1. Introduction

Serious bacterial infections can be life threatening and require prompt treatment with antibacterial agents. Empirical therapy with an antibacterial agent that has a broad spectrum of activity is administered until the infecting pathogen is identified and treatment can be switched to an agent with specific antibacterial activity against that organism.[1]

The carbapenems are members of the β-lactam class that are stable to nearly all β-lactamases. This group of agents has demonstrated bactericidal activity against a wide range of Gram-positive and Gram-negative aerobic bacteria, and against anaerobic bacteria.[2]

Meropenem (Merrem®, Meronem®)Footnote 1 is a broad-spectrum antibacterial agent of the carbapenem family. Along with imipenem/cilastatin, meropenem is one of the most established members of the carbapenem class, and is used primarily in the treatment of moderate to severely ill patients with polymicrobial or nosocomial infections.[2] Meropenem is indicated as empirical therapy prior to the identification of causative organisms, or for disease caused by single or multiple susceptible bacteria in both adults and children with a broad range of serious infections.[3]

The use of meropenem for serious bacterial infections in a variety of settings has been reviewed previously.[47] This review focuses on the clinical use of meropenem in the treatment of serious bacterial infections, and includes the specific indications of nosocomial pneumonia, complicated intra-abdominal infection (cIAI), septicaemia, febrile neutropenia, complicated skin and skin structure infection (cSSSI), bacterial meningitis, complicated urinary tract infection (cUTI), obstetric and gynaecological infections, acute pulmonary infections in patients with cystic fibrosis, and in the treatment of severe community-acquired pneumonia (CAP).

Meropenem is approved for use in cIAI, cSSSI and bacterial meningitis (in paediatric patients aged ≥3 months) in the US.[8] In most other countries, meropenem is approved for use in nosocomial pneumonia, cIAI, septicaemia, febrile neutropenia, cSSSI, bacterial meningitis, cUTI, obstetric and gynaecological infections, pulmonary infection in patients with cystic fibrosis, and severe CAP.[9]

2. Pharmacodynamic Profile

The pharmacodynamic properties of meropenem have been previously reviewed elsewhere.[4,5] This section provides an overview of the pharmacodynamic profile of meropenem, with particular focus on antibacterial activity within the period 2000–7. Susceptibility data are from the MYSTIC (Meropenem Yearly Susceptibility Test Information Collection) database. MYSTIC is a longitudinal surveillance programme launched in 1997 to monitor antimicrobial resistance patterns in hospitals using broad-spectrum carbapenems (specifically meropenem). Data have been supplemented with results from additional susceptibility studies as required. A comparison of the percentage of isolates fully susceptible to meropenem between 1993 and 1998 showed that there have been no significant alterations in the activity of meropenem over that period.[3] Furthermore, a published overview of the MYSTIC programme results for the period 1997–2004 showed there had been no significant increase in meropenem resistance.[10]

2.1 Mechanism of Action

Meropenem is a broad-spectrum carbapenem with activity against Gram-positive and Gram-negative bacteria and anaerobic bacteria. Like other carbapenems, meropenem interferes with the synthesis of the bacterial cell wall, thus inhibiting growth and resulting in cell death.[8] The drug readily penetrates bacterial cell walls and binds with high affinity to specific penicillin-binding proteins (PBP), rendering them inactive.[2] The strongest affinities are to PBPs 2, 3 and 4 of Escherichia coli and Pseudomonas aeruginosa and PBPs 1, 2 and 4 of Staphylococcus aureus.[8] Meropenem has a high level of stability to hydrolysis by all serine β-lactamases,[8] and, unlike imipenem/cilastatin, is relatively stable to human dehydropeptidase-1 (DHP-1).[2]

2.2 Antibacterial Activity

This section focuses on only the causative micro-organisms predominantly identified in trials in clinical infections (section 4) for which meropenem is currently indicated. Table I shows the infections and susceptible strains of organisms specifically indicated in the US.[8] Specific organisms are not identified for each approved indication in the UK prescribing information.[9] While its broad spectrum of antibacterial activity includes numerous other bacteria, the clinical significance of these, in some cases, remains unknown. Pathogens known to be resistant to meropenem include methicillin-resistant Staphylococcus aureus (MRSA), Enterococcus faecium and Stenotrophomonas maltophilia.

Table I
figure Tab1

Indications and designated micro-organisms for which intravenous meropenem monotherapy is approved in the US[8]

Susceptibility testing was generally performed using methods recommended by the Clinical and Laboratory Standards Institute (CLSI). For meropenem, the CLSI breakpoints indicating susceptibility, intermediate susceptibility and resistance were ≤4, 8, and ≥16 mg/L for Enterobacteriaceae, P. aeruginosa, Staphylococcus spp. and anaerobes.[11,12] Susceptibility breakpoints were ≤0.25 mg/L for Neisseria meningitidis, and ≤0.5 mg/L for Haemophilus spp. and Streptococcus spp. (excluding Streptococcus pneumoniae where breakpoints for susceptibility, intermediate susceptibility and resistance were ≤0.25, 0.5 and ≥1 mg/L).[11]

2.2.1 Gram-Negative Aerobic Bacteria

Meropenem demonstrated good in vitro antibacterial activity against clinically relevant Enterobacteriaceae, including Citrobacter freundii, C. koseri, Enterobacter aerogenes, E. cloaceae, E. coli, Klebsiella pneumoniae, K. oxytoca, Morganella morganii, Proteus mirabilis, P. vulgaris and Serratia marcescens; the minimum concentration (MIC) inhibiting 90% of strains (MIC90) was ≤0.25 mg/L and susceptibility rates were 98.1–100% (table II).[13]

Table II
figure Tab2

In vitro activity of meropenem (MEM) and other antibacterials against aerobic Gram-negative pathogens. Data from the MYSTIC database.[13] MYSTIC data included isolates collected from worldwide hospital centres between 2000 and 2007. Susceptibility testing was performed using Clinical and Laboratory Standards Institute (CLSI) methods. Data shown are minimum concentrations inhibiting 50% (MIC50) and 90% (MIC90) of strains (mg/L) and susceptibility (S; %) calculated using CLSI breakpointsa,b

Meropenem was active against extended-spectrum β-lactamase (ESBL)- and AmpC-producing Enterobacteriaceae. The MIC90 values for AmpC-producing Enterobacteriaceae versus non-AmpC-producing Enterobacteriaceae were ≤0.06 versus 0.25 mg/L for Enterobacter spp. and 0.12 versus 0.5 mg/L for S. marcescens, and for ESBL-producing Enterobacteriaceae were ≤0.06 versus ≤0.06 mg/L for E. coli and ≤0.06 versus 0.12 mg/L for K. pneumoniae (all susceptibility rates were 100%).[14] Like meropenem, imipenem/cilastatin and doripenem showed little or no increase in MIC90 for ESBL- and AmpC-producing isolates relative to wild-type isolates, whereas the MIC90 for ertapenem increased by up to four doubling dilutions.[14] With meropenem, there was no inoculum effect for ESBL-producing E. coli, or for the majority of the ESBL-producing K. pneumoniae or AmpC-producing Enterobacteriaceae strains tested.[15]

Meropenem also showed good activity against H. influenzae and N. meningitidis, with MIC90 values of 0.25 mg/L and susceptibility rates of ≈100% (table II). Against Burkholderia cepacia and Acinetobacter baumannii, meropenem had MIC90 values of 16 and 64 mg/L, and susceptibility rates of 72.9% and 71.5%; against P. aeruginosa, the MIC90 was 32 mg/L and susceptibility rate was 76.4% (table II). Meropenem and other carbapenems are not active against S. maltophilia because of the intrinsic production of carbapenemases by this organism.

Although meropenem activity against P. aeruginosa, Acinetobacter spp. and B. cepacia may be limited in some geographic regions, meropenem remains as one of the most active clinically available antimicrobial agents against these and other non-fermentative Gram-negative organisms.[1618] Furthermore, increases in meropenem resistance rates appeared to be more related to clonal dissemination of resistant organisms than antimicrobial usage.[19,20] The retention of excellent activity of meropenem against the majority of Enterobacteriaceae was confirmed in the most recently published reports on European[21] and US[22] data from the MYSTIC 2006 programme, although in Europe, meropenem and imipenem/cilastatin showed slight decreases in activity compared with MYSTIC 2002 programme results (for Enterobacteriaceae in 2002 vs 2006, susceptibility rates for meropenem and imipenem/cilastatin were 99.9% vs 98.9% and 98.2% vs 97.9%).[21] This was considered likely to be a reflection of the occurrence of serine carbapenemases and metallo-β-lactamases, and AmpC β-lactamase hyperproduction coupled with outer membrane protein changes.[21] Susceptibility rates of Acinetobacter spp. to meropenem and imipenem/cilastatin were >80% in 2002, compared with <60% in 2006.[21] However, when 2006 data were broken down by country, susceptibility rates for meropenem against Acinetobacter spp. were 100% for Belgium (n = 11 isolates), 95.5% for Sweden (22), 96.6% for Germany (29), 75.8% for Spain (33) and 38.5% for Turkey (239), possibly reflecting resistance problems in specific countries or regions.[13] Data from the US study showed a 2-fold increase in serine carbapenemase-producing Klebsiella spp. between 2005 and 2006, mainly from one geographic region.[22,23]

2.2.2 Gram-Positive Aerobic Bacteria

Meropenem had good in vitro antibacterial activity against methicillin-susceptible S. aureus (MSSA), S. epidermidis, S. pneumoniae (including penicillin-resistant isolates) and viridans group streptococci, with MIC90 values of 0.25–2 mg/L and susceptibility rates of 95.3–100% (table III). Meropenem activity against MRSA, Enterococcus faecium and E. faecalis was poor, with MIC90 values of 32, >16 and 16 mg/L, respectively.[2] In the published report on European data from the MYSTIC 2006 programme, the percent susceptibility of the carbapenems (meropenem and imipenem/cilastatin) for S. pneumoniae was slightly decreased compared with 2002 rates (from 100% to 95.2% for meropenem and 100% to 90.4% for imipenem/cilastatin); this was attributed to an increased incidence of penicillin-resistant strains.[21]

Table III
figure Tab3

In vitro activity of meropenem (MEM) and other antibacterials against aerobic Gram-positive pathogens. Data from the MYSTIC database.[13] MYSTIC data included isolates collected from worldwide hospital centres between 2000 and 2007. Susceptibility testing was performed using Clinical and Laboratory Standards Institute (CLSI) methods. Data shown are minimum concentrations inhibiting 50% (MIC50) and 90% (MIC90) of strains (mg/L) and susceptibility (S; %) calculated using CLSI breakpointsa,b

2.2.3 Anaerobic Bacteria

Meropenem demonstrated in vitro activity against a range of anaerobic pathogens including Bacteroides fragilis, Clostridium difficile, C. perfringens, Peptostreptococcus spp. and Prevotella spp. (table IV); MIC90 values were 0.125–4 mg/L with susceptibility rates of 100% for all listed anaerobes, with the exception of B. fragilis (MIC90 of 8 mg/L; 88.9% susceptibility).[13] imipenem/cilastatin, ertapenem, doripenem and piperacillin/tazobactam also showed anti-anaerobic activity, apart from imipenem/cilastatin against C. difficile (MIC90 of 16 mg/L; 37.5% susceptibility).[2,13,25]

Table IV
figure Tab4

In vitro activity of meropenem (MEM) and other antibacterials against anaerobic pathogens. Data from the MYSTIC database.[13] MYSTIC data included isolates collected from worldwide hospital centres between 2000 and 2007. Susceptibility testing was performed using Clinical and Laboratory Standards Institute (CLSI) methods. Data shown are minimum concentrations inhibiting 50% (MIC50) and 90% (MIC90) of strains (mg/L) and susceptibility (S; %) calculated using CLSI breakpointsa

2.3 Resistance Mechanisms

Meropenem shows stability against hydrolysis by most β-lactamases, including AmpC β-lactamase and ESBLs. As discussed in section 2.2.1, there was little or no change in MIC90 values in comparisons of wild-type and ESBL-producing E. coli or K. pneumoniae isolates, or wild-type and AmpC-producing Enterobacter spp. or S. marcescens.[14] Carbapenemases can affect the activity of meropenem. Among the most potent are the class B metallo-β-lactamases, the production of which is intrinsic in S. maltophilia, but can also be acquired by P. aeruginosa and other Gram-negative species.

The poor binding affinity of carbapenems to some PBPs present in some bacteria (such as Enterococcus spp. and MRSA) confer inherent resistance to β-lactam antibacterial drugs. Reduced susceptibility to carbapenems can also arise with overexpression of multidrug efflux pumps detected in some Gram-negative bacteria including P. aeruginosa. Increasing meropenem resistance in P. aeruginosa isolates as a result of the overexpression of efflux pumps has been documented,[27] although there may be other, yet to be described, mechanisms involved in P. aeruginosa carbapenem resistance.[28]

Carbapenems enter Gram-negative bacteria via passive diffusion through porins situated in the cell membrane.[4] Organisms that lack porins have reduced susceptibility to carbapenem antimicrobial agents because of the consequent reduction in permeability. Outer membrane porin protein (Opr) D2 deficiency is associated with reduced susceptibility to carbapenem but not other β-lactam agents. However, it is thought that a combination of resistance mechanisms, such as the presence of carbapenemases and reduced permeability, or overexpression of multidrug efflux pumps and reduced permeability are required for significant carbapenem resistance to emerge. For example, both reduced permeability and the presence of a carbapenemase are required in K. pneumoniae in order for detectable resistance to be achieved.[29] The combination of reduced permeability and overexpression of multidrug efflux pumps required for meropenem resistance is considered less likely to occur than the combination required for imipenem/cilastatin resistance (AmpC-β-lactamase expression plus loss of permeability (porin OprD).[30,31]

Meropenem generally appears to have a low potential for selecting resistant strains in vitro.[5] In a study comparing the potencies of meropenem, imipenem/cilastatin and doripenem for the prevention of carbapenem-resistant mutants of P. aeruginosa, mutants lacking or with decreased expression of the outer membrane protein OprD were predominantly selected; relative potencies were doripenem > meropenem > imipenem/cilastatin.[32] Cross-resistance has been seen with isolates that are resistant to other carbapenems.[8]

2.4 Bactericidal Activity

Meropenem had rapid, time-dependent bactericidal activity against staphylococci, pneumococci and Enterobacteriaceae, such as K. pneumoniae (including ESBL-producing isolates) and P. aeruginosa in vitro.[3335] For example, at a concentration of 4 μg/mL (the mean steady-state serum concentration achieved with meropenem 1 g three times daily in healthy volunteers) against standard (5 × 105 cfu/mL) and high (1 × 107 cfu/mL) inocula of K. pneumoniae, meropenem achieved a 99.9% kill at 6–8 hours that was maintained over 24 hours.[33] Conversely, increasing the inoculum size from 106 cfu/mL to 108 cfu/mL resulted in decreased bactericidal activity against a laboratory strain of S. aureus (99.9% kill at 6 hours at 2 × MIC vs no bactericidal activity at 2–16 × MIC) and a clinical isolate of P. aeruginosa (99.9% kill at 4 hours at 16 × MIC vs no bactericidal activity at 2–16 × MIC).[35] Bactericidal concentrations of meropenem (defined as a 3log10 reduction in bacterial cell counts within 12–24 hours) are generally up to 2-fold higher than bacteriostatic concentrations of the drug,[8] although activity against Listeria monocytogenes is bacteriostatic and not bactericidal.[36] Meropenem also showed bactericidal activity (99.9% kill) against a variety of anaerobes, including B. fragilis, B. thetaiotaomicron, P. bivia, Fusobacterium nucleatum, F. mortiferum, Peptostreptococcus asaccharolyticus, C. perfringens and C. difficile at 4 × MIC after 24 hours.[37]

2.5 Pharmacodynamic/Pharmacokinetic Relationship

For the time-dependent antibacterials (including meropenem; section 2.4), bactericidal activity is best when unbound drug concentrations are maintained above the MIC for specific proportions of the dosing interval (%T > MIC).[38] For concentration-dependent antibacterials, bactericidal activity occurs with an optimal maximum plasma concentration (Cmax)/MIC ratio, area under the plasma concentration-time curve (AUC)/MIC ratio, or both.[38]

The OPTAMA (Optimizing Pharmacodynamic Attainment using the MYSTIC Antibiogram) programme uses data from the MYSTIC programme to identify the most appropriate empirical antibacterial therapy for common nosocomial pathogens (i.e. antibacterial agents with the greatest probability of achieving bactericidal exposures, while taking into account variability in pharmacokinetics, dosages and MIC distribution).[39]

Bactericidal exposures were modelled for each of the antibacterial agents studied against E. coli, K. pneumoniae, A. baumannii and P. aeruginosa in various geographic regions using MIC data from the MYSTIC programme and pharmacokinetic data in healthy volunteers. Results are available for data collected in North America,[40] South America[41] and Europe[39] in 2002, and North America in 2004[42] for Enterobacteriaceae (table V; only those for meropenem are discussed here), and for data in pathogens associated with the following indications: nosocomial pneumonia,[43] nosocomial bloodstream infections,[44] paediatric meningitis,[45] cSSSI,[46] and cIAI.[47]

Table V
figure Tab5

Probability of target attainment (PTA; %)[3941] or cumulative fraction of response (CFR; %)[42] at defined bactericidal pharmacodynamic targets, and percentage susceptibility (S) for various intravenously administered antimicrobial agents against selected Enterobacteriaceae collected in North America,[40] South America[41] and Europe[39] in 2002, and in North America in 2004.[42] Bactericidal pharmacodynamic targets were defined as %T > MIC ≥40% for meropenem 0.5 g or 1 g q8h (MEM) and imipenem/cilastatin 1 g q8h or 0.5 g q6h (IPM), %T > MIC ≥50% for cefepime 1 or 2 g q12h (FEP), ceftazidime 1 or 2 g q8h (CAZ) or piperacillin/tazobactam 3.375 g q4h or q6h or 4.5 g q8h (TZP) and as AUC/MIC ratio ≥125 for ciprofloxacin 400 mg q8h or q12h (CIP)

Another OPTAMA report used data from two centres in the US to assess the likelihood of achieving an optimal pharmacodynamic target in P. aeruginosa infections in children.[48] A bactericidal cumulative fraction of response (CFR; defined as the probability of achieving the targeted exposure with a given dosage regimen for a select population of organisms[38], and similar to the probability of target attainment [PTA][38] [%T > MIC≥40% for meropenem]) ≥90% was considered optimal.[48]

The 2002 analysis estimated that meropenem 0.5 or 1 g three times daily administered as an intravenous bolus would achieve an optimal CFR against E. coli (99–100%) and K. pneumoniae (96–100%) in all regions. However, estimates for P. aeruginosa varied according to region, with an optimal CFR seen only in North America (91%).[40] CFRs were 81–87% in Northern Europe, 68–76% in Southern Europe, 59–63% in Eastern Europe[39] and 60% in South America.[41] Estimates for A. baumannii also varied by region; an optimal CFR was achieved with meropenem 1 g three times daily in Northern Europe (93%), but not with a 500 mg three times daily dosage (CFR of 89%).[39] CFRs were 88% in North America,[40] 66–82% in Southern Europe,[39] 73% in South America[41] and 54–58% in Eastern Europe.[39] A high level of agreement between susceptibility percentages and the PTA was shown for meropenem 1 g three times daily against all pathogens studied (agreement of 0.25 [95% CI −1.65, 2.15] in Europe and 0.5 [95% CI −0.64, 1.64] in South America).

The 2004 OPTAMA report showed little change in meropenem CFRs and susceptibilities in North America between 2002 and 2004, apart from A. baumannii resistance to carbapenems, which increased from 9% to 22% for meropenem and 8% to 11% for imipenem/cilastatin.[42]

Subsequent OPTAMA programme reports used the prevalence of individual bacteria causing infections to estimate CFRs for the empirical treatment of various infections. In each of these analyses it was estimated that meropenem 0.5 or 1 g three times daily would achieve optimal CFRs against most pathogens associated with nosocomial pneumonia, nosocomial blood infection, paediatric meningitis, cSSSI and cIAI (CFRs of 94.3–99.7%).[4347]

In the analysis of P. aeruginosa infections in paediatric patients, the meropenem CFR was 92% in one institution and 58% in the other.[48] Pathogens included in the nosocomial pneumonia analysis were MSSA, P. aeruginosa, S. pneumoniae, Klebsiella spp., Enterobacter spp., E. coli, Serratia spp., Acinetobacter spp., P. mirabilis and Citrobacter spp.[43] Those included in the nosocomial bloodstream infections analysis were MSSA, coagulase-negative staphylococci, β- or viridans-group streptococci, S. pneumoniae, Enterobacter spp., E. coli, Klebsiella spp., P. aeruginosa and Serratia spp.[44] When the prevalence of MRSA and methicillin-resistant coagulase-negative staphylococci were added back into the nosocomial pneumonia and bloodstream infection models or the prevalence of MRSA was increased beyond 10%, meropenem CFRs dropped below 90%.[38,43,44,46] S. pneumoniae, H. influenzae and N. meningitidis were included in the paediatric meningitis analysis,[45] S. aureus, P. aeruginosa, E. coli, Enterobacter spp., Klebsiella spp., coagulase-negative staphylococci, Proteus spp., β-haemolytic streptococci and Serratia spp. were included in the cSSSI analysis[46] and P. aeruginosa was included in the cIAI analysis.[47]

Several other analyses estimated a bactericidal CFR of 72–86% for meropenem 1 or 2 g three times daily as a bolus or a 1- or 3-hour infusion,[49,50] and that the probability of attaining an optimal outcome against P. aeruginosa with meropenem was greatest when administered as a high-dose, 3 g/day 24-hour infusion (83%) rather than as a low-dose, 1.5 g/day 24-hour infusion (76%), or as a high- or low-dose, intermittent infusion (64% and 52%).[51] Nevertheless, other factors, including the instability of the meropenem solution at room temperature and the need for dedicated intravenous line, may limit the usefulness of continuous infusion regimens.[51,52]

3. Pharmacokinetic Profile

The pharmacokinetic profile of meropenem is well established and has been reviewed in detail previously.[2,46,53]

3.1 Distribution

Mean Cmax and corresponding AUC values for intravenous meropenem administered as a 30-minute infusion in healthy volunteers increase with increasing dosages of meropenem, but there is no absolute dose-proportionality over a dose range of 250 mg to 2 g.[9] When meropenem was administered in healthy volunteers as a 30-minute intravenous infusion, the Cmax after a 500 mg dose was ≈23 μg/mL, and that after a 1 g dose was ≈49 μg/mL.[9] Administering meropenem as an intravenous bolus over 5 minutes in healthy volunteers achieved Cmax values of ≈52 and ≈112 μg/mL, respectively, with a 500 mg and 1 g dose; Cmax values with a shorter infusion period (2 or 3 minutes) did not differ from that with a 5-minute bolus infusion.[9] AUC values following 500 mg and 1 g intravenous infusions in healthy volunteers were 27.2–32.4 mg ⋅ h/L and 66.9–77.5 mg ⋅ h/L.[2] At 6 hours after intravenous administration of a 500 mg dose, plasma meropenem levels are ≤1 μg/mL.[9] Plasma protein binding of meropenem is negligible (2%).[9] Meropenem distributes into a wide variety of tissues and fluids (including interstitial fluid) and has an apparent volume of distribution at steady state (Vdss) of between 12.5 and 20.7 L in healthy volunteers.[54] Meropenem penetrates tissues well, achieving drug concentrations at or above those required to inhibit susceptible bacteria.[8] After a single intravenous dose of meropenem 500 mg or 1 g, peak concentrations were achieved in most tissues and/or fluids (including gynaecological tissues [0.3–10.2 μg/g; 500 mg], skin [0.5–12.6 and 1.3–16.7 μg/g; 500 mg and 1 g], interstitial fluid [3.2–8.6 and 20.9–37.4; 500 mg and 1 g], intra-abdominal tissues [2.5–3.9 μg/g; 1 g], peritoneal fluid [7.4–54.6 μg/mL; 1 g], bronchial mucosa [1.3–11.1 μg/g; 1 g], fascia [1.5–20 μg/g; 1 g] and cardiac tissues [5.2–25.5 μg/g; 1 g]), within 0.5-1.5 hours. The exceptions were lung tissue (1.4–8.2 μg/g; 1 g), muscle (5.3–6.9 μg/g; 1 g), bile (4.0–25.7 μg/mL; 1 g) and inflamed cerebrospinal fluid (CSF [0.2–2.8 μg/mL; 20 mg/kg and 0.9–6.5 μg/mL; 40 mg/kg]), where peak concentrations were seen 2–3 hours after administration.[8]

3.2 Metabolism and Elimination

Meropenem has one metabolite, which is microbiologically inactive.[9] Most of an intravenously administered dose of meropenem is not metabolized.[9] The elimination half-life (t½) of meropenem in individuals with normal renal function is ≈1 hour, and 70% of an administered intravenous dose is excreted in the urine as the unchanged drug over 12 hours, with negligible urinary excretion thereafter.[9] In healthy volunteers administered single doses between 250 and 1000 mg, meropenem had an apparent total body clearance of 188–328 mL/min and a renal clearance of 139–252 mL/min[54]. Over a dose range of 250 mg to 2 g, a total plasma clearance reduction from 287 mL/min to 205 mL/min has been seen.[9] Up to 5 hours after intravenous administration of a 500 mg dose, urinary concentrations of meropenem are >10 μg/mL.[8] The peritoneal t½ of meropenem was similar to the plasma t½ value.[55] Meropenem does not accumulate in plasma or urine after repeated intravenous administration (500 mg 8-hourly or 1 g 6-hourly) in healthy volunteers.[8]

3.3 Special Populations

The pharmacokinetics of meropenem in paediatric patients aged ≥2 years are consistent with those in adult patients and are linear over a dose range of 10–40 mg/kg.[8] The t½ of meropenem in paediatric patients aged 3 months to 2 years is increased to 1.5 hours.[8] Meropenem is not licensed for use in paediatric patients aged <3 months.[8]

In elderly patients, reductions in the plasma clearance of meropenem are correlated with age-related reductions in creatine clearance[9] and dosage reductions may be required.

Pharmacokinetics of meropenem are unchanged in patients with hepatic impairment.[9]

The pharmacokinetics of meropenem in patients with infection can vary from those in healthy volunteers, for example higher Vdss[56,57] and nonrenal clearance of the drug.[56] Such changes could be due to the disease state or physiological changes associated with previous treatment (e.g. surgery), rather than the infections themselves.[56,57] The pharmacokinetics of meropenem in patients with moderate or severe infection were unchanged during the course of treatment.[58] Obesity[59] and cystic fibrosis[60] as the underlying disease had no clinically significant effect on the pharmacokinetics of meropenem.

3.3.1 Renal Impairment

Meropenem is predominantly excreted via the kidneys; consequently, plasma clearance of the drug is reduced in renal impairment. Pharmacokinetic studies have shown that meropenem plasma clearance is correlated with serum creatinine clearance;[8] thus, dosage adjustments are required in adult patients with a creatinine clearance <51 mL/min (3.06 L/h). Meropenem has not been evaluated in paediatric patients with renal impairment.

Although meropenem is cleared by haemodialysis, pharmacokinetic data in patients requiring haemodialysis are considered insufficient in the US to draw any conclusions about the use of meropenem in these patients;[8] in the UK, if treatment with meropenem is required in this patient group, the unit dose appropriate for the infection should be administered after haemodialysis is completed.[9] The drug has not been evaluated in adult patients undergoing peritoneal dialysis.

3.4 Potential Drug Interactions

The protein binding of meropenem is low (section 3.1); therefore, interactions based upon this mechanism are not expected.[3] The only specific drug interaction studies conducted for meropenem to date are with probenecid. Concomitant probenecid treatment increases the t½ and plasma concentrations of meropenem due to competition for active tubular secretion.[3] As meropenem achieves an adequate antibacterial potency and duration of action when administered alone, probenecid coadministration is not required, and, in fact, not recommended.[8]

Meropenem may also reduce serum valproic acid (sodium valproate) concentrations, resulting in subtherapeutic levels in some individuals[3,61] Of note, a similar interaction has been reported with valproic acid and the carbapenem panipenem/betamipron, suggesting a possible class effect.[62]

4. Clinical Efficacy

The efficacy of meropenem as empirical therapy in serious bacterial infections has been evaluated in numerous randomized active-comparator-controlled trials in adult and paediatric patients.[63101] Most were open-label trials;[6376,78,8090,9396,98106] four were of double-blind design[79,92,107109] (one[103] also included a placebo arm) and four[77,91,96,110] were of single-blind design. The majority were multicentre trials that evaluated a single type of infection (nosocomial pneumonia [section 4.1], cIAI [section 4.2], febrile neutropenia [section 4.4], cSSSI [section 4.5], bacterial meningitis [section 4.6], complicated UTI [section 4.7], obstetric or gynaecological infection [section 4.8], chronic pulmonary infection in cystic fibrosis [section 4.9], and severe CAP [section 4.10]) and these are discussed in detail. Of the trials that included patients with different types of infections,[6374] only those that included an evaluation of the efficacy of meropenem in patients with septicaemia[63,65,67,7072] (section 4.3) are included.

The main comparator agents were another carbapenem (imipenem/cilastatin or doripenem), a third-generation cephalosporin with or without an aminoglycoside or with metronidazole, and a macrolide or a penicillin plus a β-lactamase inhibitor with or without an aminoglycoside. Meropenem was administered as an intravenous bolus or infusion over 20–30 minutes; comparator agents were usually administered as an intravenous infusion over 20–60 minutes.

All patients in these trials were hospitalized prior to beginning treatment. Exclusion criteria common to most trials included a history of immediate hypersensitivity to β-lactam antibacterials, renal or hepatic impairment, CNS disease, current seizure disorder or history of seizures, acquired or congenital immune deficiency, neutropenia (except in febrile neutropenia trials [section 4.4]), cystic fibrosis (except in cystic fibrosis trials [section 4.9]) and severe, and/or rapidly progressing and/or terminal disease or underlying medical conditions that would preclude study treatment evaluation. Patients were also excluded if they had been exposed to another investigational drug concomitantly or in the 30 days prior to study entry or had received treatment with another antibacterial agent within 3–30 days of study commencement unless persistent infection was established or drug was ineffective. Concomitant therapy with systemic antibacterial agents was generally not permitted.

In most trials, the primary efficacy endpoint was clinical or bacteriological response at end of treatment (EOT) and/or the follow-up visit. Although definitions varied between trials, clinical response was usually defined as disappearance or improvement of clinical signs and symptoms of infection and bacteriological response was usually defined as eradication or presumed eradication of the infecting pathogen(s). The EOT assessment occurred within 24 hours of ceasing treatment and the follow-up assessment occurred 1–6 weeks after treatment cessation. In trials in patients with bacterial meningitis (section 4.6), clinical efficacy assessments were based on Infectious Diseases Society of America (IDSA) guidelines, with endpoints of cure without neurological and/or audiological sequelae, and survival with neurological and/or audiological sequelae (mild or severe in one study[77]), assessed at EOT, and at 5–7 weeks and 5–7 months after treatment, or death. Microbiological efficacy was assessed by repeated CSF sample 18–36 hours (or occasionally after 36 hours[76]) after starting treatment and bacteriological response was defined as eradication, eradication with relapse, delayed sterilization (second sample positive, but with significant bactericidal effect and subsequent sterile CSF cultures) or persistence (treatment failure). In patients with febrile neutropenia (section 4.4), the primary endpoint was usually the percentage of patients in whom treatment was unmodified after 72 hours of treatment or clinical response at EOT. Efficacy endpoints in trials in patients with cystic fibrosis related to changes in pulmonary function and inflammatory status (section 4.9).

Several trials examined the noninferiority of meropenem to comparator regimens.[7981,107] Meropenem was considered noninferior if the lower limit of the two-sided 95% confidence interval for the difference between treatments (meropenem response minus the comparator response) was no less than −10%[107] or −15%.[7981]

Unless specified otherwise, this section focuses on results of per-protocol analyses (in clinically or bacteriologically evaluable patients), and does not discuss results of the supportive intent-to-treat (ITT) or modified ITT analyses that were conducted in most studies. Some studies discussed in this section are reported as abstracts and/or posters.[73,7981]

4.1 Nosocomial Pneumonia

Three randomized comparative trials have investigated the efficacy of meropenem in the treatment of adult patients with nosocomial pneumonia.[111113] In one of the studies, meropenem was compared with a ceftazidime plus tobramycin combination in patients with nosocomial lower respiratory tract infection (primarily pneumonia).[111] In the other two studies meropenem was compared with combinations of ceftazidime plus amikacin[112] or meropenem plus ciprofloxacin[113] in patients with ventilator-associated pneumonia (VAP). Pathogens isolated at enrolment in the latter open-label study included S. aureus, H. influenzae, Enterobacter spp., Klebsiella spp., and Pseudomonas spp. (although patients with known Pseudomonas or MRSA colonization or infection, or who were immunocompromized, had been excluded from this trial prior to randomization [n = 740]).[113] The most common pathogens isolated at baseline in the other two trials were P. aeruginosa,[111,112] H. influenzae,[112] MRSA[111,112] and K. pneumoniae.[111] Diagnoses were based on clinical, microbiological and radiographic evidence.

Meropenem monotherapy was effective in the treatment of patients with nosocomial pneumonia,[113] and a useful alternative to conventional combination therapies of ceftazidime with tobramycin[111] or amikacin (table VI).[112]

Table VI
figure Tab6

Efficacy of meropenem (MEM) in patients (pts) with nosocomial pneumonia. Results of two randomized open-label trials that compared MEM monotherapy with ceftazidime (CAZ) plus tobramycin (TOB) or amikacin (AMK). Study drugs were administered intravenously. Response was evaluated in the clinically evaluable population at end of treatment (EOT) and/or follow-up (FU)

In the study comparing meropenem with ceftazidime plus tobramycin, analyses of the clinically evaluable patients showed significantly higher rates of satisfactory clinical (89% vs 72%; p = 0.04) and bacteriological (89% vs 67%; p = 0.006) response at the EOT in meropenem recipients.[111] Of the pathogens isolated from evaluable patients in this study, 80% of Gram-positive aerobes and 93% of Gram-negative aerobes were eradicated or presumed eradicated with meropenem versus 65% and 79%, respectively, with ceftazidime plus tobramycin.[111]

In one of the studies enrolling patients with VAP, EOT satisfactory clinical and bacteriological response rates were significantly (p < 0.05) greater in meropenem than ceftazidime plus amikacin recipients.[112] Overall and attributed mortality rates did not significantly differ between patient groups treated with meropenem or ceftazidime plus amikacin.[112]

In the other study involving patients with suspected VAP, 28-day all-cause mortality (the primary endpoint; 18.7% overall) did not significantly differ between patients treated with meropenem (1 g three times daily) plus ciprofloxacin (400 mg twice daily) or meropenem monotherapy (relative risk in the combination therapy versus monotherapy group = 1.05; 95% CI 0.78, 1.42; p = 0.74).[113] Overall, 93.1% of patients in the combination therapy group versus 85.1% of those treated with meropenem alone (p = 0.01) were considered to have received adequate initial antibiotic therapy.[113] There were no significant between-group differences in clinical or bacteriological responses (data not presented) overall, or in the subgroup of patients (n = 56) infected with Pseudomonas spp., Acinetobacter spp. and/or another multidrug-resistant Gram-negative pathogen at enrolment. However, in this subgroup, the adequacy of initial antibiotic therapy (84.2% vs 18.8%; p < 0.001) and bacteriological eradication rates (64.1% vs 29.4%; p = 0.05) were significantly higher in the group of patients treated with combination therapy versus monotherapy.[113] The authors commented that empirical combination therapy may be a better strategy when treating patients at high risk of infection with multidrug resistant or other difficult-to-treat organisms.[113]

4.2 Complicated Intra-Abdominal Infection

Numerous randomized comparative trials have investigated the efficacy of intravenous meropenem 1.5 or 3 g/day in the treatment of patients with cIAI. Active comparators included doripenem,[7981] imipenem/cilastatin,[8285] cefotaxime/metronidazole,[86,87] and tobramycin/clindamycin.[88,89,108]

In all studies, enrolled patients were aged ≥18 years (mean age 30–62 years), were hospitalized with signs and symptoms of intra-abdominal infection requiring surgical intervention and had no known sensitivity to β-lactam antibacterial drugs. Disease severity was graded as mild to moderate,[83] moderate,[82] or moderate to severe,[86] with APACHE (Acute Physiology and Chronic Health Evaluation) II scores of ≤18,[82]≤20[85] or ≤35.[108] Disease severity in one study ranged from mild to severe.[84] Concomitant nystatin or vancomycin treatment was permitted in one study.[108] The most common pathogens isolated at baseline in these trials were E. coli[79,8287,108] and B. fragilis.[79,82,84,85,87,108]

Primary endpoints were clinical[85] or bacteriological response rates as assessed at EOT, and/or at follow-up visits between 1 and 6[8288,108] weeks after the end of study therapy. The studies comparing meropenem and doripenem were noninferiority studies.[7981]

Meropenem was as clinically and microbiologically effective as standard regimens of imipenem/cilastatin in the treatment of patients with cIAI (table VII).[8285] Clinical response at EOT and or follow-up with meropenem 1.5 or 3 g/day was 90–98% and that with imipenem/cilastatin 1.5 or 3 g/day was 88–98%; the respective bacteriological responses were 84–98% with meropenem and 79–96% with imipenem/cilastatin.

Table VII
figure Tab7

Efficacy of meropenem (MEM) in patients (pts) with complicated intra-abdominal infections. Results of randomized (two double-blind,[79,108] six open-label)[8287] trials that compared MEM with doripenem (DOR), imipenem/cilastatin (IPM), cefotaxime + metronidazole (CTX/MTR) and tobramycin + clindamycin (TOB/CLI). Study drugs were administered intravenously. Response was evaluated in the clinically evaluable population at end of treatment (EOT) and/or follow-up (FU)

Furthermore, clinical cure rates (84% vs 85%) and microbiological outcomes (85% vs 84%) did not differ between patients treated with meropenem or doripenem for cIAI (table VII) and doripenem was non-inferior to meropenem.[7981]

In the trials comparing meropenem with cefotaxime/metronidazole,[86,87] meropenem achieved high clinical and bacteriological response rates (table VII), and was associated with a significantly better overall clinical response rate at EOT in one trial;[87] clinical response rates were significantly higher in the cefotaxime/metronidazole recipients in the second trial.[86] Both treatments were effective against Gram-positive aerobes, Gram-negative aerobes and anaerobes.[86]

Meropenem and tobramycin/clindamycin did not differ with respect to efficacy in the treatment of patients with intra-abdominal bacterial infection predominantly secondary to complicated appendicitis (table VII).[108]

4.3 Septicaemia

Of the studies that investigated the efficacy of meropenem in the treatment of a wide range of serious bacterial infections, six[63,65,67,7072] specifically described outcomes of subgroups of patients with septicaemia. Across trials, satisfactory clinical response rates for meropenem were 62–100% compared with 40–100% for comparator regimens (imipenem/cilastatin,[67,70] ceftazidime with or without amikacin,[71,72] and cefotaxime-based regimens).[63,65] Satisfactory bacteriological response rates were 85–100% with meropenem and 50–100% with comparator regimens.

In a study enrolling 153 patients with septicaemia secondary to a range of serious bacterial infections, meropenem was an effective empirical therapy and a useful alternative to ceftazidime with or without amikacin.[71] At treatment end, satisfactory clinical responses were achieved in 92% of clinically evaluable meropenem recipients and 94% of clinically evaluable patients receiving ceftazidime with or without amikacin.[71]

4.4 Febrile Neutropenia

The efficacy of intravenous meropenem as empirical monotherapy for neutropenic paediatric or adult patients with cancer has been assessed in numerous randomized comparative trials using cefepime,[90,91] imipenem/cilastatin,[114] ceftazidime with[95,96] or without amikacin,[9294] and piperacillin plus tazobactam[98] as active comparators.

Across trials, patients generally had undergone cancer chemotherapy and presented with fever (>38.3°C or >37.9°C on two occasions within 12 hours) and neutropenia (absolute neutrophil count <500/mm3 or <1000/mm3 and expected to be <500/mm3 within 24–48 hours); treatment durations were mostly ≥7 days.

In some trials, patients were permitted to re-enter studies more than once in the event of repeated episodes of neutropenia and fever.[93,114] Where indicated, concomitant glycopeptide[98] or aminoglycoside[98] antibacterials were allowed.

The most common bacterial pathogens isolated included Staphylococcus spp.,[90,91,9396,98] Streptococcus spp.,[90,9296,98] E. coli,[9296,98] Klebsiella spp.[90,9294,98] and P. aeruginosa.[92,96]

Meropenem was an effective empirical monotherapy in adult and paediatric patients with cancer-related febrile neutropenia (table VIII). No significant differences in initial response rates to unmodified treatment were seen in the majority of trials that compared meropenem with other established antibacterial regimens for the treatment of high-risk patients with febrile neutropenia at 72 hours or response at EOT with or without treatment modification.[90,91,9496,114] In three trials, significantly (p < 0.05) greater initial treatment success rates at 72 hours occurred in meropenem than ceftazidime[92,93] or piperacillin/tazobactam[98] recipients. A meta-analysis of randomized comparative trials of empirical antibiotic monotherapy in patients with febrile neutropenia concluded that meropenem, imipenem/cilastatin, ceftazidime, and the piperacillin/tazobactam combination were suitable treatment options.[115] However, cefepime was associated with higher all-cause mortality than other β-lactam antibacterial agents and careful consideration prior to its use in this patient group was recommended, pending further investigation.[115]

Table VIII
figure Tab8

Efficacy of meropenem (MEM) in patients (pts) with febrile neutropenia. Results of randomized (one double-blind,[92] one single-blind[91] and seven open-label)[90,9396,98,114] trials that compared MEM with imipenem/cilastatin (IPM), cefepime (FEP), ceftazidime (CAZ) ± amikacin (AMK), and piperacillin/tazobactam (TZP). Study drugs were administered intravenously. Response was evaluated in the clinically evaluable population at 72 hours and/or at end of treatment (EOT)

4.5 Complicated Skin and Skin Structure Infection

The efficacy of intravenous meropenem 1.5 g/day has been compared with that of imipenem/cilastatin in hospitalized patients with cSSSI.[75,107] Enrolled patients (mean age 44–49 years) presented with complicated abscess or cellulitis,[75,107] infected ulcer,[75,107] surgical site or traumatic wound infection,[107] or other bacterial skin and soft tissue infections.[75,107] In one trial, patients who were subsequently found to have a pre-treatment pathogen resistant to meropenem or imipenem/cilastatin (including MRSA) were considered ineligible and were withdrawn from the study.[107] Underlying medical conditions included diabetes mellitus in approximately 30–37% of participants, and peripheral vascular disease in 5–10%.

Patients in the double-blind trial were permitted to switch to appropriate oral antibacterial therapy (most commonly amoxicillin/clavulanic acid and cefalexin) after at least 3 days of parenteral treatment, provided they demonstrated a clinical improvement in infection and were able to tolerate oral medications.[107] In the open-label study, routine oral antibacterials were prescribed at the end of study treatment where required.[75]

The primary endpoint in the double-blind trial, which was a noninferiority study, was the clinical response at post-treatment follow-up in the clinically evaluable and modified ITT populations.[107] Clinical response and bacterial response at EOT and post-treatment follow-up were the primary efficacy endpoints in the open-label study.[75]

The main pathogens isolated included methicillin-susceptible S. aureus,[75,107] Streptococcus spp.,[75,107] E. coli,[75,107] E. faecalis[107] and P. aeruginosa.[107] Approximately 50–60% of patients had infections caused by a single organism, predominantly Gram-positive aerobes. Thirty-eight percent of patients in one study,[107] and 47% in the other,[75] had evidence of polymicrobial infections at study entry. Most infections in patients with polymicrobial infections were due to a mixture of Gram-positive and Gram-negative aerobes.

Meropenem and imipenem/cilastatin were both effective treatments in patients with cSSSI (table IX).[75,107]

Table IX
figure Tab9

Efficacy of meropenem (MEM) in patients (pts) with complicated skin and skin structure infections. Results of two randomized trials (one double-blind,[107] the other open-label[75]) that compared MEM with imipenem/cilastatin (IPM). Study drugs were administered intravenously. Response was evaluated in the clinically evaluable population at end of treatment (EOT) and follow-up (FU)

Clinical response rates were 94% and 92% with meropenem and imipenem/cilastatin in the double-blind study, and noninferiority of meropenem to imipenem/cilastatin was demonstrated (95% CI for between-group difference −3.0, 5.6; estimated from a graph [table IX]).[107] Clinical response rates did not differ when patients were analysed by age or gender, pre-treatment pathogen, or infection diagnosis.[107] Furthermore, the frequency of surgical intervention (debridement, incision and drainage, amputation) did not significantly differ between treatment groups (27% of meropenem vs 25% of imipenem/cilastatin recipients; ITT analysis). A post-hoc subgroup analysis of this study based on the presence or absence of underlying diabetes showed similar clinical outcomes in the two subgroups.[116]

In the open-label study, clinical and bacteriological response rates did not significantly differ between treatment groups (table IX), nor when assessed according to infection diagnosis.[75] Eradication or presumed eradication rates for susceptible organisms were 82–100% in meropenem recipients and 50–100% in imipenem/cilastatin recipients.[75]

4.6 Bacterial Meningitis

The efficacy of intravenous meropenem 40 mg/kg (up to a maximum of 6 g/day[78]) in patients with bacterial meningitis has been evaluated in four randomized comparative trials, two involving paediatric patients[76,77] and two involving adults.[78] Data from the trials in adult patients are reported as combined data.[78] Enrolled patients were hospitalized with clinical symptoms and signs of bacterial meningitis,[7678] caused by pathogens likely to be susceptible to the study medication.[77,78]

Patients with a previous history of meningitis,[7678] polymicrobial meningitis,[77] and penetrating wounds, fractures or foreign bodies in the CNS,[76,78] or with known behavioural, motor, developmental and hearing deficits were excluded from these studies.[77]

Concurrent treatment with dexamethasone was permitted.[7678] In one trial, a proportion of patients had been treated unsuccessfully with other antibacterials prior to study entry,[78] and in another, children who had received antibacterials within 24 hours of study entry were included provided CSF and blood samples had been obtained prior to enrolment and the initial assessment included documented evidence of bacterial meningitis.[77] Efficacy parameters included rates of death, cure without sequelae (neurological and/or audiological) or survival with sequelae. Comparator drugs were cefotaxime[7678] and ceftriaxone.[78] The most common pathogens isolated were H. influenzae,[7678] N. meningitidis,[76,78] S. pneumoniae[7678] and K. pneumoniae.[77]

Meropenem was effective in the treatment of bacterial meningitis in both adult[78] and paediatric[77] patients (table X). When meropenem and cefotaxime were compared in children with bacterial meningitis who ranged from good to critical clinical condition, there were no significant between-group differences with respect to cure, survival with sequelae or death (table X).[77] The majority of sequelae were audiological; between-treatment differences in rate or severity of behavioural/developmental or neurological sequelae were not significant at any timepoint (assessed at EOT, 5–7 weeks’ follow-up and 5–7 months’ follow-up).[77] In the study comparing meropenem, cefotaxime and ceftriaxone in adults with bacterial meningitis, clinical cure with or without sequelae was achieved in 100% of clinically evaluable meropenem recipients and 77% of cephalosporin recipients (5 of 22 patients failed to respond to treatment).[78]

Table X
figure Tab10

Efficacy of meropenem (MEM) in patients (pts) with bacterial meningitis. Results of two randomized trials (one single-blind, the other open-label), that compared MEM with cefotaxime (CTX) and ceftriaxone (CRO). Study drugs were administered intravenously. Response was evaluated in the clinically evaluable population at end of treatment (EOT) and/or follow-up (FU)

All pre-treatment bacterial isolates were eradicated with meropenem treatment across trials.[7678] In an early study comparing meropenem and cefotaxime in paediatric patients with bacterial meningitis, both agents were efficacious, achieving 100% bacteriological eradication of the causative pathogens from CSF.[76] CSF sterilization was achieved within 18–36 hours in the majority of patients.[76] In patients with culture-proven bacterial meningitis, clinical cure at EOT was achieved in all meropenem, and all but two cefotaxime recipients (both of these patients died during antibacterial treatment, but death was not considered to be drug related).[76] At follow-up, most patients (72% of meropenem and 81% of cefotaxime recipients) were cured with no evidence of sequelae, while 28% and 16% of patients in the respective treatment groups had audiological and/or neurological sequelae.[76] Audiological sequelae were evident in 13% of meropenem and 13% of cefotaxime recipients, and neurological sequelae occurred predominantly in patients with pre-existing neurological abnormalities.[76]

In the second study involving paediatric patients, bacteriological eradication was achieved in all but five subjects after 24–36 hours of treatment; H. influenzae was the infecting pathogen in these subjects with delayed sterilization.[76] One meropenem recipient who relapsed had head trauma prior to the initial diagnosis of meningitis was discharged from hospital clinically and bacteriologically cured, and was then readmitted 10 days later with a new episode of meningitis.[76]

According to pooled data from four trials enrolling 446 patients with bacterial meningitis, rates of clinical cure according to infecting organism in meropenem recipients were 71% for S. pneumoniae, 80% for β-lactamase-producing H. influenzae, 75% for non-β-lactamase-producing (or untested) H. influenzae and 86% for N. meningitidis.[8]

Approximately 60% of the 139 patients with positive CSF cultures also had positive blood cultures prior to receiving treatment. At 18–36 hours after commencing treatment, all cefotaxime and all but two meropenem recipients had negative blood cultures; however, CSF cultures taken at the same time in both of these patients were sterile.[76]

4.7 Complicated Urinary Tract Infection

Intravenous meropenem 500 mg three times daily was an effective alternative to imipenem/cilastatin 500 mg four times daily in a randomized, open-label study of 235 hospitalized patients with complicated UTI.[117] Infection was community-acquired in 92% of patients, had been present for a mean of 9.1 days prior to hospitalization, and required treatment with parenteral antibacterial drugs.[117] UTI was confirmed by positive urine culture; E. coli was the most commonly isolated pathogen. Mean treatment duration was 7.5 days for meropenem and 7.3 days for imipenem/cilastatin. Satisfactory clinical and bacteriological responses were seen in 99% and 90% of meropenem recipients, and in 99% and 87% of imipenem/cilastatin recipients.[117] Two meropenem and five imipenem/cilastatin recipients developed superinfections. The rates of relapse at ≥21 days after ceasing treatment did not significantly differ between groups, occurring in five meropenem and seven imipenem/cilastatin recipients.[117]

4.8 Obstetric and Gynaecological Infections

In hospitalized women with gynaecological or obstetric pelvic infections, intravenous meropenem 1.5 g/day was an effective alternative to imipenem/cilastatin[118] or the combination of clindamycin plus gentamicin[119] (table XI). Two studies of randomized open-label design enrolled patients (mean ages 26[119] and ≈40[118] years) with endometritis, pelvic inflammatory disease, pelvic cellulitis or other pelvic infection caused by at least one pathogen susceptible to the study treatments.[118,119] Infection was identified as hospital-acquired in 75% of patients in one study.[119] The most common organisms identified at baseline included Bacteroides spp., Prevotella spp., E. coli and E. faecalis.

Table XI
figure Tab11

Efficacy of meropenem (MEM) in patients (pts) with obstetric and gynaecological infections. Results of randomized, open-label trials that compared MEM with clindamycin + gentamicin (CLI/GEN) and imipenem/cilastatin (IPM). Study drugs were administered intravenously. Response was evaluated in the clinically evaluable population at end of treatment (EOT) and/or follow-up (FU)

Rates of satisfactory clinical and bacteriological responses in evaluable patients did not significantly differ between groups treated with meropenem or clindamycin/gentamicin (table XI). There were no significant differences between meropenem and the clindamycin/gentamicin combination in terms of pathogen eradication.[119] In the comparison between meropenem and imipenem/cilastatin, meropenem recipients achieved a higher clinical response rate at EOT. However, at the follow-up visit response rates did not differ (table XI).[118] All isolated organisms were eradicated at the end of meropenem or imipenem/cilastatin treatment, although the number of bacteriologically evaluable patients was small.[118]

4.9 Pulmonary Infection in Patients with Cystic Fibrosis

The efficacy of intravenous meropenem ≤6 g/day with or without tobramycin in the treatment of chronic pulmonary infection in patients aged ≥2 years with cystic fibrosis has been investigated in three randomized clinical trials using ceftazidime with or without tobramycin as the active comparator.[105,106,110] Patients were treated for acute exacerbation of chronic pulmonary infection,[105,106,110] suppression of infection without exacerbation,[105,106] or eradication of P. aeruginosa when first detected in pulmonary secretions.[106] Where permitted, patients could be re-entered into trials more than once provided intervals between treatments were ≥8[106] or 12 weeks.[105]

Throughout studies, patients continued to receive standard care for cystic fibrosis, but non-study antimicrobial agents were not allowed.[105,106,110] Oral corticosteroids or nonsteroidal anti-inflammatory drugs were specifically excluded in one study.[106]

Meropenem with or without tobramycin significantly improved pulmonary function in the treatment of acute pulmonary infection,[105,106,110] and when utilized as a routine therapy to suppress chronic P. aeruginosa infection,[105] in patients with cystic fibrosis (table XII). In an early trial of meropenem versus ceftazidime monotherapy, in which repeated courses of treatment were permitted, clinical response rates at EOT were 98% and 90% in meropenem and ceftazidime recipients. At 4- to 6-week follow-up, the corresponding rates were 86% and 85%, and bacterial counts were reduced in 59 episodes and 20 episodes in the two respective groups.[105] Decreases in sputum production were considered to be clinically significant, with reductions from 20.8 to 8.7 mL in meropenem recipients and from 20.5 to 7.8 mL in ceftazidime recipients.[105]

Table XII
figure Tab12

Efficacy of meropenem (MEM) in patients (pts) with pulmonary infection associated with cystic fibrosis. Results of two randomized trials (one open label,[106] one with both investigator-blinded and open-label arms)[110] that compared MEM + tobramycin (TOB) with ceftazidime (CAZ) + TOB. Study drugs were administered intravenously. Response was evaluated in the clinically evaluable population at end of treatment (EOT)[106,110]

The majority of improvement in pulmonary function (measured by change in forced expiratory volume in one second from baseline) occurred over the first 7 days of treatment in the combination therapy trial in which patients with acute pulmonary exacerbations received meropenem or ceftazidime plus tobramycin.[110] After 1 week of treatment, the proportion of responders was significantly greater in the patients in the investigator-blinded treatment arms who were randomized to receive meropenem plus tobramycin or ceftazidime plus tobramycin (62% vs 44%; p = 0.04).[110] Both treatments were associated with significant decreases in sputum bacterial burden (table XII) and suppression of antibacterial-resistant P. aeruginosa emergence.[110]

In the third trial, both meropenem plus tobramycin and ceftazidime plus tobramycin combinations improved lung function and reduced bacterial sputum burden with no significant between-group difference (table XII). In addition, both treatments improved systemic inflammatory status from baseline (C-reactive protein decreased from 18.8 and 21.4 mg/L at baseline to 12.1 and 11.0 mg/L at EOT in meropenem plus tobramycin and ceftazidime plus tobramycin recipients). This was the only study to assess the effects of parenteral combination antibacterial therapy on inflammatory status.[106]

4.10 Severe Community-Acquired Pneumonia

Four randomized comparative trials have investigated the efficacy of intravenous meropenem in the treatment of severe CAP.[99,100,120] One reports combined data from two trials.[120] Comparators included imipenem/cilastatin,[99,100] ceftazidime[120] and combinations of clarithromycin with amikacin or ceftriaxone.[100] Enrolled patients were aged ≥18[99,120] or ≥70[100] years and were hospitalized with CAP requiring intravenous antibacterial treatment; diagnoses were confirmed by chest radiography.[99,100,120] In the study reporting combined data, ≈20% of patients needed mechanical ventilation.[120] The most common pathogens isolated at baseline included S. pneumoniae,[99,100,120] P. aeruginosa,[99,120] S. aureus,[99,100,120] Haemophilus spp.[99,100,120] and K. pneumoniae.[100]

Meropenem was an effective monotherapy in the empirical treatment of hospitalized patients with CAP, with satisfactory clinical responses seen in 87–91% of evaluable patients at EOT and 96–100% of patients at follow-up (table XIII).[99,100,120] Satisfactory bacteriological response rates were also high (table XIII). Neither rates significantly differed from the corresponding clinical and bacteriological response rates seen in patients treated with imipenem/cilastatin,[99,100] ceftazidime,[120] or combinations of clarithromycin + amikacin[100] or clarithromycin + ceftriaxone[100] (table XIII).

Table XIII
figure Tab13

Efficacy of meropenem (MEM) in patients (pts) with community-acquired pneumonia. Results of four randomized open-label trials that compared MEM monotherapy with imipenem/cilastatin (IPM),[99,100] ceftazidime (CAZ)[120] and clarithromycin (CLR) plus ceftriaxone (CRO) or amikacin (AMK).[100] Study drugs were administered intravenously. Response was evaluated in the clinically evaluable population at end of treatment (EOT) and/or follow-up (FU)

In the ventilated subgroup of patients, 86% and 82% of meropenem and ceftazidime recipients achieved satisfactory clinical responses at the EOT, with corresponding satisfactory bacteriological response rates of 89% and 87%.[101]

5. Tolerability

The tolerability profile of meropenem is well established, and the safety of the drug has been reviewed extensively elsewhere.[62,121,122] This section provides a brief overview of data from the most recently published in-depth review of the safety profile of meropenem, supplemented by data from the UK and US prescribing information for meropenem.[8,9]

Meropenem is generally well tolerated with favourable CNS and gastrointestinal tolerability when used in the treatment of serious bacterial infections.[62]

Data for the retrospective safety analysis was gathered from 54 predominantly international clinical studies in 6154 hospitalized patients with presumed or documented bacterial infections, including >1000 paediatric patients, who were treated with meropenem (6308 exposures). Three trials were noncomparative and 51 were randomized, controlled, prospective trials. Most trials (49 studies) were open-label in design; of the remainder, three were double-blind and two were single-blind. Comparators in the controlled studies included imipenem/cilastatin, cephalosporin-based regimens (with/without an aminoglycoside) or clindamycin plus an aminoglycoside (total of 4483 patients [4593 exposures]). Exclusion criteria included known hypersensitivity to β-lactam or other study drugs, marked hepatic disease, hepatic or renal failure and CNS disease or a history of seizures (except in trials enrolling patients with meningitis). Intravenous meropenem (adult patients: 500 mg or 1 g, three times daily, paediatric patients: 10, 20 or 40 mg/kg, three times daily) was administered as an infusion over 20–30 minutes or 5-minute bolus; comparator agents were given according to manufacturer recommendations (an intravenous infusion over 20–60 minutes is recommended for imipenem/cilastatin).[123] In three studies, meropenem was administered intramuscularly. Adverse events were self-reported or recorded by an observing clinician.[62]

The incidence of any adverse events reported with meropenem was 40% of patient exposures compared with 36–42% for the comparator regimens (imipenem/cilastatin, cephalosporin-based regimens and clindamycin-aminoglycoside-based regimens). Drug-related adverse events were reported in 16% of meropenem exposures and 12–21% of comparator regimen exposures. Diarrhoea, rash and/or nausea/vomiting were the most frequently reported adverse events possibly or probably related to treatment for all treatment regimens, although incidences were low (figure 1). For meropenem and cephalosporin- or clindamycin-based regimens, the most frequently reported adverse event was diarrhoea (2.5%, 2.5% and 3.8% of patient exposures, respectively), and for imipenem/cilastatin was nausea/vomiting (2.8% of patient exposures).[62]

Fig. 1
figure 1

Comparative tolerability of meropenem (MEM). Incidence of adverse events, possibly or probably related to treatment, occurring in >1% of patient exposures. Data were taken from safety analyses of 54 clinical trials in patients with serious bacterial infections. There were 6308 treatment exposures to MEM and 5898 exposures to comparator regimens. Other events included constipation, glossitis, hypotension, oral candidiasis and renal failure. θ = 0% of exposures; CLI = clindamycin; IPM = imipenem/cilastatin.[62]

In paediatric patients with serious bacterial infections, drug-related adverse events were seen in 16% of meropenem recipients and 11% of children treated with cephalosporin-based regimens.[62] The only meropenem-related adverse events occurring in >1% of patients were diarrhoea (4.5%) and rash (2.2%), with other gastrointestinal events being uncommon.[62]

Patient withdrawals due to adverse events were low with meropenem (2.5% of patient exposures) and the comparator regimens (1.1–3.2%), and the incidence of deaths (during or within 30 days of treatment) was 4.3% of patient exposures for meropenem and cephalosporin-based therapy, 5.9% for imipenem/cilastatin and 0% for clindamycin-based therapy.[62] There were no significant differences between the four treatment regimens in terms of the incidence of laboratory adverse events. Thrombocytosis was the most commonly occurring drug-related haematological event in meropenem recipients (1.3% of patient exposures vs 1.2–4.6% with comparator regimens). Increased ALT (3.7% vs 2.4–5.7% of patient exposures) and AST (2.9% vs 1.9–4.6%) levels were the most commonly occurring drug-related biochemical events with meropenem or the comparator regimens.[62] Other drug-related adverse events associated with meropenem treatment were uncommon (incidence of <0.1% of treatment exposures).[62]

Serious cross-hypersensitivity reactions to meropenem (and other β-lactams) have been seen in some patients with a history of penicillin hypersensitivity.[8] A review of retrospective studies of patients with documented or reported penicillin allergy found the incidence of carbapenem cross-hypersensitivity to be between 9% and 11%,[124] with no significant differences in the occurrence of allergic-type reactions seen between meropenem and imipenem/cilastatin.[125] There were no reports of meropenem-related anaphylaxis or Stevens-Johnson syndrome in any of the trials reviewed by Linden.[62]

5.1 CNS Adverse Events

Meropenem has good CNS tolerability and is the only carbapenem antibacterial to be approved for the treatment of bacterial meningitis, having a lower neurotoxic potential than imipenem/cilastatin.[121] While seizures and other adverse CNS events have been reported with meropenem treatment, events most commonly occurred in patients with CNS disorders, bacterial meningitis, and/or renal function impairment.[8] The incidence of drug-related seizures in patients with infections other than meningitis was 0.07% of patient exposures with meropenem, 0.04% with cephalosporin-based therapy, 0% with clindamycin plus aminoglycoside-based therapy, and 0.23% with imipenem/cilastatin. All meropenem recipients had pre-existing contributing factors.[8] No seizures were considered to be meropenem-related in a trial involving children with bacterial meningitis.[62]

6. Pharmacoeconomic Considerations

This section provides a brief overview of recent pharmacoeconomic analyses of meropenem in the treatment of serious bacterial infections in intensive care units (ICUs), including a fully published cost-utility analysis[126] and two cost-effectiveness analyses (available as abstracts plus posters).[127,128] The studies included are limited to well designed analyses that incorporated approved meropenem dosage regimens, appropriate comparative clinical data, cost values for the year 2002 or later and, for prospective studies, data for >50 patients in each treatment arm.

Pharmacoeconomic analyses from a healthcare payer perspective in the UK,[126] US[127] and Russia[128] predict that meropenem is a cost-effective therapy option relative to other antibacterials in patients with severe infection in ICUs (table XIV). Although the acquisition cost of meropenem was greater than that of comparator antibacterials in analyses[126,128] that considered the cost of hospital stay (table XIV), overall costs were lower with meropenem, as its higher clinical efficacy meant that meropenem recipients spent less time in an ICU[126,128] and/or did not require treatment with additional antibacterials.[128]

Table XIV
figure Tab14

Summary of pharmacoeconomic analyses with meropenem (MEM) in the treatment of adult patients (pts) with serious bacterial infections in an intensive care unit (ICU). Analyses were conducted from a healthcare payer perspective. Where stated,[126,127] agents were administered intravenously

In the UK cost-utility analysis,[126] meropenem dominated imipenem/cilastatin with regard to the cost per quality-adjusted life-year (QALY) gained in patients with severe infections (table XIV). The clinical response was higher with meropenem than with imipenem/cilastatin, resulting in predicted lower overall costs, fewer infection-related deaths in the ICU and a greater number of QALYs gained for meropenem relative to imipenem/cilastatin.[126] The results were robust to plausible changes in the input parameters, including patient age, costs and benefits. Of note, this model did not take into account the significant (p = 0.02) 13% relative reduction in all combined adverse events with meropenem relative to imipenem/cilastatin identified in the systematic review,[129] or the costs associated with the preparation and administration of the antibacterials. The analysis, therefore, potentially underestimated the cost difference between the two treatments, as imipenem/cilastatin would be associated with more frequent adverse events and also higher preparation and administration costs than meropenem.[126]

In preliminary cost-effectiveness analyses, meropenem was also predicted to be a cost effective initial empirical treatment with regard to the cost per successfully treated patient relative to imipenem/cilastatin in the treatment of P. aeruginosa infections in the US[127] and relative to conventional combination antibacterial treatments in high-risk patients with nosocomial infections in Russia[128] (table XIV).

Pharmacoeconomic analyses of meropenem, in common with all pharmacoeconomic analyses, are subject to a number of limitations. Pharmacoeconomic analyses based on clinical trials extrapolate the results of such trials to the general population; however, patient populations, rates of compliance and major outcomes in clinical trials may differ from those observed in real-life practice. Modelled analyses[126,127] rely on a number of assumptions and use data from a variety of sources, whereas prospective analyses[128] are limited by their sample size. Results of pharmacoeconomic analyses may not be applicable to other geographical regions because of differences in healthcare systems, medical practice and unit costs.

7. Dosage and Administration

Meropenem is available as a sterile powder (containing meropenem as the trihydrate blended with anhydrous sodium carbonate) for reconstitution prior to intravenous administration by either bolus injection over 5 minutes, or infusion over 15–30 minutes.[8] Following reconstitution with normal saline, meropenem is stable for 10 hours at controlled room temperature (15–25°C) and 48 hours at 4°C; stability in other infusion media ranges from 2–8 hours at room temperature and 8–48 hours under refrigeration.[3]

In adults, the dosage range is 1.5–6 g/day administered in three divided doses, generally with 500 mg to 1 g given every 8 hours dependent on the type and severity of infection, susceptibility of the pathogen, and patient condition. Exceptions to this general recommendation are in the treatment of chronic respiratory tract infection in patients with cystic fibrosis and for meningitis where 2 g should be given every 8 hours, and febrile neutropenia where the dosage should be 1 g every 8 hours.[9]

The adult dosage is recommended for use in children weighing over 50 kg. In infants and children aged between 3 months and 12 years who weigh <50 kg, the recommended dosage is 10–40 mg/kg intravenously every 8 hours, again dependent on type and severity of infection, susceptibility of the pathogen, and patient condition. For febrile neutropenia in children, a 20 mg/kg dose given every 8 hours is recommended, and 40 mg/kg should be given every 8 hours in children with meningitis and for chronic respiratory tract infection in association with cystic fibrosis.[3]

Local prescribing information should be consulted for more detailed information, including contraindications and precautions.

8. Place of Meropenem in the Management of Serious Bacterial Infections

Many studies have confirmed the importance of appropriate initial antimicrobial treatment to improve survival and reduce morbidity in patients with serious bacterial infections.[1,130134] Where empirical antimicrobial therapy has been ineffective, the underlying cause is often bacterial resistance, coupled with inappropriate choice of antibacterial agent; this frequently contributes to subsequent patient morbidity and mortality.[131] Accordingly, there has been a shift in the recommendation regarding empirical therapy selection to the use of more broad-spectrum agents, often in combination with another drug of a different class, with a view to providing adequate cover for the anticipated pathogens.[40] Following identification and susceptibility testing, treatment is narrowed to target the causative pathogen.[1,131] Ultimately, this would mean appropriate therapy for the majority of patients, based on local resistance patterns.[40] As microbiological culture results are rarely available at the time of therapeutic decision making, the success or failure of treatment depends on current, accurate and local information on the bacterial aetiology of infection and susceptibility patterns.[135]

As well as careful selection of the appropriate antibacterial agent, the dose and duration of treatment, route of administration, and use of antimicrobial resistance surveillance data are important factors in the rational use of antibacterial drugs necessary to avoid the development of ever-increasing resistance.[136] Surveillance programmes such as MYSTIC and SENTRY monitor antimicrobial resistance and play a vital role in the fight against pathogenic bacteria[40] in that the selection of suitable antibacterial agents for empirical therapy is based on results from surveillance studies.[39] An observed increase in antimicrobial resistance (including the emergence of multidrug-resistant strains) is driving the “right first time” approach to empirical therapy, and the use of the full-spectrum carbapenems.[137]

The carbapenems were identified as a new class of broad-spectrum β-lactam antibacterials in the 1970s.[2] Imipenem/cilastatin, meropenem and ertapenem are currently the most widely available carbapenems.[2] Doripenem is a new carbapenem that was approved in the US in late 2007 for use in adult patients with cIAI or complicated UTIs.[138] Meropenem, imipenem/cilastatin or doripenem are appropriate choices for serious bacterial infections, including nosocomial infections, because of their broad spectrum of antibacterial activity; however, ertapenem is best suited for use in community-acquired infections, because of an absence of activity against non-fermentative Gram-negative pathogens.[139]

Unlike imipenem/cilastatin, meropenem is stable to the human renal enzyme DHP-1 and does not need to be administered with cilastatin to achieve clinical efficacy.[140] It is also resistant to inactivation by most β-lactamases (section 2). Although the short t½ of meropenem (section 3) requires 8-hourly administration, the low incidence of nausea and vomiting, even when administered rapidly (section 5), means that it can be administered as an intravenous bolus injection or a 15- to 30-minute infusion (section 7).[62] For imipenem/cilastatin, 250 or 500 mg doses should be administered as a 20- to 30-minute infusion; the 1 g dose should be administered as a 40- to 60-minute infusion (and the infusion rate slowed in patients who develop nausea).[62,123] Doripenem must also be administered as a 1-hour intravenous infusion.[138]

Plasma concentrations of meropenem are estimated to achieve an optimal bactericidal pharmacodynamic target attainment against most pathogens associated with nosocomial pneumonia, cIAI, nosocomial bloodstream infection, cSSSI and paediatric meningitis (section 2.5), and the drug has shown good penetration into a wide range of tissues, including lung, skin blister fluid, interstitial fluid, intra-abdominal tissues, peritoneal fluid and CSF (section 3). Meropenem demonstrated in vitro activity against a wide range of Gram-negative, Gram-positive and anaerobic organisms associated with serious or nosocomially acquired infections (section 2). This broad spectrum of activity means that it is very suitable for use as an empirical treatment for serious bacterial infections, such as nosocomial pneumonia, cIAI, septicaemia, cSSSI, complicated UTI, gynaecological and obstetric infections, pulmonary infections associated with with cystic fibrosis and serious CAP, especially as these conditions are often polymicrobial, including mixed aerobic/anaerobic, infections. Moreover, the good in vitro activity against organisms, such as meningococci, N. meningitidis and H. influenzae (section 2.2), good tolerability and low propensity for inducing seizures (section 5), means that meropenem is a valuable empirical treatment in paediatric patients aged ≥3 months who have been diagnosed with bacterial meningitis, and is the only carbapenem approved in this indication.[2]

Numerous well designed clinical trials have shown meropenem to be an effective and well tolerated treatment in patients with a wide range of serious bacterial infections. Meropenem was as effective as comparator antibacterials, such as imipenem/cilastatin in cIAI (section 4.2), febrile neutropenia (section 4.4), cSSSI (section 4.5), complicated UTI (section 4.7), obstetric or gynaecological infections (section 4.8) and severe CAP (section 4.10), clindamycin plus tobramycin or gentamicin in cIAI or obstetric or gynaecological infections, cefotaxime/metronidazole in cIAI, cefepime, ceftazidime plus amikacin in septicaemia or febrile neutropenia, and ceftazidime, clarithromycin plus ceftriaxone or amikacin in severe CAP. Meropenem also showed similar efficacy to cefotaxime in paediatric and adult patients with bacterial meningitis (section 4.6), and, with or without tobramycin, to ceftazidime with or without tobramycin in patients with cystic fibrosis experiencing acute pulmonary exacerbations (section 4.9). Meropenem showed greater efficacy than ceftazidime plus amikacin or tobramycin in patients with nosocomial pneumonia (section 4.1), and ceftazidime or piperacillin/tazobactam in febrile neutropenia (section 4.4).

Of interest, a meta-analysis of 27 trials of meropenem versus imipenem/cilastatin in the treatment of serious infections concluded that meropenem therapy was associated with greater clinical and bacteriological response rates and fewer adverse events than imipenem/cilastatin.[129]

Pharmacoeconomic analyses from a UK, US or Russian perspective estimated meropenem to be a cost-effective therapy relative to imipenem/cilastatin or conventional combination antibacterial treatments in patients with serious bacterial infections in ICUs (section 6); in the UK analysis, meropenem dominated imipenem/cilastatin.

IDSA guidelines support the use of meropenem as an option in the initial treatment of polymicrobial necrotizing infections of the skin, fascia and muscle, incisional surgical site infection after intestinal or genital tract surgery, infections after a human or an animal bite,[141] in severe intra-abdominal infections,[142] in high-risk patients with febrile neutropenia (with or without an aminoglycoside or vancomycin),[143] and as an option in combination with vancomycin in bacterial meningitis secondary to head trauma, a CSF shunt or neurosurgery.[144]

American Thoracic Society[145] and European Respiratory Society/European Society for Clinical Microbiology and Infectious Diseases[146] guidelines recommend meropenem as an option in the initial empirical therapy for nosocomial pneumonia and/or severe CAP (in combination with ciprofloxacin and where there is a risk of P. aeruginosa infection in Europe). European Urological Association guidelines recommend carbapenems (including meropenem) for the treatment of complicated UTIs such as urosepsis.[147] Meropenem plus tobramycin is an alternative option to more established β-lactams plus an aminoglycoside in the treatment of exacerbations of chronic pseudomonal respiratory infection in patients with cystic fibrosis.[148] Many of the alternative therapies recommended require the use of combination therapy; as mentioned, meropenem monotherapy demonstrated similar efficacy to some of these combination regimens.

Increased and/or inappropriate use of broad-spectrum antibacterial agents, such as the third-generation cephalosporins, in serious bacterial infections has resulted in a global increase in resistant bacterial strains, including ESBL- and AmpC-producing Enterobacteriaceae and multidrug-resistant P. aeruginosa.[1,132,133,140,149] Because of their broad spectrum of activity, carbapenems are considered first-line options in the empirical treatment of serious infections that may be associated with P. aeruginosa or ESBL-producing Enterobacteriaceae.[149] Importantly, meropenem retains activity against ESBL- and AmpC-producing Enterobacteriaceae, with little or no increase in MIC90 values when compared with wild-type Enterobacteriaceae, and has a minimal inoculum effect (sections 2.2 and 2.3).

Despite having MIC90 values ≥32 mg/L, cumulative global data from the MYSTIC programme for the period 2000–7 showed that all antibacterial agents studied (including meropenem) inhibited >50% of P. aeruginosa isolates (section 2.2); susceptibility results for P. aeruginosa did not change appreciably in Europe between 2002 and 2006.[21] For Acinetobacter spp., the other nonfermentative Gram-negative bacillus of interest, susceptibility for most antibacterial agents tested had decreased considerably between 2002 and 2006 (from 83–84% to 57–58% for the carbapenems), reflecting the increasing incidence of multidrug-resistant Acinetobacter strains in Europe.[21] Regardless, meropenem is an appropriate choice as empirical monotherapy for Acinetobacter spp. and Pseudomonas spp. infections, or as part of combination therapy, depending on the treating unit’s antibiograms for these pathogens. Acinetobacter spp. are often implicated in nosocomial pneumonia (particularly VAP), nosocomial bloodstream infections, surgical site infection (including post-surgical meningitis) and UTI.[150] Group II carbapenems (including meropenem) are the standard of care for the treatment of serious bacterial infections caused by susceptible isolates of Acinetobacter spp.,[150] with combination antibacterial treatment often utilized for multidrug-resistant strains.[150,151]

As with other other currently available carbapenems, methicillin/oxacillin-resistant S. aureus, E. faecium and S. maltophilia are inherently resistant to meropenem (section 2.2).

Results from the OPTAMA programme (section 2.5) confirm that meropenem continues to be of value in a wide range of infections, including those where nosocomial pathogens of concern, such as E. coli, K. pneumoniae, and P. aeruginosa are likely pathogens. Although the prevalence of acquired metallo-β-lactamases and carbapenemases is increasing (section 2.3),[152] carbapenem resistance remains uncommon and Enterobacteriaceae resistance to meropenem (and other carbapenems) is rare (section 2.3).[31,149] However, it is important that meropenem (and other carbapenems) are used appropriately as empirical treatment to limit the likelihood of increasing future resistance.[1] As well as the strategies discussed, using the most active, rather than the least active member of an antibacterial class has also been suggested as a strategy, to reduce the risk of mechanisms of resistance that affect the whole class developing.[134] Ideally, meropenem should be used only in a hospital setting in severe infections for the shortest possible duration.

In conclusion, meropenem has a broad spectrum of in vitro activity against Gram-positive and Gram-negative pathogens, including ESBL- and AmpC-producing Enterobacteriaceae. It has similar efficacy to comparator antibacterial agents, including imipenem/cilastatin in cIAI, febrile neutropenia, cSSSI, complicated UTI, obstetric or gynaecological infections, and severe CAP; clindamycin plus tobramycin or gentamicin in cIAI or obstetric or gynaecological infections; cefotaxime/metronidazole in cIAI; cefepime, ceftazidime plus amikacin in septicaemia or febrile neutropenia; and ceftazidime, clarithromycin plus ceftriaxone or amikacin in severe CAP. Meropenem has also shown similar efficacy to cefotaxime in paediatric and adult patients with bacterial meningitis, and to ceftazidime when both agents were administered with or without tobramycin in patients with cystic fibrosis experiencing acute pulmonary exacerbations. Meropenem showed greater efficacy than ceftazidime plus amikacin or tobramycin in patients with nosocomial pneumonia and ceftazidime or piperacillin/tazobactam in febrile neutropenia. Meropenem is well tolerated and has the advantage of being suitable for administration as an intravenous bolus or infusion. Its low propensity for inducing seizures means that it is suitable for treating bacterial meningitis, and is the only carbapenem approved in this indication. Thus, meropenem continues to be an important option for the empirical treatment of serious bacterial infections in hospitalized patients.