Driven by the need for oral activity, some cephalosporins have been developed as prodrugs to reduce polarity and increase membrane permeability. Cefotiam 2, a mainstay product in Japan, employs a cyclohexylcarbonate group to prodrug the cephem carboxyl (31). More recent third-generation cephalosporins, such as cefditoren pivoxil 3 and ceftizoxime alapivoxil 4, use a lipophilic pivaloyloxymethyl ester. The prodrug, while stable in the gastrointestinal lumen, is rapidly hydrolyzed by intestinal esterases once absorbed to release the active drug. The activity and clinical utility of cefditoren pivoxil has been reviewed (32). Cefditoren has activity against most common CARTI bacteria, but is not active against atypical pathogens, including C. pneumoniae, M. pneumoniae, and Legionella spp. Cefditoren penetrates rapidly into bronchopulmonary and tonsillar tissue leading to clinical cure rates in AECB (dosed at 200 or 400mg bid for 10 days) of 88 to 89% within 48 hours of treatment completion (33). The antibacterial activity of cefditoren was compared to six other cephalosporins against 250 pneumococci, including strains resistant to macrolides and quinolones, giving the lowest MIC90S for penicillin-resistant pneumococci and excellent MBCs. MICs were also exceptional for p-lactamase producing H. influenzae (<0.016 mg/L), and overall showed low resistance frequencies (34).

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Derived from a parenteral use cephalosporin, ceftizoxime alapivoxil (CFX-AP, AS-924) has an alanine appended to the weakly basic amino group of the cephem thiazole. This bifunctional prodrug strategy balances the solubility and lipophilicity of the molecule for improved physical properties and oral bioavailability. The physicochemical properties and oral absorption of ceftizoxime alapivoxil have been reported along with its antibacterial activity (35). Ceftizoxime alapivoxil has a similar spectrum of activity to other common cephems, but has particularly good MICs against Enterobacteriaceae and H. influenzae. Oral dosing gave potent protection in mouse models of Gram-positive and -negative infections (36).

Carbapenems and Trinems - Since the discovery of thienamycin in 1976, only three carbapenems have become widely used for serious infections in the hospital and ICU settings, namely imipenem, meropenem and panipenem. In contrast to cephalosporins, carbapenems have shown a broad spectrum of activity especially against resistant hospital-acquired infections caused by MRSA, VRE, PRSP Pseudomonas spp. They can overcome a wide variety of p-lactamases and demonstrate excellent in vivo activity. However, the lack of oral bioavailability in the broad spectrum carbapenems and trinems, their short half-life, potential for convulsive activity and high cost of manufacturing have directed research in this class toward the severe hospital infection market (37-39). Carbapenems have also been associated with nephrotoxicity. For example, imipenem is coadministered with cilastatin, an inhibitor of renal dehydropeptidase enzymes (DHP-1), and panipenem is give with betamipron which may block active transport of drugs into the renal cortex (38,40). Launched in 2002, one of the newest parenteral carbapenems, ertapenem 5 (formerly MK-826), has shown excellent efficacy against CAP (1g qd, iv or im) even in patients with comorbidities (41). Ertapenem seems to have evaded many of the toxicities and liabilities observed historically in carbapenems and has thus far been well tolerated in clinical trials (42). Ertapenem is stable to DHP-1 and

Motivated by the spread of p-lactam resistance, research is yielding a new generation of oral carbapenems to address these challenges (44). CS-834 6, an oral carbapenem antibiotic, is in phase II trials in Japan and Europe for RTI (45). CS-834 is the active prodrug of R-95867 which is stable to extended spectrum p-lactamases and active against most RTI pathogens except Enterococcus spp. and Pseudomonas spp. (39). In mouse models of PRSP infections, CS-834 has shown good efficacy with tid dosing (46). Tebipenem 7 (L-084, ebipenem pivoxil) is an oral 1-p-methylcarbapenem prodrug of LJC-11036 in phase II trials for RTI in Japan (47). Tebipenem displayed a promising safety profile in healthy adults with a half-life of 30 min (48). While tebipenem showed no useful activity against Enterococcus spp. and Pseudomonas spp. (39), it was effective in vitro and in vivo against most common CARTI bacteria with good distribution to the lungs (49). From an active series of THF carbapenems, CL-191121 was orally available as the prodrug OCA-983, stable to DHP-1 and efficacious In mice, but was dropped from development (50).

Macrolides and Ketolides - Primarily prescribed for treatment of CARTIs, erythromycin and second-generation semisynthetic derivatives, such as clarithromycin and azithromycin, together account for >$3B in sales worldwide (2001) and have been comprehensively reviewed (51,52).

Macrolides exert their antibiotic activity by inhibiting protein translation by binding to the 23S rRNA of the 50S ribosomal subunit. Structural studies suggest this binding disrupts peptide elongation, leading to chain termination (53). Macrolides are generally bacteriostatic agents with broad-spectrum activity. They are effective against the principal pathogens involved in CAP, including S. aureas. as well as atypical bacteria, an advantage over p-lactams that macrolides share with fluoroquinolones (54). Second generation macrolides (e.g. clarithromycin, azithromycin) have superior activity against Gram-negative species, notably H. influenzae, compared to erythromycin, and improved pharmacokinetic properties. Azithromycin, in particular tends to accumulate in tissues, attaining lung levels several hundred-fold greater than plasma concentrations (55). These high tissue concentrations, particularly in phagocytic cells, allow clearance of infection with shorter treatment time (3-5D for pneumonia). In addition to their antibacterial effects, some macrolides are also reported to reduce lung inflammation in animal models and in patients (56,57). Macrolides are considered among the safest antibiotics available, with Gl effects the most commonly reported problem. Drug-drug interactions due to inhibition of CYP 3A4 can limit use of specific macrolides in combination with other commonly prescribed treatments. For example, cardiotoxicity (QT interval prolongation, torsade de pointes) can result when macrolides are co-administered with an H1 antagonists or cisapride (51).

The safety and efficacy of macrolides have lead to widespread use and a parallel increase in prevalence of resistance. In the US and EU, macrolide resistance in S. pneumoniae has reached levels >30% (58). Two mechanisms account for the majority of resistance to macrolides in S. pneumoniae: target modification and drug efflux (59). The most common target modification is methylation of the 23S rRNA at a key contact point, adenine 2058, by erm-encoded methylases. Erm-mediated macrolide resistance in streptococci can also confer resistance to lincosamide and streptogramins, a phenotype termed MLSb. Erm(B) in streptococci is encoded on transposable elements and has become widely disseminated (60). The balance of macrolide resistance is mediated by an efflux pump encoded by the mefA gene (M type resistance). In the US, 60-80% of macrolide-resistant S. pneumoniae are mefA positive (61), while in Europe, efflux pump-mediated macrolide resistance is less prevalent (-5%) (62). Macrolide resistance mediated by mutation in ribosomal components is also observed, either in the rRNA (ML type) or L4 ribosomal protein (MS type resistance). However, these mutations account for little of the macrolide resistance observed in CAP patients.

Efforts to develop new drugs in the macrolide class have been focused on identifying molecules that overcome existing resistance mediated by mef and erm. The ketolide modification at C-3 overcomes inducibility of Emwnediated resistance and also confers activity against Mef-dependent resistance in streptococci (62, 63). Additional advantages of ketolides over earlier macrolides include increased potency against respiratory pathogens and a longer post-antibiotic effect (62). Conformational control afforded by a cyclic C-11,12 carbamate group also contributes to the potency of ketolides against both sensitive and resistant organisms. Elaboration of several 14-member ketolide series has been pursued, including 11-N-substituted, 6-O-substituted, 2-fluoro, tricyclic, and C-13-modified ketolides (52, 62). An aryl group at the 6-0 or 11-N position contributes to the ability of ketolides to overcome Erm-mediated resistance by providing a second site of interaction with the ribosome. Addition of fluorine at C-2 can improve pharmacokinetic properties, while C-13 modifications allow elaboration of novel skeletons without loss of potency (62).

Telithromycin (previously HMR-3647), a 6-0-methyl-11,12-cyclic carbamate, is the first marketed ketolide (64,65). Telithromycin has significant in vitro activity against nearly all macrolide-sensitive and -resistant S. pneumoniae, e.g. with 99.4% of S. pneumoniae isolates susceptible to telithromycin in recent study of 157 isolates from CAP patients (66). Telithromycin is also effective against H. influenzae and atypical infections in vitro and in vivo (80). Telithromycin has shown excellent response rates in clinical trials of CAP (reviewed in 63). Clinical response rates in 3

randomized, double-blind trials ranged from 79-95% with doses of 500-1000 mg qd for 7-10 days. Telithromycin has also been shown to be effective in treating pneumococcal bacteremia in CAP patients (67). Telithromycin gained EU approval in July 2001 for community acquired infections, including those caused by resistant organisms. In 2001 an FDA advisory committee declined to approve telithromycin beyond an indication for CAP, due to concerns of potential cardiac and liver toxicity (68). Subsequently, an additional 24,000-patient Phase III trial demonstrated similar efficacy and safety for telithromycin and amoxicillin, with serious adverse event (SAE) rates of 1.3% and 1%, respectively (69). The most commonly reported SAE associated with telithromycin in this large Ph III trial was a transient blurring of vision (0.61%), while no drug-related cardiac events were observed (69). On the basis of these and previous results, the FDA advisory committee deemed telithromycin "approvable" in January 2003 for CAP, AECB, and sinusitis (70).

Cethromycin (ABT-773) is a 6-O-substituted ketolide that has also advanced to clinical trials. Like telithromycin, cethromycin has potent activity against both sensitive and macrolide-resistant S. pneumoniae, other Gram-positive organisms, and Gram-negatives including H. influenzae (63). In a Canadian study of CAP pathogen isolates from 1999-2002, MICgo of cethromycin for all S. pnuemoniae was 0.008, versus 0.25 and 0.5 for clarithryomcin and azithromycin, respectively (71). In rat models of pneumonia, cethromycin demonstrated efficacy against S. pneumoniae and H. influenzae in the range of 1-20 mg/kg/day (63). No data from cethromycin clinical trial have been published to date. Another novel 6-O-substituted ketolide, A-217213, which has equal or superior efficacy against CAP pathogens in vitro and in rodent infection models compared to telithromycin has been reported (72,73).

Recent novel 2-fluoroketolides include HMR3562 8, HMR3787, where the 4-(3-pyridinyl)-1 /-/-imidazol has been replaced with a 3H-imidazo[4,5-b]pyridine moiety, and RU64399 which is des-fluoro HMR3787. RU64399 and HMR3787 have preclinical activity against H. influenzae similar to azithromycin (74), while HMR3562 is active against enterococci, including vancomycin-resistant organisms (75). A series of clarithromycin analogues with telithromycin- or ABT-773-type side chains at C11 gave good activity against both erm and mef-mediated resistant S. pneumoniae. The best analogues had saturated linkers 4 or 5 carbons in length (76). Through application of a ring contracting metathesis, 16-membered josamycin analogues were converted into novel 14-membered macrolides 9 which retain much of the parent's activity against mef-mediated resistant S. pneumoniae (77,78). A tricyclic ketolide, TE802, has also shown activity against drug-resistant S. aureus and S. pneumoniae (79). In addition to the ketolides, new azalides related to azithromycin but having activity against some S. aureus and S. pneumoniae strains have been reported (80).

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