Comparison of ß-lactam regimens for the treatment of Gram-negative pulmonary infections in the intensive care unit based on pharmacokinetics/pharmacodynamics

David S. Burgess1,2,* and Christopher R. Frei1,3

1 College of Pharmacy, The University of Texas at Austin, 1 University Station Stop A1900, Austin, TX, USA 78712; 2 Departments of Pharmacology and Medicine, The University of Texas Health Science Center at San Antonio, Clinical Pharmacy Programs-MSC 6220, 7703 Floyd Curl Dr., San Antonio, TX, USA 78229–3900; 3 Department of Pharmacology, The University of Texas Health Science Center at San Antonio, Clinical Pharmacy Programs-MSC 6220, 7703 Floyd Curl Dr., San Antonio, TX, USA 78229–3900


* Corresponding author. Tel: +1-210-567-8329; Fax: +1-210-567-8328; Email: BurgessD{at}uthscsa.edu

Received 27 May 2005; returned 5 July 2005; revised 19 August 2005; accepted 24 August 2005


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Objectives: This study utilized pharmacokinetics/pharmacodynamics to compare ß-lactam regimens for the empirical and definitive treatment of Gram-negative pulmonary infections in the ICU.

Methods: Susceptibility data were extracted from the 2002 Intensive Care Unit Surveillance System (ISS) and pharmacokinetic parameters were obtained from published human studies. Monte Carlo simulation was used to model the free percent time above the MIC (free %T > MIC) for 18 ß-lactam regimens against all Gram-negative isolates, Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii. The cumulative fraction of response (CFR) was determined for bacteriostatic and bactericidal targets (free %T > MIC): penicillins (≥30/50%), cephalosporins/monobactams (≥40/70%) and carbapenems (≥20/40%).

Results: The 2002 ISS database contained MICs for 2408 Gram-negative isolates including 1430 Enterobacteriaceae, 799 P. aeruginosa, and 179 A. baumannii. Imipenem had the highest percentage susceptible for all Gram-negatives, Enterobacteriaceae and A. baumannii, while piperacillin/tazobactam had the highest percentage susceptible for P. aeruginosa. For empirical therapy, imipenem 0.5 g every 6 h, cefepime 2 g every 8 h and ceftazidime 2 g every 8 h demonstrated the highest CFR. For definitive therapy, imipenem 0.5 g every 6 h, ertapenem 1 g daily and cefepime 2 g every 8 h, cefepime 1 g every 8 h and cefepime 1 g every 12 h had the highest bactericidal CFR against Enterobacteriaceae; ceftazidime 2 g every 8 h, cefepime 2 g every 8 h, piperacillin/tazobactam 3.375 g every 4 h, ceftazidime 1 g every 8 h and aztreonam 1 g every 8 h against P. aeruginosa; and imipenem 0.5 g every 6 h, ticarcillin/clavulanate 3.1 g every 4 h, ceftazidime 2 g every 8 h, cefepime 2 g every 8 h and ticarcillin/clavulanate 3.1 g every 6 h against A. baumannii.

Conclusions: Based on pharmacokinetics/pharmacodynamics, imipenem 0.5 g every 6 h, cefepime 2 g every 8 h and ceftazidime 2 g every 8 h should be the preferred ß-lactam regimens for the empirical treatment of Gram-negative pulmonary infections in the ICU. The order of preference varied against Enterobacteriaceae, P. aeruginosa and A. baumannii.

Keywords: Pharmacokinetics/pharmacodynamics , Gram-negative aerobic bacteria , pneumonia , bacterial


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Antimicrobial resistance impedes effective treatment of patients with serious infections and is of particular concern for ICU patients. Enterobacteriaceae are among the most prevalent human pathogens and compose 80% of Gram-negative bacteria and 50% of all isolates identified in USA hospital laboratories.1 Pseudomonas aeruginosa and Acinetobacter baumannii are the most prevalent non-fermentative bacterial species isolated from clinical specimens of hospitalized patients.2 Furthermore, P. aeruginosa is the leading cause of nosocomial respiratory tract infections and is of particular concern for patients who require mechanical ventilation.2 Resistance among Gram-negative bacteria has increased at an alarming rate and has prompted the scientific community to develop therapeutic strategies that counteract emerging antimicrobial resistance.

Hospital-acquired pneumonia is the second most common nosocomial infection in the USA and is responsible for 25% of all ICU infections.3,4 Hospital-acquired pneumonia increases hospital stays by 7–9 days and has an attributable mortality rate of 33–50%.57 The American Thoracic Society (ATS) and the Infectious Diseases Society of America (IDSA) have published guidelines for the management of adults with hospital-acquired pneumonia.7 The general clinical strategy for empirical therapy is to administer antibiotics with efficacy against the most common and most deadly suspected pathogens. Failure to do so has been correlated with poor outcomes in multiple studies.814 Furthermore, delayed appropriate therapy has been shown to increase hospital mortality, and changing therapy when cultures return may not be enough to reduce the excess risk of hospital mortality.8,11,12,15 The ATS and IDSA guidelines for hospital-acquired pneumonia (HAP) reflect the concerns for timely, appropriate, initial empirical antibiotic therapy.7

This study evaluated the pharmacokinetics/pharmacodynamics (PK/PD) of 18 ß-lactam regimens (e.g. penicillins, cephalosporins, monobactams and carbapenems) against aerobic Gram-negative bacteria isolated from pulmonary cultures of ICU patients in the USA. The aim was to provide PK/PD information to compare ß-lactams for the empirical and definitive treatment of pulmonary infections in the ICU. These therapies were then compared with the ATS and IDSA recommendations for the empirical treatment of HAP.


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Bacterial isolates

MIC distributions were extracted from the 2002 Intensive Care Unit Surveillance System (ISS) database (Merck and Company, Inc., Rahway, NJ). Complete methodology for the ISS database has been previously described.16,17 In short, the ISS database is a multi-year, national survey of antimicrobial resistance rates among aerobic Gram- negative bacteria recovered from USA ICU patients. Each participating institution tested 100–200 consecutive Gram-negative aerobic isolates. Organisms were identified to the species level by the method used within each institution, and susceptibility tests were performed with a standardized custom microtitre MIC panel. Testing procedures were validated by determining the MICs for reference strains, as recommended by CLSI (formerly the NCCLS).18 Escherichia coli and Klebsiella spp. were tested for the presence of extended-spectrum ß-lactamases (ESBLs) by conducting susceptibility testing with cefepime with and without clavulanic acid.19 A reduction in MIC of at least fourfold in the presence of clavulanic acid was considered indicative of an ESBL.

For the purpose of this analysis, MIC distributions were based on MICs from pulmonary cultures only. MIC50, MIC90 and percentage susceptible were determined in accordance with CLSI (formerly NCCLS) standards.18 The percentage susceptible was calculated using the appropriate CLSI susceptibility breakpoint for each species. For the ‘overall’ category, the percentage susceptible was determined by dividing the sum of the Enterobacteriaceae, A. baumannii and P. aeruginosa isolates with MICs at or below the susceptible breakpoint by the sum of all Enterobacteriaceae, A. baumannii and P. aeruginosa isolates.

Antimicrobial regimens

A total of 18 ß-lactam regimens were modelled including aztreonam 1 g and 2 g every 8 h; cefepime 1 g every 12 h, 1 g every 8 h, 2 g every 12 h and 2 g every 8 h; ceftazidime 1 g and 2 g every 8 h; ceftriaxone 1 g and 2 g daily; ertapenem 1 g daily; imipenem 0.5 g every 6 h; piperacillin/tazobactam 3.375 g every 4 h, 3.375 g every 6 h, 4.5 g every 6 h and 4.5 g every 8 h; and ticarcillin/clavulanate 3.1 g every 4 h and every 6 h. For each antimicrobial regimen, the investigators obtained pharmacokinetic parameters and their variability from healthy human studies (Table 1).2027 Pharmacokinetic studies were identified through separate MEDLINE searches that combined the exploded MeSH heading ‘pharmacokinetics’ with the antibiotic generic name. The results were limited to healthy human studies published in English during 1980–2003. In addition, studies were required to meet three minimum criteria: evaluation of clinically relevant dosing regimens, use of rigorous study methods and provision of mean (SD) values for the pharmacokinetic parameters of interest.


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Table 1. ß-Lactam pharmacokinetic parameters

 
Pharmacodynamic models

Ten thousand subjects were simulated using Crystal Ball (Decisioneering, Inc., Denver, CO) for each organism–regimen combination based on published pharmacokinetic parameters, their variability, and MIC distributions from the 2002 ISS database. The percentage time that the free drug concentration remained above the MIC (free %T > MIC) was calculated according to an intravenous bolus model that permitted variation in the volume of distribution, half-life and protein binding according to a normal distribution.28 For the ß-lactam/ß-lactamase inhibitor combinations, the ß-lactam pharmacokinetic parameters and the ß-lactam/ß-lactamase inhibitor MICs were used in the models. The cumulative fraction of response (CFR) was determined for bacteriostatic and bactericidal PK/PD targets (free %T > MIC): penicillins (≥30/50%), cephalosporins/monobactams (≥40/70%) and carbapenems (≥20/40%).2931 The CFR was calculated as described by Mouton et al.32 and is defined as ‘the expected population probability of target attainment for a specific drug dose and a specific population of microorganisms’. Antimicrobial regimens were sorted in descending order according to CFR. Regimens with the highest CFR against all Gram-negative isolates were considered to be the preferred empirical therapies. Regimens with the highest CFR against Enterobacteriaceae, P. aeruginosa and A. baumannii were considered to be the preferred definitive therapies.


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Antimicrobial susceptibility

The 2002 ISS database comprised susceptibility data for 2408 Gram-negative pulmonary isolates including Enterobacteriaceae (n = 1430), P. aeruginosa (n = 799) and A. baumannii (n = 179). Enterobacteriaceae included Citrobacter spp. (n = 35), Enterobacter aerogenes (n = 128), Enterobacter cloacae (n = 277), E. coli (n = 212), Klebsiella oxytoca (n = 87), Klebsiella pneumoniae (n = 377), Morganella morganii (n = 13), Proteus mirabilis (n = 77) and Serratia marcescens (n = 224). ESBLs were identified in K. pneumoniae (14%), E. coli (10%) and K. oxytoca (9%) species.

Table 2 depicts antimicrobial activity against Gram-negative isolates from the 2002 ISS database. Imipenem demonstrated the best activity (highest percentage susceptible) against all Gram-negatives (91%), Enterobacteriaceae (100%) and A. baumannii (83%), whereas piperacillin/tazobactam demonstrated the best activity against P. aeruginosa (89%). Another notable observation was the excellent activity of ertapenem against Enterobacteriaceae (97% susceptible) compared with other antimicrobial alternatives.


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Table 2. Antimicrobial susceptibility against Gram-negative pulmonary isolates from the 2002 ISS databasea

 
Antimicrobial pharmacodynamics

Table 3 depicts the bacteriostatic and bactericidal CFR for each ß-lactam regimen against Gram-negative pulmonary isolates from the 2002 ISS database. The order of antibiotic regimens was similar regardless of whether the bacteriostatic or bactericidal CFR was used. For empirical therapy (all Gram-negative isolates), imipenem 0.5 g every 6 h, cefepime 2 g every 8 h and ceftazidime 2 g every 8 h demonstrated the highest CFR.


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Table 3. Cumulative fraction of response (CFR) for ß-lactams against Gram-negative pulmonary isolates from the 2002 ISS databasea

 
The order of preference varied somewhat for definitive antimicrobial therapy. Imipenem 0.5 g every 6 h (97%), ertapenem 1 g daily (95%), cefepime 2 g every 8 h (95%), cefepime 1 g every 8 h (92%) and cefepime 1 g every 12 h (91%) had the highest bactericidal CFRs against Enterobacteriaceae. For P. aeruginosa, the greatest likelihoods of achieving bactericidal targets were observed for ceftazidime 2 g every 8 h (83%), cefepime 2 g every 8 h (80%), piperacillin/tazobactam 3.375 g every 4 h (78%), ceftazidime 1 g every 8 h (77%) and aztreonam 1 g every 8 h (73%). Finally, against A. baumannii, relatively modest bactericidal CFRs were seen with imipenem 0.5 g every 6 h (72%), ticarcillin/clavulanate 3.1 g every 4 h (52%), ceftazidime 2 g every 8 h (49%), cefepime 2 g every 8 h (45%) and ticarcillin/clavulanate 3.1 g every 6 h (43%).


    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
This study utilized PK/PD modelling to assist in identifying preferred ß-lactams for the empirical and definitive treatment of pulmonary infections in the intensive care unit. While PK/PD studies are not the only criteria to consider when making therapeutic decisions, these studies enable clinicians to consider simultaneously the in vitro activity and pharmacokinetic profile of a given antibiotic regimen. Coupled with the knowledge of clinical trial results, resistance mechanisms, local susceptibility patterns and patient characteristics, such information enhances clinical decision making and ensures the delivery of optimal care.

Findings from the present study are consistent with two recent PK/PD studies.33,34 Both studies constructed PK/PD models based on pharmacokinetic data from healthy human subjects and MIC distributions from the 2002 Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) database; however, Kuti et al.33 used MIC distributions from the USA subset whereas Masterton et al.34 used MIC distributions from the European subset. Importantly, neither study limited the MICs to pulmonary isolates from ICU patients. While the pharmacokinetic parameters in both of the comparison studies were relatively similar to those in the present study, the MIC50 was generally 1–2 dilutions higher for the pulmonary subset of the 2002 ISS database compared with either the USA subset or the European subset of the 2002 MYSTIC database. In fact, the MIC50 was four dilutions higher for ceftazidime against Enterobacteriaceae and A. baumannii, as well as piperacillin/tazobactam against A. baumannii in the USA subset of the 2002 MYSTIC database. Nevertheless, all three studies observed similar trends. Kuti et al.33 concluded that meropenem, imipenem and cefepime attained the highest bactericidal CFRs against Enterobacteriaceae. In addition, Kuti et al.33 found that the carbapenems had the highest bactericidal CFRs versus A. baumannii. In concert with the current study, Kuti et al.33 concluded that carbapenems and higher doses of penicillins and cephalosporins would be the most appropriate choices for P. aeruginosa infections. Likewise, Masterton et al.34 found that while the CFRs varied across Europe, the carbapenems had the highest CFR against E. coli, K. pneumoniae, A. baumannii and P. aeruginosa. Finally, meropenem was not evaluated in the present study because meropenem MIC distributions were not available in the 2002 ISS surveillance database.

In most instances, findings from the current study support antibiotic choices and regimens promulgated in the 2005 ATS and IDSA guidelines for patient with HAP.7 The guidelines cite several risk factors for multi-drug resistant (MDR) pathogens, including prior antimicrobial therapy, extended hospitalization, a high frequency of resistance in the community and immunosuppressive disease or therapy. Unfortunately, patient characteristics were not evaluated in this study so it was not possible to determine how risk factors for MDR pathogens contributed to these findings; however, 42% of isolates would be considered MDR pathogens (ESBLs, P. aeruginosa, or A. baumannii) as defined in the HAP guidelines. For the treatment of patients with HAP plus risk factors for MDR pathogens, the guidelines recommend an antipseudomonal ß-lactam (cephalosporin, carbapenem, or ß-lactam/ß-lactamase inhibitor), plus an antipseudomonal fluoroquinolone or aminoglycoside, plus linezolid or vancomycin. With regard to the choice of ß-lactams, both the present study and the guidelines recommend imipenem 0.5 g every 6 h, cefepime 2 g every 8 h and ceftazidime 2 g every 8 h for patients with HAP who are at risk for MDR pathogens; however, this study would support limiting the use of ertapenem to HAP patients without risk factors for MDR pathogens and avoiding ceftriaxone as empirical therapy for HAP regardless of the presence of risk factors for MDR pathogens. Also, the guidelines recommend piperacillin/tazobactam 4.5 g every 6 h; however, this study demonstrates that the CFR could be slightly improved by increasing the dose to 3.375 g every 4 h. Alternate regimens of 3.375 g every 6 h and 4.5 g every 8 h resulted in slightly lower CFRs. Finally, for HAP patients with risk factors for MDR pathogens, the present study supports limiting the recommended cefepime dose to 2 g every 8 h, rather than 1–2 g every 8–12 h, as currently recommended by the guidelines.

Pharmacodynamic models can assist in empirical antibiotic selection, but additional criteria are also important when selecting empirical antimicrobials. Although ceftazidime, cefepime and the carbapenems seem to be very good for empirical therapy based on PK/PD models, the use of ceftazidime has been associated with increased drug resistance including vancomycin-resistant Enterococcus, ESBLs and Enterobacter spp.3539 In addition, recent reports have documented the emergence of carbapenemases in the clinical setting.40 Furthermore, while this study primarily addresses empirical therapy, it is important to recognize the basic tenets of infectious diseases pharmacotherapy. Broad-spectrum therapy is required initially and drug choice should be dictated by a high probability of success against the most likely pathogens. However, prescribers must use broad-spectrum agents sparingly. When the cultures return and the pathogen has been identified, the broad-spectrum agent should be discontinued and narrow-spectrum agents should be substituted in order to reduce selective pressure. Probably the most noteworthy benefit of PK/PD models is that they provide guidance to enhance dosing precision. PK/PD does not simply address, ‘which drug?’ but rather, ‘what dose of which drug against a specific bacterial strain?’. This treatment precision is particularly important for bacteria with elevated MICs (for example P aeruginosa).

While the present study provides useful information regarding preferred therapies on the basis of PK/PD, there are some potential limitations. First, the PK/PD equation used to construct the models represents a one-compartment intravenous bolus model and does not consider the time above the MIC allotted by the time of infusion. While the PK/PD impact is minimal for short intravenous infusions (≤30 min), prolonged or continuous infusions would enhance the ability of a given ß-lactam regimen to achieve PK/PD targets.41 Also, the PK/PD models were based on pharmacokinetic data from healthy human studies. Patients would be expected to have poorer renal function, which would thereby decrease the clearance of renally eliminated antimicrobials and could result in higher CFRs. However, it has been demonstrated that the CFR calculated using pharmacokinetic data from healthy subjects was not statistically different from that calculated using patients' pharmacokinetic data.42 Furthermore, the MIC distributions only included isolates from USA ICUs; therefore, caution should be exercised when extrapolating these results to international communities. In addition, the prevalence of organisms in the empirical therapy analysis was assumed to be consistent with the incidence of consecutive isolates identified in the ISS database; however, it is possible for the prevalence in specific institutions to vary somewhat. Notably, only Gram-negative isolates were evaluated in this study; however, Staphylococcus aureus is a common cause of nosocomial pneumonia.7 Since MRSA strains have become more prevalent, the current nosocomial pneumonia guidelines recommend an anti-MRSA antibiotic as part of appropriate empirical therapy.7 Finally, the present study employed serum pharmacokinetics rather than pulmonary pharmacokinetics. Since ß-lactams have less than 100% penetration into lung, PK/PD models based on serum pharmacokinetics may overestimate the CFR at the site of infection. Despite these limitations, this study provides insight as to the preferred ß-lactam regimens for the treatment of pulmonary infections in the ICU.

In conclusion, pharmacokinetic/pharmacodynamic models suggest that imipenem 0.5 g every 6 h, cefepime 2 g every 8 h and ceftazidime 2 g every 8 h should be preferred for the empirical treatment of Gram-negative pulmonary infections in the ICU. These recommendations are consistent with the 2005 ATS and IDSA guidelines for the treatment of patients with hospital-acquired pneumonia.

Transparency declarations

D.S.B. has received research grants, served as a consultant, or served on a speaker's bureau for the following pharmaceutical companies: Merck & Co., Ortho-McNeil Pharmaceuticals, Roche Pharmaceuticals and Wyeth Pharmaceuticals. C.R.F. has received research grants from Merck & Co., Roche Pharmaceuticals, and Wyeth Laboratories.


    Acknowledgements
 
The authors would like to thank Michelle Tomasini and Michael Carden for their excellent technical assistance. This manuscript was presented in part at the 2004 Annual Meeting of the American College of Clinical Pharmacy, October 24–27, 2004 in Dallas, TX. This study was partially supported by an unrestricted grant from Merck & Co.


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 Introduction
 Methods
 Results
 Discussion
 References
 
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