher mortality rate was seen in those treated with piperacillin-tazobactam (MIC, 32 mg/liter or 64 mg/liter) than in those treated with other antipseudomonal agents (85.7% compared to 22.2%; P = 0.004). (14). Similarly, in patients with Gram-negative bacteremia treated with levofloxacin, DeFife et al. reported longer time to clearance of infection (2.1 days compared to 1.0 day, P < 0.001) and longer length of stay (16.4 days compared to 7.3 days, P = 0.02) for patients in the high-MIC group (defined as 1 mg/liter or 2 mg/liter) than for those with lower MICs, and the susceptibility breakpoint was 2 mg/liter at the time of the study (15).
Esterly and colleagues (16) conducted the first clinical study to evaluate the effect of carbapenem MIC on outcomes in patients with Gram-negative bacteremia and reported an increased probability of mortality in patients infected by Pseudomonas aeruginosa, Acinetobacter baumannii, or ESBL-producing Gram-negative bacteria with higher MICs. A CART analysis was conducted and identified an imipenem MIC of ≥4 mg/liter was associated with higher mortality than an MIC of ≤2 mg/liter (76.9% compared to 16.1%; P ≤ 0.01). However, only 4 (5.8%) isolates with imipenem MICs of 2, 4, and 8 mg/liter were included, which limits the ability to analyze clinical outcomes for isolates in this MIC range (16). Furthermore, the heterogeneity of pathogens makes it difficult to apply these results uniformly.
Although our study successfully demonstrated poor clinical outcomes with carbapenem MICs of ≥2 mg/liter, several limitations should be noted. First, evaluating outcomes for organisms with reduced susceptibility is challenging, as these infections are relatively uncommon and patients infected with these organisms are more likely to have multiple comorbidities and advanced age, which increase the risk for mortality. Thus, we conducted a matched-cohort study, which reasonably corrected for age, comorbidities, source of infection, pathogen, and disease severity. However, other factors that could have contributed to poor clinical outcomes may be different between groups. Second, we relied on automated susceptibility testing with Vitek 2 for MIC data, which were not verified by other susceptibility methods or duplicate testing. Additionally, we were limited via the retrospective nature of this study and availability of data in the electronic health record, which limits our ability to characterize and control for additional factors that could influence clinical outcomes. Furthermore, the majority of patients in this study received the standard dose of carbapenem therapy (equivalent to meropenem at 1,000 mg every 8 h). Our small sample size limits our ability to evaluate the influence of different dosing strategies on clinical outcomes. Maximizing carbapenem dosing or utilizing extended infusion carbapenems may have resulted in improved patient outcomes, as these strategies have been associated with improved probability of attaining pharmacodynamic targets (17). Finally, we did not have a robust enough data set to detect a difference in mortality and other clinical outcomes between patients with Enterobacteriaceae infections with carbapenem MICs of 2, 4, and 8 mg/liter.
In conclusion, the results reported in this study support the CLSI recommendation to lower the susceptibility breakpoint of meropenem, imipenem, and doripenem against Enterobacteriaceae from ≤4 mg/liter to ≤1 mg/liter. CLSI's recommendation was based on eliminating the need for microbiology laboratories to conduct testing for carbapenemase production in addition to results from mathematical models and Monte Carlo simulations predicting poor pharmacodynamic target attainment (11, 12, 18–20). We present clinical data illustrating poor outcomes with higher MICs. On the basis of our results along with those of Esterly and colleagues (16), alternative treatment approaches should be considered in isolates with higher MICs.
REFERENCES
- 1.D'Agata EM. 2004. Rapidly rising prevalence of nosocomial multidrug-resistant, Gram-negative bacilli: a 9-year surveillance study. Infect Control Hosp Epidemiol 25:842–846. doi: 10.1086/502306. [DOI] [PubMed] [Google Scholar]
- 2.Rhomberg PR, Jones RN. 2009. Summary trends for the Meropenem Yearly Susceptibility Test Information Collection Program: a 10-year experience in the United States (1999-2008). Diagn Microbiol Infect Dis 65:414–426. doi: 10.1016/j.diagmicrobio.2009.08.020. [DOI] [PubMed] [Google Scholar]
- 3.Talbot GH, Bradley J, Edwards JE Jr, Gilbert D, Scheld M, Bartlett JG, Antimicrobial Availability Task Force of the Infectious Diseases Society of America . 2006. Bad bugs need drugs: an update on the development pipeline from the Antimicrobial Availability Task Force of the Infectious Diseases Society of America. Clin Infect Dis 42:657–668. doi: 10.1086/499819. [DOI] [PubMed] [Google Scholar]
- 4.Boucher HW, Talbot GH, Bradley JS, Edwards JE, Gilbert D, Rice LB, Scheld M, Spellberg B, Bartlett J. 2009. Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America. Clin Infect Dis 48:1–12. doi: 10.1086/595011. [DOI] [PubMed] [Google Scholar]
- 5.Clinical and Laboratory Standards Institute. 2009. Performance standards for antimicrobial susceptibility testing. M100-S119. Clinical and Laboratory Standards Institute, Wayne, PA. [Google Scholar]
- 6.Clinical and Laboratory Standards Institute. 2010. Performance standards for antimicrobial susceptibility testing. M100-S120. Clinical and Laboratory Standards Institute, Wayne, PA. [Google Scholar]
- 7.Ambrose PG, Bhavnani SM, Jones RN, Craig WA, Dudley MN. 2004. Use of pharmacokinetic-pharmacodynamic and Monte Carlo simulation as decision support for the reevaluation of NCCLS cephem susceptibility breakpoints for Enterobacteriaceae, abstr A-138. Abstr 44th Intersci Conf Antimicrob Agents Chemother ASM, Washington, DC. [Google Scholar]
- 8.Bhavnani SM, Ambrose PG, Craig WA, Dudley MN, Jones RN. 2006. Outcomes evaluation of patients with ESBL- and non-ESBL-producing Escherichia coli and Klebsiella species as defined by CLSI reference methods: report from the SENTRY Antimicrobial Surveillance Program. Diagn Microbiol Infect Dis 54:231–236. doi: 10.1016/j.diagmicrobio.2005.09.011. [DOI] [PubMed] [Google Scholar]
- 9.Craig WA, Bhavnani SM, Ambrose PG, Dudley MN, Jones RN. 2005. Evaluation of clinical outcomes among patients with ESBL producing Enterobacteriaceae treated with cephalosporin monotherapy, abstr K-1291. Abstr 45th Intersci Conf Antimicrob Agents Chemother. ASM, Washington, DC. [Google Scholar]
- 10.The European Committee on Antimicrobial Susceptibility Testing. 2014. Breakpoint tables for interpretation of MICs and zone diameters. Version 4.0. http://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/Breakpoint_tables/Breakpoint_table_v_4.0.pdf.
- 11.Clinical and Laboratory Standards Institute. 2010. January 2010 meeting presentation: Enterobacteriaceae WG report. Clinical and Laboratory Standards Institute, Wayne, PA. [Google Scholar]
- 12.Patel G, Huprikar S, Factor SH, Jenkins SG, Calfee DP. 2008. Outcomes of carbapenem-resistant Klebsiella pneumoniae infection and the impact of antimicrobial and adjunctive therapies. Infect Control Hosp Epidemiol 29:1099–1106. doi: 10.1086/592412. [DOI] [PubMed] [Google Scholar]
- 13.Bhat SV, Peleg AY, Lodise TP Jr, Shutt KA, Capitano B, Potoski BA, Paterson DL. 2007. Failure of current cefepime breakpoints to predict clinical outcomes of bacteremia caused by Gram-negative organisms. Antimicrob Agents Chemother 51:4390–4395. doi: 10.1128/AAC.01487-06. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Tam VH, Gamez EA, Weston JS, Gerard LN, Larocco MT, Caeiro JP, Gentry LO, Garey KW. 2008. Outcomes of bacteremia due to Pseudomonas aeruginosa with reduced susceptibility to piperacillin-tazobactam: implications on the appropriateness of the resistance breakpoint. Clin Infect Dis 46:862–867. doi: 10.1086/528712. [DOI] [PubMed] [Google Scholar]
- 15.DeFife R, Scheetz MH, Feinglass JM, Postelnick MJ, Scarsi KK. 2009. Effect of differences in MIC values on clinical outcomes in patients with bloodstream infections caused by Gram-negative organisms treated with levofloxacin. Antimicrob Agents Chemother 53:1074–1079. doi: 10.1128/AAC.00580-08. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Esterly JS, Wagner J, McLaughlin MM, Postelnick MJ, Qi C, Scheetz MH. 2012. Evaluation of clinical outcomes in patients with bloodstream infections due to Gram-negative bacteria according to carbapenem MIC stratification. Antimicrob Agents Chemother 56:4885–4890. doi: 10.1128/AAC.06365-11. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Daikos GL, Markogiannakis A. 2011. Carbapenemase-producing Klebsiella pneumoniae: (when) might we still consider treating with carbapenems? Clin Microbiol Infect 17:1135–1141. doi: 10.1111/j.1469-0691.2011.03553.x. [DOI] [PubMed] [Google Scholar]
- 18.Bhavnani SM, Dudley MN, Landersdorfer L, Drusano GL, Craig WA, Jones RN, Ambrose PG. 2010. Pharmacokinetic-pharmacodynamic basis for CLSI carbapenem susceptibility breakpoint changes, abstr A-1382. Abstr 50th Intersci Conf Antimicrob Agents Chemother. ASM, Washington, DC. [Google Scholar]
- 19.Krueger WA, Bulitta J, Kinzig-Schippers M, Landersdorfer C, Holzgrabe U, Naber KG, Drusano GL, Sörgel F. 2005. Evaluation by Monte Carlo simulation of the pharmacokinetics of two doses of meropenem administered intermittently or as a continuous infusion in healthy volunteers. Antimicrob Agents Chemother 49:1881–1889. doi: 10.1128/AAC.49.5.1881-1889.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Lee LS, Kinzig-Schippers M, Nafziger AN, Ma L, Sörgel F, Jones RN, Drusano GL, Bertino JS Jr. 2010. Comparison of 30-min and 3-h infusion regimens for imipenem/cilastatin and for meropenem evaluated by Monte Carlo simulation. Diagn Microbiol Infect Dis 68:251–258. doi: 10.1016/j.diagmicrobio.2010.06.012. [DOI] [PubMed] [Google Scholar]