Meropenem: laboratory and clinical data

George Drusano

Division of Clinical Pharmacology, Department of Melcine, Albany Medical College, Albany, New York, USA

The usefulness of many p-lactams, including the third-generation , has been threatened in recent years by the dissemination of P-lactamase-mediated resistance. The , and /, demonstrate ultra-broad spectra of antibacterial activity which encompass the majority of clinically significant Gram- positive and Gram-negative aerobic and anaerobic pathogens. Due to the unique arrangement of the moieties arocind the p-lactam ring, these agents possess unrivaled stability to almost all serine p-lactamases, including the mutant extended-spectrum types produced by Enterobacteriaceae which hydrolyze third-generation cephalosporins. Meropenem has a number of additional structural features which confer advantages over imipenem, notably stability to metabolism by dehydropeptidase-l and enhanced activity against Gram-negative organisms, including Pseudornonas aeruginosa. In the treatment of nosocomial respiratory tract infections, meropenem monotherapy has compared favorably with plus aminoglycoside combination regimens or imipenem/cilastatin, producing rates of clinical efficacy of >75%. Likewise, in patients with intra-abdominal infections, meropenem has proved to be as efficacious as clindamycin plus tobramycin, plus metronidazole and equivalent dosages of imipenem/cilastatin. Meropenem is well tolerated by the central nervous system and, unlike imipenem/cilastatin, is approved for the treatment of meningitis. Key words: Carbapenems, p-lactamase, drug resistance, meropenem

INTRODUCTION DEVELOPMENT OF CARBAPENEMS

During the last 20 years, a succession of new Carbapenem compounds were first dscovered in 1976 have been developed to counter the emergence of [1,2]. Thienamycin, isolated from Streptomycer cuttleyu, resistance to older agents. In the early 1980s, third- appeared to be the most promising of these early generation cephalosporins such as cefotaxime were compounds. However, the usefulness of thienamycin introduced. Initially these agents had enhanced stability was limited by its inherent concentration-dependent to (3-lactamases produced by Enterobacteriaceae, but chemical instability [2]. the recent emergence of mutant extended-spectrum In 1979, the stable derivative N-formimidoyl- (3-lactamases (ESBLs) has threatened the utility of these thienamycin, or imipenem, was developed. This com- agents as empiric therapy in many areas of the world. pound is extensively hydrolyzed by dehydropeptidase- This review discusses the advantages of the carbapenem I (DHP-I) in the brush border of the renal tubule [3], class of antibiotics. with two important consequences [4,5]. First, the penetration of imipenem into the urine may be insufficient for the treatment of urinary tract infections. Second, high dosages of imipenem induce proximal Corresponding author and reprint requests: tubular necrosis in laboratory animals. These problems G. Drusano, Division of Clinical Pharmacology, were overcome by the discovery of cilastatin, a reversible Department of Medicine, Albany Medical College, competitive inhibitor of DHP-I. Co-administration of Albany, New York 12202-3479,USA cilastatin (in a 1: 1 ratio) increases urinary recovery of Tel: +I 518 262 6761 Fax: +I 518 262 6333 imipenem to approximately 60-70% and prevents the Accepted 15 October 1997 aforementioned nephrotoxicity [3].

4S51 4S52 Clinical Microbiology and Infection, Volume 3 Supplement 4

Meropenem, developed during the 1980s, repre- hydroxyethyl side-chain is forced 6 to the ring, which sents a further advance in the structural chemistry of stabilizes the molecule to hydrolysis by almost all serine the carbapenems. The meropenem molecule possesses P-lactaniases, including mutant TEM- and SHV-type a 1P-methyl substitution which provides relative stability ESBLs. to DHP-I [6]. Almost 70% of a dose of meropenem is There are isolated reports of serine P-lactamases recovered intact in the urine within 12 h of admini- produced by Enterobacteriaceae which are capable of stration, and co-administration of a DHP-I inhibitor is hydrolyzing carbapenems [11,12], but these not required [7,8]. are rare and not easily transferable [13]. Interestingly, one report has described strains of carbapenemase- STRUCTURE-ACTIVITY RELATIONSHIPS producing Sevratia which were resistant to imipenem (MIC 16 mg/L) but susceptible to meropenem (MIC The five-membered thiazolidine ring of the carba- 0.12 mg/L) [12]. The carbapenems are susceptible to differs from that of in having a hydrolysis by zinc-dependent P-lactamases produced carbon atom (instead of a sulfur atom) at position 1 and by Stenotrophomonas maltophilia and some strains of an unsaturated bond between the carbon atoms at Aeromonas [14]. Reports from Japan have described positions 2 and 3 (Figure 1). In addition, the carba- a plasmid-borne zinc-dependent carbapenemase in penems have a hydroxyethyl side-chain on the p-lactam Pseudomonas aeruginosu [15,16]. ring, whereas penicillins and cephalosporins have an acylamino substituent in this position. The relatively -binding protein affinity small hydroxyethyl side-chain in the carbapenem Carbapenems, like other P-lactams, kill bacteria by molecule, in combination with the zwitterionic charge binding to penicillin-binding proteins (PBPs) on the state, allows both imipenem and meropenem to pass cytoplasmic membrane, thereby inhibiting peptido- freely through the porin channels in the outer mem- glycan () biosynthesis. Several types of PBPs branes of Gram-negative bacteria [9,10]. have been identified and the affinity shown by the carbapenems for each has been studied in certain P-Lactamase stability bacteria (Table 1). Overall, the carbapenems have hlgh In many species of Gram-negative bacteria, antibiotics affinities for the essential PBPs and one would expect which have reached the periplasm face attack by these targets to be saturated using the recommended P-lactamases. Importantly, the hydrogen atoms at dosage schedules. positions 5 and 6 in the P-lactam ring of carbapenems, Imipenem and meropenem bind to all four PBPs unlike those in other p-lactams, are arranged in a trans identified in , although meropenem configuration (i.e. on opposite sides of the ring). The has a relatively low affinity for PBP3 [17]. In , both meropenem and imipenem bind with highest affinity to PBP2 and PBP4 [10,18]. Analysis of the 1 34 morphologic changes induced by these agents indicates that PBP2 is the primary target in this organism [19]. The two carbapenems differ in their PBP-binding profiles in l? aeruginosa. Imipenem binds with high affinity to PBP2, PBPS and PBP4, with PBP2 being the primary target [19]. Meropenem has a higher affinity than imipenem for PBP2 and PBPS but the latter is the primary target for this agent [18].

Antibacterial spectra The carbapenems possess the broadest antibacterial Figure 1 Chemical structure of meropenem. 1, Hydroxy- spectra of any class of antibiotics. They are active against ethyl moiety in trans configuration confers stabhty to almost all clinically important Gram-positive and serine p-lactamases. 2, p-lactam ring provides high af5nity Gram-negative aerobic and anaerobic pathogens, with for penicillin-binding proteins. 3, Carbapenem nucleus the exceptions of -resistant staphylococci, associated with ultra-broad antibacterial spectrum. 4, C1 Enterococrusfaecium and Stenotrophomonar maltophilia [20]. methyl group improves stability to renal dehydropeptidase-I. 5, C2 moiety enhances activity against Gram-negative Imipenem is more active than meropenem against pathogens, including , and may also some Gram-positive cocci (mainly staphylococci), account for the good central nervous system tolerability of while meropenem is the more active agent against meropenem. Enterobacteriaceae, l? aeruginosa and certain other Drusano: Meropenem: laboratory and clinical data 4s53

Table 1 Penicillin-binding protein (PBP) profiles of meropenem and imipenem

Isod for PBPs

Organism Drug 1 2 3 4 - - MIC (mdL)

Staphylococcus aureusa Meropenem 0.064 0.45 >I00 0.053 - - 0.05 Imipenem 0.033 0.17 0.12 0.0092 - - 0.013 la lb 2 3 4 5 6 Escherirhia coli" Meropenem 0.82 0.58 0.011 0.72 0.04 2.4 22 0.015 Imipenem 0.18 0.81 0.031 17.3 0.02 0.9 4.3 0.06 Pseudomonas Meropenem' 0.14 0.06 0.025 0.01 0.2 >11 - 0.5 aeruginosa Imipenem' 0.08 0.22 0.06 0.06 0.08 0.12 - 2 Meropenem' 0.27 0.24 0.03 0.031 0.010 15 - 0.05 Imipenem' 0.15 0.46 0.11 0.28 0.011 1.8 - 0.78

'Data from Sumita et al [17]; 'Data from Kitzis et al [18]; 'Data from Sumita et al [19]; dConcentration of competitor (mg/L) giving 50% inhibition of binding of radiolabeled benzylpenicdhn.

Gram-negative pathogens. This enhanced activity for 35-55% of the dosing interval for a bacteriostatic against Gram-negative bacteria is due to the dimethyl- effect to occur [24]. Pharmacokinetic and in vitro carbonylpyrrolidinethio side-chain in the C2 position bacterial susceptibility data indicate that the mero- in the meropenem molecule [21]. plasma concentration following a dosage of 1 g As already stated, the potent activity of the carba- 8-hourly exceeds the MICs of virtually all clinically penems is coupled with exceptional stability to serine important pathogens for over 40% of the dosage interval p-lactamases. Table 2 demonstrates that MICs of the which provides maximal bactericidal activity. carbapenems, unlike those of comparators, are not significantly increased in Gram-negative bacteria with CLINICAL EXPERIENCE WITH MEROPENEM derepressed production of class C p-lactamases com- pared with parent strains. MICs of third-generation Meropenem has been evaluated in an extensive clinical cephalosporins,in particular ceftazidime, against Entero- trial program in patients with a variety of infections bacteriaceae are raised considerably in the presence of [25,26], includmg lower respiratory tract infections mutant plasmid-mediated ESBLs such as the TEM- (LRTIs) [27,28], intra-abdominal [29-341, skidskin derived enzymes (Table 2) [20]. The fourth-generation structure [35], urinary tract [36], and obstetric/ cephalosporins and show only a gynecologic infections [37], septicemia 1381, meningitis modest (2-4-fold) improvement over cefotaxime and [39,40] and neutropenia 1411. Studies have also been in this regard. Moreover, the MICs of performed specifically in pediatric patients [42]. Data these fourth-generation agents may be elevated further obtained with the drug in the treatment of three against large inocula or strains in which (3-lactamase important types of infection, namely nosocomial production is increased by promoter sequences. In LRTIs, intra-abdominal infection and meningitis, are contrast, the carbapenems remain highly active against reviewed here. strains which produce ESBLs, with meropenem being the more potent agent. Nosocomial LRTI The antibacterial activity of meropenem, like that Nosocomial pneumonia is the second most common of all (3-lactams, is dependent on the time for which its nosocomial infection [43]. The mortality rate associ- concentration exceeds the MIC of the target pathogen, ated with nosocomial pneumonia, higher than those rather than on the peak concentration it achieves or from other nosocomial infections, is approximately the area under the plasma concentration-time curve 30% [44] but may be even higher in patients who (AUC)/MIC [22]. Studies in animals have indicated are bacteremic, artificially ventilated or infected with that meropenem inhibits the growth of Gram-negative l? aeruginosa or Acinetobacter spp. 143,451. bacteria when its concentration exceeds the MIC for Traditionally, combinations of antibiotics have been only 20-30% of the dosing interval [23]. In contrast, used to achieve the broad spectrum of activity necessary against these organisms the concentration of third- in the empirical treatment of nosocomial LRTI. generation cephalosporins must remain above the MIC However, the ultra-broad spectrum of the carbapenems 4s54 Clinical Microbiology and Infection, Volume 3 Supplement 4

permits the use of these agents as monotherapy and, indeed, meropenem has proved to be as efficacious as combination therapy in this setting (Figure 2). In one study, meropenem (1 g three times daily) was as effective as ceftazidime (2 g three times daily) plus amikacin (15 mg/kg per day) in the treatment of a variety of serious nosocomial infections, including LRTIs [25]. In patients with serious hospital-acquired LRTIs, the clinical success rate at the end of treatment with meropenem was 30 of 37 (81%), compared with 23 of 32 (72%) with ceftazidime/amikacin. The bacteriologic success rates were similar with the two regimens (71% versus 76%). In another study in a total of 121 evaluable patients with hospital-acquired LRTIs, meropenem (1 g 8-hourly) produced significantly higher rates of clinical success (89% versus 72%, p=O.04) and bacteriologic success (89% versus 67%, p=0.006) than ceftazidime (2 g 8-hourly) plus tobra- mycin (1 mg/kg 8-hourly) [28]. A recent study compared meropenem and imi- penem/cilastatin (both 1 g 8-hourly) as empiric monotherapy in the treatment of critically ill patients (mean APACHE I1 scores 14.9 versus 14.4) with serious bacterial infections [26]. Eighty of 204 (39%) patients in this study had nosocomial LRTIs. At the end of treatment, meropenem and imipenem/cilastatin achieved similar rates of satisfactory clinical (75% versus 75%) and bacteriologic (48% versus 52%) response in these patients.

Intra-abdominal infection regimens suitable for the treatment of intra- abdominal infections must be active against Entero- bacteriaceae and anaerobes (particularly Burteroides fvagilis) [46]. A variety of combination regimens have been employed for this purpose, but since the carba- penems are active against both aerobic and anaerobic pathogens, these agents offer the opportunity for empiric monotherapy. Prospective randomized comparative studies have shown meropenem (1 g 8-hourly) to be as efficacious in the treatment of serious intra-abdominal infections as cefotaxime (2 g 8-hourly) plus metronidazole (500 mg 8-hourly) [29] or clindamycin (0.9 g 8-hourly) plus tobramycin (5 mg/kg per day) [30] (Figure 3). In these studies, the rates of clinical success and bacteriologic eradication with meropenem were 91-92% and 90-93%, respectively. Two trials compared meropenem and imipenem/ cilastatin, using both agents at a dosage of 1 g 8-hourly, in the management of serious intra-abdominal infect- ions [32,33]. The two drugs produced similar rates of clinical (96-100% versus 94-97%) and bacteriologic (84-90% versus 81-100%) success at the end of Drusano: Meropenem: laboratory and clinical data 4s55 treatment. Another study, performed mainly in patients against common pathogens responsible for meningitis with appendicitis, compared meropenem and imi- in adults and children, including Styelltococcuspneumoniae, penem/cilastatin at a lower dosage (0.5 g 8-hourly) Haemophilus influenzae and Neisseria meningitidis [48]. [34]. Again, the drugs demonstrated similar clinical and Importantly, meropenem is active in vitro against bacteriologic success rates in excess of 95%. penicillin- and -resistant Streptococcus pneu- An aforementioned study comparing meropenem moniae [48]. Resistance to p-lactams in this organism is and imipenem/cilastatin (both 1 g 8-hourly) in critically caused by alteration of PBP structure, rather than by ill patients with a variety of infections, reported that the 6-lactamase production [49]. During the last 20 years, two antibiotics produced similar rates of satisfactory resistant strains have spread throughout the world; at clinical response in patients with intra-abdominal in- present, countries in which the incidence is particularly fections (82% versus 81%, respectively) [31]. In those high (>20%) include Spain [SO], Hungary [Sl], South patients with polymicrobial intra-abdominal infections, Africa [52] and certain areas of the USA [53,54]. the satisfactory clinical success rate with meropenem In recent years cefotaxime and ceftriaxone have was 80%, compared to 70% with imipenem/cilastatin. been regarded as first-line options in the empiric Overall, both drugs achieved similar bacteriologic treatment of pneumococcal meningitis, including that response rates of 68-70%. caused by relatively penicillin-resistant strains. How- ever, strains of pneumococci with resistance to these Meningitis agents have been observed and treatment failures follow- Meropenem penetrates into the cerebrospinal fluid in ing their use as empiric therapy have been reported patients with meningitis [47]. The drug is highly active [55-571.

0Bacteriologic success rate W Clinical success rate

n=37 Meropenem

amikacin I I n=17

* n=63 Meropenem **n=63

VUILL.LI"IIII" T to b ramyci n n=58

I I I I I I I I I I 0 10 20 30 40 50 60 70 80 90 Patients (YO)

Figure 2 Comparative efficacy of meropenem and combination regimens in two separate studies in patients with nosocomial lower respiratory tract infections. Dosages: amikacin 15 mg/kg once daily; meropenem 1 g %hourly; ceftazihme 2 g %hourly; tobramycin 1 mg/kg %hourly. n=number of patients evaulated. *p=0.04 versus cefiazidime + tobramycin; **p=0.006 versus ceftazidime + tobramycin. 4856 Clinical Microbiology and Infection, Volume 3 Supplement 4

Bacteriologic success rate Clinical success rate

MEM (n=88) I CLI/TOB (n=89) I

MEM (n-70) ; CWMTR (n-78) ' I

MEM (n=99) I IPMK (n=90)

MEM (n=82) I

IPMK (n=88) I

MEM (n=28)

IPWC (n=31)

IIIIIIIIIII 0 10 20 30 40 50 60 70 80 90 100 Patients (%)

Figure 3 Eficacy of meropenem and comparators in patients with intra-abdominal infections. CTX, cefotaxime; CLI, clindamycin; IPM/C; imipenem/chstatin; MEM, meropenem; MTR, metronidazole; TOB, tobramycin; n = number of patients evaluated.

Although imipenem/cilastatin has a similar spec- daily up to a maximum of 12 g/day) or cefiriaxone (100 trum of activity, it is not indicated for the treatment mg/kg initial dose, followed by a single dady dose of of meningitis because it has been associated with a 80 mg/kg up to a maximum of 4g/day) [39,40]. relatively high risk of seizures in this patient group. Dexamethasone was administered concurrently to 91% Overall, the incidence of drug-related seizures with of patients in these studies. Meropenem produced imipenem/cilastatin has been reported to be 0.9% [58]. clinical cure and bacteriologic eradication in 100% of However, the risk of seizures is increased in patients evaluable adult and pediatric patients. Importantly, with certain risk factors, such as pre-existing central there were no significant differences between mero- nervous system disorders and renal impairment. A study penem and comparator antibiotics with respect to with imipenem/cilastatin in chldren with meningitis central nervous system tolerability. Indeed, there have was terminated when seizures were reported in 7 of been no seizures attributed to drug therapy in trials 21 (33%) patients [59]. In contrast, meropenem has performed to date with meropenem in pediatric demonstrated a relatively low propensity to induce patients with meningitis [64]. seizures in animal models 160-631 and clinical studies in children and adults [64]. CONCLUSION In comparative clinical studies involving a total of 246 patients with meningitis, meropenem (up to The carbapenems possess several advantageous pro- 6g/day in adults and 120 mg/kg daily in children) perties, including rapid penetration of Gram-negative proved as efficacious as cefotaxime (225-300 mg/kg bacterial cells, high PBP affinities, unrivaled anti- Drusano: Meropenem: laboratory and clinical data 4S57

bacterial spectra and exceptional (3-lactamase stability. 12 Yang Y, Puijun W, Livermore D. Biochemical character- These properties would seem to be increasingly im- isations of a 0-lactamase which hydrolyses penems and portant as the development of resistance, particularly carbapenems &omtwo Serratia marcescens isolates. Antimicrob that mediated by 6-lactamases, has compromized the Agents Chemother 1990; 34: 755-8. usefulness of many other (3-lactams. Meropenem, a 13 Livingstone D, Gdl MJ, Wise R. Mechanisms uf resistance new carbapenem, has proved as eficacious as combina- to the carbapenems. J Antimicrob Chemother 1995; 35: 1-5. tion regimens and other monotherapy options in the 14 Iaconis JF’,Sanders CC. Purification and characterization of as treatment of serious infections such nosocomial inducible 0-lactamases in Aeromonas spp. Antinlicrob Agents LRTIs and intra-abdominal infections. 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