Problems with current recommendations for susceptibility testing of Haemophilus influenzae

We compared results of MIC and disk susceptibility tests on Haemophilus test medium (HTM) and those on comparative media. Ampicillin MICs were determined with seven ampicillin-resistant, non-beta-lactamase-producing (AmprNBLP) isolates by using HTM and supplemented brain heart infusion (sBHI) agar. Ampicillin and amoxicillin-clavulanate disk tests with 16 AmprNBLP strains, 18 ampicillin-susceptible (Amps) isolates, and 17 ampicillin-resistant, beta-lactamase-producing (AmprBLP) strains were performed by using five media: laboratory-prepared HTM (PHTM), commercial HTM (CHTM), sBHI, enriched chocolate agar, and Mueller-Hinton chocolate agar. We observed that five of seven and three of seven AmprNBLP strains were misclassified as susceptible with PHTM (MIC, less than 2 micrograms/ml) with inocula of 10(3) and 10(5) CFU, respectively, but were resistant with sBHI (MIC, greater than or equal to 2 micrograms/ml). Whereas Mueller-Hinton chocolate agar and enriched chocolate agar plates supported the growth of all 51 strains by the disk tests, 37% (19 of 51) and 8% (4 of 51) of strains did not grow on PHTM and CHTM, respectively. Lack of growth on PHTM was observed for all three phenotypes; 7 of 18 Amps, 4 of 17 AmprBLP, and 8 of 16 AmprNBLP strains did not grow. The four strains that did not grow on CHTM were all AmprNBLP isolates. Zone sizes were significantly larger on PHTM than on the other media. Of the strains that were evaluable by the new National Committee for Clinical Laboratory Standards guidelines with either PHTM or CHTM, all Amps strains were classified as susceptible. Among the AmprBLP strains, CHTM correctly identified all as resistant, whereas PHTM detected two isolates to be intermediate. Among the AmprNBLP strains, CHTM and PHTM misclassified four (33%) and five (62%) isolates, respectively, as susceptible; an additional isolate was identified as intermediate on both media. We conclude that there is strain-dependent growth on HTM, that adoption of this medium for routine Haemophilus susceptibility testing is problematic due to this growth variability, and that detection of AmprNBLP isolates would be unreliable.     

In vitro activity of ceftibuten against Haemophilus influenzae and Branhamella catarhallis

The in vitro activity of ceftibuten, a new orally administered cephalosporin, was assessed against clinical isolates of Haemophilus influenzae and Branhamella catarrhalis. The activity of ceftibuten was compared to that of ampicillin, amoxicillin-clavulanic acid, and three oral cephalosporins, cefaclor, cefuroxime, and cefixime. With the exception of rare beta-lactamase-negative ampicillin-resistant strains of H. influenzae, resistance to ceftibuten was not observed with any of the study isolates. Ceftibuten was more active than amoxicillin/clavulanic acid for beta-lactamase-positive and -negative strains of H. influenzae; it was less active than this combination for B. catarrhalis. Ceftibuten was essentially equivalent in activity to cefixime against both Haemophilus and Branhamella but more active than cefaclor and cefuroxime against these two organisms.     

Antimicrobial activity and disk diffusion susceptibility testing of U-76,253A (R-3746), the active metabolite of the new cephalosporin ester, U-76,252 (CS-807).

Compound U-76,253A (R-3746), the active metabolite sodium salt of the prodrug ester U-76,252 (CS-807), was demonstrated to be active against members of the family Enterobacteriaceae with 82 and 85% of strains inhibited by less than or equal to 2.0 and less than or equal to 4.0 micrograms/ml, respectively. In addition, U-76,253A inhibited all strains of Branhamella catarrhalis, Haemophilus influenzae, pathogenic Neisseria spp., oxacillin-susceptible Staphylococcus aureus, beta-hemolytic streptococci, and pneumococci at less than or equal to 4.0 micrograms/ml. Pseudomonas spp., Acinetobacter spp., enterococci, and oxacillin-resistant staphylococci were resistant to U-76,253A. This U-76,253A antimicrobial activity and spectrum was generally superior to that of comparison orally administered cephems (cefaclor, cefuroxime, and cefixime) and the amoxicillin-clavulanic acid combination. Tests with beta-lactamase-producing isolates indicated that U-76,253A was bactericidal and that its MICs were only influenced by high inoculum concentrations (10(7) CFU/ml) against type Ia and IVc enzyme-producing strains. Preliminary disk diffusion interpretive zone criteria were calculated for 10- and 30-micrograms U-76,253A disks and several possible susceptible MIC breakpoints. The absolute interpretive agreement between MICs and zone diameters ranged from 87.8 to 95.6%. Final selection of interpretive criteria awaits further U-76,252 pharmacokinetic information.     

Activities and postantibiotic effects of gemifloxacin compared to those of 11 other agents against Haemophilus influenzae and Moraxella catarrhalis

The activity of gemifloxacin against Haemophilus influenzae and Moraxella catarrhalis was compared to those of 11 other agents. All quinolones were very active (MICs, 相似文献   

Activities of ceftobiprole, a novel broad-spectrum cephalosporin, against Haemophilus influenzae and Moraxella catarrhalis

Ceftobiprole, a broad-spectrum pyrrolidinone-3-ylidenemethyl cephem currently in phase III clinical trials, had MICs between 0.008 microg/ml and 8.0 microg/ml for 321 clinical isolates of Haemophilus influenzae and between < or =0.004 microg/ml and 1.0 microg/ml for 49 clinical isolates of Moraxella catarrhalis. Ceftobiprole MIC(50) and MIC(90) values for H. influenzae were 0.06 microg/ml and 0.25 microg/ml for beta-lactamase-positive strains (n = 262), 0.03 microg/ml and 0.25 microg/ml for beta-lactamase-negative strains (n = 40), and 0.5 microg/ml and 2.0 microg/ml for beta-lactamase-negative ampicillin-resistant strains (n = 19), respectively. Ceftobiprole MIC(50) and MIC(90) values for beta-lactamase-positive M. catarrhalis strains (n = 40) were 0.12 microg/ml and 0.5 microg/ml, respectively, whereas the ceftobiprole MIC range for beta-lactamase-negative M. catarrhalis strains (n = 9) was < or =0.004 to 0.03 microg/ml. Ceftriaxone MICs usually were generally at least twofold lower than those of ceftobiprole, whereas amoxicillin-clavulanate MICs usually were higher than those of ceftobiprole. Azithromycin and telithromycin had unimodal MIC distributions against H. influenzae, with MIC(90) values of azithromycin and telithromycin of 2 microg/ml and 4 microg/ml, respectively. Except for selected quinolone-nonsusceptible H. influenzae strains, moxifloxacin proved highly active, with MIC(90) values of 0.12 microg/ml. Time-kill analyses showed that ceftobiprole, ceftriaxone, cefpodoxime, amoxicillin-clavulanate, azithromycin, telithromycin, and moxifloxacin were bactericidal at 2x MIC by 24 h against all 10 H. influenzae strains surveyed. Only modest increases in MICs were found for H. influenzae or M. catarrhalis clones after 50 serial passages in the presence of subinhibitory concentrations of ceftobiprole, and single-passage selection showed that the selection frequency of H. influenzae or M. catarrhalis clones with elevated ceftobiprole MICs is quite low.     

Antibacterial activities of cefpodoxime, cefixime, and ceftriaxone.

Cefpodoxime, cefixime, and ceftriaxone inhibited Branhamella catarrhalis at less than or equal to 1 microgram/ml, beta-hemolytic streptococci at less than or equal to 0.25 microgram/ml, Neisseria meningitidis at less than or equal to 0.06 microgram/ml, and Haemophilus influenzae (other than beta-lactamase-negative, ampicillin-resistant isolates) at less than or equal to 0.12 microgram/ml. The MICs for 50% of isolates of the family Enterobacteriaceae other than Citrobacter freundii, Enterobacter aerogenes, and Enterobacter cloacae were less than or equal to 1 microgram/ml for all three cephalosporins. The MICs of each cephalosporin for 90% of staphylococci, enterococci, and Pseudomonas aeruginosa isolates were greater than 16 micrograms/ml. Inoculum effects were noted with cefpodoxime and cefixime with beta-lactamase-positive H. influenzae.     

The in-vitro activity of cefpodoxime: a comparison with other oral cephalosporins

The in-vitro activity of cefpodoxime was studied in 529 clinical isolates and compared with the activity of other oral beta-lactams. Amongst the Enterobacteriaceae cefpodoxime was very active (MIC90 less than or equal to 1 mg/l--other than genera commonly possessing chromosomal beta-lactamases). Against these strains cefpodoxime was comparable in activity to cefixime and about eight-fold more active than cefuroxime and 8-16-fold more active than cefaclor and cephalexin. Staphylococcus aureus strains were moderately susceptible (MIC90 4 mg/l) to cefpodoxime in comparison with cefixime (16 mg/l). The respiratory pathogens, Haemophilus influenzae, Streptococcus pneumoniae and Branhamella catarrhalis were susceptible to less than or equal to 0.5 mg/l cefpodoxime. An increase in inoculum from 10(4) to 10(6) cfu had little effect upon activity. Studies in beta-lactamase hydrolysis of cefpodoxime showed it to be stable to TEM-1, SHV-1 and BRO-1 enzymes but with high affinity for the P99 enzyme. The primary target of cefpodoxime is PBP3 (I50 1 mg/l) in Escherichia coli K12. The protein binding of the agent to human serum was 14.3-18.3% at 1 and 5 mg/l respectively.     

Antimicrobial activity, spectrum, and recommendations for disk diffusion susceptibility testing of ceftibuten (7432-S; SCH 39720), a new orally administered cephalosporin.

The antimicrobial activity and spectrum of ceftibuten (7432-S; SCH 39720) was determined on a wide variety of bacterial species selected for resistance to oral and parenteral beta-lactam antimicrobial agents. Ceftibuten was found to be the most active beta-lactam tested against members of the family Enterobacteriaceae, inhibiting 81.6% of strains at less than or equal to 8.0 micrograms/ml compared with 75.0 and 54.8% of strains inhibited by cefixime and cefuroxime, respectively. All strains of Haemophilus influenzae (MIC for 90% of strains [MIC90], less than or equal to 0.06 microgram/ml), Branhamella catarrhalis (MIC90, 3.0 micrograms/ml), and pathogenic Neisseria spp. (MIC90, less than or equal to 0.06 and 0.019 microgram/ml) were susceptible to ceftibuten. Beta-hemolytic Streptococcus spp. (serogroups A, B, C, and G) were also inhibited by ceftibuten, but penicillin-resistant pneumococci were generally resistant to cefixime and ceftibuten. The activity and spectrum of ceftibuten seem most applicable to infections of the respiratory and urinary tract plus those infections caused by pathogenic Neisseria spp. Ceftibuten disks (30 micrograms) were evaluated and found to have an acceptable correlation (r = 0.88) with ceftibuten MICs. Preliminary zone size interpretive criteria for MIC breakpoints of less than or equal to 4.0 and less than or equal to 8.0 micrograms/ml were calculated.     

Comparative antimicrobial spectrum and activity of ceftibuten against clinical isolates from West Germany

The in vitro activity of a new oral cephalosporin, ceftibuten, was determined against 837 clinical isolates by agar dilution technique and compared with that of the oral cephalosporins, cefaclor, cefuroxime, cefixime, cefpodoxime, and cefprozil. Against Enterobacteriaceae, ceftibuten was the most active of the compounds. Ceftibuten MIC90s were less than or equal to 0.25 micrograms/ml for most members of the family Enterobacteriaceae, 0.13 microgram/ml for Haemophilus influenzae, 4 micrograms/ml for Moraxella catarrhalis, and 0.5 microgram/ml for Neisseria gonorrhoeae. Ceftibuten also was active against beta-haemolytic streptococci (serogroups A, C, and G) and penicillin-susceptible strains of Streptococcus pneumoniae (MIC90, 4 micrograms/ml), but was not active against Staphylococcus spp. or the anaerobic bacteria studied. Cefpodoxime and cefuroxime were the most active of the cephalosporins against nonenteric streptococci; cefprozil and cefuroxime were the most active against staphylococci, and cefaclor demonstrated the greatest activity against some Bacteroides spp. Most strains of Acinetobacter baumanii, Pseudomonas spp., and methicillin-resistant staphylococci, as well as all strains of Clostridium difficile, were resistant to each of the cephalosporins tested.     

Comparative bactericidal activity of cefixime, carumonam, enoxacin and roxithromycin with those of other antibiotics against resistant Haemophilus influenzae including beta-lactam tolerant strains

One hundred isolates of Haemophilus influenzae including 50 beta-lactamase producing, five ampicillin-resistant non-beta-lactamase producing and five beta-lactam tolerant strains were tested for susceptibility (MICs and MBCs) to ampicillin, aztreonam, carumonam, cefixime, cefaclor, cefamandole, cefotaxime, imipenem, enoxacin, ciprofloxacin, roxithromycin, erythromycin, chloramphenicol, and co-trimoxazole, by a microdilution broth method. Cefotaxime, enoxacin and ciprofloxacin with MIC90 and MBC90 of less than 0.03 mg/l) were the most active antimicrobial agents tested. Cefixime, carumonam, aztreonam, and co-trimoxazole (MIC90 and MBC90 less than 0.25 mg/l) showed good activity against most strains. Roxithromycin and erythromycin had limited antibacterial activity (MIC90, 8 and 4 mg/l respectively). There were no chloramphenicol-resistant strains. Five beta-lactamase-negative strains were resistant to ampicillin, cefaclor and cefamandole but susceptible to other beta-lactams tested. Different patterns of tolerance were observed: four of five tolerant strains were tolerant to ampicillin and cefamandole, three to cefixime, cefaclor and cefotaxime, one to aztreonam. One tolerant strain was a beta-lactamase producer. Two other strains were tolerant only to co-trimoxazole.     

In vitro activity of RU29246. The metabolite of a new HR916 cephalosporin ester.

Compound RU29246 (RU) is the active metabolite of an orally absorpted cephalosporin ester HR916. The RU spectrum of activity includes the majority of Enterobacteriaceae species, Haemophilus influenzae, pathogenic Neisseria spp., Moraxella catarrhalis, Acinetobacter antiratus, staphylococci, and Streptococcus spp. Pseudomonas species and enterococci were routinely resistant to RU. The RU spectrum was most similar to cefixime against the Gram-negative bacilli and to cefuroxime against the Gram-positive organisms. RU was bactericidal and its mean inhibitory concentrations (MICs) were not greatly increased by high inoculum concentrations. Many strains producing various beta-lactamases generally remained susceptible to RU by MIC tests. However, isolates with extended broad spectrum beta-lactamases capable of hydrolyzing cefotaxime and ceftazidime were also resistant to RU. Broth and agar RU MICs were comparable. Its activity was increased against enterococci in the presence of blood products.     

Determination of the in vivo pharmacodynamic profile of cefepime against extended-spectrum-beta-lactamase-producing Escherichia coli at various inocula

Cefepime was evaluated in vivo against two inoculum sizes of four strains of Escherichia coli that produced extended-spectrum beta-lactamases (ESBLs) in a murine neutropenic thigh infection model to characterize the pharmacodynamic activity of cefepime in the presence of ESBL-producing bacteria and to evaluate if differences in lengths of cefepime exposure are required with various inocula. Three strains possessed a single enzyme each: TEM-10, TEM-12, and TEM-26. The fourth strain possessed two TEM-derived ESBLs and a third uncharacterized enzyme. Two non-ESBL-producing E. coli strains were included for comparison. Mice received various doses of cefepime to achieve a spectrum of percentages of time the drug was above the MIC (%T>MICs) for each isolate at both inocula. No significant difference in cefepime exposure was required to achieve similar bactericidal effects for ESBL- and non-ESBL-producing isolates when the starting inoculum was 10(5) CFU of E. coli per thigh. The increased MICs observed in vitro for the ESBL-producing strains at 10(7) CFU/ml did not predict the amount of exposure required to achieve a comparable level of bactericidal activity in vivo at the corresponding starting inoculum of 10(7) CFU/thigh. Compared to the cefepime exposure in tests with the lower inoculum (10(5) CFU/thigh), less exposure was required when the starting inoculum was 10(7) CFU/thigh (%T>MIC, 6% versus 26%), such that similar doses (in milligrams per kilogram of body weight) produced similar bactericidal effects with both inocula of ESBL-producing isolates. Equivalent exposures of cefepime produced similar effects against the microorganisms regardless of the presence of ESBL production. Pharmacodynamic profiling undertaken with conventional cefepime MIC determinations predicted in vivo microbial outcomes at both inoculum sizes for the ESBL-producing isolates evaluated in this study. These data support the use of conventional MIC determinations in the pharmacodynamic assessment of cefepime.     

Amino acid substitutions in mosaic penicillin-binding protein 2 associated with reduced susceptibility to cefixime in clinical isolates of Neisseria gonorrhoeae

The molecular mechanisms of reduced susceptibility to cefixime in clinical isolates of Neisseria gonorrhoeae, particularly amino acid substitutions in mosaic penicillin-binding protein 2 (PBP2), were examined. The complete sequence of ponA, penA, and por genes, encoding, respectively, PBP1, PBP2, and porin, were determined for 58 strains isolated in 2002 from Japan. Replacement of leucine 421 by proline in PBP1 and the mosaic-like structure of PBP2 were detected in 48 strains (82.8%) and 28 strains (48.3%), respectively. The presence of mosaic PBP2 was the main cause of the elevated cefixime MIC (4- to 64-fold). In order to identify the mutations responsible for the reduced susceptibility to cefixime in isolates with mosaic PBP2, penA genes with various mutations were transferred to a susceptible strain by genetic transformation. The susceptibility of partial recombinants and site-directed mutants revealed that the replacement of glycine 545 by serine (G545S) was the primary mutation, which led to a two- to fourfold increase in resistance to cephems. Replacement of isoleucine 312 by methionine (I312M) and valine 316 by threonine (V316T), in the presence of the G545S mutation, reduced susceptibility to cefixime, ceftibuten, and cefpodoxime by an additional fourfold. Therefore, three mutations (G545S, I312M, and V316T) in mosaic PBP2 were identified as the amino acid substitutions responsible for reduced susceptibility to cefixime in N. gonorrhoeae.     

Ceftibuten: a new orally absorbed cephalosporin. In vitro activity against strains from the United Kingdom

The in vitro activity of ceftibuten was studied in 572 bacterial strains and was compared with the activity of other orally administered beta-lactams. Ceftibuten displayed high activity against the Enterobacteriaceae, generally being 16-fold more active than cefuroxime, cefaclor, cephalexin, or amoxicillin-clavulanic acid. Its activity was comparable to cefixime. There was little ceftibuten or cefixime activity against staphylococci (MIC90s greater than or equal to 64 micrograms/ml) and reduced activity against Streptococcus pneumoniae (MIC90, 16 micrograms/ml). Haemophilus influenzae and Neisseria spp. were highly susceptible to ceftibuten and cefixime. The protein binding of ceftibuten was 77%, and the primary target site was PBP 3. A high degree of stability to beta-lactamase hydrolysis was observed.     

In vitro susceptibility of Haemophilus influenzae to cefixime.

The in vitro activity of cefixime against 2,458 clinical isolates of Haemophilus influenzae was determined. All the strains were inhibited by less than or equal to 2 micrograms of cefixime per ml, and the modal MIC was 0.03 micrograms/ml. Activity was unaffected by the presence of beta-lactamase produced by 157 isolates. Nineteen of the twenty-four isolates for which cefixime MICs were greater than or equal to 0.5 micrograms/ml were beta-lactamase negative but showed reduced susceptibility to ampicillin.     

Activity of LBM415 compared to those of 11 other agents against Haemophilus species

When tested against 254 Haemophilus influenzae strains, LBM415, a peptide deformylase inhibitor, gave MIC50 and MIC90 values of 2.0 microg/ml and 8.0 microg/ml, respectively. The MICs were independent of beta-lactam or quinolone susceptibility and the presence or absence of macrolide efflux or ribosomal protein mutations. The MICs of LBM415 against 23 H. parainfluenzae strains were similar to those against H. influenzae. In contrast, erythromycin, azithromycin, and clarithromycin gave unimodal MIC distributions, and apart from beta-lactamase-negative, ampicillin-resistant strains, all strains were susceptible to the beta-lactams tested. Apart from selected quinolone-resistant strains, all strains were susceptible to ciprofloxacin, levofloxacin, gatifloxacin, moxifloxacin, and gemifloxacin. Resistance to trimethoprim-sulfamethoxazole was common. The potencies of all drugs against 23 H. parainfluenzae strains were similar to those against H. influenzae. Time-kill studies with 10 Haemophilus strains showed LBM415 to be bactericidal at 2 x the MIC against 8 of 10 strains after 24 h. For comparison, the macrolides and beta-lactams were bactericidal against 8 to 10 strains each at 2 x the MIC after 24 h. Quinolones were bactericidal against all 10 strains tested at 2 x the MIC after 24 h. Against six H. influenzae strains, postantibiotic effects for LBM415 lasted between 0.8 and 2.2 h. In multistep resistance selection studies, LBM415 produced resistant clones in 7 of the 10 strains tested, with MICs ranging from 4 to 64 microg/ml. No mutations in deformylase (def) and formyltransferase (fmt) genes were detected in any of the LBM415-resistant mutants.     

In vitro activity of cefprozil (BMY 28100) and cefepime (BMY 28142) against Streptococcus pneumoniae, Branhamella catarrhalis, and Haemophilus influenzae, and provisional interpretive criteria for disk diffusion and dilution susceptibility tests with Haemophilus influenzae.

The in vitro activities of two new cephalosporins, an oral agent, cefprozil and a parenteral compound, cefepime, were assessed against recent clinical isolates of Streptococcus pneumoniae, Moraxella (Branhamella) catarrhalis, and Haemophilus influenzae. In general, both cefprozil and cefepime MICs were higher for beta-lactamase-producing strains of M. catarrhalis in comparison to strains that lacked beta-lactamase. By contrast, beta-lactamase-positive and -negative strains of H. influenzae had similar cefprozil and cefepime minimum inhibitory concentrations (MICs). The MIC90 values for cefprozil were 0.12, 32, 4.0, and 0.5 micrograms/ml versus S. pneumoniae, H. influenzae, and beta-lactamase-positive and negative strains of M. catarrhalis, respectively. In comparison to three other oral cephalosporins included in this study, cefaclor, cefuroxime axetil, and cefixime, cefprozil was the most active agent against S. pneumoniae, the least active against B. catarrhalis, and equivalent in activity to cefaclor against H. influenzae. The cefepime MIC values against S. pneumoniae, H. influenzae, and beta-lactamase-positive and negative strains of M. catarrhalis were 0.03, 0.25, 2.0, and 0.5 micrograms/ml, respectively. Cefepime was less active than ceftriaxone for all three organism groups, however, was in all cases more active than cefixime, cefuroxime, cefaclor, and cefprozil.(ABSTRACT TRUNCATED AT 250 WORDS)     

Susceptibilities of Haemophilus influenzae and Moraxella catarrhalis to ABT-773 compared to their susceptibilities to 11 other agents

The activity of the ketolide ABT-773 against Haemophilus and Moraxella was compared to those of 11 other agents. Against 210 Haemophilus influenzae strains (39.0% beta-lactamase positive), microbroth dilution tests showed that azithromycin and ABT-773 had the lowest MICs (0.5 to 4.0 and 1.0 to 8.0 microg/ml, respectively), followed by clarithromycin and roxithromycin (4.0 to >32.0 microg/ml). Of the beta-lactams, ceftriaxone had the lowest MICs (32.0 microg/ml). Against 50 Moraxella catarrhalis strains, all of the compounds except amoxicillin and cefprozil were active. Time-kill studies against 10 H. influenzae strains showed that ABT-773, at two times the MIC, was bactericidal against 9 of 10 strains, with 99% killing of all strains at the MIC after 24 h; at 12 h, ABT-773 gave 90% killing of all strains at two times the MIC. At 3 and 6 h, killing by ABT-773 was slower, with 99.9% killing of four strains at two times the MIC after 6 h. Similar results were found for azithromycin, with slightly slower killing by erythromycin, clarithromycin, and roxithromycin, especially at earlier times. beta-Lactams were bactericidal against 8 to 10 strains at two times the MIC after 24 h, with slower killing at earlier time periods. Most compounds gave good killing of five M. catarrhalis strains, with beta-lactams killing more rapidly than other drugs. ABT-773 and azithromycin gave the longest postantibiotic effects (PAEs) of the ketolide-macrolide-azalide group tested (4.4 to >8.0 h), followed by clarithromycin, erythromycin, and roxithromycin. beta-Lactam PAEs were similar and shorter than those of the ketolide-macrolide-azalide group for all strains tested.     

Ceftibuten and bactericidal kinetics. Comparative in vitro activity against Enterobacteriaceae producing extended spectrum beta-lactamases

Ceftibuten, compared to cefixime, cefetamet, cefpodoxime, loracarbef, cefprozil, cefuroxime, cefaclor, and cefadroxil, was the most active oral cephalosporin derivative against Enterobacteriaceae producing plasmid-encoded broad spectrum beta-lactamases. In a pharmacodynamic model, ceftibuten was bactericidal for Haemophilus influenzae and Streptococcus pneumoniae at concentrations simulating human serum levels following 200 mg, p.o., b.i.d.     

In vitro selection of resistance in haemophilus influenzae by 4 quinolones and 5 beta-lactams

We tested abilities of ciprofloxacin, levofloxacin, gatifloxacin, moxifloxacin, amoxicillin, amoxicillin/clavulanate, cefixime, cefpodoxime, and cefdinir to select resistant mutants in 5 beta-lactamase positive and 5 beta-lactamase negative Haemophilus influenzae strains by single and multistep methodology. In multistep tests, amoxicillin, amoxicillin/clavulanate and cefpodoxime exposure did not cause >4-fold minimum inhibitory concentration (MIC) increase after 50 days. One mutant selected by cefdinir had one amino acid substitution (Gly490Glu) in PBP3 and became resistant to cefdinir. Cefixime exposure caused 8-fold MIC-increase in 1 strain with TEM but the mutant remained cefixime susceptible and had no alteration in PBP3 or TEM. Among 10 strains tested, ciprofloxacin, moxifloxacin, gatifloxacin, levofloxacin caused >4-fold MIC increase in 6, 6, 5, and 2 strain, respectively. Despite the increases in quinolone MICs, none of the mutants became resistant to quinolones by established criteria. Quinolone selected mutants had quindone resistance-determining region (QRDR) alterations in GyrA, GyrB, ParC, ParE. Four quinolone mutants had no QRDR alterations. Among beta-lactams cefdinir and cefixime selected one mutant each with higher MICs however amoxicillin, amoxicillin/clavulanate, and cefpodoxime exposure did not select resistant mutants.