ADIS DRUG EVALUATION Drugs 2000 Mar; 59 (3): 653-680 0012-6667/00/0003-0653/$25.00/0 © Adis International Limited All rights reserved Meropenem A Review of its Use in Patients in Intensive Care Miriam Hurst and Harriet M Lamb Adis International Limited, Auckland, New Zealand Various sections of the manuscript reviewed by: J.L Blumer, Division of Paediatric Pharmacology and Critical care, Rainbow Babies and Children’s hospital, University Hospitals of Cleveland, Cleveland, Ohio, USA; F Colardyn, Department of Intensive Care, University Hospital Ghent, Ghent, Belgium; B.A Cunha, Infectious Disease Division, Winthrop-University Hospital, Mineola, New York, USA; J Garau, Department of Medicine, Hospital de Mutua de Terrassa, Barcelona, Spain; I.M Hoepelmann, University Hospital Utrecht, Division of Infectious Diseases and AIDS, Utrecht, The Netherlands; T Horii, Department of Bacteriology, Nagoya University School of Medicine, Nagoya, Japan; C.E Nord, Karolinska Instituet, Department of Immunology, Microbiology, Pathology and Infectious Diseases, Huddinge University Hospital, Huddinge, Sweden; S.R Norrby, Department of Infectious Diseases and Medical Microbiology, University of Lund, Lund, Sweden; M.A Pfaller, Medical Microbiology Division, Department of Pathology, University of Iowa College of Medicine, Iowa City, Iowa, USA; J.P Quinn, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA; E.C Reisinger, Department of Internal Medicine, Infectious Diseases and Tropical Medicine, University of Rostock, Rostock, Germany; F Thalhammer, Department of Internal Medicine, Division of Infectious Diseases, University of Vienna, Vienna, Austria; C Verwaest, Department of Intensive Care Medicine, Universitair Ziekenhuis Gasthuisberg, Leuven, Belgium Data Selection Sources: Medical literature published in any language since 1966 on Meropenem, identified using AdisBase (a proprietary database of Adis International, 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were identified from the reference lists of published articles Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug Search strategy: AdisBase search terms were ‘Meropenem’ or ‘ICI-194660’ or ‘ICI-213689’ or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 ‘Bacterial-Infections’ Medline search terms were ‘Meropenem’ or ‘ICI 194660’ or ‘ICI 213689’ or ‘SM 7338’ and ‘Bacterial-Infections’ Searches were last updated March 2000 Selection: Studies in patients with serious infections in intensive care units who received meropenem Inclusion of studies was based mainly 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, bacterial infections, intensive care, serious infections, pharmacodynamics, pharmacokinetics, therapeutic use Contents Summary Infections in the Intensive Care Unit Pharmacodynamic Properties 2.1 Antibacterial Activity 2.1.1 Gram-Negative Aerobic Bacteria 2.1.2 Gram-Positive Aerobic Bacteria 2.1.3 Anaerobic Bacteria 2.2 Mechanisms of Resistance 2.2.1 Production of β-Lactamases 2.2.2 Alterations in Permeability 2.2.3 Alterations in Penicillin-Binding Proteins 2.3 Other Properties 654 657 658 658 658 660 661 661 661 662 662 662 654 Hurst & Lamb 2.3.1 Effect on Endotoxin Release 2.3.2 Postantibiotic Effect 2.3.3 Additive/Synergistic Effects Pharmacokinetic Profile 3.1 Special Patient Groups 3.1.1 Patients with Serious Infections 3.1.2 Renal and Hepatic Impairment 3.1.3 Children and the Elderly Clinical Efficacy 4.1 Adults 4.1.1 Compared with Imipenem/Cilastatin 4.1.2 Compared with Cephalosporin-Based Regimens 4.2 Special Patient Groups 4.2.1 Children 4.2.2 Neonates 4.2.3 Elderly Patients Tolerability 5.1 CNS Toxicity 5.2 Special Patient Groups Dosage and Administration Place of Meropenem in the Management of Patients in Intensive Care 662 662 663 663 663 663 663 664 665 665 665 667 667 667 668 668 669 671 672 672 673 Summary Abstract Meropenem is a carbapenem antibacterial agent that has antimicrobial activity against Gram-negative, Gram-positive and anaerobic micro-organisms In vitro studies involving isolates from patients in intensive care units (ICUs) indicate that meropenem is more active against most Gram-negative pathogens than other comparators (including imipenem), although, compared with imipenem, meropenem is less active against most Gram-positive organisms Resistance to meropenem is uncommon in most bacteria Treatment with meropenem as initial empirical monotherapy was effective in a range of serious infections in adult and paediatric ICU patients Meropenem monotherapy was as effective as imipenem/cilastatin in comparative trials in terms of satisfactory clinical and bacteriological responses Meropenem monotherapy was significantly more effective than ceftazidimebased combination treatments in trials in patients with nosocomial lower respiratory tract infections (LRTIs) in terms of both clinical and bacteriological responses Meropenem was also more active than ceftazidime-based treatments against both Gram-positive and Gram-negative organisms However, studies in patients with a range of serious infections found no significant differences between meropenem and cephalosporin-based treatments in terms of clinical or bacteriological response Meropenem was also as effective as cephalosporinbased treatments in comparative trials in children with serious infections Meropenem is well tolerated as either a bolus or an infusion, and clinical trials have shown similar incidences of adverse events to those observed with cephalosporin-based treatments It is well tolerated by the CNS, with seizures reported infrequently, and can therefore be used at high doses and in patients with meningitis The incidence of drug-related nausea and vomiting is low and, in contrast to imipenem/cilastatin, does not increase with dose or speed of administration © Adis International Limited All rights reserved Drugs 2000 Mar; 59 (3) Meropenem: A Review 655 Conclusions: Meropenem is a well tolerated broad spectrum antibacterial agent that, when used as initial empirical monotherapy, is as effective as imipenem/cilastatin in the treatment of a range of serious infections (including nosocomial) in adults and children in ICUs Compared with cephalosporin-based combination treatments, meropenem monotherapy may be more effective in the treatment of nosocomial LRTIs and can be used as monotherapy Meropenem has an important role in the empirical treatment of serious infections in adults and children in ICUs Pharmacodynamic Properties Meropenem has a broad spectrum of activity against most common intensive care unit (ICU) pathogens in in vitro studies, and, in particular, was more active than most other agents (including imipenem) against Enterobacteriaceae A survey of 14 857 isolates (not all from ICUs) found that values for the minimum drug concentration required to inhibit the growth of 90% of bacterial strains (MIC90) with meropenem were 4- to 16-fold lower than those with imipenem (≤0.06 to 0.5 mg/L and 0.25 to mg/L, respectively) All Enterobacteriaceae isolated from 13 ICUs were highly susceptible to meropenem, with MIC90 values ranging from 0.13 to mg/L; values for imipenem ranged from to mg/L Haemophilus influenzae and Neisseria meningitidis were also highly susceptible to meropenem (MIC90 ≤1 mg/L); data from North American centres indicated that meropenem was more active than imipenem against H influenzae (99.4 and 85.3% of isolates were susceptible, respectively) Isolates of Pseudomonas aeruginosa from ICU patients were of intermediate susceptibility to meropenem and resistant to all other agents tested, including imipenem Stenotrophomonas maltophilia was resistant to both carbapenems Gram-positive bacteria susceptible (MIC90 ≤4 mg/L) to meropenem include methicillin-sensitive Staphylococcus aureus and S epidermidis, and Streptococcus pneumoniae Meropenem is less active than imipenem against Enterococcus faecalis Methicillin-resistant staphylococci and E faecium are resistant to meropenem Meropenem is highly active against most anaerobic bacteria, with review finding that 99.1% of 2257 isolates were susceptible Meropenem, like imipenem, is highly resistant to hydrolysis by most of the serine-based β-lactamases produced by Gram-negative bacteria; however, both drugs are susceptible to the metallo-β-lactamases and clavulanic acid-inhibited carbapenemases produced by S maltophilia and some Flavobacterium spp Hyperproduction of β-lactamases by some bacteria is also associated with decreased susceptibility when expressed in conjunction with certain porin deficiencies Alterations in penicillin-binding proteins account for the inherent resistance of E faecium and methicillin-resistant S aureus Meropenem has demonstrated additive or synergistic activity when used in combination with a range of antibacterial agents in in vitro studies Like imipenem, meropenem has a postantibiotic effect on Gram-negative bacilli Meropenem may cause less release of endotoxin from Gram-negative bacteria than other agents such as the cephalosporins, although results are inconsistent Pharmacokinetic Profile Meropenem has linear pharmacokinetics and distributes into a wide range of body fluids and tissues Mean values for peak plasma concentrations (Cmax) in healthy volunteers were 54.8 to 61.6 mg/L after single dose meropenem 1g; these values were similar hour after either bolus or infusion administration Mean values for elimination half-life (t1⁄2) were 1.0 to 1.4 hours, and volume of distribution was 12.5 to 23L Meropenem is largely excreted renally, with 54 to 79% of a 1g dosage © Adis International Limited All rights reserved Drugs 2000 Mar; 59 (3) 656 Hurst & Lamb excreted unchanged in the urine and 19 to 27% excreted as an inactive metabolite Unlike imipenem, meropenem is stable to human renal dehydropeptidase-1 Data relating to the effects of serious infections on the pharmacokinetics of meropenem are limited, but the changes seen in studies in small numbers of patients appear to result from factors other than infection (such as recent surgery) However, dosage adjustments are necessary in patients with renal impairment Meropenem is primarily excreted through the kidneys; because of this, total body and renal clearance of meropenem decrease, and t1⁄2 increases, as creatinine clearance decreases Patients with renal failure requiring continuous veno-venous haemofiltration may require higher dosages of meropenem than those recommended for their level of renal impairment in order to maintain adequate serum concentrations Hepatic impairment had no significant effect on the pharmacokinetics of meropenem Clinical Efficacy Meropenem is effective in the treatment of serious infections, including those acquired in hospital or the ICU The most common diagnosis in these studies was pneumonia or another lower respiratory tract infection (LRTI); intra-abdominal infections were also diagnosed frequently In randomised nonblind comparative trials, intravenous meropenem and imipenem/cilastatin (both 1g every hours) demonstrated similar efficacy, with satisfactory clinical responses observed in 76 to 88% of meropenem recipients compared with 68 to 85% of imipenem/cilastatin recipients; 67 to 94% and 60 to 88% of patients, respectively, experienced satisfactory bacteriological responses Eradication of Gram-negative organisms was observed in 70 to 100% of meropenem recipients and 64 to 84% of imipenem/cilastatin recipients; eradication rates for Gram-positive organisms were 69 to 83% and 87 to 96%, respectively, and there were no statistical comparisons Significantly more evaluable patients experienced satisfactory clinical and/or bacteriological responses with meropenem than with ceftazidime-based treatments in randomised nonblind multicentre trials in patients with nosocomial LRTIs; rates of satisfactory clinical response were 83 and 89% with meropenem, compared with 66 and 72% with ceftazidime-based treatments (p ≤ 0.04) Bacteriological success was observed in 74 and 89% of meropenem recipients, compared with 54 and 67% of ceftazidime-based treatment recipients (p ≤ 0.042) Meropenem was more active than ceftazidime-based treatments in terms of eradication of both Gram-negative (83 and 93% vs 72 and 79%, respectively) and Gram-positive (89 and 80% vs 62 and 65%, respectively) organisms However, other studies in patients with serious bacterial infections (including those aged ≥65 years) found no significant differences between meropenem and cephalosporin-based treatments in terms of clinical or bacterial response, including effects on Gram-negative and Gram-positive organisms Although there are no comparative studies focusing solely on paediatric ICU patients, multicentre trials in children (aged month to 15 years) with serious bacterial infections (not including meningitis) found that meropenem 10 to 20 mg/kg every hours was as effective as either ceftazidime alone (10 to 30 mg/kg every hours) or cefotaxime-based therapies (100 to 160 mg/kg daily in to divided doses) Satisfactory clinical responses ranged from 97 to 98% with meropenem, compared with 93 to 96% with cephalosporin-based treatments; 88 to 97% of bacterial responses were satisfactory with meropenem, compared with 89 to 93% with comparative treatments The use of meropenem in children aged © Adis International Limited All rights reserved Drugs 2000 Mar; 59 (3) Meropenem: A Review 657 < months is ‘off label’; however, small noncomparative studies have found meropenem to be effective in the treatment of invasive infections in neonates, including those who failed to respond to previous antibacterial therapy Tolerability In a safety analysis of 9514 patients with serious bacterial infections, the incidences of adverse events and drug-related adverse events with meropenem were similar to those seen with imipenem/cilastatin or cephalosporin-based treatments The most frequently reported drug-related adverse events for meropenem were diarrhoea (2.3% of treatment exposures), rash (1.4%), nausea and vomiting (1.4%) and inflammation at the injection site (1.1%), with all other drug-related adverse events occurring in 128 K pneumoniae (62) 0.13 128 128 >128 64 Proteus mirabilis (44) 0.13 0.5 2 Pseudomonas aeruginosa (171) 16 32 32 128 >128 32 Serratia marcescens (41) 0.25 16 128 16 16 Gram-positive aerobes Enterococcus faecalis (128) 32 >128 >128 32 >128 >128 0.25 16 4 Staphylococcus aureus (MS) (276) ICU = intensive care unit; MIC90 = minimum drug concentration required to inhibit the growth of 90% of bacterial strains; MS = methicillin-sensitive intermediate susceptibility to meropenem and resistant to all other agents tested (see table II);[19] meropenem was more active against P aeruginosa than comparators (including imipenem, ciprofloxacin, and ceftazidime), with susceptibility rates of 89 to 100%, in other studies involving isolates from ICU patients[17,21] or patients with serious infections.[18] The percentages of Pseudomonas spp (other than P aeruginosa) that were susceptible to meropenem ranged from 50 to 95% in the few studies that included these data;[16-18,22] however, studies found higher susceptibility rates with other agents (ceftazidime,[16,17] ciprofloxacin,[17] cefepime[16] and piperacillin[17]) North American studies found that meropenem had more activity than imipenem against H influenzae (99.4 and 85.3% susceptible, respectively), although no marked difference was evident in European studies (100 and 98.2%, respectively).[11] Meropenem and imipenem were the most effective agents tested against Acinetobacter spp (94% susceptible).[18] © Adis International Limited All rights reserved 2.1.2 Gram-Positive Aerobic Bacteria Gram-positive bacteria that were highly susceptible to meropenem (MIC90 ≤1 mg/L) included methicillin-sensitive S aureus and Streptococcus pneumoniae (table I) Methicillin-sensitive S epidermidis was also susceptible (MIC90 ≤4 mg/L) Meropenem had variable activity against Enterococcus faecalis (MIC90 ≤8 mg/L) and no activity against methicillin-resistant staphylococci or E faecium (MIC90 values ≥16 mg/L).[11] Meropenem was less active than imipenem against E faecalis and S epidermidis (2- to 4-fold and 4- to 8-fold differences in MIC90, respectively).[11] In ICU patients, meropenem was less active than imipenem against isolates of E faecalis (MIC90 32 and mg/L, respectively; see table II).[19] However, MIC90 values for methicillin-sensitive S aureus were 8-fold lower with meropenem than with imipenem in ICU isolates (see table II) In the review by Pfaller and Jones, North American isolates of S pneumoniae were 2- to 4-fold less susceptible to meropenem than to imipenem and cefotaxime (MIC90 values 0.5, 0.13 and 0.25 mg/L, respectively); this difference was not seen in Drugs 2000 Mar; 59 (3) Meropenem: A Review the European results (MIC90 values 0.06, 0.06 and 0.25, respectively).[11] The higher prevalence of penicillin-resistant S pneumoniae in North America was thought to be responsible (27% of isolates vs 10% in Europe) However, although only 60% of all isolates of penicillin-resistant S pneumoniae were susceptible to meropenem at concentrations of ≤0.12 mg/L, 97% were susceptible at ≤1 mg/L (MIC90 values for penicillin-resistant S pneumoniae were not given).[11] 2.1.3 Anaerobic Bacteria Overall, 99.1% of 2257 isolates of anaerobic bacteria were susceptible to meropenem in the review by Pfaller and Jones.[11] Clostridium perfringens and Bacteroides fragilis were highly susceptible (MIC90 ≤0.5 mg/L); C difficile was also susceptible (100% inhibited at mg/L) More European isolates of C difficile were susceptible to meropenem (100%) than imipenem (67.9%), although in North American studies 100% of isolates were susceptible to both drugs (table I) 2.2 Mechanisms of Resistance Resistance to β-lactam antibacterial agents can result from a number of mechanisms and may be intrinsic or acquired.[23] Reduced susceptibility to the carbapenems, although less common than with other β-lactam agents, has been observed in bacteria (such as P aeruginosa) that exhibit multiple resistance mechanisms;[24] in addition, there are increasing numbers of reports of organisms with acquired carbapenemases.[25] In spite of the widespread use of meropenem, there has been no clinically significant resistance seen in P aeruginosa or Klebsiella, Enterobacter or Serratia spp.[26] The potential of antibacterial agents to select resistant strains and the incidence of cross-resistance should also be considered when choosing an antibacterial agent, although data are limited In in vitro study, meropenem selected for resistant strains of Enterobacter cloacae to a greater degree than imipenem (although data from MYSTIC indicate that meropenem is highly active against this pathogen; see table II);[27] in another study, neither meropenem nor imipenem selected for mutant iso© Adis International Limited All rights reserved 661 lates of P aeruginosa that were cross-resistant to other β-lactam agents.[28] Cross-resistance data from isolates of P aeruginosa, however, suggest that imipenem-resistant strains are more likely to be susceptible to meropenem than vice versa.[29-32] 2.2.1 Production of β-Lactamases The production of enzymes capable of hydrolysing β-lactam rings enables certain bacteria to inactivate β-lactam antibacterial agents Carbapenems such as meropenem are highly resistant to hydrolysis by serine-based β-lactamases (such as the chromosomal and plasmid-mediated βlactamases produced by most Gram-negative bacteria).[33,34] This may be of clinical significance; study (reported as an abstract) found that mortality rates in 80 patients infected with extended spectrum β-lactamase producing strains of K pneumoniae were significantly lower in those who received a carbapenem in the first days of treatment, compared with those who received other antibacterial agents (5 vs 43%, p = 0.01).[35] However, carbapenems are susceptible to the metallo-β-lactamases (Bush groups 3a and 3b) and clavulanic acid-inhibited carbapenemases (group 2f) produced by S maltophilia and some Flavobacterium spp.[33,34] Acquired metallo-β-lactamases conferring resistance or decreased susceptibility to carbapenems have been reported in resistant isolates of P aeruginosa from patient in Italy[36] and Japan;[25] a specific metallo-β-lactamase (IMP-1) has also been reported in Japanese isolates of Serratia marcescens[25] and, in case, a Japanese isolate of K pneumoniae.[25] Carbapenemase resistance is also increasingly common in clinical isolates of Acinetobacter, with plasmid-mediated carbapenemases and metallo-β-lactamases reported.[25,37,38] Hyperproduction of β-lactamases by Escherichia coli,[30,39,40] P aeruginosa,[28] K pneumoniae[41-43] and Citrobacter freundii[44] was also associated with decreased susceptibility to meropenem when expressed in combination with decreased permeability due to porin deficiencies (see section 2.2.2) Drugs 2000 Mar; 59 (3) 662 2.2.2 Alterations in Permeability Carbapenems enter Gram-negative bacteria by passive diffusion through porins in the cell membrane.[45] The zwitterionic nature and low molecular weight of meropenem mean that it is able to penetrate most cells;[46] however, organisms that lack porins can have decreased susceptibility to carbapenems because of the reduction in permeability Deficiency of outer membrane porin protein D2 is associated with decreased susceptibility to carbapenems, but not other β-lactam agents;[45,47] in addition, a number of different porin deficiencies associated with decreased susceptibility have been described in isolates of P aeruginosa.[23,48-50] One in vitro study also found that meropenem selected for porin-deficient mutants of K pneumoniae;[50] however, clinical data indicate that isolates of K pneumoniae are still highly susceptible to meropenem (section 2.1.1) Some organisms with these deficiencies may demonstrate a reduction in susceptibility only if they also hyperproduce β-lactamases (see section 2.2.1) Multidrug efflux pumps capable of excreting antibacterial agents have been detected in some Gram-negative bacteria, including P aeruginosa, and these can also contribute towards decreased susceptibility to carbapenems.[23,51] These pumps are usually capable of excreting a broad range of antibacterial agents, including β-lactams, fluoroquinolones and tetracyclines; it is unclear how common they are among resistant bacterial isolates 2.2.3 Alterations in Penicillin-Binding Proteins Some bacteria, such as E faecium, have penicillin-binding proteins (PBPs) that confer inherent resistance to β-lactam antibacterial agents In addition, many isolates of methicillin-resistant S aureus produce supplementary PBPs that make them resistant to carbapenems or other β-lactam agents.[45] However, meropenem and imipenem differ in their affinities for bacterial PBPs; in particular, meropenem has a greater affinity for PBP3 than imipenem.[52] In study (reported in abstract form), imipenem resistance in isolates of H influenzae appeared to relate to the low affinity of © Adis International Limited All rights reserved Hurst & Lamb imipenem for PBP4 and PBP5, as these isolates were still susceptible to meropenem.[53] 2.3 Other Properties 2.3.1 Effect on Endotoxin Release Endotoxin release from Gram-negative bacteria plays a major part in the pathogenesis of septic shock; the overall mortality rate in patients with this condition is approximately 45%.[54] Antibacterials, although vital in the treatment of such infections, have been shown experimentally to induce endotoxin release because of their ability to disrupt bacterial outer membranes.[54] It is important to note, however, that the clinical significance of these in vitro findings is unknown, and the choice of an antibacterial agent should still be based on efficacy against the likely pathogens Some in vitro studies[55-60] and animal models,[61] however, have shown that meropenem causes significantly less endotoxin release from P aeruginosa, E coli, S marcescens and K pneumoniae than non-carbapenems (including ceftazidime, ceftriaxone, cefepime and ciprofloxacin); in study in P aeruginosa, endotoxin concentrations were 2.7to 10-fold lower with meropenem than with ceftazidime.[55] The effects of meropenem were generally similar to those seen with imipenem in these studies However, in an in vitro study meropenem caused more endotoxin release from P aeruginosa than either imipenem or panipenem.[61] In addition, an animal model of Gram-negative sepsis (using E coli and mice pretreated with hepatotoxin) found that endotoxin release was greater with meropenem than with imipenem; however, both agents were given as single doses and only mice received meropenem.[62] 2.3.2 Postantibiotic Effect Meropenem, like imipenem and unlike most other β-lactam antibacterial agents, has a postantibiotic effect against Gram-negative bacilli.[63] Delayed regrowth following exposure to meropenem has been reported in Enterobacteriaceae,[64-66] S aureus,[67] P aeruginosa,[64-66,68] B fragilis[69] and E faecalis[70]; however, duration depends on the method of assessment used.[65] Drugs 2000 Mar; 59 (3) 666 Hurst & Lamb Table IV Comparative efficacy of meropenem (MEM) in the empirical treatment of patients with serious infections; summary of randomised nonblind multicentre studies All drugs were administered intravenously (bolus or infusion) every hours unless otherwise stated Study Diagnosis and patient status [no of pts enrolled] Drug and daily dosage Percentage of pts with satisfactory responsea [no of evaluable pts] clinical bacteriological Compared with imipenem/cilastatin (IPM/C) Colardyn et al.[107] Garau et al.[108] [104] Hartenauer et al Verwaest et al.[109] Serious bacterial infections; 67% of MEM 3g clinically evaluable pts in ICUs[204] IPM/C 3g 76 [90] 77b [61] 77 [87] 83b [54] 87c [66] 79c [42] Severe nosocomial infections; 90% of pts in ICUs [151] MEM 3g Serious bacterial infections; all pts in ICUs [80] MEM 3g 88 [34] 94 [17] IPM/C 3g 85 [39] 88 [25] Serious bacterial infections; all pts in ICUs [212] MEM 3g 77 [87] 67 [73] IPM/C 3g 68 [91] 60 [73] IPM/C 3g c 71c [42] 74 [67] Compared with ceftazidime (CAZ) plus amikacin (AN) or tobramycin (TM) Alvarez-Lerma et al.[112] Mouton et al.[110] Mechanical ventilation-associated pneumonia; all pts in ICU [140] Serious bacterial infections; 42% of pts in poor/critical condition [237] MEM 3g 83* [59] 74* [53] CAZ 6g + AN 15 mg/kg q12h 66 [59] 54 [48] MEM 3g 93 [43]d 100 [30]d e 71 [24]e f 100 [12]f g 56 [9]g d 79 [39] 87 [30]d 72 [32]e 76 [17]e 81 [37] 83 [12] 87 [15] CAZ 6g + AN 15 mg/kg q8 or 12h f 100 [17]f 94 [17] g 100 [25] Sieger et al.[105] Nosocomial LRTIs; 70% of pts required mechanical ventilation [211] 100 [12]g MEM 3g 89* [63] 89** [63] CAZ 6g + TM mg/kg 72 [58] 67 [58] Compared with cefuroxime (CXM) plus gentamicin (GM) Jaspers et al.[111] Serious infections in the elderly; mean APACHE II score 18 for MEM recipients, 20 for CXM + GM recipients [79] MEM 3g 70 [37] 68 [22] CXM 4.5g + GM mg/kgh 73 [33] 63 [19] a Clinical response was satisfactory if either cure or improvement of symptoms occurred Bacteriological responses were satisfactory if proven or presumptive eradication of the causative organism(s) took place Responses were assessed at the end of treatment b Percentage calculated on the number of clinical isolates obtained from these patients; 110 isolates from MEM recipients, 109 from IPM/C recipients c Weighted to allow for different sites of infection d Results for community-acquired LRTI e Results for nosocomial-acquired LRTI f Results for septicaemia g Results for complicated UTI h Ten patients also received metronidazole 500mg q6h APACHE = Acute Physiology and Chronic Health Evaluation; ICU = intensive care unit; LRTI = lower respiratory tract infection; pts = patients; qxh = every x hours; UTI = urinary tract infection; * p < 0.05, ** p = 0.006 vs comparator © Adis International Limited All rights reserved Drugs 2000 Mar; 59 (3) Meropenem: A Review 667 Table V Comparative efficacy of meropenem against Gram-positive, -negative and anaerobic bacteria in randomised nonblind multicentre trials in patients with serious infections All drugs were administered intravenously every hours unless otherwise stated Study Drug and daily dosage Organisms eradicated (%) [total number of isolates] Gram-negative Compared with imipenem/cilastatin (IPM/C) Colardyn et al.[107] MEM 3g Hartenauer et al.[104] Verwaest et al.[109] 94 [16] 70 [64] 83 [30] 78 [67] 87 [31] 100 [11] MEM 3g 100 [14] 69 [16] NR IPM/C 3g 84 [25] 96 [24] NR MEM 3g 82 [71] 70 [30] 100 [8] IPM/C 3g 64 [85] 96 [28] 94 [18] CAZ 6g + AN 15 mg/kg q12h Sieger et al.[105] anaerobic IPM/C 3g Compared with ceftazidime (CAZ) plus amikacin (AN) or tobramycin (TM) Alvarez-Lerma et al.[112] MEM 3g 83 [54] Mouton et al.[110] Gram-positive 72 [47] 89 [18] NR 62 [13] 100 [1] MEM 3g 79 [58] 97 [34] NR CAZ 6g + AN 15 mg/kg q8 or 12h 86 [65] 96 [28] NR MEM 3g 93 [80] 80 [15] NR CAZ 6g + TM mg/kg 79 [78] 65 [23] NR NR = not reported; pts = patients; qxh = every x hours 4.1.2 Compared with Cephalosporin-Based Regimens Significantly more patients with serious nosocomial respiratory infections experienced a satisfactory clinical and bacteriological response with meropenem (1g every hours) than with ceftazidime (2g every hours) and either amikacin (7.5 mg/kg twice daily)[112] or tobramycin (1 mg/kg every hours)[105] in randomised multicentre studies (table IV, fig 2) Satisfactory clinical responses were observed in 83 and 89% of evaluable meropenem recipients compared with 66 and 72% of those who received ceftazidime and either amikacin (p = 0.035) or tobramycin (p = 0.04) Eradication or presumptive eradication of pathogens occurred in 74 and 89% of meropenem recipients (compared with 54 and 67% with ceftazidime and either amikacin or tobramycin, respectively; p = 0.042 and 0.006, respectively)[table IV] Meropenem was more effective than ceftazidime-based treatments in eradicating both Gram-negative (83 and 93% vs 72 and 79%, respectively) and Grampositive (89 and 80% vs 62 and 65%, respectively) organisms in these studies, although there were no statistical comparisons (table V) In contrast, other studies found no significant differences in clinical and bacterial responses be© Adis International Limited All rights reserved tween patients who received meropenem and those who received cephalosporin-based treatments (table IV); only of these studies included data relating to effects on Gram-negative and Gram-positive organisms, which were similar between treatments (table V).[110] However, patients in these studies had been diagnosed with a range of infections, including respiratory, intra-abdominal, urinary tract and bloodstream One of these studies involved only patients aged ≥65 years (see section 4.2.3).[111] 4.2 Special Patient Groups 4.2.1 Children Meropenem is effective in the treatment of a range of serious non-CNS infections in children (also reviewed in Bradley et al.[113]) It can be administered as an intravenous bolus (see sections and 6), making it useful in paediatric treatment where small intravenous volumes are often required; this type of administration has been well tolerated clinically (see section 5.2) In nonblind multicentre trials in children (aged month to 15 years) with serious bacterial infections (not including meningitis), meropenem monotherapy (10 to 20 mg/kg every hours) was as effective as either ceftazidime monotherapy (10 to 30 mg/kg every hours) or cefotaxime-based Drugs 2000 Mar; 59 (3) Patients experiencing satisfactory response (%) 668 Hurst & Lamb MEM CAZ-based 100 * ** * 80 * 60 40 20 Clinical Bacteriological [105] Sieger et al Clinical Bacteriological [112] Alvarez-Lerma et al Fig Comparative efficacy of meropenem (MEM) and ceftazidime (CAZ)-based treatments in randomised nonblind clinical trials in patients with nosocomial lower respiratory tract infections (LRTIs).[105,112] Percentage of patients experiencing satisfactory clinical (cure or improvement of symptoms) or bacteriological (presumed or confirmed eradication of causative organisms) responses One trial involved 140 patients with mechanical ventilation-associated pneumonia who received either MEM (1g every hours) or CAZ (2g every hours) plus amikacin (7.5 mg/kg twice daily); 118 patients were clinically evaluable and 101 were bacteriologically evaluable.[112] The other involved 211 patients with hospital-acquired LRTIs who received either MEM 1g or CAZ 2g and tobramycin mg/kg (all drugs given every hours); 63 MEM recipients and 58 CAZbased tretment recipients were evaluable clinically and bacteriologically.[105] * p < 0.05, ** p = 0.006 vs CAZ-based treatment therapies (100 to 160 mg/kg daily in to divided doses)[table VI].[106,114,115] However, these trials did not state whether these patients were in ICUs and only of them included information on patient condition In trial,[115] 36% of the children were considered to be in poor condition and in the other approximately 10% of patients were described as poor or critical,[106] although similar rates of satisfactory clinical and bacteriological responses were seen in all studies (97 to 98% and 88 to 97% with meropenem vs 93 to 96% and 89 to 93% with comparators)[table VI] The most common diagnosis in all studies was that of LRTI (43 to 63% of patients), although children with urinary tract, intra-abdominal, skin and © Adis International Limited All rights reserved bloodstream infections were also included Only studies included a break-down of bacteriological response according to the nature of the organism; meropenem treatment eradicated 93 to 100% of Gram-negative isolates and 92 to 94% of Grampositive isolates, compared with 80 to 95% and 83 to 100%, respectively, with cefotaxime-based therapies.[106,115] Cure or improvement was observed in 16 of 20 paediatric ICU patients (aged month to 14 years) who received meropenem, either as monotherapy or in combination with other agents; 18 of these children had been previously treated unsuccessfully with other antibacterial agents.[116] Most patients were diagnosed with sepsis (11); the most common pathogens were Acinetobacter spp., Pseudomonas spp and Enterobacter 4.2.2 Neonates Although not formally approved for use in neonates, meropenem has been used with success in small noncomparative studies (3 reported in abstract form[117-119]) in neonatal ICU patients with a range of serious infections.[117-120] Pneumonia and sepsis were the most common diagnoses, with P aeruginosa and Enterobacter, Klebsiella and Acinetobacter spp most commonly isolated as causative pathogens In studies (n = 15[120] and n = 7[117]), all of the neonates showed clinical improvement; in the others, 16 of 24[118] and 13 of 15[119] patients were cured or improved with meropenem Total daily doses of meropenem ranged from 15 mg/kg to 120 mg/kg, usually given in divided doses; in of the studies,[118] of the 24 patients received meropenem in combination with vancomycin or a cephalosporin Most or all of the neonates involved in these studies had failed to respond to previous antibacterial therapy 4.2.3 Elderly Patients Meropenem was as effective as cefuroxime plus gentamicin (with or without metronidazole) in 79 patients with serious bacterial infections aged ≥65 years (see table IV).[111] Clinical responses were satisfactory in 70% of meropenem recipients and 73% of patients who received cefuroxime-based treatment; bacterial responses were satisfactory in Drugs 2000 Mar; 59 (3) Meropenem: A Review 669 68 and 63% of patients, respectively Most patients had been diagnosed with pneumonia (52%) or intra-abdominal infection (13%) Treatment location was not stated, but mean APACHE II scores for both patient groups indicated severe illness Tolerability There are no meta-analyses that assess the tolerability of meropenem in patients in ICU alone However, a recent review of the tolerability profile of meropenem analysed data from 46 clinical trials involving 9514 hospitalised patients with serious bacterial infections.[121] All except of the trials were prospective, controlled and randomised (the exception being a noncomparative study in bone and joint infections) and compared meropenem (5026 treatment exposures) with either cephalosporin-based treatments (2423 treatment exposures), imipenem/cilastatin (1802 treatment exposures) or clindamycin and an aminoglycoside (527 treatment exposures) The most common infections were LRTIs (2196 treatment exposures), intraabdominal infections (2131 treatment exposures) and urinary tract infections (1192 treatment expo- sures); patients with febrile neutropenia (772 treatment exposures) and children (926 treatment exposures) were also included in the analysis Overall, the total incidences of adverse events and drug-related adverse events were similar with all treatment regimens (fig 3a), although no statistical data were provided The most frequently reported drug-related adverse events with meropenem were diarrhoea (2.3% of treatment exposures), rash (1.4%), nausea and vomiting (1.4%) and inflammation at the injection site (1.1%) [fig 3b] Imipenem/cilastatin was associated with more nausea and vomiting than other treatments, and cephalosporin-based treatments with less; however, there were no statistical comparisons Other adverse events associated with meropenem which were considered to be drug-related (headache, sepsis, abdominal pain and pruritus) all occurred in 0.1 to 0.4% of treatment exposures.[121] Analysis by dosage did not indicate any significant difference in the incidence of diarrhoea, rash, pruritus and nausea and vomiting However, oral thrush appeared to be more common in patients receiving >50 mg/kg/day (approximately vs Table VI Comparative efficacy of meropenem (MEM) in the empirical treatment of children with serious infections; summary of multicentre randomised nonblind studies All drugs were administered intravenously (as a bolus or an infusion) every hours unless otherwise stated Study Diagnosis and patient status [age range] Principi & Marchisio Severe acute bacterial infections [4mo- 15.2y] [114] Schuler[115] Snedden et al.[106] Hospitalised with bacterial infections requiring parenteral therapy; 36% in poor condition, ≈50% with pre-existing disorders [4mo-12.9y] Non-CNS infections, ≈10% in poor or critical condition [1mo-13y] Treatment (mg/kg) Response ratea (%) [no of evaluable pts] 98 MEM 20 97 [90] 88 [16] 87 CAZ 10 to 30 95 [85] 93 [14] No of pts enrolled 119 51 clinical bacteriological MEM 10 or 20 98 [96] 89 [28] CTXb 100 to 150c 93 [46] 90 [10] 253 MEM 20 98 [205] 97 [112] 252 CTXd 40 q6h 96 [178] 89 [48] a Clinical response was satisfactory if either cure or improvement of symptoms occurred Bacteriological responses were satisfactory if proven or presumptive eradication of the causative organism(s) took place b 35 children received CTX alone, received CTX and metronidazole 7.5 mg/kg q8h and 11 received CTX and amikacin 15 mg/kg daily (in to equal doses) c In to equal doses d Clindamycin 10 mg/kg and/or tobramycin to 2.5 mg/kg (both administered q8h) could be added at the discretion of the investigator; 80% of pts received CTX alone CAZ = ceftazidime; CTX = cefotaxime; pts = patients; qxh = every x hours © Adis International Limited All rights reserved Drugs 2000 Mar; 59 (3) 670 Hurst & Lamb a 50 MEM IPM/C CPH-based CLN + AMG 40 30 Incidence (% of treatment exposures) 20 10 All adverse events Drug-related adverse events Withdrawal Mortality Diarrhoea Rash Nausea/vomiting Injection site inflammation b Fig Comparative tolerability of meropenem (MEM) Data from a meta-analysis of 46 clinical trials in patients with serious bacterial infections.[121] (a) Percentage of treatment exposures associated with adverse events, drug-related adverse events, treatment withdrawal and death, (b) drug-related adverse events occurring in >1% of patients receiving MEM Patients received either MEM (5026 treatment exposures), imipenem/cilastatin (IPM/C; 1802 treatment exposures), cephalosporin-based treatment (CPH-based; 2423 treatment exposures) or clindamycin and an aminoglycoside (CLN + AMG; 527 treatment exposures); all except of these trials were comparative and randomised Most adult MEM recipients received either 1g (2391 patients) or 500mg (1215 patients) every hours; dosages of comparators were those recommended by the manufacturers © Adis International Limited All rights reserved Drugs 2000 Mar; 59 (3) Meropenem: A Review 5.1 CNS Toxicity Animal[127,128] and human[124,129,130] data show that meropenem is well tolerated by the CNS in doses of up to 2g every hours, even in patients with bacterial meningitis In contrast, although the © Adis International Limited All rights reserved overall incidence of seizures in hospitalised patients receiving treatment with imipenem/ cilastatin ranged from 0.2 to 1.5% in large reviews, the higher incidences reported in some studies in patients with CNS pathology and/or renal impairment (20 to 32%) or children with meningitis (48%) mean that this agent is not recommended for use in these groups; in other patients, the maximum recommended dosage of imipenem/cilastatin is 4g daily.[131] However, in a recent comparative randomised double-blind study in patients with severe pneumonia, 11 of the 200 patients (6%) who received imipenem/cilastatin 1g every hours experienced seizures (all during treatment), compared with of the 202 patients (1%) receiving ciprofloxacin (p = 0.028).[132] In a meta-analysis of data from 46 clinical trials involving 9514 patients with serious bacterial infections, patients without meningitis (0.08%) experienced seizures that were thought to be related to meropenem treatment compared with (0.28%) imipenem/cilastatin recipients (fig 4); patients with a history of CNS disorders were excluded from the trials.[121] All patients who experienced seizures during meropenem treatment were elderly (aged >70 years) and had renal impairment [creIncidence (% of treatment exposures) 0.1% with 25 to 50 mg/kg/day and 0.3% with