Novel Macrolides To Overcome Bacterial Resistance

Macrolide derivatives having activity against erythromycin resistant S. pyogenes were first reported in 1989 (79). Several 11,12 carbamate clarithromycin analogs and several 11,12-carbonate erythromycin analogs with additional modifications at the 4" position of the cladinose were found to be active against both inducible and constitutive-resistant S. pyogenes . Based on this initial discovery, recent chemical modifications of erythromycin have generated several new classes of macrolide derivatives having potent activity against erythromycin resistant bacteria.

Ketolides - Ketolides are the 3-descladinosyl-3-oxo-11,12-cyclic carbamate analogs of erythromycin or clarithromycin. They were found to be active against penicillin-resistant and erythromycin-resistant S. pneumoniae. These derivatives do not induce MLSb resistance in staphylococci and streptococci (80). Three ketolides undergoing clinical development reported so far are the HMR 3004, HMR 3647 and ABT-773. All three compounds were found to be highly active against respiratory pathogens including erythromycin-resistant strains (81, 82).

Oerskovia Species

The ketolide HMR 3004 was found to be very active when tested against penicillin- and erythromycin-resistant pneumococci (MICgo = 0.25 pg/ml) (83,84). Tested against 379 anaerobes, it had a MICso of 1.0 pg/ml (85). Tested against 500 Gram-positive organisms, including multiply resistant enterococci, streptococci and staphylococci, HMR 3004 had a 100% susceptibility at a concentration of s 1 pg/ml (81,86). It was found to be strongly and rapidly accumulated by polymorphonuclear leukocytes (87) and very active against respiratory infections in animal study (88). This compound was active against beta-lactamase-producing H. influenzae in a murine model of experimental pneumonia and was found to be more active than azithromycin, ciprofloxacin, clarithromycin, erythromycin and pristinamycin (89).

A closely related ketolide, HMR 3647 (telithromycin), was prepared and is undergoing extensive clinical development (90). A new drug application (NDA) to the U.S. Food and Drug Administration (FDA) for telithromycin was filed on March 6, 2000. IHMR 3647 was found to be as active as HMR 3004 against anaerobes (91). When tested against 419 human anaerobic isolates, its MIC90 values (in pg/ml) against Peptostreptococcus species, Bacteroides fragilis, Clostridium perfringens, C. difficile, Prevotella bivia, P. orisbuccae, Bilophila wadsworhtia, Veillonella species and

Fusobacterium ulcerans were < 0.06, 2, 0.06, 1, 0.5, 1, 2, 4 and >16, respectively (92). The activity of telithromycin against anaerobic bacteria, compared to those of eight antibacterial agents by time-kill methodology was examined. HMR 3647 had the lowest MICs, especially against non-S. fragilis group with MIC < 2 pg/ml (93). The MICgo values for telithromycin against penicillin- and erythromycin-susceptible pneu-mococci was 0.03 pg/ml and against penicillin- and erythromycin-resistant pnemococci was 0.25 pg/ml (94). A recent study gave the MICgo value of 0.5 pg/ml for S. pneumoniae (81).

HMR 3647 was active (MICgo values ranged from <0.015-2 pg/ml) against most of aerobic and facultative non-spore-forming Gram-positive bacilli tested with the exception of Corynebacterium striatum, corynefonv CDC group 12 and Oerskovia species (95). Another study, however, reported high activity for HMR 3647 against Corynebacterium species except C. jeikeium and C. urealyticum with MICgo values ranging from 0.06-0.25 pg/ml (96). It was generally more active than other marketed macrolide antibiotics against almost all the aerobic and fastidious facultative isolates with MICgo value of 1 pg/ml (97). Against H. influenzae, it is as active as azithromycin having MICgo value of 4 pg/ml (98). When tested against Moraxella catarrhalis, Neisseria meningitidis and N. gonorrhoeae, HMR 3647 has MICgo values of 0.12, 0.12 and 0.25 pg/ml, respectively (99). It was found to have high activity against Chlamydia pneumoniae, Mycoplasma pneumoniae, E. faecalis, Bordetella pertussis. Toxoplasma gondii, Lactobacillus, Leuconostoc, and Pediococcus species as well as rapidly growing mycobacteria (100-106).

In a murine model of experimental pneumonia, HMR 3647 was effective against P-lactamase-producing H. influenzae (89). It was found to be effective for the treatment of Legionella pneumophia in a guinea pigs pneumonia experimental model (107). The interaction between tetithromycin and human polymorphonuclear neutrophils (PMNs) was studied (108). HMR 3647 is trapped in PMNs, where it is concentrated up to 300 times. It is poorly released by these cells with 80% of the compound still remain in cell after 2 hours in fresh medium. In PMNs and NB4 cells, more than 75% and 63%, respectively, of the molecules were found to accumulate in the azurophil granule fraction (109). The pharmacodynamic properties of HMR 3647 demonstrated by time-kill kinetics and postantibiotic effects on enterococci and B. fragilis were found to be similar to those obtained with macrolides (110). Additional studies such as in vitro activities against various organisms, pharmacodynamic properties, post-antibiotic effect and bactericidal activity, in vitro selection of resistance, resistance phenotype and uptake by myelomonocytic cell lines of HMR 3647 were presented in the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) (111).

Two 2-fluoro ketolides, HMR 3562 and HMR 3787 were found to have potent in vitro antibacterial activity against inducibly resistant S. aureus and S. pneumoniae as well as constitutively resistant S. pneumoniae. They possess better activity against H. influenzae compared to their corresponding non-2-fluorinated parent (112). Both HMR 3562 and HMR 3787 display high therapeutic efficacy in mice infected by different

o F HMR 3787

o F HMR 3787

common respiratory pathogens, such as multidrug resistant pneumococci and H. influenzae (113).

A novel series of 6-O-substituted ketolides was prepared and reported to possess excellent activity against inducibly resistant S. aureus and S. pneumoniae as well as constitutively resistant S. pneumoniae (114). Analogs with aryl group at the 6-O-position with the propenyl spacer in combination with a 11,12-cyclic carbamate and a 3-keto group exhibited the best activity. In this study, the unsubstituted 11,12-carbamate analogs are more active than both the carbazate or tricyclic analogs (ABT-773 vs. A-201316 vs. A-197579). The MIC90 value in pg/ml for ABT-773 against penicillin-susceptible and -resistant S. pneumoniae was < 0.06 and 0.03, respectively (115). Against 1529 isolates of H. influenzae, ABT-773 has a MIC90 of 4 pg/ml identical to the azithromycin value. ABT-773 is very active when tested against M. catarrtialis having a MIC90 value of 0.06 pg/ml. The activity of ABT-773 was compared to the activity of HMR 3647 against over 500 Gram-positive clinical isolates including 298 S. pneumoniae, 97 S. aureus and 120 S. pyogenes. Macrolide resistant isolates with ribosomal methylase ErmAM (erm) or macrolide efflux (mef) were tested. ABT-773 had superior activity against macrolide resistant S. pneumoniae: MIC90 value in pg/ml; erm 0.015 vs. 0.12 for HMR 3647, mef 0.12 vs. 1 pg/ml for HMR 3647. ABT-773 also had superior activity against macrolide resistant S. pyogenes: MIC90 value in pg/ml: erm 0.5 vs. > 8 for HMR 3647, mef 0.12 vs. 1 pg/ml for HMR 3647 (116). The high activity of ABT-773 against S. pneumoniae is probably due to several factors. ABT-773 rapidly accumulates in both macrolide sensitive and resistant S. pneumoniae

  • 117). The accumulation to MLS phenotype of S. pneumoniae suggests that ABT-733 possesses some affinity to methylated ribosome. The inactivation of a macrolide efflux pump (mef) had no effect on ABT-773 accumulation rate. It binds to unmethylated ribosome 10-100 fold tighter than erythromycin and does not induce erm
  • 118). ABT-773 is active against H. pylori (MIC9o=0.25 pg/ml) and L. pneumophila (MIC=0.015 pg/ml) (119). It has significant activity against T. gondii both in vitro and in two murine models of acute toxoplasmosis (120). ABT-773 has favorable pharmacokinetic properties. Plasma elimination half-lives averaged 1.6, 4.5, 3.0 and 5.9 hours after IV dosing in mouse, rat, monkey and dog, respectively. Peak plasma concentrations averaged 1.47, 0.52, 0.56 and 0.84 pg/ml with bioavailability of 49.5, 60.0, 35.8 and 44.1% after oral dosing in the same species. Lung concentration of ABT-773 was >25-fold higher than plasma concentration after oral dosing in rat (121). In an experimental rat lung infections caused by S. pneumoniae, ABT-773 was found to be 5-fold more efficacious than azithromycin against mefE -bearing strain and has excellent efficacy against ermAM-bearing strain while azithromycin was inactive (122). ABT-773 and HMR 3647 were found to be equivalent in efficacy against macrolide susceptible S. aureus and S. pneumoniae in mouse protection tests and rat pulmonary infections. ABT-773 showed 3 to 16-fold improved efficacy over HMR 3647 against constitutive macrolide resistant S. pneumoniae (ermAM) in rat pulmonary infection. It also showed improved efficacy over HMR 3647 in rat lung infections caused by S. pneumoniae (mefE) and H. influenzae (123).

Anhvdrolides and Acvlides - A series of anhydrolides (the 2,3-anhydroerythromycin analogs, exemplified by A-179461) in which a carbon-carbon double bond was common respiratory pathogens, such as multidrug resistant pneumococci and H. influenzae (113).

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