Drugs 60: 619-646, Sep 2000

MeropenemAn Updated Review of its Use in the Management of Intra-Abdominal Infections

Matthew N. Lowe and Harriet M. LambAdis International Limited, Auckland, New Zealand

Various sections of the manuscript reviewed by: F. Colardyn, Department of Intensive Care, University Hospital Ghent, University of Ghent, Ghent, Belgium;S.J. Geroulanos, Onassis Cardiac Surgery Center, Athens, Greece; S.D.R. Lang, Middlemore Hospital andDiagnostic Medlab, Auckland, New Zealand; A. Lovering, Department of Medical Microbiology, SouthmeadHospital, Bristol, Avon, England; P. Montravers, Centre Hospitalier Universitaire d’Amiens, Amiens, France;J.S. Solomkin, Division of Surgical Infectious Diseases, University of Cincinnati College of Medicine,Cincinnati, Ohio, USA; S.E. Wilson, Department of Surgery, University of California Irvine Medical Center,Orange, California, USA.

Contents

Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6191. Overview of Intra-Abdominal Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6232. Antibacterial Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 624

2.1 Overview of In Vitro Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6242.1.1 Gram-Negative Bacteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6242.1.2 Gram-Positive Bacteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6252.1.3 Anaerobes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 626

2.2 Overview of Resistance Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6262.2.1 β-Lactamase Hydrolysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6262.2.2 Impermeability Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6272.2.3 Alterations in Penicillin-Binding Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6272.2.4 Selection of Resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 627

2.3 Other Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6272.3.1 Effects on Intestinal Flora . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6272.3.2 Inoculum Effect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6272.3.3 Postantibiotic Effect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 628

3. Pharmacokinetic Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 628

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Data SelectionSources: Medical literature published in any language since 1983 on meropenem, identified using AdisBase (a proprietary database of AdisInternational, Auckland, New Zealand) and Medline. Additional references were identified from the reference lists of published articles.Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.Search strategy: AdisBase search terms were ‘Meropenem’ or ‘ICI-194660’ or ‘ICI-213689’ or ‘SM-7338’ and ‘Intra-abdominal-infections’.Medline search terms were ‘Meropenem’ or ‘SM-7338’ and ‘intra abdominal infections’.Searches were last updated 17 Jul 2000.Selection: Studies in patients with intra-abdominal infections or serious infections who received meropenem. Inclusion of studies was basedmainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred.Relevant pharmacodynamic and pharmacokinetic data are also included.Index terms: Meropenem, intra-abdominal infections, antibacterial activity, pharmacokinetics, therapeutic use, adverse events.

3.1 Overview of Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6283.1.1 Absorption and Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6283.1.2 Metabolism and Elimination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 629

3.2 Special Patient Groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6293.2.1 Elderly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6293.2.2 Renal and Hepatic Impairment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 629

4. Therapeutic Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6304.1 Moderate Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6324.2 Moderate to Severe Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 632

4.2.1 Comparisons with Imipenem/Cilastatin . . . . . . . . . . . . . . . . . . . . . . . . . . . 6324.2.2 Comparisons with Cefotaxime plus Metronidazole . . . . . . . . . . . . . . . . . . . . . 6334.2.3 Comparison with Clindamycin plus Tobramycin . . . . . . . . . . . . . . . . . . . . . . 634

4.3 Severe Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6344.4 Efficacy According to Infection Site . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6344.5 Persistent Pathogens and Superinfections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 635

5 Pharmacoeconomic Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6366. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 637

6.1 Overview of Tolerability Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6386.2 Gastrointestinal Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6386.3 Seizure Potential . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6396.4 Laboratory Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6406.5 Elderly Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 640

7. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6408. Place of Meropenem in the Management of Patients with Intra-Abdominal

Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641

SummaryAbstract Meropenem is a carbapenem antibacterial agent with a broad spectrum of activity

which encompasses Gram-negative, Gram-positive and anaerobic bacteria.Like other carbapenems, meropenem is stable against chromosomal and ex-tended-spectrum β-lactamases.

In patients with moderate to severe intra-abdominal infections, empiricalmonotherapy with meropenem achieved clinical response rates ranging from 91to 100% in 7 randomised comparative trials. Efficacy rates were similar to thoseof imipenem/cilastatin (94 to 97%), clindamycin plus tobramycin (93%) and,overall, to cefotaxime plus metronidazole (75 to 100%), although there weredifferences between trials versus this combination regimen. According to limiteddata, meropenem also achieved clinical response rates of over 80% in patientswith severe intra-abdominal infections.

Meropenem is well tolerated, the most common adverse events being diar-rhoea, rash, nausea/vomiting and inflammation at the injection site which arereported in <2.5% of patients each. Meropenem also has an improved CNS tol-erability profile compared with imipenem/cilastatin.

Conclusions: Extensive comparative clinical data demonstrate that mero-penem can be used effectively as empirical monotherapy in moderate to severeintra-abdominal infections. It also shows potential in the most severe forms ofinfection, although experience in this infection type remains limited. Comparedwith standard combination regimens, meropenem offers the benefits of ease ofadministration without the need for monitoring. It also offers improved CNStolerability compared with imipenem/cilastatin with the option of a higher

620 Lowe & Lamb

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maximum dosage, which may be a particular advantage in patients with severeintra-abdominal infections.

Antibacterial Activity Meropenem has consistently strong activity against Enterobacteriaceae; over98% of European and North American isolates in a large in vitro study weresusceptible to the drug. Imipenem showed 4- to 32-fold less activity against thesame pathogens. According to the same survey, 91% of Pseudomonas aeruginosaare susceptible to meropenem [minimum concentration required to inhibit 90%of isolates (MIC90) 4 mg/L] and meropenem exhibited good activity againstAcinetobacter baumannii (MIC90 values of 1 or 2 mg/L), although infrequentisolates with decreased susceptibility or resistance to the carbapenems have beendocumented worldwide.

Meropenem has good activity (MIC90 ≤1 mg/L) against Gram-positive bac-teria relevant to intra-abdominal infections including viridans streptococci,methicillin-susceptible Staphylococcus epidermidis and S. aureus. 71 and 79%of Enterococcus faecalis isolated from Europe and North America, respectively,were susceptible to meropenem. Imipenem had slightly more activity (up to4-fold) than meropenem against Gram-positive bacteria.

Stenotrophomonas maltophilia, E. faecium and methicillin-resistant S. aureusare inherently resistant to the carbapenems.

Meropenem has good activity against anaerobes, including Bacteroidesfragilis; over 98% of all species studied were susceptible to the drug. Imipenemseemed to have similar or slightly less (up to 4-fold) activity than meropenemagainst these bacteria.

Meropenem produces only minor alterations in the intestinal microflora ofhealthy volunteers; numbers of streptococci, enterobacteria, bacteroides,veillonella/acidaminococci and clostridia decreased and those of enterococci in-creased during a 7-day course of intravenous meropenem 1.5 g/day but all gutflora returned to normal within 2 weeks of completing treatment.

Meropenem, like other β-lactams, does exhibit an inoculum effect in vitro.However, MIC values reported at an inoculum of ≈107 colony forming units(cfu)/spot did not exceed 4 mg/L for any organism including Enterobacteriaceaeexpressing chromosomal or plasmid-mediated β-lactamases.

Meropenem has a postantibiotic effect against both Gram-negative and Gram-positive bacteria.

Pharmacokinetic Profile Meropenem has linear pharmacokinetics over the dose range 0.25 to 2g. Meanpeak plasma concentrations (Cmax) of meropenem following a single intravenous1g dose ranged from 54.8 to 61.6 mg/L in healthy volunteers.

Meropenem is distributed in the extracellular (interstitial) fluid. Typically,meropenem concentrations achieved in the abdominal tissues are in the range of2 to 4 mg/L, although concentrations in the bile are higher and range from 7 to15 mg/L. In patients with intra-abdominal infections, the volume of distribution(Vd) tends to be up to approximately 2-fold higher compared with values ob-served in healthy volunteers.

Meropenem is cleared predominantly in the kidney by both glomerular filtra-tion and tubular secretion. Excretion is rapid and over 95% of an administereddose is excreted within 8 hours. Biliary excretion of meropenem is thereforelimited; 2.1% of a drug dose is recovered in the faeces.

Meropenem has a single open-ring metabolite formed by hydrolysis which is

Meropenem: A Review 621


pharmacologicallyinactive.Theeliminationhalf-life(t1⁄2) of meropenem is ap-proximately 1 hour.

In patients with renal impairment, the clearance of meropenem is decreasedand t1⁄2 prolonged. Dosage adjustment is therefore required based on creatinineclearance (CLCR). Meropenem is cleared by haemodialysis and continuous veno-venous haemofiltration, and dosage adjustment may be required in these patients.The pharmacokinetics of meropenem are, however, unaltered in patients withhepatic impairment.

Therapeutic Efficacy In intra-abdominal infections of moderate severity, meropenem 1.5 g/dayachieved a satisfactory clinical response in 92 and 98% of patients compared withrates of 94 and 96% with imipenem/cilastatin 1.5 or 2 g/day in 2 multicentre,randomised trials.

In patients with moderate to severe infections, meropenem 3 g/day achievedclinical response rates ranging from 91 to 100% in 7 randomised trials. Efficacyrates were similar to those of imipenem/cilastatin (94 to 97%) and clindamycinplus tobramycin (93%). Compared with cefotaxime plus metronidazole in 3 trials,the regimens were similar in one trial (satisfactory clinical response in 93 vs 92%)but significantly different in the remaining 2 trials (95 with meropenem vs 75%with the combination regimen in one trial and 91 vs 100% in the other). Slightdifferences in bacteriological outcome were observed between regimens on a perpathogen basis, but statistical analyses were not performed.

The efficacy of meropenem appeared to be unaffected by the site of intra-ab-dominal infection according to a retrospective analysis of 4 clinical trials;meropenem consistently achieved a satisfactory response in over 89% of patientswhich was similar to that of comparator regimens.

In 2 comparative trials which recruited patients with severe infections, clinicalresponse rates were 82 and 96% with meropenem 3 g/day versus 81 and 77% withimipenem/cilastatin 3 g/day in those patients with severe intra-abdominal infec-tions (>50 patients per study).

In patients with intra-abdominal infections who failed therapy (4 to 16%), themost common persistent organisms following failure of meropenem therapy in-cluded Escherichia coli, other Enterobacteriaceae, enterococci, Streptococcusspp. and P. aeruginosa. Superinfections developed in similar numbers of patientsreceiving meropenem and comparator regimens.

PharmacoeconomicConsiderations

In the 2 cost analyses that compared delivery methods of meropenem, bolusadministration was associated with delivery cost savings of approximately 30%in an Australian study and 45% in a UK study compared with an infusion of thedrug.

Tolerability A recent overview of clinical trial data involving 9514 patients found that theoverall incidence of adverse events, drug-related adverse events, adverse eventsleading to withdrawal and mortality were similar between meropenem, im-ipenem/cilastatin and combination regimens. Drug-related events mostfrequently associated with meropenem are diarrhoea (2.3%), rash (1.4%),nausea/vomiting (1.4%) and local inflammation at the injection site (1.1%). Aconcern with imipenem/cilastatin is that the incidence of gastrointestinal eventsis linked to the rate of administration and dosage of the drug, although these eventscan be managed by slowing the rate of infusion of the drug. Meropenem can,however, can be administered without regard to the rate of infusion or dose.

622 Lowe & Lamb


A tolerability concern with β-lactam agents is their potential to cause CNStoxicity and seizures. With regard to the CNS, meropenem appears to be welltolerated, whereas imipenem/cilastatin is associated with a risk of seizures, par-ticularly in those with predisposing factors such as renal dysfunction, underlyingCNS pathology or advanced age. In an overview of 46 clinical trials, whichexcluded patients with meningitis and a history of CNS disorders, the incidenceof meropenem-related seizures was 0.08% of treatment exposures compared with0.28% with imipenem/cilastatin, 0.05% with cephalosporin-based regimens and0% with clindamycin plus an aminoglycoside.

Laboratory events most commonly associated with meropenem includedthrombocytosis (1.6%) and increases in ALT (4.3%), AST (3.4%) and alkalinephosphatase (1.5%).

Dosage andAdministration

Meropenem is indicated as monotherapy for the treatment of intra-abdominalinfections. According to the manufacturer’s recommendations, meropenemshould be administered at a dosage of 1.5 to 3 g/day in 3 divided doses dependingon the type and severity of infection, the susceptibility of the pathogen(s) and thecondition of the patient. This dosage range may, however, differ from thatrecommended on a national level. Meropenem can be administered as an intra-venous bolus injection or infusion.

Dosage adjustment is required in patients with renal impairment (CLCR ≤3L/h) but not in the elderly (CLCR >3 L/h) or in patients with impaired hepaticfunction.

1. Overview of Intra-AbdominalInfections

Intra-abdominal infections encompass a widespectrum of conditions.[1] Most arise from themovement of micro-organisms from the gastroin-testinal tract to sterile areas within the abdomen.[2]

This can be caused by damage to the intestinal wallas a result of spontaneous perforation (appendi-citis, perforated ulcer or diverticulitis), trauma orsurgical intervention.

Fundamental principles for the management ofintra-abdominal infections include general sup-portive measures, prompt surgical intervention andeffective antibacterial therapy.[3] However, bothhost- and disease-specific factors can affect out-come. These factors include severity of illness,underlying disease including immune status, thetype and timing of intervention and infectionsite.[4,5] For example, biliary tract infections andappendicitis are associated with mortality rates of0 to 8%, whereas much higher rates of mortalityare observed with infections involving the small

intestine and large bowel (20 to 25% and 20 to50%, respectively) and those occurring after intra-abdominal surgery (40 to 60%).[4] Infections thatresult after initial surgery or antibacterial therapyare particularly difficult to treat because they caninvolve drug-resistant pathogens, e.g. Gram-negative facultative bacilli, staphylococci andPseudomonas aeruginosa.[6,7] These are quite dis-tinct from most intra-abdominal infections whichinvolve pathogens acquired from endogenousflora.

The aim of antimicrobial therapy is to preventrecurrent infections, reduce surgical wound com-plications and control bacteraemia. Once an infec-tion is suspected, treatment is invariably empiricalbecause the identity of the infecting pathogen(s)may not be known for 2 to 4 days after initiation oftherapy.[8] The basic premise is that empirical ther-apy should cover Escherichia coli, other Entero-bacteriaceae and Bacteroides fragilis;[6] the use ofempirical regimens with broader coverage, e.g.other anaerobes, P. aeruginosa[3] and enterococci,is more controversial.



Traditionally, empirical regimens for intra-ab-dominal infections have consisted of combinationsof 2 or 3 antibacterials in order to achieve sufficientcoverage, generally clindamycin or metronidazolecombined with either a cephalosporin or an amino-glycoside.[9] However, the advent of single agentswith a broad antibacterial spectrum, such as thecarbapenems and extended-spectrum cephalospo-rins, has allowed effective monotherapy against in-tra-abdominal infections.

This review focuses on meropenem, a parenteralcarbapenem antibacterial agent, and its use in pa-tients with intra-abdominal infections. It updatesthe review of meropenem previously published inDrugs[10] which considered its use in a range ofinfection types. The specific use of meropenem inpatients with febrile neutropenia has been reviewedin Disease Management & Health Outcomes,[11] andmore recently, its use in serious bacterial infectionshas also been reviewed in Drugs.[12]

2. Antibacterial Activity

2.1 Overview of In Vitro Activity

The activity profile of meropenem has been wellestablished in both early in vitro studies and, morerecently, in large surveillance studies. With the ex-ception of one clinical trial which reported suscep-tibility data for isolated pathogens,[13] there is nolarge in vitro study which looks at the activity ofmeropenem against isolates taken exclusively frompatients with intra-abdominal infections.

In the absence of data concerning this patientgroup, the 1997 study of Pfaller and Jones,[14]

which tested the activity of meropenem againstover 30 000 clinical isolates from Europe andNorth America, will form the basis of this over-view. A summary of data from this study concern-ing pathogens relevant for intra-abdominal infec-tions is provided in table I.

The results of several other large in vitro studies(over 4000 to 18 000 isolates per study) investigat-ing the activity of meropenem are also avail-able;[15-18] however, since their results are in closeagreement with those of Pfaller and Jones, they will

not be discussed in detail in this overview. In addi-tion, the MYSTIC (Meropenem Yearly Suscepti-bility Test Information Collection) surveillancestudy is an ongoing assessment of the activity ofmeropenem against isolates collected from hospi-tal sources. The most recent results, presented onlyas an abstract, suggest that the activity ofmeropenem has remained unaltered during the first3 years of the study (1997 to 1999).[19]

2.1.1 Gram-Negative Bacteria

EnterobacteriaceaeMeropenem has consistently strong activity

against Enterobacteriaceae. Over 98% of strainstested by Pfaller and Jones[14] in Europe and NorthAmerica were susceptible to meropenem. Theminimum concentrations required to inhibit thegrowth of 90% of strains (MIC90) ranged from<0.06 to 0.5 mg/L (table I). Imipenem demonstrated4- to 32-fold less activity against the same patho-gens (table I).[14]

Meropenem retained activity against ceftazidime-resistant (MIC >16 mg/L) Enterobacteriaceae:MIC90 values ranged from 0.06 to 2 mg/L.[14,20]

Consistent with this, meropenem was active at aconcentration of 0.25 mg/L against all but 3 of433 Klebsiella spp. known to produce extended-spectrum β-lactamases; the remaining 3 isolateswere inhibited at concentrations of 2 to 4 mg/L.[21]

Non-Enteric BacteriaIn both Europe and North America, 91% of P.

aeruginosa were susceptible to meropenem(MIC90 4 mg/L; table I). By comparison, imipeneminhibited 79.6 or 86.2% of strains, depending onthe geographic location, with an MIC90 of 16mg/L.[14] Meropenem also compared well withceftazidime (which inhibited 79 and 87% of strains)and ciprofloxacin (81 and 82%), and showedsimilar activity to piperacillin/tazobactam (92 and95%) in this study.[14]

Meropenem exhibited good activity againstAcinetobacter baumannii inhibiting ≥99% ofstrains with an MIC90 of 1 or 2 mg/L (table I). Al-though the activity of the carbapenems generallyremains strong against these difficult-to-treat

624 Lowe & Lamb


pathogens, infrequent outbreaks of isolates withdecreased susceptibility or resistance to theseagents have been documented worldwide.[15,17,22-24]

Stenotrophomonas maltophilia are inherently re-sistant to the carbapenems (section 2.2.1).[14]

2.1.2 Gram-Positive BacteriaMeropenem had good activity against viridans

streptococci with respective MIC90 values of 0.25,0.12 and 1 mg/L against Streptococcus sanguis(n = 31), S. milleri (n = 22) and S. mitis (n = 12).[25]

In a Canadian study, the MIC90 of meropenem was2 mg/L against viridans group streptococci (n =153).[26]

71 and 79% of Enterococcus faecalis isolatedfrom Europe and North America, respectively,were susceptible to meropenem (table I); theserates were lower than those reported for imipenem(97 and 98%), piperacillin (91 and 99%) andpiperacillin/tazobactam (98 and 95%).[14] 82% ofE. durans and E. avium (n = 120) were susceptibleto meropenem in a German study.[18]

Table I. Overview of the in vitro activity of meropenem and imipenem against pathogens commonly implicated in intra-abdominal infections[14]

Species Europe North America

no. ofisolates

meropenem imipenem no. ofisolates

meropenem imipenem

S(%)a

MIC90

(mg/L)S(%)a

MIC90

(mg/L)S(%)a

MIC90

(mg/L)S(%)a

MIC90

(mg/L)

Gram-negative aerobesAcinetobacter baumannii 116 100 1.0 100 2.0 152 98.7 2.0 98.7 2.0

Citrobacter freundii 445 99.8 0.13 99.8 1.0 433 99.1 0.06 98.6 1.0

C. koseri 85 100 0.13 100 2.0 205 99.5 <0.06 99.5 0.5

Enterobacter aerogenes 167 100 0.25 99.4 1.0 535 99.1 0.13 98.7 2.0

E. cloacae 683 100 0.25 99.3 2.0 1014 99.5 0.25 99.2 1.0

Escherichia coli 2228 100 0.06 100 0.5 2126 99.7 <0.06 99.8 0.25

Klebsiella oxytoca 354 100 0.06 99.7 0.5 334 99.7 0.06 99.4 0.5

K. pneumoniae 860 100 0.06 99.5 1.0 1206 99.3 0.06 99.2 0.5

Morganella morganii 372 100 0.25 94.0 4.0 320 99.4 0.25 95.9 4.0

Proteus mirabilis 997 100 0.13 94.3 4.0 750 100 0.25 96.7 4.0

P. vulgaris 266 100 0.13 97.2 4.0 150 100 0.25 96.7 4.0

Providencia rettgeri 118 100 0.25 94.1 4.0 111 100 0.25 97.3 2.0

P. stuartii 192 100 0.5 85.4 8.0 167 99.4 0.25 100 2.0

Pseudomonas aeruginosa 2184 91.0 4.0 79.6 16 1870 91.0 4.0 86.2 16

Serratia marcescens 394 99.7 0.13 99.2 2.0 654 98.8 0.25 98.1 2.0

Gram-positive aerobesEnterococcus faecalis 901 70.8 8.0 97.1 4.0 523 78.8 8.0 97.5 2.0

E. faecium 175 23.4 128 53.8 64 54 31.5 64 51.4 >8.0

Staphylococcus aureus (MS) 1478 99.1 0.25 99.5 0.13 1691 98.6 0.25 98.3 0.13

AnaerobesBacteroides fragilis 1130 98.2 0.5 98.6 1.0 161 99.4 0.5 99.3 1.0

Clostridium perfringens 230 100 <0.06 99.1 0.25 108 100 0.06 100 0.25

C. difficile 106 100 2.0 67.9 8.0 34 100 2.0 100 4.0

Peptostreptococcusanaerobius

102 100 1.0 100 1.0 40 100 0.25 100 0.5

Prevotella bivia 158 100 0.25 100 0.25 41 97.6 0.25 97.6 0.5

P. melaninogenica 44 100 0.13 100 0.13 45 100 0.13 100 0.13

a Percentage of organisms considered to be susceptible (S) to meropenem or imipenem at the breakpoint set by the National Committeefor Clinical Laboratory Standards (≤4 mg/L for all organisms listed).

MIC90 = minimum drug concentration required to inhibit the growth of 90% of isolates; MS = methicillin-sensitive.



Meropenem showed good activity against meth-icillin-susceptible Staphylococcus epidermidis(MIC90 0.5 mg/L; n = 31)[27] and S. aureus (MIC90

0.25 mg/L; table I). Imipenem had slightly moreactivity (up to 4-fold) than meropenem againstthese bacteria (table I).

As for other β-lactam agents, the carbapenemsare inactive against E. faecium and methicillin-resistant S. aureus (MRSA).[14]

2.1.3 AnaerobesMeropenem has good activity against anaer-

obes; over 98% of all studied species were suscep-tible to meropenem (table I). MIC90 values for allanaerobes ranged from <0.06 mg/L for Clostridiumperfringens to 2 mg/L for C. difficile.[14] Imipenemseemed to have similar or slightly less (up to4-fold) activity than meropenem against these bac-teria (table I).[14] A point of interest with regard tothe treatment of intra-abdominal abscesses is thatthe in vitro activity of meropenem against B.fragilis group was virtually unaffected by alter-ations in pH (fig. 1).[28]

In 2 longitudinal studies, the susceptibility of B.fragilis to the carbapenems was unchanged[29] oreven slightly improved[30] over 7- or 8-year studyperiods. In 2 other studies, which specificallylooked at unusual anaerobes, meropenem inhibited90% of all strains at concentrations of ≤2 mg/L, withthe exception of Actinomyces spp. (n = 11; 4 mg/L)and Lactobacillus spp. (n = 15; 8 mg/L).[31,32]

2.2 Overview of Resistance Issues

For pathogens involved in intra-abdominal in-fections, the most likely resistance problem to beencountered is β-lactamase production. Other re-sistance mechanisms, because of the pathogens in-volved, are likely to be unusual and therefore willbe discussed briefly for the purposes of complete-ness only.

2.2.1 ββββ-Lactamase HydrolysisThe carbapenems are distinguished by their ex-

cellent stability against a wide range of serine-based β-lactamases.[33] These enzymes includechromosomally mediated β-lactamases and ex-

tended-spectrum variants of TEM and SHV.[34] Al-though stability against these common enzymesis not complete, the rate of hydrolysis is slowand only becomes significant when coupled withreduced outer membrane permeability (section2.2.2).[34]

Some β-lactamases or carbapenemases, how-ever, can effectively hydrolyse carbapenems (forreviews see Rasmussen & Bush[33] andLivermore[34]). These include: chromosomal en-zymes which are ubiquitous in some unusualpathogens [e.g. S. maltophilia, Aeromonas spp.,Flavobacterium (now Chryseobacterium) spp.];chromosomal enzymes found rarely in other

0 20 40 60 10080

Resistant strains (%)

pH 7.1pH 6.3pH 5.8

Meropenem

Imipenem

Piperacillin/tazobactam

Clindamycin

Ciprofloxacin

B. f

ragi

lis (

n =

59)

Meropenem

Imipenem

Piperacillin/tazobactam

Clindamycin

CiprofloxacinOth

er B

. fra

gilis

gro

up s

pp. (

n =

60)

Fig. 1. Effect of pH on the in vitro activity of antibacterial agentsagainst Bacteroides fragilis group.[28] Other B. fragilis group spp.were B. thetaiotaomicron (n = 18), B. ovatus (n = 12), B. distasonis(n = 11), B. vulgatus (n = 10) and B. uniformis (n = 9).

626 Lowe & Lamb


species (e.g. CcrA in a small subgroup of B. fragilis;IMP-1 in P. aeruginosa and Enterobacteriaceae);and plasmid-mediated carbapenemases.[22,33,34]

Imipenem is hydrolysed faster than meropenemby serine-based carbapenemases resulting inhigher MIC values for relevant organisms.[22,33]

Both imipenem and meropenem induce chromo-somal β-lactamases, although they do not appearto select stably derepressed mutants.[35]

2.2.2 Impermeability MechanismsImpermeability mechanisms constitute the ma-

jor mechanism of resistance to the carbapenemsand are most commonly found in P. aeruginosa.[36]

Among Enterobacteriaceae, isolated strains withouter membrane protein deficiencies have alsobeen reported.[36]

2.2.3 Alterations in Penicillin-Binding ProteinsModification of target penicillin-binding pro-

teins (PBP) appears to be the least important of the3 possible mechanisms of resistance for the carba-penems. Although unusual in Gram-negative bac-teria, this mechanism of resistance has been impli-cated in A. baumannii.[36]

2.2.4 Selection of ResistanceIn general, meropenem seems to have a low po-

tential for selecting resistant strains in vitro, al-though the pattern of selection differs from that ofimipenem. In one study, meropenem selected sta-bly resistant mutants of Enterobacter cloacae (un-characterised), but only at concentrations of ≥32× MIC. Imipenem did not select resistant strainsunder the same conditions.[37] In another study,meropenem selected porin-deficient mutants from2 strains of K. pneumoniae known to produce ex-tended-spectrum β-lactamases. MIC values in-creased from 0.03 mg/L to 0.5 and 2 mg/L in the 2strains. Imipenem also selected mutant strains(MIC values increased from 0.12 mg/L to 0.25 and0.5 mg/L), although they were not porin defi-cient.[38]

2.3 Other Effects

2.3.1 Effects on Intestinal FloraMeropenem produces only minor alterations in

the intestinal microflora of healthy volunteers,which is consistent with the fact that only about 2%of the drug is excreted in the faeces (section 3.1.2).Numbers of streptococci, enterobacteria, bacter-oides, veillonella/acidaminococci and clostridiadecreased and those of enterococci increased dur-ing a 7-day course of intravenous meropenem0.5g every 8 hours in 10 healthy volunteers. Allother intestinal flora were unaffected, althoughdata were not supplied for fungi. C. difficile wasnot isolated and colonisation with meropenem-resis-tant strains was not observed in any volunteer. Allgut flora returned to normal within 2 weeks ofcompleting treatment.[39] There are currently nodata concerning the 1g dose of meropenem or itseffects in patients with intra-abdominal infections.

2.3.2 Inoculum EffectBacteria are present throughout the gastro-

intestinal tract, although their distribution andnumbers vary according to the precise anatomicalsite. Bacterial numbers range from <103/ml inthe stomach to as high as 1010 to 1012/ml in thecolon[1,40] and may also reach 109/ml of pus inabscesses.[41] β-lactams are affected to differentdegrees by the size of the bacterial inoculum, usuallybecause of β-lactamase production.[41] Given thehigh bacterial numbers in the gastrointestinal tract,this is an effect that may have clinical relevance inthe treatment of intra-abdominal infections.

Meropenem, like other β-lactams, does exhibitan inoculum effect. However, the MIC values re-ported at a heavy inoculum [≈107 colony formingunits (cfu)/spot] remained generally low and rangedfrom 0.25 to 0.5 mg/L for B. fragilis,[42] 0.03 to 2mg/L for Enterobacteriaceae, P. aeruginosa and S.aureus,[27] 0.03 to 1 mg/L for Enterobacteriaceaeexpressing characterised chromosomal or plasmid-mediated broad- or extended-spectrum β-lactamases[43,44] and 2 to 4 mg/L for P. aeruginosaexpressing a plasmid-mediated β-lactamase.[44] Agreater inoculum effect was observed withmeropenem in strains expressing chromosomal



β-lactamases (4- to 32-fold increase in MIC at 107

cfu/ml) than in those expressing plasmid-mediatedβ-lactamases (0- to 4-fold change).[44]

2.3.3 Postantibiotic EffectCarbapenems have a postantibiotic effect

(PAE), defined as continued suppression of bacte-rial growth after short exposure to an antibiotic,against both Gram-negative and Gram-positivebacteria.[45] The size of the effect is, however, de-pendent on the assessment method used. If as-sessed using viable counts, PAE were consistently≤1.5 hours at meropenem concentrations of up to75 mg/L against P. aeruginosa, E. coli, K. oxytoca,K. pneumoniae and E. cloacae.[45-48] However, ifassessed using bioluminescence, PAEs rangedfrom 3.9 to 5.2 hours for P. aeruginosa, E. coli, K.pneumoniae and E. cloacae and 2.3 hours forSerratia marcescens.[47]

3. Pharmacokinetic Profile

The pharmacokinetic profile of meropenem iswell established and described (for reviews seeMouton & van den Anker[52] and Drusano &Hutchison[53]). A summary of the pharmacokinet-ics of meropenem in patients with intra-abdominalinfections is provided in table II; for comparison,

single dose data from healthy volunteers are alsoincluded in the table.

3.1 Overview of Pharmacokinetics

3.1.1 Absorption and DistributionAs for other β-lactam agents, meropenem has

linear pharmacokinetics over the dose range 0.25to 2g.[53] Mean peak plasma concentrations (Cmax)of meropenem following a single 1g dose rangedfrom 54.8 to 61.6 mg/L in healthy volunteers(table II). However, in adult patients with intra-abdominal infections, both Cmax and area underthe plasma concentration-time curve (AUC) wereslightly lower compared with healthy volunteers(table II). Steady-state trough concentrations areapproximately 0.25 mg/L with a dosage regimen ofmeropenem 1g administered 8-hourly in healthyvolunteers.[53]

Meropenem is distributed in the extracellular(interstitial) fluid. In patients with intra-abdominalinfections, the volume of distribution (Vd) tendedto be up to approximately 2-fold higher comparedwith values observed in healthy volunteers (tableII). Increases in Vd have been described with otherantibacterial agents in surgical patients, includingthose with intra-abdominal sepsis.[54,55] Body-fluidshifts, possibly attributable to altered micro-

Table II. Steady-state pharmacokinetics of intravenous meropenem in patients with intra-abdominal infections. Pharmacokinetic parameterswere assessed after surgery. For comparison, single dose pharmacokinetic data of meropenem in healthy volunteers are also included[12,49]

Patient group(no. patients/volunteers)

Meropenem(g)

Mean value(s)

Cmax

(mg/L)AUC(mg/L • h)

Vd(L)

CL(L/h)

CLR

(L/h)t1⁄2(h)

Healthy volunteersAdults[12] (n = 6-30/study) 1 54.8-61.6 66.9-77.5 12.5-23 11.3-16.8 7.9-11.9 1-1.4

Adults[12] (n = 4-8/study) 0.5 21.1-35.6 28-39.6 11.7-26.1 11.2-19.8 7.6-15.1 0.8-1.54

Elderly[49]a (n = 8) 0.5 37 58.4 13.2b 8.3b 5.9b 1.3

Patients with intra-abdominal infectionsAdults[50] (n = 12) 1 q8h 47.6 57.5 26.7 18.9 8.2 1.0

Adults/elderly[51]c (n = 8) 1 q8h NR 100 20.7 11.4 NR 1.3

a The age range of the volunteer group was 67-80 (mean 73) years.

b Unit given per 1.73m2 of body surface area.

c Patients had moderate/severe surgical infections [peritonitis (n = 5), cellulitis (n = 2) or cholangitis (n = 1)]. The age range of the patientgroup was 23-79 (mean 60) years.

AUC = area under plasma concentration-time curve; CL = total body clearance; CLR = renal clearance; Cmax = peak plasma concentration;NR = not reported; q8h = every 8 hours; t1⁄2 = elimination half-life; Vd = volume of distribution.

628 Lowe & Lamb


vascular permeability during sepsis or post-operative fluid sequestration, may explain thesedifferences.[54,55]

Meropenem concentrations in abdominal tis-sues and plasma following administration of a sin-gle 1g dose are shown in figure 2. Typically,meropenem concentrations in these tissues were inthe range of 2 to 4 mg/L or 10 to 20% of Cmax, andwere detectable in the colonic tissue for thewhole dosing interval (fig. 2).[56]

In normal and chronically inflamed pancreatictissue, mean meropenem concentrations were 1.59(range 0.24 to 3.16) mg/kg and 1.25 (range 0.33to 2.31) mg/kg 2.3 to 5.5 hours after pancreaticresection and administration of a 1g dose (n =10).[59] Meropenem concentrations in the bile werehigher than those in abdominal tissues and rangedfrom 7 to 15 mg/L up to 3.5 hours after adminis-tration of a 1g dose.[56,60] Meropenem was also dis-tributed into the bile of patients with an obstructedbiliary tree (mean 8.1 mg/L; n = 13), although these

concentrations were significantly lower than thoseachieved in patients without biliary obstruction(14.8 mg/L; n = 11; p < 0.05).[60] Plasma proteinbinding of meropenem is low (<20%).[53,56]

3.1.2 Metabolism and EliminationMeropenem is cleared predominantly in the kid-

ney by both glomerular filtration and tubular secre-tion.[52] Excretion is rapid and over 80% of an ad-ministered dose is excreted within 3 hoursincreasing to 95% within 8 hours.[61] Over a 12-hour period, 71% of the parent drug was recoveredfrom the urine and 19% as the metabolite.[61] Bil-iary excretion of meropenem is therefore limited;2.1% of a drug dose is recovered in the faeces.[61]

Meropenem has a single open-ring metabolite(ICI 213689) which is pharmacologically in-active.[53] It is formed by hydrolysis either by renaldehydropeptidase-I (DHP-I) or spontaneouschemical breakdown.[61] The elimination half-life(t1⁄2) of meropenem is approximately 1 hour (table II).

3.2 Special Patient Groups

3.2.1 ElderlyIn elderly patients, the clearance of meropenem

is decreased and t1⁄2 prolonged secondary to theage-related decline in renal function. Following asingle 0.5g dose of meropenem, the total bodyclearance of meropenem was 8.3 L/h • 1.73m2 in 8healthy elderly volunteers versus 12.2 L/h • 1.73m2

in 8 younger volunteers. The respective values fort1⁄2 were 1.3 and 0.8 hours (table II).[49] Dosage ad-justment is therefore required in elderly patientswith a creatinine clearance (CLCR) of ≤3 L/h (sec-tion 7). The pharmacokinetics of meropenem ap-pear to be otherwise unaltered in older patientswith intra-abdominal infection (table II).[51]

3.2.2 Renal and Hepatic ImpairmentIn keeping with the renal elimination of mero-

penem, the clearance (total body and renal) of thedrug decreases and t1⁄2 increases as CLCR de-clines.[12] For this reason, dosage reductions arerecommended in patients with a CLCR of ≤51ml/min (≤3 L/h; section 7).

Since meropenem is effectively cleared byhaemodialysis, administration of a unit dose is

Mer

open

em c

once

ntra

tion

(mg/

L or

mg/

kg)

0

5

10

15

20

25

30

35

Time (hours)

0.5-1.5 1.5-2.5 2.5-3.5 3.5-4.5 4.5-5.5 5.5-6.5 6.5-7.5 7.5-8.5

PlasmaPeritoneal exudateColon tissueGallbladder tissueOmentum tissue

Fig. 2. Distribution of meropenem in abdominal tissues. Abdom-inal tissue samples were taken from patients undergoing elec-tive intra-abdominal surgery (n = 66),[56] peritoneal exudatesamples from patients undergoing elective laparotomy (n =26)[56,57] and plasma samples from healthy volunteers (n = 6).[58]

All patients and volunteers received a single 1g dose ofmeropenem administered as a 30-minute intravenous infusion.



recommended following haemodialysis in order torestore plasma drug concentrations (section 7). Inpatients undergoing continuous veno-venoushaemofiltration, an estimated 45 to 47% of a doseof meropenem is removed giving rise to the sug-gestion that a dosage of at least 1g once dailyshould be given to this patient group.[12]

The pharmacokinetics of meropenem are, how-ever, unaltered in patients with chronic stable alco-holic cirrhosis compared with controls[62] andtherefore no dosage adjustment is required in thispatient group (section 7).

4. Therapeutic Efficacy

The efficacy of empirical monotherapy withmeropenem in hospitalised patients with intra-ab-dominal infections has been assessed in severalcomparative clinical trials. Patients with infectionsof varying severities were included in these trials;for ease of understanding, they have been dividedinto moderate, moderate to severe and severe cate-gories. All studies were multicentre andrandomised, and 1 trial was double-blind.[63] Al-though most clinical studies recruited patients withintra-abdominal infections only, 3 trials also in-cluded patients with other infection types.[64-66]

Patients with moderate infections were definedas those who generally had an Acute Physiologyand Chronic Health Evaluation (APACHE) II scoreof ≤10 and mainly comprised patients with appen-dicitis (table III). Patients with moderate to severeinfections were those with more difficult-to-treatinfections, including lower bowel traumatic perfo-rations and infections arising from previous sur-gery (tables IV and V). These infections were usu-ally community acquired (77 to 96%).[63,64,69]

Patients with severe infections were generally inintensive care and had difficult-to-treat infectionswhich were often nosocomial or hospital acquired(table VI). Mortality rates in trials of patients withmoderate to severe infection varied from 1 to10%;[13,63,68,69,72,73] higher rates (16 to 28%) werereported in trials that recruited patients with moresevere infections.[64-66]

Meropenem was administered intravenouslygenerally at a dosage of 1g every 8 hours in patientswith moderate to severe infections for a duration of5 to 10 days. A lower dosage of 0.5g every 8 hourswas used in 2 trials of patients with moderate in-fections.[13,68] Most patients underwent surgery inconjunction with antibacterial therapy.

Primary end-points included clinical and bacte-riological response. A satisfactory clinical re-

Table III. Comparative efficacy of meropenem (MEM) in the empirical treatment of patients with moderate intra-abdominal infections: summaryof multicentre randomised trials. Patients generally had appendicitis and an APACHE II score of ≤10 (80-91% of pts). Drugs were administeredintravenously every 8 hours for a period of between 5 to 10 days

Study Most common diagnoses(% of pts)

No. ofenrolledpts

Drug and dosage(g/day)

Percentage of pts with satisfactoryresponsea (no. of evaluable pts)

clinical bacteriological

Basoli et al.[67] Appendicitis (36%), cholecystitis(13%), diverticulitis (12%)

148 MEM 3 95 (100) 98 (100)

139 IPM/C 1.5 98 (101) 96 (101)

Brismar et al.[13] Appendicitis (65%) whichwas usually perforated

132 MEM 1.5 98 (99) 98 (94)

117 IPM/C 1.5 96 (90) 95 (81)

Zanetti et al.[68] Diverticulitis (42%), appendicitis(30%), colitis (14%),duodenal/gastric ulcer (13%)

82 MEM 1.5 92 (71) 87b

79 IPM/C 2c 94 (64) 93b

a Clinical response was satisfactory if symptoms were either cured or improved. Bacteriological response was satisfactory if therewas proven or presumptive (satisfactory clinical response but no specimen obtained for culture) eradication of primary pathogens.All responses were assessed at the end of treatment.

b Percentage of isolated pathogens eradicated.

c Administered every 6 hours.

APACHE = Acute Physiology and Chronic Health Evaluation; IPM/C = imipenem/cilastatin; pts = patients.

630 Lowe & Lamb


sponse was defined as either complete resolutionor improvement of symptoms at the end of treat-ment; a satisfactory bacteriological response wasdefined as proven or presumptive eradication ofcausative pathogen(s). Although overall clinicaland bacteriological outcomes were generally re-ported, microbiological data, specifically in treat-ment failures, were limited in some investigations.

Most studies included a 2- to 4-week follow-upperiod to assess rates of relapse and failure but fewstudies actually reported these results.

The efficacy of meropenem monotherapy hasalso been evaluated in 2 clinical trials enrollingchildren;[74,75] however, the proportion of childrenwith intra-abdominal infections in these studieswas small (<8%), and consequently, these data along

Table IV. Comparative efficacy of meropenem (MEM) in the empirical treatment of patients with moderate to severe intra-abdominal infections:summary of multicentre randomised trials, 1 of which was double-blind.[63] All drugs were administered intravenously every 8 hours for aperiod of between 5 to 10 days

Study Infection severity and site(% of pts)

No. ofenrolledpts

Drug and dosage(g/day)

Percentage of pts withsatisfactory responsea

(no. of evaluable pts)


Comparisons with imipenem/cilastatin (IPM/C) monotherapyGeroulanoset al.[69]

Moderate (60%) to severe (25%) infection,mainly appendicitis (34%), small/large bowel(21%) caused by previous surgery(18%), cholangitis (15%)

116 MEM 3 96b (82) 84b (82)

116 IPM/C 3 94b (88) 81b (88)

Kanellakopoulouet al.[70]

Moderate to severe infection, mainlyappendicitis (42%), gastric or duodenal ulcerperforation (26%) or cholecystitis (15%)

30 MEM 3 100c (28) 90d (NR)

32 IPM/C 3 97c (31) 100d (NR)

Tonelli[71] Peritonitis (76%) 43 MEM 3 98 (43) 96 (27)

43 IPM/C 3 95 (41) 96 (27)

Comparisons with cefotaxime (CTX) ++++ metronidazole (MTR)Huizinga et al.[72] Moderate to severe (26% severe) infections,

mainly appendicitis (34%), stomach (17%),small bowel (16%), colon/rectum (14%)

77 MEM 3 91*e (70) 90 (48)

83 CTX 6 + MTR 1.5 100 (78) 92 (52)

Kempf et al.[73] Perforated appendix (37%), colon (33%),epigastric region (30%)

48 MEM 3 95* (43) 94 (33)

46 CTX 6 + MTR 1.5 75 (40) 81 (32)

Mehtar et al.[64] Serious bacterial infections includingintra-abdominal infections (76%)

81 MEM 3 93f (68) NR

80 CTX 3 + MTR 1.5 92f (63) NR

Comparison with clindamycin (CM) ++++ tobramycin (TM)Wilson[63] Complicated appendicitis (73%), large/small

bowel perforation (13%), abscess (4%)215 MEM 3 96g (97) 96g (97)

212 CM 2.7 + TM 15 mg/kg 93g (94) 93g (94)

a Clinical response was satisfactory if symptoms were either cured or improved. Bacteriological response was satisfactory if there wasproven or presumptive (satisfactory clinical response but no specimen obtained for culture) eradication of primary pathogens. Allresponses were assessed at the end of treatment.

b At follow-up 2 to 4 weeks after the end of treatment, 90 and 88% of pts receiving MEM and IPM/C, respectively, had a satisfactoryclinical response and 84 and 79% of pts had a satisfactory bacteriological response.

c At follow-up ≥1 month after the end of treatment, 97 and 94% of pts receiving MEM and IPM/C, respectively, had a satisfactory clinicalresponse.

d Percentage of isolated pathogens eradicated.e Three treatment failures occurred because of surgical misadventure.f At follow-up 8 weeks after the end of treatment, 96 and 93% of pts receiving MEM and CTX + MTR, respectively, had a satisfactory

clinical response.g At follow-up 4 to 14 days after the end of treatment, 98 and 93% of pts receiving MEM and CM + TM, respectively, had a satisfactory

clinical response and 100% of pts in both the MEM and CM + TM groups had a satisfactory bacteriological response.NR = not reported; pts = patients; * p < 0.008 vs comparator.



with those from noncomparative studies[76-79] willnot be discussed further. Currently there are noavailable data on the use of meropenem in patientswith chronic ambulatory peritoneal dialysis-associated peritonitis.

4.1 Moderate Infections

A satisfactory clinical response was obtained in92 and 98% of patients with intra-abdominal infec-tions of moderate severity treated with meropenem1.5 g/day compared with rates of 94 and 96% withimipenem/cilastatin 1.5 or 2 g/day in 2 multicentre,randomised trials (table III).[13,68] Similar results(95 vs 98%) were obtained in an Italian-basedstudy in which patients received a 3 g/day dosageof meropenem but a reduced 1.5 g/day dosage ofimipenem/cilastatin.[67]

Bacteriological response rates (95 to 98% forboth drugs) were similar to the rates of clinical re-sponse in 2 trials,[13,67] although slightly lowerrates were documented in the remaining trial whichgave results on a per pathogen basis (87% withmeropenem vs 93% with imipenem/cilastatin).[68]

4.2 Moderate to Severe Infections

4.2.1 Comparisons with Imipenem/Cilastatin

Clinical ResponseIn patients with moderate to severe infections,

clinical response rates were similar in patients whoreceived either meropenem or imipenem/cilastatin(both 1g every 8 hours) in 3 multicentre,randomised trials (table IV).[69-71] In these trials,patients receiving meropenem had response ratesranging from 96 to 100%; corresponding responserates in imipenem/cilastatin recipients ranged from94 to 97%.

At follow-up (generally 2 to 4 weeks after theend of treatment), clinical responses in evaluablepatients were similar to those obtained at the endof treatment.[69-71]

Bacteriological ResponseIn patients receiving meropenem, satisfactory

bacteriological eradication rates ranged from 84 to96%; those in patients receiving imipenem/cilastatinranged from 81 to 100% (table IV).

On a per pathogen basis, meropenem and im-ipenem/cilastatin were similar in the eradication ofGram-negative pathogens at a dosage of 3 g/day(87 to 95% vs 93 to 100%) in 3 multicentre trials

Table V. Comparative bacteriological efficacy of meropenem (MEM) in patients with moderate to severe intra-abdominal infections: summaryof multicentre, randomised studies of which 1 was double-blind.[63] All drugs were administered intravenously every 8 hours for a period ofbetween 5 to 10 days

Study Drug and dosage (g/day) Percentage of pathogens eradicated (total number of isolates)

Gram-negative Gram-positive anaerobes

Comparisons with imipenem/cilastatin (IPM/C)Geroulanos et al.[69] MEM 3 87 (92) 87 (79) 93 (76)

IPM/C 3 93 (86) 90 (58) 91 (64)

Kanellakopoulou et al.[70] MEM 3 94 (18) 80 (10) 100 (3)

IPM/C 3 100 (20) 100 (11) 100 (12)

Tonelli[71] MEM 3 95 (21) 100 (13) 100 (7)

IPM/C 3 100 (30) 92 (13) 100 (3)

Comparisons with cefotaxime (CTX) ++++ metronidazole (MTR)Huizinga et al.[72] MEM 3 95 (62) 93 (30) 100 (18)

CTX 6 + MTR 1.5 97 (65) 100 (33) 100 (17)

Kempf et al.[73] MEM 3 94 (35) 89 (9) 88 (8)

CTX 6 + MTR 1.5 81 (42) 100 (4) 80 (5)

Comparison with clindamycin (CM) ++++ tobramycin (TM)Wilson[63] MEM 3 99 (114) 99 (73) 97 (147)

CM 2.7 + TM 15 mg/kg 90 (116) 90 (73) 87 (159)

632 Lowe & Lamb


which provided details (table V).[69-71] Variableeradication rates were obtained for meropenem(range 80 to 100%) and imipenem/cilastatin (range90 to 100%) against Gram-positive pathogens. Al-though meropenem and imipenem/cilastatin pro-duced similar high eradication rates against an-aerobic bacteria, the number of isolates was smallin 2 of 3 studies (table V). No statistical compari-sons were available for these data.

4.2.2 Comparisons with Cefotaxime plusMetronidazole

Clinical ResponseThree clinical trials which compared mero-

penem with a cephalosporin-based regimen con-sisting of cefotaxime (1 or 2g every 8 hours) plusmetronidazole (0.5g every 8 hours) reported con-trasting results (table IV).[64,72,73] Patients receiv-ing meropenem (1g every 8 hours), however,achieved high rates (91 to 95%) of satisfactoryclinical response in all trials.

One study found that a significantly higher pro-portion of patients receiving meropenem achieveda satisfactory clinical response compared withthose receiving the cephalosporin-based regimen(95 vs 75%; p = 0.008) [table IV].[73] However, inanother study in patients with local or diffuse peri-

tonitis, those receiving the cephalosporin-basedregimen had a significantly better response ratecompared with those receiving meropenem (100 vs91%; p = 0.008).[72] This apparent difference inclinical response may have been attributable to aslight imbalance between treatment groups: ahigher proportion of patients in the meropenemgroup had APACHE II scores between 11 and 20(19 vs 12% of patients receiving cefotaxime plusmetronidazole), and were more likely to havenasogastric tubes (74 vs 59%), indwelling cathe-ters (68 vs 55%) or, more significantly, infectionsattributable to previous intra-abdominal surgery(9 vs 1 patient).[72]

In the third trial, meropenem 3 g/day produceda similar rate of clinical response compared withlow dose cefotaxime (1g every 8 hours) plus met-ronidazole (0.5g every 8 hours) in patients with arange of serious bacterial infections (table IV);76% of patients in this study had intra-abdominalinfections.[64]

Bacteriological ResponseBacteriological eradication rates with mero-

penem were consistently similar to those achievedwith cefotaxime plus metronidazole in 2 trialsreporting these data (table IV).[72,73]

Table VI. Comparative efficacy of meropenem (MEM) in the empirical treatment of patients with serious infections, including those with severeintra-abdominal infections (IAI): summary of multicentre randomised trials which included >50 clinically evaluable pts with IAI. Both drugswere administered intravenously every 8 hours and the mean duration of treatment ranged from 9.8 to 11.5 days

Study Diagnosis and patient status Drug anddosage(g/day)

Percentage of pts with satisfactory responsea

(no. of evaluable pts)


overall IAI overall IAI

Colardyn et al.[65] Serious bacterial infections; 67% ofclinically evaluable pts in ICU; 53%had failed to respond to previousantibiotic therapy. IAI involvedcolon/rectum, stomach/duodenum,peritonitis, appendix and other

MEM 3 76 [90] 82 [38] 69 [61] 68 [25]

IPM/C 3 77 [87] 81 [37] 72 [54] 70 [27]

Verwaest et al.[66] Serious bacterial infections; all ptsin ICU; 75% of infections werehospital-acquired

MEM 3 77 [87] 96 [22] 67 [73] 78 [18]

IPM/C 3 68 [91] 77 [30] 60 [73] 70 [23]

a Clinical response was satisfactory if either cure or improvement of symptoms occurred. Bacteriological responses were satisfactory ifproven or presumptive (satisfactory clinical response but no specimen obtained for culture) eradication of the causative organism(s)took place. Responses were assessed at the end of treatment.

ICU = intensive care unit; IPM/C = imipenem/cilastatin; pts = patients.



When analysed by pathogen in 2 studies (tableV), meropenem showed similar eradication rates tothe cephalosporin-based regimen against Gram-negative and anaerobic pathogens in 1 study.[72] Inanother study,[73] meropenem was marginally moreeffective than cephalosporin-based treatmentagainst Gram-negative pathogens (94 vs 81%), al-though a statistical analysis was not provided.

In both studies, the cephalosporin-based regi-men tended to be slightly more effective againstGram-positive pathogens with eradication ratesof 100 vs 89 and 93%; there were only 13 Gram-positive isolates in 1 study[73] and statistical datawere not provided in either study (table V).[72,73]

4.2.3 Comparison with Clindamycin plusTobramycin

Clinical ResponsePreliminary data from the trial of Wilson[63]

have been previously reported by Berne et al.[80]

and Condon et al.[81] but these papers will not bediscussed further. According to Wilson,[63]

meropenem (1g every 8 hours) when comparedwith clindamycin (0.9g every 8 hours) plus tobra-mycin (15 mg/kg/day) produced similar clinical re-sponse rates in a multicentre, randomised, double-blind study (table IV); rates were 96% aftermeropenem and 93% after clindamycin plus tobra-mycin.[63] The rate of satisfactory clinical responsewas maintained at follow-up performed 4 to 14 and28 to 42 days later.

Bacteriological ResponseBacteriological response rates were 96 and

93%, respectively, after meropenem andclindamycin plus tobramycin (table IV).[63] Theserates improved to 100% in both treatment groupsat follow-up 4 to 14 days later, and were maintainedthrough to day 42 in the aminoglycoside-basedgroup versus 94% of patients in the meropenemgroup.[63]

Meropenem demonstrated marginally higherrates of eradication compared with clindamycinand tobramycin against Gram-negative (99 vs90%), Gram-positive (99 vs 90%) and anaerobic

organisms (97 vs 87%) [table V];[63] however, nostatistical analyses were reported.

4.3 Severe Infections

Meropenem and imipenem/cilastatin demon-strated similar clinical efficacy in 2 comparativetrials which recruited patients with serious infec-tions and included over 50 patients each withsevere intra-abdominal infections (table VI). Ad-ministered at dosages of 3 g/day, clinical responserates were 82 and 96% with meropenem versus 81and 77% with imipenem/cilastatin in patients withintra-abdominal infections in the 2 trials.[65,66]

Relapses were observed during the follow-upperiod in 1 meropenem and 3 imipenem/cilastatinrecipient(s) with intra-abdominal infections in onetrial which provided details.[65] In those for whomempirical treatment was unsuccessful, a total of 11of 14 patients had infections from previous surgery,confirming that this is a difficult-to-treat patientgroup.[65]

Bacteriological response rates were also similarwith meropenem and imipenem/cilastatin (68 and78% vs 70 and 70%; table VI). Although details ofbacteriological outcome according to causativepathogen and of superinfections were provided inboth trials, they were not detailed on a per infectionbasis and so will not be discussed further.

Good results were also obtained with mero-penem in 3 other randomised studies which re-cruited patients with serious infections includinga very small proportion of patients with intra-abdominal infections. Ten of 13 patients receivingmeropenem 3 g/day versus 5 of 7 patients treatedwith imipenem/cilastatin 3 g/day achieved a satis-factory clinical response in 1 trial[82] as did 3 of 3versus 3 of 5 patients in another.[83] In the last trial,which recruited patients aged ≥65 years,[84] 4 of7 recipients of meropenem 3 g/day and 2 of 3recipients of cefuroxime 4.5 g/day plus gentamicin4 mg/kg achieved a satisfactory outcome.

4.4 Efficacy According to Infection Site

Clinical trials investigating the efficacy of antibac-terial regimens in the treatment of intra-abdominal

634 Lowe & Lamb


infections invariably recruit a mixed group ofpatients with infections at different anatomicalsites. Not all infections have a similar outcome;infections involving the lower gastrointestinaltract tend to have a poorer outcome than someother infection types, including appendicitis(section 1).[1,85]

In a retrospective analysis of 4 clinical trials,[85]

meropenem consistently achieved a satisfactoryresponse rate in over 89% of patients regardlessof the anatomical site of intra-abdominal infection(n = 217; fig. 3). Comparator regimens generallyperformed equally well (n = 212), although sta-tistical analysis was inappropriate because the datawere combined from different clinical trials. Notablyall regimens, with the possible exception of im-ipenem/cilastatin, performed best in patients withcomplicated appendicitis (fig. 3).[85]

The efficacy of meropenem was also retained inboth diffuse and localised peritonitis (fig. 4) and inpatients with concurrent septicaemia. In 3 clinicaltrials that provided data on the outcome of patientswith septicaemia, meropenem 3 g/day achieved asatisfactory response in 3 of 3 patients in 2 trials[69,72]

and 35 of 38 patients in another.[64]

4.5 Persistent Pathogens andSuperinfections

Superinfections and bacteriological failureswere documented in a number of stud-ies.[13,69,72,73,80,81] In those which reported bacteri-ological results, bacteriological failure was re-ported in 4 to 16% of patients (table IV) and themost common persistent organisms followingmeropenem therapy included E. coli, other En-terobacteriaceae, enterococci, Streptococcus spp.and P. aeruginosa.[63,64,67-73,80,81] The resistancephenotypes of persistent pathogens were not char-acterised in any study.

This picture is consistent with an overview of 6clinical trials[86] which reported eradication ratesachieved with meropenem in patients with intra-abdominal infections on a per pathogen basis.Eradication rates exceeded 90% for E. coli (n = 185),K. pneumoniae (n = 26), B. fragilis (n = 67) and S.

epidermidis (n = 14). Other pathogens were eradi-cated at a rate of 78% for E. faecalis (n = 18), 80%for E. cloacae (n = 10) and 89% for P. aeruginosa(n = 28).

Superinfections in meropenem recipients werereported in 3 studies: these occurred in 2 of 48patients,[72] 5 of 82 patients,[69] and 9 of 94

Per

cent

age

of p

atie

nts

100

80

60

40

20

0

MEMIPM/CCTX + MTRCM + TMClinical response

100

80

60

40

20

0UGI CAPX LGI

Bacteriological response

Fig. 3. Comparative clinical and bacteriological efficacy ofmeropenem (MEM) and comparator regimens in the empiricaltreatment of intra-abdominal infections by anatomical site. MEMwas administered at a dosage of 1g every 8 hours (n = 217).Comparator regimens included imipenem/cilastatin 1g every 8hours (IPM/C; n = 81), cefotaxime 2g + metronidazole 0.5gevery 8 hours (CTX + MTR; n = 42) and clindamycin 0.9g +tobramycin 5 mg/kg every 8 hours (CM + TM; n = 89). Data weretaken from an analysis of 4 randomised trials involving 429patients with intra-abdominal infections.[85] Upper gastro-intestinal infections (UGI) included complicated cholecystitis,cholangitis, perforated gastric or duodenal ulcer, intra-abdominalabscess, pancreatic infection and perforation of the upper smallbowel. Complications of appendicitis (CAPX) were mainly per-forations, and lower gastrointestinal infections (LGI) consistedmostly of perforation of the colon, intra-abdominal abscessessecondary to ileocolonic ischaemia and perforations due tostrangulated bowel obstruction.



patients.[13] Similar rates were observed with com-parator regimens: 3 of 52 with cefotaxime plusmetronidazole,[72] and 12 of 88[69] and 5 of 81[13]

patients with imipenem/cilastatin. Superinfectingpathogens, which were reported in 2 studies, wereE. faecalis and coagulase-negative staphylococciin 1 study,[72] and E. coli (2 isolates), K. oxytoca(1), E. aerogenes (1), E. faecalis (3), Enterococcusspp. (1), S. milleri (3), Peptostreptococcus spp. (1),C. innocuum (1), B. fragilis (3), other Bacteroidesspp. (5), Fusobacterium prausnitzii (1) and Candida

spp. (1) in the other.[13] Resistant superinfectingorganisms reported in 1 study were enterococci,S. milleri and coagulase-negative staphylococci;10 strains were resistant to meropenem comparedwith 9 to imipenem/cilastatin.[69]

5. Pharmacoeconomic Considerations

This section provides a brief overview of thepublished pharmacoeconomic data on meropenemthat are relevant to its use in the treatment ofintra-abdominal infections. The cost analysesavailable for meropenem pertain to direct drug-related costs only; a summary of these is providedin table VII (for review see Holliday & Benfield[90]).A single cost-effectiveness study in patients withintra-abdominal infections has also recently beenpublished.[91]

Unlike imipenem/cilastatin, meropenem can beadministered by bolus injection or infusion (sec-tion 7). In 2 clinical trials in patients with intra-ab-dominal infections which provided appropriatedata,[64,66] meropenem was administered by bolusinjection in just over half (≤60%) of the patientgroup.

In the 2 cost analyses that compared deliverymethods of meropenem, bolus administration wasassociated with delivery cost savings of approxi-mately 30% in an Australian study (table VII)[88]

and 45% in a UK study[89] compared with an infu-sion of the drug. Savings were related to the use offewer consumables,[88,89] and slightly lower labourcosts in one study.[88] Any differences in total directcosts between the various meropenem and imipenem/cilastatin regimens was predominantly a reflectionof these differences in delivery costs (table VII).

Of interest also are the delivery costs forceftazidime 2g plus metronidazole 0.5g given 3times daily by infusion which were approximately£110 compared with £90 for meropenem 1g given3 times daily (delivery method not stated; dataestimated from a graph).[92]

The duration of hospitalisation, a major health-care cost, also has implications for the overall costsof treatment. In 3 clinical trials in patients withintra-abdominal infections that presented these

Sat

isfa

ctor

y re

spon

se (

% p

atie

nts)

100

80

60

40

20

0

b

MEMIPM/CCTX + MTR

100

80

60

40

20

0

(n = 77) (n = 49)

(n = 53)

Local peritonitis

(n = 30)

Diffuse peritonitis

a

Fig. 4. Efficacy of meropenem (MEM) 1g every 8 hours com-pared with imipenem/cilastatin (IPM/C) 1g every 8 hours (a) andcefotaxime (CTX) 2g plus metronidazole (MTR) 0.5g every 8hours (b) according to extent of peritonitis. Data was taken from2 studies that reported clinical response rates for local and dif-fuse peritonitis.[69,73]. Asatisfactory clinical response was definedas either complete resolution or improvement of symptoms atthe end of treatment.

636 Lowe & Lamb


data, 2 reported similar mean durations ofhospitalisation with meropenem versus cefotaximeplus metronidazole (11.5 vs 11.7 days)[64] andimipenem/cilastatin (17 vs 16.9 days),[68] but theremaining study reported a significantly shorterhospital stay with meropenem than with clinda-mycin plus tobramycin (8 vs 9.4 days; p = 0.01).[80]

A retrospective cost-effective analysis, whichcompared meropenem and imipenem/cilastatinbased on the data from the trial by Basoli et al.[67]

(table III), is available.[91] The analysis, however,was based on a study which used nonequivalentdosages of the 2 agents (imipenem/cilastatin 1.5g/day vs meropenem 3 g/day), a factor which islikely to have had a considerable effect on the costoutcome as direct costs only were considered inthe analysis. From the perspective of the Italian

National Health Service, it was estimated thattreatment with imipenem/cilastatin 1.5 g/day costL3.6 million/patient versus L4.5 million formeropenem administered at the higher dosage of3 g/day. The results were similar from the per-spective of a private health insurer also.

6. Tolerability

The tolerability of meropenem has been evalu-ated in a number of safety analyses conducted inpatients with a wide range of infections, includingintra-abdominal infections.[93-95] This review fo-cuses on an overview of tolerability data obtainedfrom clinical trials of meropenem compared withother therapeutic regimens in 9514 patients.[93]

Data from 46 trials (45 comparative and 1 non-comparative) were evaluated in this overview

Table VII. Direct drug-related costs of meropenem (MEM) and imipenem/cilastatin (IPM/C): summary of 3 cost analyses

Reference Country (year) Dosage regimen(g)

Method of delivery Costsa

acquisition(per dose)

delivery(per dose)b

total(per day)

Marquina et al.[87] Spain (NA) MEM 0.5 tid Infusion Pta2.52 Pta0.12 Pta7.91

MEM 1 tid Infusion Pta4.37 Pta0.12 Pta13.46

IPM/C 0.5 qid Infusion Pta2.07 Pta0.10 Pta9.41

IPM/C 1 tid/qid Infusion Pta4.13 Pta0.16 Pta15.86

Plumridge[88] Australia(1997)

MEM 0.5 tid Bolus A$26.67 A$6.26 A$98.79

MEM 1 tid Bolus A$53.34 A$6.86 A$180.60

MEM 0.5 tid Infusion A$26.67 A$9.24 A$107.73

MEM 1 tid Infusion A$53.34 A$9.99 A$189.99

IPM/C 0.5 tid Infusion A$24.81 A$11.23 A$108.12

IPM/C 1 tid Infusion A$49.62 A$14.52 A$192.42

IPM/C 0.5 qid Infusion A$24.81 A$11.23 A$144.16

IPM/C 1 qid Infusion A$49.62 A$14.52 A$256.56

Smyth et al.[89] UK (1996) MEM 0.5 tid Bolus £15.00 NA £52.86c

MEM 1 tid Bolus £30.00 NA £97.14c

MEM 0.5 tid Infusion £15.00 NA £58.57c

MEM 1 tid Infusion £30.00 NA £103.57c

IPM/C 0.5 tid Infusion £15.00 NA £60.71c

IPM/C 1 tid Infusion £30.00 NA £107.14c

IPM/C 0.5 qid Infusion £15.00 NA £77.14c

IPM/C 1 qid Infusion £30.00 NA £141.43c

a Conversion factors as of 20 June 2000: $US1.00 = A$0.38 = £0.66 = Pta172.39.

b Included the costs associated with labour (preparation, administration and observation),[87] labour and consumables (needles,syringes, diluent, ethanol swab, minibag of sterile solution, minibag label and saline flushes for intravenous lines)[88] and costsof labour (preparation, administration), consumables (gloves, needles, diluent, syringes, etc) and waste disposal.[89]

c Data estimated from a graph.

NA = not available; Pta = peseta; qid = 4 times daily; tid = 3 times daily.



which compared meropenem (5026 treatment ex-posures) with imipenem/cilastatin (1801 treatmentexposures), cephalosporin-based regimens (2423treatment exposures) and clindamycin plus amino-glycoside regimens (527 treatment exposures). Nostatistical comparisons were made between

meropenem and the comparator regimens.[93] Themost common types of infections included lowerrespiratory tract (2196 treatment exposures), intra-abdominal (2131 treatment exposures) and urinarytract infections (1192 treatment exposures); chil-dren were also included in this review (926 treat-ment exposures).[93]

Data from clinical trials in patients with intra-abdominal infections (section 4) are also includedwhere they expand on the information provided bythe overview.

6.1 Overview of Tolerability Profile

The overall incidences of adverse events, drug-related adverse events (definitely, probably orpossibly related to the drug), adverse events lead-ing to withdrawal and mortality were similar be-tween meropenem and its comparators (fig. 5).These results are generally supported by thosefrom trials involving patients with intra-abdominalinfections which showed a similar incidence ofclinical adverse events with meropenem and com-parator regimens.[13,63,64,67,69,71-73,80]

Drug-related events most frequently associatedwith meropenem were diarrhoea (2.3%), rash(1.4%), nausea/vomiting (1.4%) and local inflam-mation at the injection site (1.1%; fig. 6). Otherevents (headache, pruritus, abdominal pain, andsepsis) were reported at an incidence of <0.4%.There was no indication that the incidence of diar-rhoea, rash or nausea/vomiting with meropenemwas dose related.[93]

6.2 Gastrointestinal Events

Gastrointestinal events, a characteristic adverseeffect of most antibacterial agents, are likely to beparticularly relevant to patients who have recentlyundergone intra-abdominal surgery. A concernwith imipenem/cilastatin is that the incidence ofnausea and vomiting is linked to the rate of admin-istration and dosage of the drug.[96-98] With mero-penem, however, the incidence of nausea and vom-iting is not dose related (n = 3504)[93] and the agentcan be administered without regard to the rate ofinfusion (section 7).

0 105 15 20 25 30 35 40

All adverse events

Drug-relatedadverse events

Withdrawalsbecause of

adverse events

Mortality

Incidence (% of treatment exposures)

MeropenemImipenem/cilastatinCephalosporin-based regimensClindamycin/aminoglycoside regimens

Fig. 5. Percentage of treatment exposures associated with ad-verse events, drug-related adverse events, treatment with-drawal and mortality with meropenem and comparatorregimens. Data were taken from a safety analysis of 46 clinicaltrials (all but 1 were comparative) in patients with serious bac-terial infections including intra-abdominal infections.[94] Therewere 5026 treatment exposures to meropenem, 1801 to im-ipenem/cilastatin, 2423 to cephalosporin-based treatments and527 to clindamycin plus aminoglycoside regimens. Most patientsreceived intravenous meropenem 0.5 (n = 1215) or 1g (n = 2391)every 8 hours. Dosages of comparator drugs were thoserecommended by the manufacturers. Drug-related events weredefined as definitely, probably or possibly related to the drug.

638 Lowe & Lamb


Gastrointestinal events associated with im-ipenem/cilastatin can be managed, to some degree,by decreasing the rate of infusion of the drug.[96]

This option was pursued in some of the trials in-volving patients with intra-abdominal infections(imipenem/cilastatin was infused over 30- to 60-minutes);[13,65,66,69,70] consequently, the reportedincidence of gastrointestinal events in these trialswas generally low (3 reports of nausea and vomit-ing with imipenem/cilastatin[68,69] vs 2 reports withmeropenem[69]).

In trials of patients with intra-abdominal infec-tions that reported relevant details, one case of C.difficile-related colitis was reported with mero-penem 3 g/day and one case also with the compa-rator regimen (cefotaxime plus metronidazole).[64]

In 2 other trials which tested stool specimens in

patients who developed diarrhoea, no sample wasfound to be positive for C. difficile toxin.[63,81]

6.3 Seizure Potential

A tolerability concern with β-lactam agents istheir potential to cause CNS toxicity and seizures.With regard to the CNS, meropenem appears to bewell tolerated and is therefore indicated in thosewith meningitis.[99] Imipenem/cilastatin, on theother hand, is associated with a risk of seizures,particularly in those with predisposing factors suchas renal dysfunction, underlying CNS pathology oradvanced age, and is not recommended at dosagesin excess of 4 g/day because of associated neuro-toxicity.[96,100,101]

In an overview of 46 clinical trials, which ex-cluded patients with meningitis and a history of

MeropenemImipenem/cilastatinCephalosporin-based regimensClindamycin/aminoglycoside regimens

Inci

denc

e (%

of t

reat

men

t exp

osur

es)

3.5

3

2.5

0.5

1

1.5

2

0

4

Rash

Nause

a/vo

mitin

g

Loca

l infla

mm

ation

Heada

che

Sepsis

Consti

patio

n

Diarrh

oea

Abdom

inal p

ain

Prurit

us

Fig. 6. Comparative incidence of drug-related adverse events occurring in >1% of patients receiving meropenem 0.5 or 1g every 8hours or comparator regimens. Dosages of comparator drugs were those recommended by the manufacturers. Data were takenfrom a safety analysis of 46 clinical trials (all but 1 were comparative and randomised) in patients with serious bacterial infectionsincluding intra-abdominal infections.[94] There were 5026 treatment exposures to meropenem, 1801 to imipenem/cilastatin, 2423 tocephalosporin-based treatments and 527 to clindamycin plus aminoglycoside regimens.



CNS disorders, the incidence of meropenem-related seizures was 0.08% of treatment expo-sures.[93] In comparison, the incidence of seizureswith imipenem/cilastatin was 0.28% and 0.05%with cephalosporin-based therapies. No seizuresassociated with clindamycin plus aminoglycosidewere reported. The 4 patients who developed sei-zures with meropenem were elderly and 2 had renalimpairment (CLCR 2.5 and 3.1 L/h).[93]

In clinical trials in patients with intra-abdominalinfections which compared meropenem with im-ipenem/cilastatin,[13,65,67-71] cefotaxime plus met-ronidazole[64,72,73] or clindamycin plus tobramy-cin,[63,80,81] there were no reports of seizures withmeropenem. Convulsions were reported in 2 pa-tients treated with imipenem/cilastatin[13,66] andthere was also 1 report of a patient with convul-sions after cefotaxime plus metronidazole.[72] Moststudies excluded those with a history of CNS dis-orders or seizures.[63-66,68,69,71-73,81]

6.4 Laboratory Events

The incidence of laboratory adverse events wassimilar between meropenem and imipenem/cilastatin recipients. However, cephalosporin-based regimens tended to produce a lower inci-dence and clindamycin plus aminoglycoside aslightly higher incidence of events; no statisticalanalysis of the results was provided.[93] Laboratoryevents most commonly associated (≥1% of treat-ment exposures) with meropenem includedthrombocytosis (1.6%) and increases in ALT(4.3%), AST (3.4%) and alkaline phosphatase(1.5%).[93]

These findings were consistent with those ob-served in clinical trials,[13,63,68-70,72,73,81] although ahigher incidence of increases in ALT and AST wereobserved with meropenem in 1 study.[63]

6.5 Elderly Patients

Elderly patients (>65 years of age) experiencedmore adverse events compared with younger patientsafter receiving meropenem (45 vs 39%) accordingto an overview of clinical trial data.[95] However, thefrequency of drug-related events and drug-related

withdrawals was similar between groups.[95] Similartrends were seen in the imipenem/ cilastatin andcephalosporin comparator groups.[95]

Most clinical trials in patients with intra-ab-dominal infections comparing meropenem withimipenem/cilastatin,[13,67-69,71] cefotaxime plusmetronidazole[64,72,73] or clindamycin plus tobra-mycin[63,81] included a proportion of elderly pa-tients in their study population. Except for 2 elderlypatients receiving meropenem 3 g/day who died ofcomplications caused by underlying disease sub-sequent to septic shock, no other studies specific-ally reported adverse events in the elderly associ-ated with meropenem.

7. Dosage and Administration

Meropenem is indicated as monotherapy for thetreatment of intra-abdominal infections.[102,103] Ac-cording to the manufacturer’s recommenda-tions,[99] meropenem should be administered intra-venously at a dosage of 1.5 to 3 g/day in 3 divideddoses depending on the type and severity of infec-tion, the susceptibility of the pathogen(s) and thecondition of the patient.[99] However, at a nationallevel, dosage recommendations may vary. For ex-ample, in the US a fixed dosage of 1g every 8 hoursis recommended for adult patients with intra-ab-dominal infections[104] and, in the UK,[102] a similardosage is recommended for the treatment of peri-tonitis. Meropenem can be administered as an in-travenous bolus injection over approximately 3 to5 minutes or an intravenous infusion over approx-imately 15 to 30 minutes.[99,102,103]

Dosage recommendations for meropenem inspecial patient groups is presented in table VIII.Additionally, because meropenem is cleared byhaemodialysis, a unit dose relative to the type andseverity of infection should be administered afterhaemodialysis.[102,103] There are currently no dos-age recommendations for patients undergoingperitoneal dialysis or haemofiltration; however,an estimated 45 to 47% of a dose of meropenemis removed in those undergoing continuous veno-venous haemofiltration giving rise to the suggestion

640 Lowe & Lamb


that the dosage in this patient group should be in-creased to at least 1g daily.[12]

8. Place of Meropenem in theManagement of Patients withIntra-Abdominal Infections

Antibacterial therapy forms only part of anyprogramme for the management of intra-abdominalinfections. Early intervention, appropriate surgeryand respiratory, haemodynamic and nutritionalsupport are also key components. The exact contri-bution of any antibacterial regimen can thereforebe difficult to isolate, but its function is to reducethe incidence of abscesses or peritonitis and woundcomplications.

A debate that is central to the effective manage-ment of intra-abdominal infections is that ofbreadth of coverage of the initial empirical regi-men, but there is little consensus on this issue.Many question the need for a regimen which coversmore than the common facultative and obligateanaerobes in the treatment of milder community-acquired infections.[1,5,6] This viewpoint is sup-ported by the purpose-designed trial of Christouet al.[3] which demonstrated similar clinical out-comes with broad- (imipenem/cilastatin) andlimited-spectrum (cefoxitin) agents in patientswith moderate intra-abdominal infections. Thishas lead some to suggest that broad-spectrum re-gimens should be reserved for second-line therapyor for the treatment of more severe or difficult-to-treat infections.[105]

Another concern regarding the unnecessary useof broad-spectrum agents, as with any bacterial in-fection, is the possible development of unwantedbacterial resistance. However, it is interesting tonote in the trial by Christou et al.[3] that resistancedeveloped in significantly more cefoxitin thanimipenem/cilastatin recipients (12 vs 1; p = 0.003)and also that treatment failure resulted in death in2 cefoxitin recipients, suggesting that the broaderspectrum agent did offer some added benefit to thispatient group.

In the treatment of more severe or nosocomialinfections, it is well recognised that broad anti-bacterial coverage is needed and indeed may belife-saving.[105] Nosocomial intra-abdominal in-fections are associated with high levels of morbid-ity and mortality.[7] Further, it has been demon-strated that the number of treatment failuresincreases as a function of infection severity (as-sessed by APACHE II score).[106]

It is against this background that the resultsachieved with meropenem in the treatment of intra-abdominal infections should be viewed. Mero-penem is a broad-spectrum agent with an activityprofile that encompasses Gram-negative, Gram-positive and anaerobic bacteria. As empiricalmonotherapy, meropenem achieved satisfactoryclinical response rates in excess of 90% of patientswith moderate to severe infections acquired pre-dominantly in the community. The efficacy ofmeropenem was similar to that of other standardregimens in this patient group; bacteriological datadid not reveal any differences between regimens.

Clearly a range of effective empirical optionsare available for the treatment of moderate to severeintra-abdominal infections and appropriate selec-tion for an individual patient is important. Al-though there is little to distinguish between thestandard combination regimens of cefotaxime plusmetronidazole or clindamycin plus tobramycin andmeropenem in terms of efficacy in this patientgroup, meropenem does offer some theoreticalbenefits. As a β-lactam agent, meropenem does nothave the renal and auditory tolerability problemsassociated with aminoglycoside-containing

Table VIII. Dosages recommendations for intravenous meropenemin special patient groups[99,102,104]

Patient group Recommended dosage

Elderly patients 1g q8ha

Patients with hepatic impairment None

Patients with renal impairment

CLCR 1.56 to 3 L/h 1g q12h

CLCR 0.6 to 1.5 L/h 0.5g q12h

CLCR <0.6 L/h 0.5g q24h

a No dosage adjustment is necessary in patients with a CLCR

>3 L/h.CLCR = creatinine clearance; qxh = every x hours; .



regimens nor does it require therapeutic drugmonitoring or renal function tests. It also offers theconvenience of a single agent with a relativelysimple administration schedule compared to that ofthe combination regimens. Preliminary reportssuggesting that delivery costs are 18% lower withmeropenem compared with combination regimensare also worth investigating further from a costperspective.

Meropenem and imipenem/cilastatin alsoshowed similar efficacy in the treatment of patientswith moderate to severe intra-abdominal infec-tions. This is despite subtle differences betweentheir in vitro activity profiles. For example, mero-penem has greater activity against Gram-negativeorganisms, imipenem against Gram-positive or-ganisms and meropenem is more stable against hy-drolysis by serine-based β-lactamases. The similarclinical results are possibly a function of the num-bers of patients involved in these trials or the factthat most infections were community acquired.

Meropenem and imipenem/cilastatin do, how-ever, differ with regard to their tolerability profiles.The risk of seizures with meropenem is comparableto that of the cephalosporins. Imipenem/cilastatin,on the other hand, is associated with a risk of seizures,particularly in certain patients groups. For thisreason, meropenem can be administered in patientswith CNS disorders and up to a maximum dosageof 6 g/day versus 4 g/day for imipenem/cilastatin.Another point of difference, one that is potentiallyimportant in those who have recently undergoneintra-abdominal surgery, is that of gastrointestinalevents which with imipenem/cilastatin are linkedto rate of administration and dosage. Althoughthese can be managed by slowing the rate of in-fusion, this contrasts with meropenem which canbe administered without regard for this factor.

In some trials in patients with infections of mod-erate severity, meropenem was administered suc-cessfully at a lower dosage of 1.5 g/day andachieved similar results to imipenem/cilastatin1.5[13] or 2 g/day.[68] These findings are in contrastto 2 other trials[107,108] which reported treatmentfailure in 19 to 24% of patients with intra-abdominal

infections following treatment with imipenem/cilastatin 1.5 g/day. Both study groups suggestedthat a higher dosage of imipenem/ cilastatin mayhave yielded a better response rate.[68,107] Furtherstudies are therefore required to confirm that the1.5 and 3 g/day dosages of carbapenems are inter-changeable in patients with moderate infections.

At the other end of the severity spectrum,meropenem achieved a satisfactory clinical re-sponse in over 80% of patients with severe infec-tions, most of whom were in intensive care andhad nosocomial infections. Response rates ap-peared to be better than or similar to those withimipenem/cilastatin in the same trials, althoughsmall patient numbers did not permit a statisticalcomparison of the 2 agents. In one trial,[65] mostfailures were observed in those who had infectionssecondary to previous surgery, a patient group thatis particularly difficult to treat.[7]

Bacteriological data were not available specif-ically for patients with severe intra-abdominal in-fections, although Colardyn et al.[65] suggested thata higher off-label dosage of 6 g/day or combinationtreatment should be considered for difficult-to-treat pathogens such as P. aeruginosa. Further trialswhich specifically recruit patients with severe in-tra-abdominal infections or large trials, in whichpatients are stratified according to infection se-verity, are required to confirm the efficacy ofmeropenem in severe disease.

In conclusion, extensive comparative clinicaldata demonstrate that meropenem can be used ef-fectively as empirical monotherapy in moderate tosevere intra-abdominal infections. It also showspotential in the most severe forms of infection, al-though experience in this infection type remainslimited. Compared with standard combination re-gimens, meropenem offers the benefits of ease ofadministration without the need for monitoring. Italso offers improved CNS tolerability comparedwith imipenem/cilastatin with the option of a highermaximum dosage, which may be a particularadvantage in patients with severe intra-abdominalinfections.

642 Lowe & Lamb


References1. Barie PS. Management of complicated intra-abdominal infec-

tions. J Chemother 1999 Dec; 11 (6): 464-772. Solomkin JS, Hemsell DL, Sweet R, et al. General guidelines

for the evaluation of new anti-infective drugs for the treat-ment of intraabdominal and pelvic infections: evaluation ofnew anti-infective drugs for the treatment of intra-abdominalinfections. Clin Infect Dis 1992 Nov; 15 Suppl. 1: S33-42

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Correspondence and reprints: Harriet M. Lamb, Adis Inter-national Limited, 41 Centorian Drive, Private Bag 65901,Mairangi Bay, Auckland 10, New Zealand. E-mail: [email protected]

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Drugs 60: 619-646, Sep 2000