Sunday, May 28, 2006

Doripenem (S-4661), a novel carbapenem

Doripenem (S-4661), a novel carbapenem: comparative activity against contemporary pathogens including bactericidal action and preliminary in vitro methods evaluations

Journal of Antimicrobial Chemotherapy 2004

Ronald N. Jones1,2,*, Holly K. Huynh1, Douglas J. Biedenbach1, Thomas R. Fritsche1 and Helio S. Sader1
1The JONES Group/JMI Laboratories, 345 Beaver Kreek Centre, Suite A, North Liberty, IA 52317; 2Tufts University School of Medicine, Boston, MA, USA


Objectives: To investigate the potency of doripenem, a broad-spectrum carbapenem characterized by a wider spectrum of activity combining antimicrobial and bactericidal features of imipenem and meropenem.

Methods: This parenteral compound was studied against recent clinical isolates (2001–2002) from a worldwide organism collection. A total of 902 strains were susceptibility tested by reference methods against doripenem and six to 28 comparators including ertapenem, imipenem and meropenem. The organisms tested included: Enterobacteriaceae (281 strains), Acinetobacter spp. (33), Pseudomonas aeruginosa (35), Stenotrophomonas maltophilia (36), other non-fermenters (22), Haemophilus influenzae (61), Moraxella catarrhalis (33), oxacillin-susceptible staphylococci (39), enterococci (84), streptococci (163), various anaerobes (98), and other Gram-positive species such as Corynebacterium and Bacillus spp. (17).

Results: Against Enterobacteriaceae, the average doripenem MIC90 was 0.03 mg/L (range, 0.015–0.25 mg/L). Doripenem was two- to 16-fold more potent than imipenem and comparable to ertapenem and meropenem; all doripenem MIC values with enteric bacilli were 4 mg/L. Doripenem was active against Aeromonas (MIC50, 0.03 mg/L), Bacillus spp. (MIC50, 0.03 mg/L) and all tested anaerobic species (MIC range, 0.015–4 mg/L), but was less active against S. maltophilia (MIC90, >32 mg/L) and Enterococcus faecium (MIC90, >32 mg/L) among the enterococcal species. Time-dependent bactericidal action was observed for doripenem and broth MIC results were slightly greater when compared to agar MIC results. In pilot testing, the optimal doripenem disc concentration was 10 µg, identical to standardized reagents for other clinically available carbapenems.

Conclusions: Doripenem appears to be a potent carbapenem with a spectrum resembling currently marketed antipseudomonal carbapenems, but with greater activity when tested against some non-fermentative bacillary strains. Continued evaluation of doripenem against isolates resistant to other ß-lactams appears to be warranted.

Keywords: resistance , broad-spectrum , ß-lactams , MBC , susceptibility testing


Doripenem (formerly S-4661, Shionogi Co., Ltd. Japan) is a novel, broad-spectrum parenteral carbapenem antimicrobial with initial research reports dating from international meetings in 1994.17 The chemical formula for doripenem is (+)-(4R,5S,6S)-6-[(1R)-1-1hydroxyethyl]-4-methyl-7-oxo-3[[3S,5S)-S-(sulfamoylaminomethyl) pyrrolidin-3-yl]thio]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid monohydrate (Figure 1). This structure confers ß-lactamase stability and resistance to inactivation by renal dehydropeptidases. Information from presented in vitro studies indicates that doripenem has a spectrum and potency against Gram-positive cocci most similar to imipenem or ertapenem,813 and a Gram-negative activity most like meropenem (two- or four-fold superior to imipenem).14
The long-recognized problems of emerging resistances among Gram-positive species15 have been complicated by dissemination of multidrug-resistant (MDR) Gram-negative organisms, some refractory to carbapenem therapy.16,17 Carbapenem development continues to discover agents with greater potency or improved pharmacokinetic properties,8 and stability to various enzymes such as metallo-ß-lactamases (L1 enzyme characteristic within Stenotrophomonas maltophilia) that can hydrolyse carbapenem compounds.
In this report, we summarize the results of testing doripenem and selected comparators against contemporary, wild-type isolates (2001–2002) worldwide. Over 900 strains were tested by reference dilution methods described by the National Committee for Clinical Laboratory Standards (NCCLS)
18 and the categorical interpretations of MIC results were made using NCCLS document criteria.19

Material and Methods

Bacteria tested

A total of 902 recent clinical isolates were tested from patients with documented infections in hospitals located in the Americas and Europe. The distribution of species and strain counts was as follows: Enterobacteriaceae (281 strains); Acinetobacter baumannii (33 strains); Pseudomonas aeruginosa (35 strains); S. maltophilia (36 strains; 30.6% resistant to trimethoprim/sulfamethoxazole) other non-fermentative Gram-negative bacilli (22 strains); Haemophilus influenzae (61 strains; 28 ampicillin-resistant); Moraxella catarrhalis (33 strains; 76% penicillin-resistant); oxacillin-susceptible staphylococci (39 strains); Enterococcus spp. (84 strains; all E. faecium tested were carbapenem-resistant); streptococci (163 strains; three species groups); anaerobes (98 strains); and other Gram-positive cocci (17 strains).

Unless specified, the isolates were contemporary wild-type populations of the specified species, not enriched with resistant organisms. Identifications were determined in at least two laboratories by routine procedures utilized by those institutions.

Susceptibility testing

Doripenem reagent standard powder was supplied by Peninsula Pharmaceuticals, Inc. (Alameda, CA, USA). Comparison agents were purchased from Sigma Chemical Co. (St. Louis, MO, USA) or were provided by their domestic manufacturers (ertapenem and imipenem from Merck; meropenem from AstraZeneca; cefepime from Bristol-Myers Squibb; clavulanic acid from GlaxoSmithKline; and piperacillin/tazobactam from Wyeth).

All susceptibility tests were carried out by the reference NCCLS methods18 and interpretation of MIC values was by criteria published in NCCLS M100-S13.19 Disc diffusion tests20 with 5, 10 and 20- µg concentrations of doripenem prepared by the investigators were compared against ertapenem (10 µg), imipenem (10 µg) and meropenem (10 µg) commercially prepared (BD Microbiologic Systems, Cockeysville, MD, USA) control discs to determine the optimal disc drug content. A total of 10 wild-type and NCCLS19 quality control strains were used to determine the doripenem disc concentration. Supplements to the media were applied as specified in the NCCLS1820 procedures to maximize growth for fastidious species such as the streptococci and H. influenzae. The anaerobes were tested by the NCCLS21 agar dilution method on Brucella blood agar.

Escherichia coli and Klebsiella spp. strains conforming to the phenotype for an extended-spectrum ß-lactamase (ESBL; MIC of 2 mg/L for aztreonam, cefotaxime, ceftazidime or ceftriaxone) were confirmed by the Etest ESBL strip (AB Biodisk, Solna, Sweden).22 Also to avoid over-representing various resistance phenotypes (example ESBLs), clustered antimicrobial-resistant strains appearing in an institution in a close interval (time), ward or service, were subjected to molecular epidemiological study by pulsed-field gel electrophoresis or automated ribotyping.23 Only a single strain from proven clusters was entered into the study, if appropriate.

Quality control was provided by the concurrent testing of strains recommended by the NCCLS19 such as E. coli ATCC 25922 and 35218, Staphylococcus aureus ATCC 25923 and 29213, Enterococcus faecalis ATCC 29212, P. aeruginosa ATCC 27853, H. influenzae ATCC 49247 and 49766, Streptococcus pneumoniae ATCC 49619, Bacteroides fragilis ATCC 25285 and Bacteroides thetaiotaomicron ATCC 29741. All recorded control results were within published ranges for comparison agents.19

Minimum bactericidal tests were carried out by methods described earlier11 and published by the NCCLS.24,25 Killing curves for doripenem were carried out on 10 organisms including NCCLS19 quality control strains. Concentrations of doripenem at 2x, 4x and 8x MIC were used, monitored at baseline (T0) and at 2 (T2), 4 (T4) and 8 (T8) h.

The reference MIC results for doripenem determined by broth microdilution and agar dilution were directly compared for 100 selected strains,26 with ertapenem used as a carbapenem-class control.

Tentative interpretations of the doripenem MIC results were made using the criteria of susceptible at 4 mg/L and resistant at 16 mg/L.

These breakpoints conform to those widely used for imipenem and meropenem19 and recommended by Bhavnani et al.27 using pharmacokinetic/pharmacodynamic target attainment calculations via Monte Carlo simulations for drug dosing schedules projected for the Phase II and III doripenem clinical trials.

Results and discussion

Activity against Enterobacteriaceae

Table 1 shows the activity of doripenem and six broad-spectrum ß-lactam comparison agents tested against 281 strains of Enterobacteriaceae without ESBL production. Against E. coli (31 strains), nearly all strains had a doripenem MIC of 0.015 mg/L. Imipenem was at least 16-fold less potent than doripenem. Doripenem potency against Klebsiella spp. (46 strains) was comparable to ertapenem and meropenem, but generally two- to four-fold superior to imipenem. The 23 P. mirabilis strains were slightly less susceptible to doripenem, however, the highest MIC was only 0.12 mg/L. Ertapenem and meropenem were more active, with doripenem being 16-fold more potent than imipenem (MIC90, 2 mg/L). Citrobacter spp. (29 strains) were 100.0% susceptible to doripenem. Imipenem among the carbapenems was least active (MIC90, 1 mg/L) against the citrobacters. Similarly, against two species of Enterobacter, doripenem and meropenem were the most active overall. S. marcescens MIC results showed that doripenem, ertapenem and meropenem were the most active agents with MIC90 values of 0.12 mg/L and 100.0% susceptibility rates; 16-fold more potent than imipenem. Indole-positive Proteae (four species; 39 strains) were most susceptible to ertapenem (MIC90, 0.03 mg/L) > meropenem (0.12) > doripenem (0.25) > cefepime (0.5) > imipenem (2). Only the four carbapenems, piperacillin/tazobactam and aztreonam (data not shown) inhibited all wild-type indole-positive Proteae isolates at concentrations defining susceptibility by NCCLS standards.19

Among the carbapenems, ertapenem and meropenem were most active against the Salmonella spp. followed by doripenem (MIC90, 0.06 mg/L) and imipenem (MIC90, 0.25 mg/L). The highest MIC for the Shigella spp. versus the carbapenems was 0.25 mg/L (imipenem), but the highest for doripenem was only 0.06 mg/L. Five more species of Enterobacteriaceae were tested (nine strains; see Table 1 footnote), and quite different patterns of susceptibility were observed. All carbapenems, however, were effective in vitro, but the MIC50 results varied from 0.03 mg/L (ertapenem) to 0.25 mg/L (imipenem).

Activity against non-fermentative Gram-negative bacilli

Table 2 illustrates the doripenem activity against A. baumannii (33 strains) compared to six ß-lactams. Only doripenem (75.8% inhibited at 4 mg/L), imipenem and meropenem were active against these wild-type isolates. Overall, doripenem and imipenem were the most potent agents (MIC50, 0.5 mg/L) and inhibited strains at potentially achievable breakpoint concentrations. Wild-type P. aeruginosa (Table 2) were consistently more susceptible than the Acinetobacter spp. in contemporary practice samples. Ertapenem among the tested carbapenems was not active (MIC90, >32 mg/L) and doripenem was two- and four-fold more potent than meropenem and imipenem against P. aeruginosa, respectively. Cefepime among the cephalosporins had the lowest resistance rate (0.0%; ceftazidime at 4.2%) and 8.3% of P. aeruginosa were resistant to piperacillin/tazobactam.

Doripenem, other tested carbapenems, levofloxacin and trimethoprim/sulfamethoxazole (data not shown) were the only drugs with susceptibility rates of greater than 80% when testing the remaining Gram-negative non-fermentative species (17 strains). A small number of S. (formerly Xanthomonas) maltophilia strains (36; data not shown) were very resistant to tested agents and particularly refractory to carbapenems (97.2–100.0% resistance). Eleven of these strains (30.6%) were resistant to the ‘drug-of-choice’ (trimethoprim/sulfamethoxazole).

Activity against fastidious respiratory tract pathogens

Doripenem was tested against H. influenzae (61 strains) and M. catarrhalis (33 strains) compared to ertapenem, two ß-lactam/ß-lactamase inhibitor combinations and three parenteral cephalosporins (Table 2). Doripenem MIC results were essentially equal for both groups of H. influenzae (ß-lactamase-positive and -negative by nitrocefin test), demonstrating no adverse effect of the TEM-like enzyme on its activity. Ertapenem was four-fold more active than doripenem. The doripenem MIC results tested against M. catarrhalis are also found in Table 2, and all antimicrobials except ampicillin (also penicillin, data not shown) showed an excellent spectrum and potency. ß-Lactamase production (detected by the chromogenic cephalosporin test) was noted for 25 strains (75.8%).

Activity against Gram-positive organisms

Table 3 lists the activity of doripenem and selected comparison agents tested against oxacillin-susceptible S. aureus (MIC, 2 mg/L; 20 strains). Doripenem was equal to the most potent agent (imipenem; MIC90, 0.06 mg/L) for the dilution ranges utilized. Doripenem was 128-fold more active than ceftazidime and 32-fold more potent than cefepime against these staphylococci. Among the other tested carbapenems, doripenem (MIC90, 0.06 mg/L) was four-fold more active than ertapenem (MIC90, 0.25 mg/L). Doripenem was equally potent against oxacillin-susceptible (MIC, 0.5 mg/L) coagulase-negative staphylococci isolates (MIC90, 0.06 mg/L), as that demonstrated for S. aureus. Ertapenem was generally eight-fold less active than doripenem.

E. faecalis (45 strains including six vancomycin-resistant [VRE] isolates) susceptibility testing results for doripenem showed that all of the VRE strains were resistant to doripenem at MIC values of 8 mg/L (Table 3). Doripenem was four-fold less active than imipenem, but four-fold more potent than ertapenem. Only 2.2% of E. faecalis were ampicillin-resistant and one isolate was linezolid-resistant (MIC, 8 mg/L), but susceptible to doripenem. Tests with E. faecium (29 strains, 20 VRE; data not shown) showed that none of the carbapenems displayed activity (MIC90, 8 mg/L) against this species. Ten strains of ‘other enterococci’ were also tested (Table 3) and these strains included four different species and single isolates of E. durans and E. gallinarum that had elevated doripenem MIC results (>32 mg/L). Doripenem and imipenem were four-fold more active than ertapenem against these more rarely encountered enterococci.

Doripenem MIC results for S. pneumoniae strains were grouped by their susceptibility category to penicillin [susceptible (0.06 mg/L), intermediate (0.12–1 mg/L), resistant (2 mg/L); see Table 3]. The doripenem MIC values increased as the penicillin MIC increased with MIC90 results at 0.015, 0.25 and 1 mg/L for penicillin-susceptible, -intermediate, and -resistant category pneumococcal strains, respectively. Similar increases were also noted for ertapenem, imipenem, other tested ß-lactams as well as unlisted antimicrobials such as the macrolides, chloramphenicol, tetracyclines and trimethoprim/sulfamethoxazole. Doripenem was the most active carbapenem or ß-lactam tested against the penicillin-resistant S. pneumoniae (23 strains using the tentative breakpoint of 4 mg/L).

Against viridans group streptococci (49 strains; Table 3) indexed by their susceptibility to penicillin (0.12 mg/L), doripenem activity was adversely affected by elevated penicillin MIC values (similar to S. pneumoniae). The doripenem MIC90 results increased from 0.06 to 0.5 to 4 mg/L for the penicillin-susceptible (0.12 mg/L), -intermediate (0.25–2 mg/L), and -resistant (4 mg/L) strains. Doripenem showed similar activity when compared to imipenem versus all viridans group streptococci, but exhibited a two- to four-fold greater activity than ertapenem. Ertapenem at breakpoints approved by the NCCLS19 was only effective against 7.7% of penicillin-resistant viridans group streptococci. Doripenem exhibited a potency equal to those of penicillin, clindamycin and imipenem (all at 0.06 mg/L for MIC90 results) against ß-haemolytic streptococci. For the Bacillus spp. (eight strains), doripenem was very active with an MIC50 of only 0.03 mg/L. The remaining nine isolates were Aerococcus spp. (three species, three strains), Gemella morbillorum (two strains),Lactococcus spp. (one strain), Leuconostoc spp. (two strains) and Stomatococcus mucilaginosis (one strain). Doripenem was not active versus the Leuconostoc spp. isolates (MIC, 8 mg/L).

Activity against strict anaerobic bacteria

Table 4 shows the MIC results of doripenem and four selected agents tested against six groups of strict anaerobes (98 strains). All carbapenems tested were active against this population of anaerobes with only ertapenem having non-susceptible values (MIC, 8 mg/L) for single strains of Fusobacterium spp. and Clostridium difficile. Metronidazole susceptibility rates varied from 7.1% (other Gram-positive species) to 100.0%. Clindamycin activity and potency versus the Gram-negative species was quite compromised (MIC90, >16 mg/L).

Determinations of bactericidal activity

Ten strains including eight NCCLS19 quality control organisms were tested to compare doripenem MIC and MBC results. The doripenem MBC values ranged from two- to eight-fold greater than the measured MIC with a median result of four-fold higher. Kill curves were also carried out using doripenem concentrations at 2x, 4x and 8x the measured organism MIC. Bactericidal results for doripenem were generally observed at 4x and 8x MIC for the S. aureus, E. faecalis, S. pneumoniae (Figure 2), E. coli and K. pneumoniae isolates. Occasional regrowth at 24 h to subvisible levels was noted and only to the initial inoculum level for the in 2x or 4x MIC tests (P. aeruginosa; Figure 3) possibly due to drug inactivation via induced AmpC expression.

Preliminary determinations of in vitro testing parameters

Table 5 lists the disc diffusion zones of inhibition around doripenem discs containing 5, 10, or 20 µg of drug. These tests were carried out in replicate (three discs of each concentration/strain) with two technologist observers (six doripenem results with averages shown in Table 5). Linear increases in the zone diameter were observed for doripenem discs as the disc concentration increased, progressing from a millimetre zone range of 15.3–33.8 mm for the 5 µg disc to 21.8–39.5 mm for the 20 µg disc. The 10 µg doripenem disc performed similarly to the same content discs for other control carbapenems (Table 5) when compared to their corresponding MIC values. The 10 µg disc could be recommended as a doripenem diagnostic test reagent, conforming to those concentrations used for the carbapenem class.

A comparison of agar dilution and broth microdilution MIC test results was carried out using 106 strains (NCCLS M23-A2 criteria, 100 strains) and ertapenem as a control carbapenem agent (Figure 4). Nearly 60% of values were identical by both methods. However, a slight trend toward a one log2 higher MIC by the broth-based method was observed. A total of 99.1% of doripenem MIC results were within ±one log2 dilution by both NCCLS methods.20 Ertapenem comparisons showed equality between methods, but a lower percentage (97.2%) of results within±one log2 dilution step. These results for both carbapenems were considered to be within acceptable levels of intermethod variation.26


This in vitro evaluation studied doripenem, a novel parenteral carbapenem,1,4 against recently isolated strains from a worldwide organism collection. Earlier reports of the microbiology features of doripenem can be summarized as follows: 1) bactericidal action;3,7,28,29 2) high affinity for PBP targets that are species-specific (PBP3 in P. aeruginosa; PBPs1, 2 and 4 in S. aureus; PBP2 in E. coli);30 3) a post-antibiotic effect of 1.8 (in vitro) to 4.3 (in vivo) h for P. aeruginosa;28,31 4) influx in Gram-negative species by OprD channels with efflux sensitivity via the MexAB-OprM system;32 5) pharmacokinetic parameters resembling meropenem with a T1/2 of approximately 1 h;6 6) low serum protein binding at 8–9%;6,7 7) low risk of convulsive side effects secondary to weak inhibition of GABA receptors;2 8) stability to a wide variety of ß-lactamases;3,7 9) success within in vivo animal models;28,29 10) endotoxin release comparable to other carbapenem class agents;29 11) high-level stability to human recombinant dehydropeptidase-I;5 12) synergy with glycopeptides when tested against oxacillin-resistant S. aureus;33 and 13) clinical success from the early human trials in Japan.34,35

The doripenem spectrum of activity was previously presented in a limited number of publications appearing between 1998 and 2002.3,4,7,8 In those studies, the strains used were collected from Japan and the susceptibility methods used were not NCCLS assays. The consensus MIC90 results for key pathogens were: oxacillin-susceptible S. aureus (0.06 mg/L) or CoNS (0.06–12.5 mg/L), oxacillin-resistant staphylococci (>32 mg/L), E. faecalis (4–16 mg/L), E. faecium (>32 mg/L), S. pneumoniae (0.008–0.5 mg/L; varies with penicillin susceptibility), serogroup A and B streptococci (0.004–0.03 mg/mL), Enterobacteriaceae (0.12–0.5 mg/L), P. aeruginosa (2–16 mg/L), Acinetobacter spp. (4 mg/L), M. catarrhalis (0.03 mg/L), H. influenzae (0.5 mg/L), anaerobes (0.12–1 mg/L) and Burkholderia cepacia complex or S. maltophilia (8–>128 mg/L). These in vitro results from early development trials clearly place doripenem as a very broad-spectrum ß-lactam only having a compromised spectrum when used alone33 against oxacillin-resistant staphylococci, E. faecium, some Burkholderia spp. and S. maltophilia, i.e. a spectrum most similar to imipenem or meropenem,8,14 but markedly superior to ertapenem.913 These features for doripenem were confirmed in the study reported here, where the new carbapenem was four- to 32-fold more active than imipenem against wild-type strains of Enterobacteriaceae (MIC range, 0.015–0.5, median MIC, 0.06 mg/L). Furthermore, doripenem exhibited potency and/or spectrum advantages compared with both imipenem and meropenem against the entire group of non-fermentative Gram-negative bacilli tested.

These findings have been enhanced by the early pharmacokinetic and pharmacodynamic study results27,36,37 that show doripenem to have a pharmacodynamic target producing efficacy like that of other ß-lactams (%T > MIC), dosages (short or prolonged) that can be adjusted to treat organisms (MICs at 8 mg/L) previously refractory to carbapenem therapy, and a Phase I safety/pharmacokinetic study that confirms earlier Japanese investigation results for doses up to 1000 mg every 8 h.6 These recent pharmacodynamic investigations also validated the tentative breakpoint for doripenem susceptibility at 4 mg/L used in this presentation for doses projected for the Phase 3 clinical trials.27

As resistance among key nosocomial pathogens increases,1517 the need for broad-spectrum agents becomes critical to initial patient care or the selection of empirical regimens. The carbapenems will need to assume a greater therapeutic role, especially in those institutions and patient populations where multidrug-resistant strains have become prevalent. However, the potential exists for some metallo-ß-lactamases that can actively destroy carbapenem compounds to be more widely disseminated.16,17 Surveillance programmes and prudent prescibing practice should screen multidrug-resistant isolates for this resistance mechanism at the regional, national and local level. Only with this type of epidemiological effort will the carbapenems and new, promising compounds like doripenem be able to maintain their wide spectrum of activity and potential clinical utility.


The co-authors wish to thank the following individuals for their assistance in manuscript preparation and review: K.L. Meyer, M.L. Beach and P. Rhomberg. This study was funded by an educational/research grant from Peninsula Pharmaceuticals, Inc.


* Corresponding author. Tel: +1-319-665-3370; Fax: +1-319-665-3371; Email:


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29 . Miwa, H., Matsuda, H., Shimada, J., et al. (1996). Effect of S-4661, a new carbapenem antibiotic, on endotoxin release from Pseudomonas aeruginosa. In Program and Abstracts of the Thirty-sixth Interscience Conference on Antimicrobial Agents and Chemotherapy, New Orleans, 1996. Abstract F114. American Society for Microbiology, Washington, DC, USA.
30 . Hanaki, H., Kondo, N., Inaba, Y. et al. (1996). In vitro activity of S-4661, a new 1b-methyl carbapenem, against Gram-positive and Gram-negative bacterial isolates. In Program and Abstracts of the Thirty-sixth Interscience Conference on Antimicrobial Agents and Chemotherapy, New Orleans, 1996. Abstract 111. American Society for Microbiology, Washington, DC, USA.
31 . Totsuka, K., Shiseki, M., Uchiyama, T., et al. (1996). In vitro postantibiotic effect and in vivo antimicrobial activity of novel carbapenem, S-4661. In Program and Abstracts of the Thirty-sixth Interscience Conference on Antimicrobial Agents and Chemotherapy, New Orleans, 1996. Abstract 113. American Society for Microbiology, Washington, DC, USA.
32 . Yamano, Y., Nishikawa, T., Komatsu, Y., et al. (1997). Effect of alterations in proins and efflux pumps of Pseudomonas aeruginosa on the in vitro antipseudomonal activity of S-4661. In Program and Abstracts of the Thirty-seventh Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, 1997. Abstract F214. American Society for Microbiology, Washington, DC, USA.
33 . Kobayashi, Y., Kizaki, M. & Mutou, A. (1997). Synergy with S-4661 and vancomycin or teicoplanin against imipenem-resistant MRSA identified by the PCR method. In Program and Abstracts of the Thirty-seventh Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, 1997. Abstract F216. American Society for Microbiology, Washington, DC, USA.
34 . Arakawa, S., Kamidono, S., Inamatsu, T., et al. (1997). Clinical studies of S-4661, new parenteral carbapenem antibiotic, in complicated urinary tract infections. In Program and Abstracts of the Thirty-seventh Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, 1997. Abstract F218. American Society for Microbiology, Washington, DC, USA.
35 . Saito, A., Inamatsu, T. & Shimada, J. (1997). Clinical studies of S-4661, new parenteral carbapanem antibiotic, in chronic respiratory tract infections. In Program and Abstracts of the Thirty-seventh Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, 1997. Abstract F219. American Society for Microbiology, Washington, DC, USA.
36 . Andes, D. R., Kiem, S. & Craig, W. A. (2003). In vivo pharmacodynamic activity of a new carbapenem, doripenem (DOR), against multiple bacteria in a murine thigh infection model. In Program and Abstracts of the Forty-third Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, 2003. Abstract A308. American Society for Microbiology, Washington, DC, USA.
37 . Thye, D. A., Kilfoil, T., Leighton, A., et al. (2003). Doripenem: A Phase I study to evaluate safety, tolerability and pharmacokinetics in a western healthy volunteer population. In Program and Abstracts of the Forty-third Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, 2003. Abstract A21. American Society for Microbiology, Washington, DC, USA.

Oxford Journals

Sunday, May 21, 2006


Update on linezolid: the first oxazolidinone antibiotic

October 2005, Vol. 6, No. 13, Pages 2315-2326

Mark H Wilcox
Old Medical School, Department of Microbiology, Leeds General Infirmary, Leeds LS1 3EX, UK.


Linezolid is the first of an entirely new class of antibiotics, the oxazolidinones, in decades. It has a spectrum of activity against virtually all important Gram-positive pathogens. The unique mechanism of action of linezolid makes cross-resistance with other antimicrobial agents unlikely. Linezolid has both intravenous and oral formulations and the latter is 100% bioavailable. Since its first approval and marketing in March 2000 in the US, linezolid has gained approval for use in many other countries for the treatment of community-acquired and nosocomial pneumonia, complicated and uncomplicated skin and soft-tissue infections, and infections caused by methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci, including cases with concurrent bacteraemia. Several earlier comprehensive reviews summarised the chemistry, mechanism of action, pharmacokinetics, clinical efficacy and safety profile of linezolid. The present review provides an update on the latest data regarding the antimicrobial activity of linezolid versus other commonly used agents, the clinical and health-economic outcomes of linezolid versus vancomycin and teicoplanin, and safety issues.

Full Text Article Available

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Linezolid: A new antibioticXiong, Y.-Q., et al.

The U.S. Food and Drug Administration recently approved linezolid for the treatment of patients with methicillin-resistant staphylococcal and vancomycin-resistant enterococcal infections. This oxazolidinone antibacterial agent represents the first approved antibiotic of a new structural class in 35 years. Linezolid is a synthetic compound that acts by inhibiting the initiation complex formation in bacterial protein synthesis, a mechanism of action distinct from other commercially available antibiotics. Thus, cross-resistance between linezolid and other current antimicrobial agents has not been demonstrated to date. Linezolid has a wide spectrum of in vitro activity against Gram-positive organisms, including methicillin-resistant staphylococci, penicillin-resistant pneumococci and vancomycin-resistant enterococci. Some anaerobes, such as Clostridium spp., Peptostreptococcus spp. and Prevotella spp. are also susceptible to linezolid. In addition, linezolid has exhibited good efficacy in experimental animal models of acute otitis media, endocarditis and meningitis due to many common aerobic Gram-positive bacteria. In clinical trials involving hospitalized patients with skin/soft tissue infections, community-acquired pneumonia and serious Gram-positive bacterial infections, linezolid appeared to be an effective treatment option, comparable in efficacy to vancomycin.

Journals on the Web

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Linezolid--a review of the first oxazolidinone.

Norrby R.

The Swedish Institute for Infectious Disease Control, SE17182 Solna, Sweden.

Linezolid is the first of a truly new class of antibiotics, the oxazolidinones. It acts as an inhibitor of bacterial protein synthesis by blocking the formation of the 70S ribosomal initiation complex. Its activity is bacteriostatic against some species (e.g., enterococci) and bactericidal against others (e.g., pneumococci). The antibacterial spectrum of linezolid includes Gram-positive pathogens and some Gram-negative anaerobic species but not Gram-negative aerobes.

Importantly, multi-drug resistant organisms such as methicillin-resistant staphylococci, staphylococci with reduced susceptibility to vancomycin, penicillin- and macrolide-resistant pneumococci and vancomycin-resistant enterococci are fully susceptible to linezolid. Linezolid has almost 100% bioavailability and the area under the plasma concentration curve is identical after oral and iv. administration. This enables initial oral administration of linezolid in those patients who can absorb the drug normally and also an early step-down therapy from iv. to oral. Controlled, randomised clinical studies have documented efficacy and safety of linezolid in hospital- and community-acquired pneumonia, uncomplicated and complicated skin and soft tissue infections and infections caused by vancomycin-resistant enterococci. The safety and tolerability of linezolid are advantageous.

Linezolid is a weak and reversible monoamine oxidase (MAO) inhibitor and although no increased frequency of adrenergic or serotonergic adverse events has been reported, it is recommended that linezolid is used with caution in patients treated with other MAO inhibitors.

Full Text Article

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Efficacy of linezolid versus comparator therapies in Gram-positive infections.

Wilcox MH.

Department of Microbiology, University of Leeds and The General Infirmary, Leeds LS2 9JT, UK.

Treatment of Gram-positive bacterial infections is currently a therapeutic challenge because many of these pathogens are now resistant to standard antimicrobial agents. The emergence of multidrug-resistant, Gram-positive pathogens emphasizes the need for new antimicrobial therapy. Linezolid is an oxazolidinone antibiotic with a novel mechanism of action that works by inhibiting bacterial protein synthesis by blocking formation of the initiation complex. It is active against Gram-positive organisms resistant to other antibiotics, including methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae and vancomycin-resistant enterococci (VRE). Results are encouraging from several large-scale, randomized, Phase III trials comparing the efficacy and safety of linezolid with standard comparator agents for the treatment of nosocomial pneumonia, community-acquired pneumonia, skin and skin structure infections, and infections due to MRSA and VRE. Intravenous/oral linezolid is a promising antimicrobial agent and provides the clinician with an additional treatment option, particularly among the limited therapies for resistant Gram-positive bacterial infections.

Full text Article

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Linezolid versus vancomycin for treatment of resistant Gram-positive infections in children.

Linezolid versus vancomycin for treatment of resistant Gram-positive infections in children.Kaplan SL, Deville JG, Yogev R, Morfin MR, Wu E, Adler S, Edge-Padbury B, Naberhuis-Stehouwer S, Bruss JB; Linezolid Pediatric Study Group.Baylor College of Medicine and Texas Children's Hospital, 6621 Fannin Street, MC3-2371, Feigin Center No. 1150, Houston, TX 77030, USA.

BACKGROUND: Pediatric infections caused by resistant Gram-positive infections are an increasing concern with limited treatment options. Linezolid, a new oxazolidinone, is active against staphylococci, streptococci and enterococci.

OBJECTIVE: To assess clinical efficacy and safety of linezolid vs.vancomycin in antibiotic-resistant Gram-positive infections in children.DESIGN Hospitalized children (birth to 12 years of age) with nosocomial pneumonia, complicated skin/skin structure infections, catheter-related bacteremia, bacteremia of unknown source or other infections caused by Gram-positive bacteria were randomized 2:1 to receive linezolid intravenously followed by oral linezolid or vancomycin and then by an appropriate oral agent. Treatment duration was 10 to 28 days.

RESULTS: There were 321 patients enrolled (linezolid 219, vancomycin 102). Clinical cure rates were 79% vs.74% (P = 0.36) and 89% vs.85% (P = 0.31) for linezolid and vancomycin in intent-to-treat and clinically evaluable patients, respectively. Cure rates were similar by age and infection diagnosis. Pathogen eradication rates in microbiologically evaluable patients were high for linezolid and vancomycin, respectively, for methicillin-susceptible S. aureus (95% vs.94%; P = 0.82), methicillin-resistant S. aureus (88% vs.90%; P = 0.89) and methicillin-resistant coagulase-negative staphylococci (85% vs.83%, P = 0.87). In clinically evaluable patients, linezolid-treated patients required significantly fewer days of intravenous therapy compared with vancomycin-treated patients (8.0 +/- 4.8; 10.9 +/- 5.8 days, respectively; P < p =" 0.003).">

CONCLUSIONS: Linezolid was well-tolerated and as effective as vancomycin in treating serious Gram-positive infections in children.

Publication Types:
Clinical Trial
Clinical Trial, Phase III
Multicenter Study
Randomized Controlled Trial

PMID: 12913766 [PubMed - indexed for MEDLINE]

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Linezolid - Indian Pediatrics

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Pharmacoeconomics. 2005;23(9):945-64.

Linezolid: a pharmacoeconomic review of its use in serious Gram-positive infections.

Plosker GL, Figgitt DP.Adis International Limited, Auckland, New Zealand.

Linezolid (Zyvox), the first available oxazolidinone antibacterial agent, has good activity against Gram-positive pathogens, including multidrug-resistant organisms such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium. Randomised multicentre trials in patients with various types of serious Gram-positive infections showed that clinical cure rates with linezolid were similar to those with vancomycin or teicoplanin. In some subgroup analyses, which must be interpreted with a degree of caution, clinical advantages were noted for linezolid (e.g. versus vancomycin in confirmed MRSA nosocomial pneumonia and MRSA-complicated skin and soft tissue infections). Although generally well tolerated, gastrointestinal adverse effects are relatively common with linezolid and it has been associated with thrombocytopenia and myelosuppression. The oral bioavailability of linezolid is approximately 100%, thus allowing sequential intravenous-to-oral administration without changing the drug or dosage regimen. Healthcare resource use data from various countries indicate that this practical advantage translates into at least a trend towards reduced length of hospital stay compared with vancomycin, which may offset its several-fold higher acquisition cost. Modelled analyses from the US, despite some limitations, indicate that, compared with vancomycin, linezolid is associated with lower total hospitalisation costs for the treatment of patients with cellulitis and has a favourable incremental cost-effectiveness ratio of approximately US30,000 dollars per QALY gained (2001 value) for patients with ventilator-associated pneumonia. Broadly similar results have also been reported in modelled analyses from other countries. In conclusion, for patients with serious Gram-positive infections, including those caused by suspected or proven multidrug-resistant pathogens such as MRSA, linezolid is an effective and generally well tolerated therapeutic option. Linezolid is currently the only antibacterial agent with good activity against MRSA that can be administered orally (as well as intravenously). It may be particularly useful as an alternative to vancomycin in patients who have impaired renal function, poor or no intravenous access, require outpatient therapy, or who have been unable to tolerate glycopeptides. Healthcare resource use studies and pharmacoeconomic analyses generally support the use of linezolid in some subgroups of patients, although results should be interpreted with due consideration of the study limitations.

Publication Types:

PMID: 16153136 [
PubMed - indexed for MEDLINE]

Platensimycin is a selective FabF inhibitor with potent antibiotic properties

Nature. 2006 May 18;441(7091):358-361.

Wang J, Soisson SM, Young K, Shoop W, Kodali S, Galgoci A, Painter R, Parthasarathy G, Tang YS, Cummings R, Ha S, Dorso K, Motyl M, Jayasuriya H, Ondeyka J, Herath K, Zhang C, Hernandez L, Allocco J, Basilio A, Tormo JR, Genilloud O, Vicente F, Pelaez F, Colwell L, Lee SH, Michael B, Felcetto T, Gill C, Silver LL, Hermes JD, Bartizal K, Barrett J, Schmatz D, Becker JW, Cully D, Singh SB.

[1] Merck Research Laboratories, Rahway, New Jersey 07065, USA [2] *These authors contributed equally to the work.

Bacterial infection remains a serious threat to human lives because of emerging resistance to existing antibiotics. Although the scientific community has avidly pursued the discovery of new antibiotics that interact with new targets, these efforts have met with limited success since the early 1960s. Here we report the discovery of platensimycin, a previously unknown class of antibiotics produced by Streptomyces platensis. Platensimycin demonstrates strong, broad-spectrum Gram-positive antibacterial activity by selectively inhibiting cellular lipid biosynthesis. We show that this anti-bacterial effect is exerted through the selective targeting of beta-ketoacyl-(acyl-carrier-protein (ACP)) synthase I/II (FabF/B) in the synthetic pathway of fatty acids. Direct binding assays show that platensimycin interacts specifically with the acyl-enzyme intermediate of the target protein, and X-ray crystallographic studies reveal that a specific conformational change that occurs on acylation must take place before the inhibitor can bind. Treatment with platensimycin eradicates Staphylococcus aureus infection in mice. Because of its unique mode of action, platensimycin shows no cross-resistance to other key antibiotic-resistant strains tested, including methicillin-resistant S. aureus, vancomycin-intermediate S. aureus and vancomycin-resistant enterococci. Platensimycin is the most potent inhibitor reported for the FabF/B condensing enzymes, and is the only inhibitor of these targets that shows broad-spectrum activity, in vivo efficacy and no observed toxicity.PMID: 16710421

[PubMed - as supplied by publisher]

Related Article:

Discovery of FabH/FabF inhibitors from natural products.

Wednesday, May 17, 2006


WEDNESDAY, May 17 (HealthDay News) -- Researchers report that they've unearthed a new antibiotic that might become a potent weapon against two dangerous germs that are bedeviling hospitals.

The antibiotic, discovered in South African soil, hasn't been tested in humans and is years away from showing up on pharmacy shelves. Still, the researchers said it has plenty of potential, especially since no other similar drugs have landed on the market since 2000.

At issue are several bacteria that have developed resistance against existing antibiotics, and are starting to creep into the community. One is a staph infection known as methicillin-resistant Staphylococcus aureus (MRSA), which can cause pneumonia in hospital settings and skin infections in the general population. Another is vancomycin-resistant Enterococcus(VRE).

"It's just an inevitable process that eventually all these bacteria will be resistant to the compounds we have now," said study author Stephen Soisson, a senior scientist at Merck Research Laboratories. "It's a looming global health crisis."

In their search for a new antibiotic, Soisson and his colleagues looked at 250,000 extracts from natural products, including samples of soil and leaf debris from around the world. They think they may have found what they're looking for in a soil sample from South Africa.

The researchers tested an antibiotic derived from a substance found in the soil. They report their findings in the May 18 issue of Nature.In mice, the antibiotic, known as platensimycin, vanquished both MRSA and VRE. Apparently, the antibiotic works by disrupting the way cells synthesize crucial fatty acids.

Frank Myers, a clinical infectious disease epidemiologist at Scripps Mercy Hospital in San Diego, said the findings about platensimycin are "very encouraging," and the drug could become another treatment option for doctors, especially those treating patients who develop MRSA-related pneumonia in hospitals. Those cases, he said, are especially hard to treat.

However, there are caveats, Myers added. Infectious disease specialists will want to know if the germs develop resistance to the new antibiotic and whether it kills healthy bacteria and contributes to a diarrheal illness.Also, he said, doctors may be cautious about using platensimycin except in the most dire cases, to avoid creating antibiotic resistance.

Yahoo News


New Antibiotic Aimed at Resistant Germs

May 17, 2006 05:01:19 PM PST

Scientists have found a chemical that might one day prove critical in the ongoing fight against germs that have developed resistance to existing antibiotics.

The compound, discovered by researchers from the pharmaceutical firm Merck & Co., could herald the first major new class of antibiotics in decades. It has already proven effective in curing mice infected with antibiotic-resistant bacteria.

That doesn't mean it will work in people, but outside experts are impressed with the results, which are reported in this week's issue of the journal Nature.

The researchers found the compound in a scoop of soil from South Africa. They named it platensimycin, because it is produced by the soil bacterium Streptomyces platensis as a weapon in its own battles against other microbes.

"We need to continuously find antibiotics," said Sheo Singh, Merck's director of natural products chemistry.

With the recent emergence of "superbugs" that are resistant to even the most potent antibiotics, there is a real possibility that in the near future some infections will simply be incurable.

Part of the problem is that most antibiotics are just modifications of drugs that have been around for half a century. In addition, despite all the recent advances in genetics and molecular biology, the hunt for new antibiotics is still conducted by trial and error.

The Merck researchers addressed both problems with a clever genetic trick that made an existing drug-hunting process more effective and also targeted novel types of antibiotics.

Their innovation was to test extracts of fungi, plants and other natural substances against bacteria with a genetically engineered Achilles' heel. Because the bacteria were weakened, any compound that harmed them would have a more dramatic effect and thus be easier to identify.

The Merck scientists also chose the genetic handicap carefully, placing it in a metabolic pathway that is not attacked by any major existing antibiotics. That increased the likelihood that any promising compound they discovered would be something for which the bacteria had not yet developed a resistance.

"We screened over 250,000 extracts that came from things isolated all the way around the world," said Merck scientist Stephen M. Soisson.

One of them, platensimycin, showed exceptional promise in vitro. It also proved highly effective when tested in mice infected with a common and troublesome strain of Staphylococcus aureus.

"I'm guessing that this is a very promising molecule," said Eric D. Brown, a biochemist at McMaster University in Hamilton, Ontario.

He noted that the majority of potential antibiotics never reach the pharmacy even after proving effective in mice. But by publishing a report about platensimycin in one of the world's most influential journals, Merck is signaling an unusual level of confidence in the compound's prospects.

"I think it's probably going somewhere," Brown said.

If so, it would be a bright spot for the besieged New Jersey pharmaceutical company, which is fending off thousands of lawsuits over its painkiller Vioxx, pulled off the market in 2004.

Of course, even if platensimycin turns out to be a clinically useful antibiotic, bacteria will inevitably become resistant to it just as they have existing drugs.

Saturday, May 13, 2006

Staphylococcus aureus resistance to antibiotics and spread of phage types.

Staphylococcus aureus resistance to antibiotics and spread of phage types.

Kareiviene V, Pavilonis A, Sinkute G, Liegiute S, Gailiene G.

Department of Microbiology, Kaunas University of Medicine, A. Mickeviciaus 9, 44307 Kaunas, Lithuania.


The aim of this study was to identify the phage groups of Staphylococcus aureus strains, their prevalence, and resistance of different phage groups to antibiotics.


A total of 294 Staphylococcus aureus strains in Kaunas hospitals were obtained; they were phage typed and their resistance to antibiotics was determined. We used the method of routine dilution to test 17 antibiotics against the isolates. Susceptibility of Staphylococcus aureus to studied antibiotics was estimated on the basis of National Committee for Clinical Laboratory Standards according to minimal inhibition concentration of each antibiotic. Staphylococcus aureus strains were phage typed by the international diagnostic set of Staphylococci bacteriophages (Moscow, Russia).


After evaluating the resistance of obtained Staphylococcus aureus strains to oxacillin/methicillin, it was determined that 5.8% of Staphylococcus aureus were resistant to methicillin. Almost all strains (93.75%) of methicillin-resistant Staphylococcus aureus were susceptible to the fusidic acid, 18.75% - to ciprofloxacin; 31.25% of methicillin-resistant Staphylococcus aureus strains were susceptible to gentamicin, 37.5% - to doxycycline, and just 6.25% - to erythromycin. The strains of methicillin-susceptible Staphylococcus aureus are susceptible to many studied antibiotics. The strains of methicillin-susceptible Staphylococcus aureus are most resistant to penicillin - 83.1% and to erythromycin - 29.9%. Phage typing revealed that 20.9% of methicillin-susceptible Staphylococcus aureus and 56.2% of methicillin-resistant Staphylococcus aureus were nontypable.


Using the international set of bacteriophages, 79.1% of methicillin-susceptible Staphylococcus aureus and 43.8% of methicillin-resistant Staphylococcus aureus strains were phage typed. Among the strains of methicillin-resistant Staphylococcus aureus, phagotype 77 of phagogroup III was the most common and among the strains of methicillin-susceptible Staphylococcus aureus - phagotype 3C of phagogroup II.

PMID: 16687905 [PubMed - as supplied by publisher]

A study on Staphylococcus aureus strains submitted to a reference laboratory.

Mehndiratta PL, Vidhani S, Mathur MD.

National Staphylococcal Phage Typing Center, Department of Microbiology, Maulana Azad Medical College, New Delhi, India.


Staphylococcus aureus is regarded as one of the most devastating human pathogens. Recently there have been reports of increasing incidence of S. aureus strains resistant to methicillin (MRSA). A surveillance study was undertaken to record the occurrence of MRSA and to study the prevalence of various phage groups in India.


A total of 7574 strains of S. aureus received during 1992-98 at the National Staphylococcal Phage Typing Centre, New Delhi were tested for methicillin resistance and susceptibility to phages of the International basic set. The occurrence of various phage groups between MRSA and MSSA (methicillin sensitive S. aureus) was compared. Results were analyzed according to the geographical origin and source of isolation of the strains.


The dominant phage group from different parts of the country was phage group III. Prevalence of phage group III among the MRSA and MSSA isolates was 62.32 and 33.95 per cent respectively. The highest isolation of phage group III strains was from nasal carriers (45.94%), phage group II strains from skin (8.74%), phage group I strains from blood (19.44%) and nontypable strains from the environment (80.68%). An increase in the occurrence of MRSA has been noticed from 9.83 per cent in 1992 to 45.44 per cent in 1998.


S. aureus strains of phage group III are prevalent in India. The increase in occurrence of MRSA indicates an alarming spread of these organisms. A constant monitoring is important to take appropriate and timely measures to control their spread.PMID: 11873403

[PubMed - indexed for MEDLINE]

Saturday, May 06, 2006

Treatment of acute maxillary sinusitis in adults. Comparison of cefpodoxime-proxetil and amoxicillin-clavulanic acid

Polonovski JM, El Mellah M. Centre hospitalier A. Mignot, Le Chesnay.

Jan 2006


The aim was to demonstrate the equivalence of the clinical efficacy and safety of cefpodoxime-proxetil (200 mg bid for 5 days) to that of amoxicillin-clavulanic acid (1 g/125 mg bid for 8 days) in adults with acute maxillary sinusitis.


In this prospective, multicenter, centrally-randomized, open-label study, 73 general practitioners and 11 ear, nose, and throat specialists included 512 patients with unilateral acute maxillary sinusitis.


The clinical success rates at day 12-19 in the per-protocol population (primary analysis) were 92.3% (215/233) in the cefpodoxime-proxetil group and 93.6% (204/218) in the amoxicillin-clavulanic acid group. The 95% confidence interval of [6.5%; 3.9%] demonstrated that cefpodoxime-proxetil was not inferior to amoxicillin-clavulanic acid. Cure rates at follow-up (day 25-30) were 90.6% and 92.7%, respectively. Results were similar in the intent-to-treat population. Compliance was significantly better in the cefpodoxime-proxetil group (99.2% versus 95.5%; p=0.011). Tolerance was also significantly better: 1.2% (3/247) of cefpodoxime-proxetil patients reported a treatment-related adverse event, compared with 10.7% (26/244) in the amoxicillin-clavulanic acid group (p<0.001).>


In this study, a 5-day course of cefpodoxime-proxetil at 200 mg bid was as clinically effective as amoxicillin-clavulanic acid 1 g/125 mg bid for 8 days with a significantly better safety profile and compliance.

Publication Types:
Evaluation Studies
Multicenter Study
Randomized Controlled Trial

PMID: 16462661 [PubMed - indexed for MEDLINE]

Related Abstracts/Articles

A multicenter, randomized, investigator-blinded study of 5- and 10-day gatifloxacin versus 10-day amoxicillin/clavulanate in patients with acute bacterial sinusitis.

Efficacy and tolerability of telithromycin for 5 or 10 days vs amoxicillin/clavulanic acid for 10 days in acute maxillary sinusitis.

Once daily clarithromycin extended-release vs twice-daily amoxicillin/clavulanate in patients with acute bacterial sinusitis: a randomized, investigator-blinded study.