Infectious Diseases

Comparing Outcomes of Meropenem Administration Strategies
Based on Pharmacokinetic and Pharmacodyn...
J Perrott et al.

fect.4-7 However, none of these articles represented the         mortality, clinical or bacteriological ...
Outcomes of Meropenem Administration Strategies Based on Pharmacokinetic and Pharmacodynamic Principles

ed from patients ...
J Perrott et al.

of achieving pharmacodynamic targets. Important to note,          changed to 500 mg every 8 hours. Their...
Outcomes of Meropenem Administration Strategies Based on Pharmacokinetic and Pharmacodynamic Principles

tional intermitte...
J Perrott et al.

Patel and Duquaine,24 Patel et al.,25 Arnold et al.,26 and         verse effects with these various regi...
Outcomes of Meropenem Administration Strategies Based on Pharmacokinetic and Pharmacodynamic Principles

 9. Craig WA, Ebe...
J Perrott et al.

alternativas para meropenem fueron estudiadas mayormente en                     La mesure de résultats p...
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Comparing outcomes of meropenem administration strategies 2010

  1. 1. Infectious Diseases Comparing Outcomes of Meropenem Administration Strategies Based on Pharmacokinetic and Pharmacodynamic Principles: A Qualitative Systematic Review Jerrold Perrott, Vincent H Mabasa, and Mary HH Ensom eropenem is a broad-spectrum an- M tibiotic indicated for the treatment of a broad range of infections.1 Pharma- OBJECTIVE: To systematically review evidence comparing traditional and alternative dosing strategies for meropenem, based on clinical and pharmaco- cokinetically, meropenem exhibits linear economic outcomes. behavior and has an average steady-state DATA SOURCES: MEDLINE (1950–September 2009), EMBASE (1980–September 2009), and International Pharmaceutical Abstracts (1970–September 2009) were volume of distribution of 20.6 L, mean searched, using the terms meropenem, carbapenems, pharmacodynamics, and total clearance of 253 mL/min, mean re- pharmacokinetics. Reference citations from publications identified were reviewed. nal clearance of 182 mL/min, and a ter- STUDY SELECTION AND DATA EXTRACTION: Articles discussing administration of minal elimination half-life of 1.1 hours meropenem to adults with normal renal function and comparing at least 2 in healthy volunteers.2 When reconstitut- regimens, 1 of which included the manufacturer-recommended regimen of 0.5 g ed in 0.9% NaCl at concentrations up to or 1 g every 8 hours infused over 30 minutes, with clinical, pharmacodynamic, or 2000 mg in 50 mL, it is stable for up to pharmacoeconomic endpoints, were included. The pharmacodynamic endpoint of interest was percent time that the unbound drug concentration exceeded the 17 hours at room temperature,3 although minimal inhibitory concentration for a bacterial pathogen. the product monograph1 quotes stability DATA SYNTHESIS: Sixteen studies were reviewed, which included 13 pharmaco- for only 4 hours. kinetic and dynamic assessments using Monte Carlo simulations, 5 clinical evalu- Meropenem’s in vitro effect is best de- ations, and 3 pharmacoeconomic appraisals. Data on clinical and economic scribed by its minimum inhibitory con- outcomes are largely nonrandomized retrospective analyses and case reports. centration (MIC) against specific patho- Meropenem via intermittent prolonged infusion potentially increases the likelihood of gens, whereas its in vivo effect is aug- achieving pharmacodynamic targets. However, a strong link with improved clinical outcomes is lacking. Smaller doses with shorter intervals appear to provide mented by host immune function; thus, pharmacodynamic target attainment rates and clinical outcomes similar to those pharmacodynamic modeling is utilized with traditional dosing, with potential pharmacoeconomic benefits. Meropenem via to predict its activity. Meropenem ex- continuous infusion appears to increase the likelihood of achieving pharma- hibits time-dependent bactericidal activi- codynamic targets, compared with intermittent infusions. The sparsity of clinical ty, whereby its efficacy is best predicted evidence supporting this practice limits its broad application to practice. No studies by the pharmacodynamic parameter of have formally examined adverse effects with alternative dosing regimens. percent time that the unbound drug con- CONCLUSIONS: Meropenem alternative dosing strategies provide similar pharma- codynamic target attainment rates compared with traditional dosing strategies. centration exceeds the MIC for a bacteri- Small doses with shorter interval dosing provide additional pharmacoeconomic al pathogen (%fT>MIC). Previous articles benefits and similar clinical outcomes. Alternative dosing strategies for mero- have identified that achieving greater penem were largely studied in healthy subjects; individuals with pharmacokinetic than or equal to 40% fT>MIC correlates parameters that differ significantly may be ideal subjects for empiric dose modi- with bactericidal efficacy in vivo, while fication. achieving greater than or equal to 20% KEY WORDS: dosing, meropenem, pharmacodynamics, pharmacokinetics. fT>MIC correlates with bacteriostatic ef- Ann Pharmacother 2010;44:557-64. Published Online, 2 Feb 2010,, DOI 10.1345/aph.1M339 Author information provided at end of text. The Annals of Pharmacotherapy I 2010 March, Volume 44 I 557
  2. 2. J Perrott et al. fect.4-7 However, none of these articles represented the mortality, clinical or bacteriological cure rates, and adverse original research, cited only in abstracts.8,9 To our knowl- event rates. The pharmacodynamic endpoint of interest edge, the 40% rule has been accepted with little scientific was %fT>MIC. support, as only one published full article has studied the 40% rule and only for Pseudomonas aeruginosa express- Literature Review ing efflux pumps.10 Other β-lactam antibiotics also exhibit time-dependent bactericidal characteristics but have vary- A total of 456 reference titles were reviewed for rele- ing pharmacodynamic targets. As such, extrapolating out- vance, 108 abstracts were screened, and 20 unique articles come data between agents may not be appropriate, though were retrieved for full review. Reference lists of published the general principles hold true. review articles and recent conference proceedings were Numerous pharmacodynamic-based strategies have manually screened for additional references, yielding 5 been proposed for meropenem to enhance its clinical effi- further results. Nine articles were excluded from this re- cacy. The purpose of this qualitative systematic review is view, leaving a total of 16 references summarized below to answer the question: For adults requiring therapy with (Figure 1). Commonly used terminology within these stud- meropenem, do alternative dosing strategies, including ad- ies included: cumulative fraction of response (CFR), de- ministration by continuous or prolonged infusion or by fined as the expected population probability of attaining smaller doses given more frequently, compared with tradi- greater than or equal to 40% fT>MIC, given the specified tional dosing, enhance effectiveness as assessed by clinical population of pathogens; and probability of target attain- response rates or decrease cost without increasing the risk ment (PTA), defined as the likelihood that a specific phar- of adverse effects? macodynamic index will be achieved at a given MIC.11 Data Sources and Selection PROLONGED INFUSION TIME MEDLINE (1950 –September 8, 2009), EMBASE Eight references12-19 examined, via Monte Carlo simula- (1980–September 8, 2009), and International Pharmaceu- tions, the effects of prolonging the administration of each tical Abstracts (1970–September 8, 2009) were systemati- meropenem dose from the traditional infusion time of 30 cally searched to identify relevant published references, minutes to a prolonged infusion time of 2– 4 hours, with 3 utilizing the search terms meropenem, carbapenems, phar- hours being most commonly used. The idea of utilizing ap- macodynamics, pharmacokinetics, and combinations proximately one half of the dosing intervals for the infusion thereof. No language restriction was applied to the search. still allows administration of other incompatible medications Articles discussing the administration of meropenem to to patients with limited intravenous access. Six12-15,17,18 of adults and comparing at least 2 regimens, 1 of which in- these studies used a common endpoint of CFR , whereas cluded the manufacturer-recommended regimen of 0.5 g or one study16 presented the PTA. Results are outlined in Ta- 1 g every 8 hours infused over 30 minutes,1 with either bles 1 and 2.12-20 Only data for Monte Carlo models of P. clinical or pharmacodynamic endpoints, were included in aeruginosa MICs are presented in the tables, as this organism this review. Specific clinical endpoints of interest were represents the most common gram-negative pathogen isolat- Figure 1. Search strategy flow diagram. 558 I The Annals of Pharmacotherapy I 2010 March, Volume 44
  3. 3. Outcomes of Meropenem Administration Strategies Based on Pharmacokinetic and Pharmacodynamic Principles ed from patients in intensive care units in the US.21 The studies of healthy volunteers. Zelenitsky et al.17 stated that eighth study, by Jaruratanasirikul et al.19 compared the mean their model utilized pharmacokinetic data from a population calculated % fT>MIC of 9 patients who received meropenem model with 3 levels of renal function. in 3 consecutive regimens: 1-g intravenous bolus injection Similarly, MIC data were not uniformly used in these over 10 minutes and 3-hour intravenous infusions of 1 g and studies. Lomaestro and Drusano,12 Kuti et al.,15 and Zelenit- 2 g. At their specified MICs of 4 µg/mL, the mean %fT>MICs sky et al.17 utilized MIC data from the MYSTIC (Mero- were 57%, 73%, and 86% (p < 0.05 vs bolus), respectively. penem Yearly Susceptibility Test Information Collection)22 In developing the Monte Carlo simulations, various program to generate MIC distributions for use within their sources for the patient pharmacokinetic parameters were uti- Monte Carlo models. They did use different periods for lized. Lomaestro and Drusano12 obtained their patient data their MIC data; however, this is not a limitation but rather a from AstraZeneca, which provided a collection obtained reflection of the evolving data on MICs, with Lomaestro from 18 studies, including 110 healthy volunteers and 46 pa- and Drusano taking their data from 1997–2002 and Kuti et tients. The studies by Kiffer et al.13 and Ludwig et al.14 uti- al. generating their curves from 1997–1998 data. Kiffer et lized pharmacokinetic data from previously published studies al.,13 Ludwig et al.,14 and Wang et al.16 utilized local isolate of healthy volunteers. Jaruratanasirikul et al.19 obtained their data from Brazil, Hungary, and China, respectively, in 2004 pharmacokinetic data from 9 patients who were admitted to to generate their MIC distributions within their Monte Car- their facility with ventilator-associated pneumonia (VAP). Li lo models. Taking an alternative approach and utilizing set et al.18 utilized pharmacokinetic data from 3 previous trials in MIC values, Li et al.18 and Jaruratanasirikul et al.19 utilized patients with intraabdominal infections, community-acquired a meropenem sensitivity breakpoint within their models. pneumonia, or VAP. Kuti et al.15 and Wang et al.16 both ob- Overall, it appears that administering meropenem via in- tained their pharmacokinetic data from previously published termittent, prolonged infusion does increase the likelihood Table 1. Cumulative Fraction of Response Against Pseudomonas aeruginosa Isolates Cumulative Fraction of Response (≥40% fT>MIC), % Clearance, Volume of 0.5 g 0.5 g 0.5 g 1g 1g 2g 2g 2g Mean Distribution, q6h q8h q8h q8h q8h q8h q8h q12h Reference (L/h) Mean (L) TI TI PI TI PI TI PI PI Lomaestro (2005)12 13.6 13.4a 76 68 79 80 86 Kiffer (2007)13 NSb NSb 81 88 Ludwig (2006)14 NSb NSb 77 84 84 88 Kuti (2003)15 14.4–15.6 18.6–22.3c 74d 75d 79d 80d 84d 76d Wang (2007)16 18.7 31.0e 81 78 83 85 90 Zelenitsky (2009)17 NSf NSf 100 100 100 100 MIC = minimum inhibitory concentration; NS = not stated; %fT>MIC = percent time that unbound drug concentration exceeds bacterial MIC; PI = pro- longed infusion; TI = traditional infusion. a Central volume of distribution. b Data source referenced within publication. c Volume of distribution at steady-state. d Cumulative fraction of response calculated as greater than or equal to 50% fT>MIC. e Calculated by volume of distribution = clearance/(0.693/half-life), from data within publication. f Data source not referenced within publication. Table 2. Probability of Target Attainment Across Studies Clearance, Volume of Probability of Target Attainment at MIC = 4 µg/mL (%) Mean Distribution, Reference (L/h) Mean (L) 0.5 g q6h 1 g q6h 1 g q8h 1 g q8h PI 2 g q8h Li (2006)18 12.3 10.3a 64 90 Kuti (2003)20 NSb 17.8–19.1 44 61 46 58 MIC = minimum inhibitory concentration; NS = not stated; PI = prolonged infusion. a Central volume of distribution. b Data source referenced within publication. The Annals of Pharmacotherapy I 2010 March, Volume 44 I 559
  4. 4. J Perrott et al. of achieving pharmacodynamic targets. Important to note, changed to 500 mg every 8 hours. Their review of 100 pa- however, is the lack of a strong link with improved clinical tient records preconversion and 114 patient records post- outcomes with the use of this strategy. conversion yielded an average time to infection resolution of 3.2 days versus 2.1 days, respectively, and a treatment ALTERNATIVE SMALL-DOSE, SHORT-INTERVAL REGIMENS failure rate of 8% versus 6.1%, respectively (no statistical comparison provided). As well, the authors quoted a hos- Four studies examined the effects of administering pital cost savings of approximately $17,000 for the post- smaller doses of meropenem more frequently, by means of conversion patients over the historical controls. Monte Carlo simulations. The most common regimen ex- The final study, also by Patel et al.,25 was another histor- plored in this way is the use of 500 mg administered every ical cohort analysis. They looked at 100 patient records 6 hours instead of the standard 1 g every 8 hours. Data are from preconversion and compared the results with those of presented in Tables 1 and 2,12,16,17,20 utilizing MICs for P. 192 patients who received the alternative regimen, as de- aeruginosa and MIC breakpoints, respectively, to provide scribed in their previous publication.24 Their results conservative estimates of effect. showed that the traditional regimen and the alternative reg- Kuti et al.20 utilized pharmacokinetic data from a previ- imen provided similar clinical efficacy in terms of in-hos- ously published study of healthy volunteers and the Clini- pital mortality (8% vs 11.5%, respectively; p = 0.24), clini- cal and Laboratory Standards Institute meropenem suscep- cal success (91% vs 92%, respectively; p = 0.72), and tibility MIC breakpoint of 4 µg/mL in their Monte Carlo meropenem-related length of stay (7 days vs 9 days, re- model. The methodologies of the studies by Wang et al.,16 spectively; p = 0.141). Economic analysis provided a me- Lomaestro and Drusano,12 and Zelenitsky et al.17 are de- dian antibiotic cost per patient of $439 versus $234, re- scribed in the previous section. Kuti et al.20 reported, in spectively, for the traditional and alternative regimens. their economic analysis, a net savings of approximately A study by Arnold et al.26 compared the clinical out- $38 per day (medication acquisition and supply costs only) comes of patients receiving imipenem/cilastatin 500 mg ev- with the modified dosing regimen. ery 6 hours (n = 40), meropenem 1 g every 8 hours (n = 29), Three studies23-25 examined the effect of using these al- or meropenem 500 mg every 6 hours (n = 58) in patients ternative dosing strategies on clinical endpoints. Kotapati et with neutropenic fever after cefepime failure or intolerance. al.23 conducted a retrospective review of all patients who This was a retrospective, single-center, cohort study. Prima- received meropenem in 2002 and grouped them according ry outcomes, respectively, for time to defervescence (median to the regimen they received. Group 1 included patients 3 vs 2 vs 3 days), need for additional antibiotics (20% vs who received 500 mg every 6 hours (every 8 h if creatinine 17% vs 14%, p = 0.71), and time to receipt of antibiotics clearance [CrCl] was 25– 49 mL/min), and group 2 pa- (median 5 vs 2 vs 1 day) were not significantly different. tients received 1000 mg every 8 hours (every 12 h if CrCl Similarly, no significant difference was found in secondary was 25– 49 mL/min). Of note, any patient who received outcomes of treatment duration (median 10 vs 8 vs 8 days) dosages outside of these classifications or had an infection or in-hospital mortality (5% vs 7% vs 7%, p = 0.82). caused by a meropenem-resistant organism was excluded Overall, the practice of administering meropenem as from their analysis. In the 85 patients assessed, no signifi- smaller doses with shorter intervals appears to provide cant differences were observed between groups in terms of pharmacodynamic target attainment rates and clinical out- clinical success rate (78% vs 82%, respectively; p = 0.86), comes similar to those with traditional dosing, with poten- microbiologic success rate (63% vs 79%, respectively; p = tial pharmacoeconomic benefits. 0.33), or infection-related length of stay (14 days vs 13 days, respectively; p = 0.97). In addition, economic evalu- CONTINUOUS INFUSIONS ation showed statistically significantly lower meropenem- related costs per patient in group 1 compared with group 2 Two studies comparing intermittent versus continuous ($1035 vs $1797, respectively; p = 0.008), but no signifi- infusion of meropenem in terms of pharmacokinetic/dy- cant difference in cost of total hospital stay ($19,934 vs namic endpoints were found. A randomized, open-label, 2- $16,087, respectively; p = 0.420). The study is limited by way crossover study by Krueger et al.27 obtained pharma- its retrospective design, small sample size (~40 per treat- cokinetic data from 16 healthy volunteers who were ad- ment arm), and patients’ relatively low severity of illness ministered either 0.5 g intermittently every 8 hours or 1.5 g (APACHE scores ~15). continuously over 24 hours (group 1; n = 8) or 1 g inter- Patel and Duquaine24 conducted a historical control study mittently every 8 hours or 3 g continuously over 24 hours examining patient outcomes, pre- and postimplementation, (group 2; n = 8). Using MIC data for P. aeruginosa from of a pharmacist-initiated auto-conversion policy, whereby the MYSTIC program (2002–2004), a Monte Carlo simu- patient regimens of 1 g every 8 hours were changed to 500 lation provided the CFR for these dosing regimens. The mg every 6 hours and regimens of 1 g every 12 hours were 1.5-g/day group attained CFRs of 52% vs 76% for tradi- 560 I The Annals of Pharmacotherapy I 2010 March, Volume 44
  5. 5. Outcomes of Meropenem Administration Strategies Based on Pharmacokinetic and Pharmacodynamic Principles tional intermittent infusions and continuous infusions, re- a fairly young cohort (up to 63 y of age) and had pharma- spectively, whereas the 3-g/day group attained CFRs of cokinetic parameters similar to those of healthy people. 64% and 83%, respectively. Among studies that utilized patient-derived parameters, A randomized, open-label study by Roberts et al.28 ob- only small numbers of clinically heterogeneous patients tained pharmacokinetic data from 10 critically ill patients made up their samples, as evidenced by the wide variabili- with normal renal function and sepsis after administration ty in pharmacokinetic parameters shown in Tables 1 and 2. of either 3 g continuously (following a 500-mg loading Additionally, there is inconsistency in the way that MIC dose) over 24 hours or 1 g intermittently every 8 hours data were applied to these simulations. For example, a (following a 1.5-g loading dose). Using MIC data for number of studies12,15,17,25,28 applied distributions from the gram-negative pathogens from the MYSTIC program MYSTIC program, which may not provide a representa- (2004–2005), a Monte Carlo simulation provided the CFR tive sample of pathogens at all centers, while others13,14,16 for 3 intermittent-infusion regimens (500 mg q8h, 1 g q8h, utilized MICs obtained from local isolates, or utilized set 2 g q8h), 3 prolonged-infusion regimens (500 mg q8h, 1 g MIC breakpoints.18,19 As well, MICs change over time and, q8h, 2 g q8h over 4 h), and 3 continuous-infusion regi- as such, extrapolating data from previous years to current mens (1.5 g/day, 3 g/day, 6 g/day). Pharmacokinetic pa- practice may not be ideal. rameters used in the simulation included a clearance of Given the highly heterogeneous approach to the devel- 13.6 L/h and a total volume of distribution of 22.7 L. Us- opment of the Monte Carlo models, it is surprising to see ing MIC data for P. aeruginosa, a target PTA of 40% the relatively narrow range of values for the CFRs that fT>MIC was chosen. The results showed CFRs of, respec- were calculated. To highlight this, one needs only to exam- tively, 12.5%, 40.6%, and 68.8% for the intermittent-dos- ine the CFR results of the 1 g every 8 hours traditional in- ing regimen, 50%, 68.8%, and 96.9% for prolonged-infu- fusion column of Table 1, which shows a CFR that varies sion regimens; and 43.8%, 100%, and 100%, for continu- from 75% to 100% in different models.12-17 ous-infusion regimens. When looking at the results of these simulations, one Searching for the clinical evidence of utilizing continu- must also keep in mind that these models are mathematical ous infusions compared with traditional intermittent dos- estimates of what is essentially a surrogate marker of an- ing, we found 1 study, by Lorente et al.29 This retrospective tibiotic efficacy in vivo. Further, PTA could be interpreted, cohort study involved 89 patients with VAP caused by in a Bayesian manner, as the likelihood of an individual gram-negative bacilli. Patients were administered either patient’s achieving clinical bactericidal effects from his/her meropenem 1 g every 6 hours by intermittent infusion or 4 dosing regimen. Thus, an ideal dosing regimen would pro- g/day by continuous infusion, both in combination with vide a PTA approaching 100% for a given pathogen and an once-daily tobramycin, for 14 days. Investigators exam- MIC such that every patient would receive optimal bacteri- ined the comparative efficacy of the 2 regimens in attain- cidal effects. ing clinical cure, defined as “complete resolution of all Examining the commonly cited references establishing clinical signs and symptoms of pneumonia.” Clinical cure meropenem’s pharmacodynamic bactericidal target of was assessed in all 89 patients, with 60% and 90% attain- greater than or equal to 40% fT>MIC,4-7 it is surprising that this ing cure in the intermittent- and continuous-infusion target is derived from animal infection models predominantly groups, respectively (p < 0.001). from unpublished works,8,9 though 1 reference has further Overall, the administration of the total daily dose of corroborated it.10 There is a paucity of data supporting this meropenem as a continuous infusion appears to increase target in human patients, with 1 study30 finding that 54% the likelihood of achieving pharmacodynamic targets and fT>MIC correlated with clinical outcomes, but a better associa- may improve clinical outcomes. The sparsity of clinical tion with unbound trough concentration to MIC ratio of 5. As evidence supporting this practice, however, limits its broad well, this target requires that the host immune system is func- application to practice. tioning appropriately to enhance the effect of meropenem; in cases of compromised immune function (eg, febrile neu- Limitations tropenia), higher proportions of the dosing interval with con- centrations above the MIC (ie, greater than 40% fT>MIC) may There are a number of limitations to the data presented. be necessary to obtain optimal clinical response, as evi- First, regarding the use of Monte Carlo models, we must denced by a study conducted in febrile neutropenic patients,31 bear in mind that the data produced are from simulations which demonstrated greater than 80% clinical response when based on parameters entered into a computer program. The the fT>MIC exceeded 75%. majority of the Monte Carlo studies included in this review The published clinical studies on this topic provide very utilized pharmacokinetic parameters derived from studies limited data, with what is essentially a collection of Level of healthy volunteers.12-17,25 One study28 derived data from 3 and 4 evidence,32 that being nonrandomized retrospective a critically ill population. However, these patients included analyses and case reports. The studies by Kotapati et al.,23 The Annals of Pharmacotherapy I 2010 March, Volume 44 I 561
  6. 6. J Perrott et al. Patel and Duquaine,24 Patel et al.,25 Arnold et al.,26 and verse effects with these various regimens, leaving us with the Lorente et al.29, while informative, are limited by their ret- presumption of safety but lacking supporting evidence. Addi- rospective and/or historical control designs. Specifically, tionally, the resources required to implement these changes the results are subject to confounding due to changes in pa- could potentially be better spent on other policies that im- tient management and practice over time, possible selec- prove antibiotic stewardship.33 tion bias in the choice of controls, and lack of randomiza- tion to help reduce baseline dissimilarity between groups. Summary In addition, the study by Arnold et al.26 may have been un- derpowered to see a difference in outcomes. None of these Meropenem alternative dosing strategies provide similar studies was designed statistically to examine the topic pharmacodynamic target attainment rates compared with from a noninferiority standpoint. As such, we cannot traditional dosing strategies. Small doses with shorter in- definitively state that the comparative regimens are equiva- terval dosing also provide pharmacoeconomic benefits and lent when the statistical testing allows us to infer only that similar clinical outcomes. Although alternative dosing one is not better than another. strategies for meropenem were largely studied in healthy subjects, patients with pharmacokinetic parameters that de- viate significantly from those of healthy volunteers may be Discussion ideal subjects for empiric modification of dose. The lack of Despite the limitations of the available data, some useful adverse effects data for alternative dosing strategies leaves conclusions can be drawn. Given that P. aeruginosa tends us with the presumption of safety that lacks supporting evi- to have higher MICs, infections caused by this organism dence. represent a worst-case scenario. Despite this, the majority of studies showed that reasonable response rates can be at- Jerrold Perrott BSc(Pharm) ACPR, Faculty of Pharmaceutical Sci- ences, University of British Columbia, Vancouver, BC, Canada tained with most dosing regimens of meropenem. There- Vincent H Mabasa BSc(Pharm) ACPR PharmD, Faculty of Phar- fore, one can argue that utilizing the most economical regi- maceutical Sciences, University of British Columbia; Department of Pharmacy, Fraser Health Authority, Burnaby General Hospital, Burnaby, men would be the best option. BC Although the majority of the evidence available for al- Mary HH Ensom PharmD FASHP FCCP FCSHP FCAHS, Facul- ternative dosing strategies for meropenem comes from stud- ty of Pharmaceutical Sciences, University of British Columbia; De- partment of Pharmacy, Children’s and Women’s Health Centre of ies in healthy volunteers, one can argue that, for patients with British Columbia, Vancouver pharmacokinetic parameters that deviate significantly from Reprints: Dr. Mabasa, Department of Pharmacy, Fraser Health Au- those of healthy volunteers, including those with altered thority, Burnaby General Hospital, 3935 Kincaid St., Burnaby, British Columbia V5G 2X6, Canada, fax 604/412-6187, vincent.mabasa@ clearance rates or excessively large or small volumes of dis- tribution (due to body habitus or comorbid condition) and Financial disclosure: None reported those with pharmacodynamic deviations (including those with impaired immune response), empiric dosage modifica- References tion would be ideal. Altered dosing strategies for these pa- tients should undertake to achieve better PTA and reduce the 1. Merrem (meropenem) product monograph. In: Repchinsky C, Welbanks L, Bisson R, eds. Compendium of pharmaceuticals and specialties: the risk of over- or underdosing. Ideally, the success of specific Canadian drug reference for health professionals. 2004 ed. Ottawa, strategies in these populations would be published to encour- Canada: Canadian Pharmacists Association, 2004:1176. age optimal use by all clinicians, as is done commonly with 2. Wise R, Logan M, Cooper J, Ashby J, Andrews J. Meropenem pharma- dose modifications for renal impairment. cokinetics and penetration into an inflammatory exudate. Antimicrob Agents Chemother 1990;34:1515-7. It has become increasingly common for hospitals to 3. Walker SE, Varrin S, Yannicelli D, Law S. Stability of meropenem in seek to contain antibiotic use and expenditures through saline and dextrose solutions and compatibility with potassium chloride. various policies, including changing meropenem’s tradition- Can J Hosp Pharm 1998;51:156-68. al 1 g every 8 hours dosing to 500 mg every 6 hours, thereby 4. Drusano G. Prevention of resistance: a goal for dose selection for antimi- crobial agents. Clin Infect Dis 2003;26(suppl 1):S42-50. decreasing daily meropenem usage by one third. While the 5. Lodise T, Lomaestro B, Drusano G. Application of antimicrobial phar- published evidence does show that this strategy provides macodynamic concepts into clinical practice: focus on beta-lactam an- similar simulated response rates and clinical outcomes, with tibiotics. Pharmacotherapy 2006;26:1320-32. potentially significant cost savings, the methodological limi- 6. Turnidge J. The pharmacodynamics of beta-lactams. Clin Infect Dis 1998;27:10-22. tations may preclude the widespread adoption of this strate- 7. Nicolau D. Pharmacokinetic and pharmacodynamic properties of gy. However, one must keep in mind that conducting the ide- meropenem. Clin Infect Dis 2008;47:S32-40. al studies to compare the multitude of dosing options would 8. Craig WA, Ebert S, Watanabe Y. Differences in time above MIC re- quired for efficacy of beta-lactams in animal infection models (abstract be economically and logistically difficult. Worsened out- 86). Abstracts of the 33rd Interscience Conference on Antimicrobial comes through the use of these strategies have not been Agents and Chemotherapy (San Francisco), Washington, DC: American demonstrated, but no studies have formally examined ad- Society for Microbiology, 1993. 562 I The Annals of Pharmacotherapy I 2010 March, Volume 44
  7. 7. Outcomes of Meropenem Administration Strategies Based on Pharmacokinetic and Pharmacodynamic Principles 9. Craig WA, Ebert S, Watanabe Y. Differences in time above MIC re- and subcutaneous tissue distribution. J Antimicrob Chemother 2009;64: quired for efficacy of beta-lactams in animal infection models (abstract 142-50. 86). Program and abstracts of the 35th Interscience Conference on An- 29. Lorente L, Lorenzo L, Martin MM, Jimenez A, Mora ML. Meropenem timicrobial Agents and Chemotherapy (New Orleans), Washington, DC: by continuous versus intermittent infusion in ventilator-associated pneu- American Society for Microbiology, 1995. monia due to gram-negative bacilli. Ann Pharmacother 2006;40:219-23. 10. Ong C, Tessier P, Li C, et al. Comparative in vivo efficacy of meropen- DOI 10.1345/aph.1G467 em, imipenem, and cefepime against Pseudomonas aeruginosa express- 30. Li C, Du X, Kuti J, et al. Clinical pharmacodynamics of meropenem in ing MexA-MexB-OprM efflux pumps. 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Infectious Diseases Society of mize empirical antibiotic therapy for gram-negative bacteria in a Brazil- America and the Society for Healthcare Epidemiology of America ian intensive care unit. Braz J Infect Dis 2007;11:183-5. guidelines for developing an institutional program to enhance antimicrobial 14. Ludwig E, Konkoly-Thege M, Kuti J, Nicolau D. Optimising antibiotic stewardship. Clin Infect Dis 2007;44:159-77. dosing regimens based on pharmacodynamic target attainment against Pseudomonas aeruginosa collected in Hungarian hospitals. Int J Antimi- crob Agents 2006;28:433-8. 15. Kuti J, Dandekar P, Nightingale C, Nicolau D. Use of Monte Carlo simu- lation to design an optimized pharmacodynamic dosing strategy for Comparando Resultados de las Estrategias de Administración de meropenem. J Clin Pharmacol 2003;43:1116-23. Meropenem Basadas en Principios Farmacocinéticos y 16. Wang H, Zhang B, Yuxing N, et al. Pharmacodynamic target attainment Farmacodinámicos: una Revisión Sistemática Cualitativa of seven antimicrobials against gram-negative bacteria collected from J Perrott, VH Mabasa, y MHH Ensom China in 2003 and 2004. Int J Antimicrob Agents 2007;30:452-7. 17. Zelenitsky S, Zvonar R, Ariano R. Monte Carlo simulations (MCSs) of Ann Pharmacother 2010;44:557-64. meropenem in patients with varying degrees of renal function (abstract). Can J Hosp Pharm 2009;62:68. 18. Li C, Kuti J, Nightingale C, Nicolau D. Population pharmacokinetic EXTRACTO analysis and dosing regimen optimization of meropenem in adult pa- OBJETIVO: Revisar sistemáticamente la evidencia que compara tients. J Clin Pharmacol 2006;46:1171-8. estrategias de dosificación tradicional y alternativa para meropenem 19. Jaruratanasirikul S, Sriwiriyajan S, Punyo J. Comparison of the pharma- basadas en resultados clínicos y fármacoeconómicos. codynamics of meropenem in patients with ventilator-associated pneu- FUENTES DE DATOS: Las bases de datos MEDLINE, EMBASE, monia following administration by 3-hour infusion or bolus injection. Abstractos Farmacéuticos Internacionales (1950–septiembre de 2009) Antimicrob Agents Chemother 2005;49:1337-9. fueron revisadas usando los términos meropenem, carbapenemos, 20. Kuti J, Maglio D, Nightingale C, Nicolau D. Economic benefit of a farmacodinámica, farmacocinética. Las referencias de las citaciones de meropenem dosage strategy based on pharmacodynamic concepts. Am J las publicaciones identificadas fueron revisadas. Health Syst Pharm 2003;60:565-8. SELECCIÓN DE ESTUDIOS Y EXTRACCIÓN DE DATOS: Los artículos 21. Lockhart S, Abramson M, Beekmann S, et al. Antimicrobial resistance discutiendo la administración de meropenem en adultos con función among gram-negative bacilli causing infections in intensive care unit pa- renal normal y comparando por lo menos dos regimenes, uno que tients in the United States between 1993 and 2004. J Clin Microbiol 2007; incluya el régimen de 0.5g ó 1g cada 8 horas infundido por 30 minutos 45:3352-9. recomendado por el fabricante, con los objetivos clínicos, 22. Masterton R, Turner P. Overview of the meropenem yearly susceptibility farmacodinámicos y fármacoeconómicos incluidos. El objetivo test information collection (1997–2004). Diagn Microbiol Infect Dis farmacodinámico de interés era % fT>MIC (por ciento de tiempo que la 2005;53:247-56. concentración de fármaco libre exceda la concentración minima 23. Kotapati S, Nicolau D, Nightingale C, Kuti J. Clinical and economic inhibitoria del patógeno bacteriano). benefits of a meropenem dosage strategy based on pharmacodynamic SÍNTESIS DE DATOS: Dieciséis estudios fueron revisados, de los que concepts. Am J Health Syst Pharm 2004;61:1264-70. incluían 13 avaluaciones farmacocinéticas y dinámicas usando la 24. Patel G, Duquaine S. Impact of a pharmacist initiated conversion from simulación de Monte Carlo, 5 evaluaciones clínicas, y 3 traditional to optimized pharmacodynamic dosing of meropenem at a fármacoeconómicas. Los datos de los resultados clínicos y económicos community hospital (abstract). American Society of Hospital Pharma- son mayormente de análisis retrospectivos no aleatorios y reportes de cists Midyear Clinical Meeting 2005;40:644E. casos. Meropenem por la vía de infusión prolongada intermitente aumenta potencialmente el alcance de los objetivos farmacodinámicos. 25. Patel G, Duquaine S, McKinnon P. Clinical outcomes and cost mini- Sin embargo, no existe un enlace fuerte con mejores resultados clínicos. mization with an alternative dosing regimen for meropenem in a com- Dosis más bajas a intervalos más cortos parece que permiten alcanzar munity hospital. Pharmacotherapy 2007;27:1637- 43. objetivos farmacodinámicos y resultados clínicos similares a los de la 26. Arnold H, McKinnon P, Augustin K, et al. Assessment of an alternative dosificación tradicional, con beneficios fármacoeconómicos potenciales. meropenem dosing strategy compared with imipenem-cilastatin or tradi- Meropenem por la vía de infusión continua aparenta aumentar la tional meropenem dosing after cefepime failure or intolerance in adults probabilidad de alcanzar los objetivos farmacodinámicos más que las with neutropenic fever. Pharmacotherapy 2009;29:914-23 infusiones intermitentes. La escasez evidencia clínica apoyando esta 27. Krueger W, Bulitta J, Kinzig-Schippers M, et al. Evaluation by Monte práctica limita su aplicación amplia. No hay estudios examinando Carlo simulation of the pharmacokinetics of two doses of meropenem formalmente los efectos adversos con el régimen de dosis alternativo. administered intermittently or as a continuous infusion in healthy volun- CONCLUSIONES: Las estrategias de dosificación alternativas para teers. Antimicrob Agents Chemother 2005;49:1881-9. meropenem proveen la obtención de objetivos farmacodinámicos 28. Roberts J, Kirkpatrick C, Roberts M, et al. Meropenem dosing in critical- similares a las estrategias de dosificación tradicional. Dosis más bajas a ly ill patients with sepsis and without renal dysfunction: intermittent bo- intervalos más cortos proveen beneficios farmacodinámicos adicionales lus versus continuous administration? Monte Carlo dosing simulations y resultados clínicos similares. Las estrategias de dosificación The Annals of Pharmacotherapy I 2010 March, Volume 44 I 563
  8. 8. J Perrott et al. alternativas para meropenem fueron estudiadas mayormente en La mesure de résultats pharmacodynamique d’intérêt était le %fT>CMI pacientes saludables; pacientes con parámetros farmacocinéticos que (pourcentage du temps que la concentration du médicament libre excède difieran significativamente pueden ser ideales para modificación la concentration minimale inhibitrice pour le pathogène). empírica de la dosis. RÉSUMÉ: Seize études ont été revues dont 13 évaluations pharmacociné- Traducido por Sonia I Lugo tiques et pharmacodynamiques utilisant une simulation Monte Carlo, 5 évaluations cliniques, et 3 évaluations pharmacoéconomiques. Les données cliniques et économiques sont issues majoritairement d’analyses rétro- Comparaison des Résultats Cliniques Obtenus Selon Divers Protocoles spectives non randomisées et de rapports de cas. Le protocole où le d’Administration du Méropénem Basés sur les Principes de méropénem est administré par infusion prolongée intermittente est le plus susceptible d’atteindre les cibles pharmacodynamiques visées. Pharmacocinétique et de Pharmacodynamie: Cependant, les données permettant d’établir un lien direct avec de meilleurs une Revue Complète Qualitative résultats cliniques sont manquantes. De plus petites doses administrées à J Perrott, VH Mabasa, et MHH Ensom intervalles plus courts, comparativement à la posologie traditionnelle, semblent permettre d’atteindre les cibles pharmacodynamiques dans les Ann Pharmacother 2010;44:557-64. mêmes proportions et les mêmes résultats cliniques, avec des bénéfices pharmacoéconomiques. Le méropénem administré en perfusion continue semble augmenter l’atteinte des cibles pharmacodynamiques compara- RÉSUMÉ tivement aux infusions intermittentes. Le peu d’évidence clinique OBJECTIF: Revoir toutes les données comparatives des divers protocoles supportant la perfusion continue limite son utilisation plus étendue dans d’administration et de posologie (traditionnels vs alternatifs) du méro- la pratique clinique. Aucune étude n’a ciblé exclusivement les effets pénem basées sur les résultats cliniques et pharmacoéconomiques. indésirables des protocoles d’administration autres que celui recommandé REVUE DE LA LITTÉRATURE: Les bases de données informatisées MEDLINE, par le fabricant. EMBASE, et International Pharmaceutique Résumé (1950–septembre CONCLUSIONS: Les protocoles d’administration du méropénem autres que 2009) ont permis d’identifier les articles pertinents en utilisant les mots- celui recommandé par le fabricant permettent d’atteindre les cibles phar- clé méropénem, carbapénems, pharmacodynamie, et pharmacocinétique. macodynamiques dans une même proportion que le protocole traditionnel. D’autres articles ont été identifiés à partir des références bibliographiques De plus petites doses administrées à intervalles plus courts procurent des des articles retenus pour cette revue. bénéfices pharmacoéconomiques additionnels et les mêmes mesures de SÉLECTION DES ÉTUDES ET DE L'INFORMATION: Les articles concernant résultats cliniques. Ces nouveaux protocoles ont été largement étudiés l’administration du méropénem à des adultes ayant une fonction rénale chez des sujets en santé; des patients présentant des paramètres pharma- normale et comparant au moins 2 protocoles d’administration différents, cocinétiques différents pourraient être des sujets idéaux pour des dont le protocole recommandé par le fabricant (0.5 g à 1 g aux 8 h, modifications empiriques de la posologie. perfusé en 30 min); les articles devaient de plus inclure des mesures de Traduit par Denyse Demers résultats cliniques, pharmacodynamiques, ou pharmaco-économiques. 564 I The Annals of Pharmacotherapy I 2010 March, Volume 44