Chemical and Microbiologic Aspects of Penems, a Distinct Class of β-Lactams: Focus on Faropenem

Jeremy M. T. Hamilton-Miller, D.Sc., FRCPath

Disclosures

Pharmacotherapy. 2003;23(11) 

In This Article

In Vitro Studies

Many penems have been developed and studied for their in vitro activity, β-lactamase stability, and activity against resistant strains. Reducing agents break down penem molecules. Therefore, to obtain meaningful results, it is important, for example, to avoid culture media supplemented with Vitox or Isovitalex, which contain cysteine, commonly used to grow gonococci.[15]

Agents tested include the alkylpenems MEN 10700, ritipenem, and CGP 31608; a thiopenem, sulopenem; and an arylpenem, faropenem daloxate. Compared with other β-lactams, penems generally exhibit good in vitro activity against most gram-positive and gram-negative bacteria, with the exception that most penems are not active against Pseudomonas aeruginosa[3] (which is thought to actively eject penem molecules from cells by means of an efflux pump[16]), methicillin-resistant Staphylococcus aureus,[17] and some enterococci.[18]Table 1[19] shows a comparison of the activity of the penem faropenem with that of representatives of other β-lactam classes against common pathogens. Significantly, penems appear to have lower minimum inhibitory concentrations (MICs) than those of most third-generation cephalosporins, for example cefotaxime and ceftriaxone.[3]

In 17 genera tested, MEN 10700 was found to have lower MICs than those of amoxicillin plus clavulanate in all but three: Proteus sp, the enterococci, and clostridia.[20] Although MEN 10700 had a similar MIC to that of meropenem against Enterococcus sp (MIC for 90% of tested strains [MIC90] = 8 mg/L), higher MIC90 values were recorded with imipenem (32 mg/L), cefotaxime (64 mg/L), and ceftriaxone (64 mg/L), and the lowest MIC90 values were recorded with ciprofloxacin (2 mg/L).[13] Another study showed that MEN 10700 had similar MICs to those of meropenem and imipenem in most gram-positive and gram-negative clinical isolates tested, with the exceptions of Morganella morganii, Serratia marcescens, and Acinetobacter sp, where MICs were lower for the carbapenems.[21] The greatest bactericidal effects of MEN 10700 were seen 4-6 hours after incubation with bacterial cultures, at which time a 2-3 and 3-4 log decline in colony-forming units was observed at 2 and 4-8 times the MIC of MEN 10700, respectively.[14] This rapid and potent bactericidal effect might be accounted for by the high affinity of MEN 10700 for PBP2 and PBP1a/b (concentration for 50% inhibition of penicillin binding [IC50] = 0.1 and 1 mg/L, respectively) as revealed by competition experiments using membranes isolated from Escherichia coli.[14]

The penem MEN 10700 also was investigated in bacterial isolates resistant to other antibiotics and showed activity against cefotaxime-resistant gram-negative strains (MIC90 = 4 mg/L),[13] penicillin-resistant pneumococci (MIC90 = 1 mg/L),[13] ciprofloxacin-resistant E. coli (MIC90 = 0.25 mg/L),[21] and extended-spectrum β-lactamase-producing strains of Klebsiella, Enterobacter, and Serratia sp (MIC90 = 2 mg/L).[21] Time-kill kinetics of MEN 10700 against 12 penicillin-susceptible and penicillin-resistant pneumococci were similar to those of amoxicillin plus clavulanate relative to MIC values, with all 12 isolates killed after 24 hours incubation at 4 times MIC for both agents.[22]

One group of authors[14] investigated MEN 10700's stability to β-lactamases, its capacity to induce expression of these enzymes, and its rate of passage through the outer membrane of gram-negative bacteria.[14] MEN 10700 was highly stable to the common plasmid-mediated β-lactamases OXA-1, OXA-2, TEM-1, TEM-2, SHV-1, and CEP-1, but was 3 times less stable than imipenem to CphA carbapenemase. Despite a lower penetration rate than that of imipenem across the outer membrane of E. coli, the rate was sufficiently high for MEN 10700 to have activity against CphA carbapenemase-producing strains. The induction of class I β-lactamase by MEN 10700 was similar to that of cefotaxime but lower than that of imipenem and ritipenem.[14]

Although MEN 10700 had demonstrably lower MICs than those of meropenem, imipenem, cefotaxime, ceftriaxone, and ciprofloxacin against methicillin-sensitive S. aureus and Staphylococcus epidermidis (MIC90 values 0.06 and 0.5 mg/L, respectively), it was not found to be active against methicillin-resistant strains.[13,20]

Ritipenem (FCE 22101, FCE 22891) has MIC90 values of 4 mg/L or less against a range of organisms, including Enterobacteriaceae, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus ducreyi, Neisseria gonorrhoeae, Branhamella catarrhalis, S. aureus, S. epidermidis, and group B streptococci.[23] Ritipenem reportedly has higher MICs in vitro than those of MEN 10700 for a number of species, in particular staphylococci, streptococci, E. coli, Klebsiella pneumoniae, Enterobacter sp, and Citrobacter sp.[14,20] Like that of MEN 10700, the greatest bactericidal effect observed with ritipenem occurred 4-6 hours after incubation with bacterial cultures.[14]

Ritipenem also was tested against drug-resistant isolates and showed potent in vitro activity against Enterobacter sp resistant to cefotaxime and ceftazidime,[24] and β-lactamase-producing ampicillin-resistant H. influenzae.[25]

One study of H. influenzae that examined the link between bacteriolytic activity and PBP affinities for ritipenem, cefotaxime, cefsulodin, faropenem, and cefdinir found that ritipenem bound with highest affinity to PBP1b (IC50 = 0.04 times MIC) and with lower affinity to PBP2 and PBP1a.[26] Like faropenem and cefsulodin, ritipenem had low affinity for PBP3a and PBP3b (IC50 = 4.6 and 1.2 times MIC, respectively), but ritipenem induced more cell lysis than did faropenem. By comparison, cefdinir had moderately high affinities for PBP3a and PBP3b (IC50 = 0.9 and 0.2 times MIC, respectively) despite its low lytic potency. Coincubation of the selective PBP3 inhibitor aztreonam with ritipenem caused the cells to become spindle-shaped and enabled them to evade lysis.[26] A similar phenomenon occurred when a culture was treated with ritipenem and cefotaxime. It was concluded therefore that, for H. influenzae, inactivation of PBP3a and PBP3b might interfere with the bacterial lysis caused by PBP1b inactivation. One group of authors[26] suggest that H. influenzae may be treated more effectively with agents such as ritipenem that have selectivity for PBP1b over PBP3a and PBP3b, since this will result in more rapid bacteriolysis.[26]

The activity of CGP 31608 was tested against 480 clinical isolates.[27] This penem had similar MICs for isolates from the genera Enterobacter, Haemophilus, Corynebacterium, and Bacteroides sp (MIC90 = 2-8 mg/L). Unusual for a penem, it also demonstrated activity against P. aeruginosa (MIC90 = 4 mg/L). Time-kill tests performed by using log- and stationary-phase broth cultures of S. aureus and E. coli showed that CGP 31608 was more rapidly bactericidal than was cefotaxime, but not as fast as ciprofloxacin. By contrast, CGP 31608 had 2-8-fold higher MICs against 993 aerobic gram-positive and gram-negative strains compared with those of ritipenem.[28]

CGP 31608 showed moderate activity against both methicillin-sensitive and methicillin-resistant S. aureus (MIC90 for both = 0.25 mg/L).[27]

The thiopenem sulopenem (CP 65207) showed good activity against both gram-positive and gram-negative bacteria with the exception of P. aeruginosa.[29] The MIC90 values were 1 µg/ml or less for most of the 1101 clinical pathogens tested. Sulopenem had MICs 10-100-fold lower than those of cefoxitin, cefotaxime, ceftazidime, and ceftriaxone against gram-positive bacteria and anaerobes. However, sulopenem had higher MICs than those of imipenem against staphylococci, group A streptococci, and Enterococcus faecalis, although it had 2-fold lower MICs than those of imipenem against members of the Enterobacteriaceae. Interestingly, sulopenem was more bactericidal than imipenem, ceftazidime, and cefotiam against S. aureus, E. coli, Enterobacter cloacae, and Citrobacter freundii,[30] and for some strains, efficacy was seen at concentrations much lower than those required to achieve a similar level of kill with broad-spectrum cephalosporins.[29] This may be a consequence of sulopenem's high affinity for PBP2, 1a, 1b, and 3, as detected by using cell-free preparations of E. coli W-7.[29]

Microbial resistance was investigated by a group of authors[29] who observed that sulopenem was only slightly susceptible to hydrolysis by type 1 cephalosporinases and TEM-1, SHV-1, and PSE-2 plasmid-encoded β-lactamases.[29] In another study, sulopenem was found to have lower MICs than those of imipenem, ceftazidime, and cefotiam against a range of β-lactamase- producing gram-positive and gram-negative strains (with the exception of P. aeruginosa and Stenotrophomonas maltophilia).[30] However, unlike MEN 10700 and CGP 31608, sulopenem was not active against penicillin-resistant staphylococci.[29]

BRL 42715 (no longer in clinical development) is a penem molecule with no antibacterial effects, but it is a potent β-lactamase inhibitor. This compound acts as a class C β-lactamase inhibitor and has shown activity against cephalosporinases, oxyiminocephalosporinases, and types I, II, III, and IV penicillinases.[31] BRL 42715 has shown 104- to 106-fold greater inhibitory activity against cephalosporinases compared with that of clavulanic acid.[31]

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