Antibacterial Effects of Amoxicillin-Clavulanate against Streptococcus pneumoniae and Haemophilus influenzae Strains for Which MICs Are High, in an In Vitro Pharmacokinetic Model

ABSTRACT The antibacterial effect of amoxicillin-clavulanate in two formulations, pharmacokinetically enhanced 16:1 amoxicillin-clavulanate twice a day (b.i.d.) and standard 7:1 amoxicillin-clavulanate b.i.d., were studied in an in vitro pharmacokinetic model of infection. Five strains of Streptococcus pneumoniae and two of Haemophilus influenzae, all associated with raised MICs (2 to 8 mg/liter), were used. The antibacterial effect was measured over 24 h by the area under the bacterial kill curve (AUBKC) and the log change in viable count at 24 h (Δ24). A high 108 CFU/ml and low 106 CFU/ml initial inocula were used. Employing the Δ24 effect measure, the time above MIC (T>MIC) 50% maximum effect (EC50) for S. pneumoniae was in the range 21 to 28% with an 80% maximal response of 41 to 51%, for the AUBKC measure, the value was 26 to 39%, irrespective of inoculum. For H. influenzae, the T>MIC EC50 was 28 to 37%, and the 80% maximum response was 32 to 48% for the Δ24 measure and 20 to 48% for AUBKC. The maximum response occurred at a T>MIC of 50 to 60% for both species and inocula. The S. pneumoniae data were analyzed by analysis of variance to assess the effect of inoculum, formulation, and MIC on antibacterial effect. Standard and enhanced formulations had different effects depending on MIC, with the standard formulation less effective at higher amoxicillin-clavulanate MICs. This is explained by the greater T>MICs of the enhanced formulation. Although resistant to amoxicillin-clavulanate by conventional breakpoints, S. pneumoniae and H. influenzae strains for which MICs are 2 or 4 mg/liter may well respond to therapy with pharmacokinetically enhanced formulation amoxicillin-clavulanate.

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1582. Delafloxacin Activity Against Drug-Resistant Streptococcus pneumoniae, Haemophilus influenzae, Haemophilus parainfluenzae, and Moraxella catarrhalis from US Medical Centers (2014–2018)

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz360.1446 ◽

2019 ◽

Vol 6 (Supplement_2) ◽

pp. S577-S578

Author(s):

Dee Shortridge ◽

Jennifer M Streit ◽

Michael D Huband ◽

Robert K Flamm

Keyword(s):

Streptococcus Pneumoniae ◽

Haemophilus Influenzae ◽

Moraxella Catarrhalis ◽

Active Agent ◽

The United States ◽

Multidrug Resistant ◽

In Vitro Susceptibility ◽

Amoxicillin Clavulanate ◽

Tract Infections

Abstract Background Delafloxacin (DLX) is an anionic fluoroquinolone (FQ) antimicrobial that was approved in 2017 by the United States (US) Food and Drug Administration for the treatment of acute bacterial skin and skin structure infections. DLX recently successfully completed a clinical trial for the treatment of community-acquired bacterial pneumonia (CABP). In the present study, in vitro susceptibility (S) results for DLX and comparator agents were determined for CABP pathogens including Streptococcus pneumoniae (SPN), Haemophilus influenzae (HI), H. parainfluenzae (HP) and Moraxella catarrhalis (MC) clinical isolates from US hospitals participating in the SENTRY Program during 2014–2018. Methods A total of 1,975 SPN, 1,128 HI, 684 MC, and 43 HP isolates were collected from community-acquired respiratory tract infections (CARTI) during 2014–2018 from US hospitals. Sites included only 1 isolate/patient/infection episode. Isolate identifications were confirmed at JMI Laboratories. Susceptibility testing was performed according to CLSI broth microdilution methodology, and CLSI (2019) breakpoints were applied where applicable. Other antimicrobials tested included levofloxacin (LEV) and moxifloxacin (MOX; not tested in 2015). Multidrug-resistant (MDR) SPN isolates were categorized as being nonsusceptible (NS) to amoxicillin-clavulanate, erythromycin, and tetracycline; other SPN phenotypes were LEV-NS or penicillin (PEN)-NS. β-Lactamase (BL) presence was determined for HI, HP, and MC. Results The activities of the 3 FQs are shown in the table. The most active agent against SPN was DLX, with the lowest MIC50/90 values of 0.015/0.03 mg/L. DLX activities were similar when tested against the MDR or PEN-NS for SPN phenotypes. LEV-NS isolates had DLX MIC50/90 results of 0.12/0.25 mg/L. DLX was the most active FQ against HI, HP, and MC. BL presence did not affect FQ MIC values for HI or MC; only 2 HP isolates were BL-positive. Conclusion DLX demonstrated potent in vitro antibacterial activity against SPN, HI, HP, and MC. DLX was active against MDR SPN that were NS to the agents commonly used as treatments for CABP. DLX had excellent activity against LEV-NS SPN. These data support the continued study of DLX as a potential treatment for CABP. Disclosures All authors: No reported disclosures.

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Mechanism of Fluoroquinolone Resistance Is an Important Factor in Determining the Antimicrobial Effect of Gemifloxacin against Streptococcus pneumoniae in an In Vitro Pharmacokinetic Model

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.47.3.1096-1100.2003 ◽

2003 ◽

Vol 47 (3) ◽

pp. 1096-1100 ◽

Cited By ~ 7

Author(s):

Alasdair P. MacGowan ◽

Karen E. Bowker

Keyword(s):

Streptococcus Pneumoniae ◽

Pharmacokinetic Model ◽

Drug Exposure ◽

Antibacterial Effect ◽

Population Analysis ◽

Antimicrobial Effect ◽

Fluoroquinolone Resistance ◽

Mechanism Of Resistance ◽

Emergence Of Resistance

ABSTRACT Antibacterial effect and emergence of resistance to gemifloxacin and levofloxacin were studied in an in vitro pharmacokinetic model of infection. A panel of Streptococcus pneumoniae strains with known mechanisms of resistance were used; two strains had no known resistance mechanism, two had efflux pumps, three had gyrA plus parC mutations, and one had only a parC mutation. Gemifloxacin MICs were in the range of 0.016 to 0.25 mg/liter, and levofloxacin MICs ranged from 1 to 16 mg/liter. Antimicrobial effect was measured by area under the bacterial-kill curve up to 72 h, and emergence of resistance was determined by population analysis profile before and during drug exposure. The area under the curve (AUC)/MIC ratios for gemifloxacin and levofloxacin were 35 to 544 and 3 to 48, respectively. As expected on the basis of these AUC/MIC ratio differences, antibacterial effect was much greater for gemifloxacin than levofloxacin. In the gemifloxacin simulations, mechanism of resistance as well as MIC determined the antibacterial effect, as indicated by gemifloxacin’s greater effect against efflux strains compared to those with gyrA or parC mutations despite similar MICs. This was not true of levofloxacin. Emergence of resistance was not easily demonstrated with either agent, and mechanism of resistance did not have any impact on it.

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Pharmacodynamics of Moxifloxacin against Anaerobes Studied in an In Vitro Pharmacokinetic Model

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.49.10.4234-4239.2005 ◽

2005 ◽

Vol 49 (10) ◽

pp. 4234-4239 ◽

Cited By ~ 18

Author(s):

Alan R. Noel ◽

Karen E. Bowker ◽

Alasdair P. MacGowan

Keyword(s):

Pharmacokinetic Model ◽

Antibacterial Effect ◽

Maximum Effect ◽

Wild Type ◽

Time Curve ◽

Concentration Time ◽

Effect Measure ◽

Dose Ranging ◽

Emergence Of Resistance

ABSTRACT The antibacterial effects of moxifloxacin against Bacteroides fragilis, Clostridium perfringens, and gram-positive anaerobic cocci (GPAC) were studied in an in vitro pharmacokinetic model. Initially, a dose-ranging study with area under the concentration-time curve (AUC)/MIC ratios of 6.7 to 890 was used to investigate the effect of anaerobic conditions on the AUC/MIC antibacterial effect (ABE) relationship with Escherichia coli. The AUC/MIC ratios for 50% and 90% effects, using a log CFU drop at 24 h as the antibacterial effect measure, were 34 and 59, respectively, aerobic and 54 and 96, respectively, anaerobic. These values are not significantly different. Dose ranging at AUC/MIC ratios of 9 to 216 against the anaerobes indicated a differing AUC/MIC ABE pattern, and the AUC/MICs for 50% and 90% effects were lower: for B. fragilis, they were 10.5 and 25.7, respectively; for C. perfringens, they were 8.6 and 16.2; and for GPAC, they were 7.3 and 17.4. The maximum-effect log drops were as follows: for B. fragilis, −3.2 ± 0.2 logs; for C. perfringens, −3.7 ± 0.1 logs; and for GPAC, −2.5 ± 0.1 logs. Although the anaerobes were not eradicated, there was no emergence of resistance. Comparison of the ABE of moxifloxacin to that of ertapenem against B. fragilis indicated that moxifloxacin was superior at 24 h and 48 h. In contrast, ertapenem was superior to moxifloxacin against GPAC at 24 h and 48 h and against C. perfringens at 48 h. Both drugs performed equivalently against C. perfringens at 24 h. Monte Carlo simulations using human serum AUC data and an AUC/MIC anaerobe target of 7.5 suggests a >90% target achievement at MICs of <2 mg/liter. This divides the B. fragilis wild-type MIC distribution. The pharmacodynamic properties of moxifloxacin against anaerobes are different than those against aerobic species. The clinical implications of these differences need further exploration.

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Bacteriological Efficacies of Three Macrolides Compared with Those of Amoxicillin-Clavulanate againstStreptococcus pneumoniae and Haemophilus influenzae

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.42.12.3193 ◽

1998 ◽

Vol 42 (12) ◽

pp. 3193-3199 ◽

Cited By ~ 18

Author(s):

Valerie Berry ◽

Christine E. Thorburn ◽

Sarah J. Knott ◽

Gary Woodnutt

Keyword(s):

Respiratory Tract ◽

Haemophilus Influenzae ◽

Respiratory Tract Infections ◽

Antibacterial Effect ◽

Empiric Therapy ◽

Once Daily ◽

Amoxicillin Clavulanate ◽

Tract Infections

ABSTRACT Comparative antibacterial efficacies of erythromycin, clarithromycin, and azithromycin were examined againstStreptococcus pneumoniae and Haemophilus influenzae, with amoxicillin-clavulanate used as the active control. In vitro, the macrolides at twice their MICs and at concentrations achieved in humans were bacteriostatic or reduced the numbers of viable S. pneumoniae slowly, whereas amoxicillin-clavulanate showed a rapid antibacterial effect. AgainstH. influenzae, erythromycin, clarithromycin, and clarithromycin plus 14-hydroxy clarithromycin at twice their MICs produced a slow reduction in bacterial numbers, whereas azithromycin was bactericidal. Azithromycin at the concentrations achieved in the serum of humans was bacteriostatic, whereas erythromycin and clarithromycin were ineffective. In experimental respiratory tract infections in rats, clarithromycin (equivalent to 250 mg twice daily [b.i.d.]) and amoxicillin-clavulanate (equivalent to 500 plus 125 mg b.i.d., respectively) were highly effective against S. pneumoniae, but azithromycin (equivalent to 500 and 250 mg once daily) was significantly less effective (P < 0.01). Against H. influenzae, clarithromycin treatment (equivalent to 250 or 500 mg b.i.d.) was similar to no treatment and was significantly less effective than amoxicillin-clavulanate treatment (P < 0.01). Azithromycin demonstrated significant in vivo activity (P < 0.05) but was significantly less effective than amoxicillin-clavulanate (P < 0.05). Overall, amoxicillin-clavulanate was effective in vitro and in vivo. Clarithromycin and erythromycin were ineffective in vitro and in vivo against H. influenzae, and azithromycin (at concentrations achieved in humans) showed unreliable activity against both pathogens. These results may have clinical implications for the utility of macrolides in the empiric therapy of respiratory tract infections.

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Comparative in vitro study of the activity of moxifloxacin and other antibiotics against 150 strains of penicillin non-susceptible Streptococcus pneumoniae and against 110 strains of ampicillin-resistant Haemophilus influenzae isolated in 1999-2000 in Spain

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/48.1.145 ◽

2001 ◽

Vol 48 (1) ◽

pp. 145-148 ◽

Cited By ~ 6

Author(s):

J. I. Alos

Keyword(s):

Streptococcus Pneumoniae ◽

Haemophilus Influenzae ◽

In Vitro Study ◽

Vitro Study

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Pharmacodynamics of Razupenem (PZ601) Studied in anIn VitroPharmacokinetic Model of Infection

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00936-10 ◽

2011 ◽

Vol 55 (4) ◽

pp. 1436-1442 ◽

Cited By ~ 16

Author(s):

Alasdair P. MacGowan ◽

Alan Noel ◽

Sharon Tomaselli ◽

Heather Elliott ◽

Karen Bowker

Keyword(s):

Antibacterial Effect ◽

Population Analysis ◽

Viable Count ◽

Bacteriostatic Effect ◽

Series Of Experiments ◽

Initial Clearance ◽

Mrsa Strains ◽

Unit Reduction ◽

Recovery Medium

ABSTRACTSimulations of administration of razupenem at 1 g every 12 h by 1-h intravenous (i.v.) infusion were performed in anin vitropharmacokinetic model of infection. The antibacterial effect of this razupenem dosing regimen against six strains ofStaphylococcus aureus(one methicillin-sensitiveS. aureus[MSSA] strain [MIC, 0.015 μg/ml] and five methicillin-resistantS. aureus[MRSA] strains [MIC range, 0.09 to 3 μg/ml]) and five strains ofEnterobacteriaceae(threeEscherichia colistrains [two containing extended-spectrum β-lactamases {ESBLs}] and twoEnterobactersp. strains [one with an AmpC enzyme and the other with a raised razupenem MIC; MIC range, 0.09 to 6 μg/ml]) was assessed. Against the MSSA and MRSA strains, razupenem produced a >3.5-log-unit reduction in viable count after 24 h. There were no changes in population profiles. In a second series of experiments, over 5 days there was rapid initial clearance of MRSA from the model followed by regrowth after 48 h. MRSA colonies appeared on 2× MIC recovery medium after 72 h with strain 33820 (MIC, 3.0 μg/ml) and at 120 h with strain 27706 (MIC, 1.5 μg/ml). AgainstE. coliandEnterobacterspp., razupenem produced a >3.5-log-unit reduction in bacterial counts for all strains except that with an MIC of 6 μg/ml, where razupenem had a notably poorer antibacterial effect. Population profiles were unchanged after 48 h of exposure to razupenem except forEnterobacterstrain 34425 (MIC, 6.0 μg/ml), where colonies were recovered from media containing 2×, 4×, and 8× MIC. In dose-ranging studies with MRSA strains, the percentage of the dosing interval that the free drug concentration remained higher than the pathogen MIC (fT>MIC) for a 24-h bacteriostatic effect was 5.0% ± 1.4%, and that for a 1-log-unit reduction in count was 12.5% ± 5.8%. Population profiles indicated growth on 2× MIC recovery medium atfT>MIC values of 1 to 35% but not at a value of >35%. In a similar set of experiments withEnterobacteriaceae, thefT>MIC for a 24-h bacteriostatic effect was 34.2% ± 7.6% and that for a 1-log-unit reduction in count was 42.5% ± 7.8%. Population analysis profiles indicated growth on recovery media with 2×, 4×, and 8× MIC atfT>MICs in the range of 1 to 69% but rarely at values of ≥70%. In conclusion, razupenem at simulated human doses of 1 g i.v. every 12 h has a marked antibacterial effect on MSSA and MRSA strains with MICs of ≤3.0 μg/ml andEnterobacteriaceaewith MICs of ≤0.4 μg/ml.fT>MIC targets of ≥35% for MRSA and ≥70% forEnterobacteriaceaeshould provide significant antibacterial effects combined with low risks of changing pathogen antibiotic population profiles.

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In Vitro Selection of Resistance in Haemophilus influenzae by Amoxicillin-Clavulanate, Cefpodoxime, Cefprozil, Azithromycin, and Clarithromycin

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.46.9.2956-2962.2002 ◽

2002 ◽

Vol 46 (9) ◽

pp. 2956-2962 ◽

Cited By ~ 30

Author(s):

Catherine Clark ◽

Bülent Bozdogan ◽

Mihaela Peric ◽

Bonifacio Dewasse ◽

Michael R. Jacobs ◽

...

Keyword(s):

Haemophilus Influenzae ◽

Ribosomal Protein ◽

Ribosomal Proteins ◽

In Vitro Selection ◽

Fold Increase ◽

Single Step ◽

23S Rrna ◽

Gene Encoding ◽

Amoxicillin Clavulanate

ABSTRACT Abilities of amoxicillin-clavulanate, cefpodoxime, cefprozil, azithromycin, and clarithromycin to select resistant mutants of Haemophilus influenzae were tested by multistep and single-step methodologies. For multistep studies, 10 random strains were tested: 5 of these were β-lactamase positive. After 50 daily subcultures in amoxicillin-clavulanate, MICs did not increase more than fourfold. However, cefprozil MICs increased eightfold for one strain. Clarithromycin and azithromycin gave a >4-fold increase in 8 and 10 strains after 14 to 46 and 20 to 50 days, respectively. Mutants selected by clarithromycin and azithromycin were associated with mutations in 23S rRNA and ribosomal proteins L4 and L22. Three mutants selected by clarithromycin or azithromycin had alterations in ribosomal protein L4, while five had alterations in ribosomal protein L22. Two mutants selected by azithromycin had mutations in the gene encoding 23S rRNA: one at position 2058 and the other at position 2059 (Escherichia coli numbering), with replacement of A by G. One clone selected by clarithromycin became hypersusceptible to macrolides. In single-step studies azithromycin and clarithromycin had the highest mutation rates, while amoxicillin-clavulanate had the lowest. All resistant clones were identical to parents as observed by pulsed-field gel electrophoresis. The MICs of azithromycin for azithromycin-resistant clones were 16 to >128 μg/ml, and those of clarithromycin for clarithromycin-resistant clones were 32 to >128 μg/ml in multistep studies. For strains selected by azithromycin, the MICs of clarithromycin were high and vice versa. After 50 daily subcultures in the presence of drugs, MICs of amoxicillin-clavulanate and cefpodoxime against H. influenzae did not rise more than fourfold, in contrast to cefprozil, azithromycin, and clarithromycin, whose MICs rose to variable degrees.

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