Comparative in vitro activity of gemifloxacin to other fluoroquinolones and non-quinolone agents against Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis in the United States in 1999–2000

doi:10.1016/S0924-8579(01)00431-9

International Journal of Antimicrobial Agents

Volume 19, Issue 1, January 2002, Pages 33-37

https://doi.org/10.1016/S0924-8579(01)00431-9 Get rights and content

Abstract

This study was undertaken to assess the in vitro activity of gemifloxacin, five other fluoroquinolone antimicrobial agents (ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin and ofloxacin) and other non-quinolone comparator agents (ampicillin, erythromycin, clindamycin, doxycycline, penicillin and trimethoprim/sulphamethoxazole) against Streptococcus pneumoniae collected in the United States. Susceptibility testing of 550 S. pneumoniae, 290 Haemophilus influenzae and 205 Moraxella catarrhalis showed that 38.2% of pneumococci were penicillin nonsusceptible, while 26.2 and 95.6% of H. influenzae and M. catarrhalis, respectively, produced β-lactamase. Overall new fluoroquinolones were the most active agents. The in vitro activity (based on MIC₉₀ in mg/l) of the six fluoroquinolones was gemifloxacin>moxifloxacin>gatifloxacin>levofloxacin>ciprofloxacin and ofloxacin.

Introduction

The majority of bacterial community acquired respiratory tract infections (RTI) are caused by Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis [1], [2]. As a result of increases in resistance of these key respiratory pathogens, physicians have been advised to modify their treatment practices [1], [3], [4]. Recent empirical first-line recommendations include the newer fluoroquinolones, macrolides and doxycycline for community acquired pneumonia (CAP), and amoxycillin, amoxycillin/clavulanate, cefpodoxime, cefuroxime and newer fluoroquinolones for acute bacterial sinusitis [3], [4].

Section snippets

Methods

This study was performed to determine the activity of agents used to treat RTI against contemporary isolates of S. pneumoniae, H. influenzae and M. catarrhalis. A total of 550 S. pneumoniae, 290 H. influenzae and 205 M. catarrhalis were collected from 16 hospitals in the United States (33.8% northeast, 8.7% northwest, 13.5% north central, 12.7% southeast, 14.4% southwest and 16.9% south central). Isolates were recovered from cultures of blood (17.2%), sputum (62.4%), bronchoalveolar lavage

Results

Results of the MICs of non-fluoroquinolones are shown in Table 1 and to quinolone antibiotics in Table 2.

Discussion

This study has shown that the primary RTI pathogens are susceptible to the new quinolones. Agents that were inactive against at least one of the three bacterial species tested included erythromycin, doxycycline and trimethoprim/sulphamethoxazole.

There were no major changes in susceptibilities of S. pneumoniae to fluoroquinolones compared with 1997 surveillance data [5], [7], [8], [9]. S. pneumoniae susceptibility to erythromycin was similar to that reported for azithromycin in 1997 by Jacobs et

Acknowledgements

This work was supported by a grant from GlaxoSmithKline.

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Cited by (15)

Differential effect of P-gp and MRP2 on cellular translocation of gemifloxacin
2011, International Journal of Pharmaceutics
Citation Excerpt :
Gemifloxacin exhibits a broad spectrum of activity against Gram-positive and Gram-negative bacteria (Cormican and Jones, 1997; Hohl et al., 1998; Johnson et al., 1999; Oh et al., 1996). The compound showed excellent antimicrobial activity with low minimum inhibitory concentrations (MIC90) of 0.03, 0.06 and 0.008 μg/ml against Streptococcus pneumoniae, S. pyrogenes and Haemophilus influenzae, respectively (Fuchs et al., 2000; Goldstein et al., 2002; King et al., 2000; Koeth et al., 2002; Rittenhouse et al., 2000). Potent antibacterial activity against clinical isolates and reference strains was observed with gemifloxacin in both in vitro as well as in vivo infectious animal models (Berry et al., 2000; Erwin and Jones, 1999; Johnson et al., 1999; Ramji et al., 2001).
Fluoroquinolones are broad spectrum antibiotics widely indicated in the treatment of both human and animal diseases. The primary objective of this study was to assess short and long term affinities of gemifloxacin towards efflux transporters (P-gp, MRP2) and nuclear hormone receptor (PXR). Uptake and dose dependent inhibition studies were performed with [¹⁴C] erythromycin (0.25 μCi/ml) on MDCKII-MDR1 and MDCKII-MRP2 cells. Cellular accumulation of calcein-AM was further determined to confirm the affinity of gemifloxacin towards P-gp and MRP2. Transport studies were conducted to determine bi-directional permeability and to assess efflux ratio of gemifloxacin. LS-180 cells were treated with three different concentrations of gemifloxacin for 72 h and real-time PCR analysis was performed to study the quantitative gene expression levels of PXR, MDR1 and MRP2. Further, [¹⁴C] erythromycin uptake was also performed on LS-180 treated cells to better delineate the functional activity of efflux transporters. Results from our study suggest that gemifloxacin may be a substrate of both the efflux transporters studied. This compound inhibited both P-gp and MRP2 mediated efflux of [¹⁴C] erythromycin in a dose dependent manner with IC₅₀ values of 123 ± 2 μM and 16 ± 2 μM, respectively. The efflux ratio of [¹⁴C] erythromycin lowered from 3.56 to 1.63 on MDCKII-MDR1 cells and 4.93 to 1.26 on MDCKII-MRP2 cells. This significant reduction in efflux ratio further confirmed the substrate specificity of gemifloxacin towards P-gp and MRP2. Long term exposure significantly induced the expression of PXR (18 fold), MDR1 (6 fold) and MRP2 (6 fold). A decrease (20%) in [¹⁴C] erythromycin uptake further confirmed the elevated functional activity of P-gp and MRP2. In conclusion, our studies demonstrated that gemifloxacin is effluxed by both P-gp and MRP2. Long term exposure induced their gene expression and functional activity. This substrate specificity of gemifloxacin towards these efflux transporters may be one of the major factors accounting for low oral bioavailability (71%). Better understanding of these mechanistic interactions may aid in the development of newer strategies to achieve adequate therapeutic levels and higher bioavailability.
Streptococcus pneumoniae in vitro development of resistance to amoxicillin/clavulanic acid, cefaclor, levofloxacin and azithromycin
2004, International Journal of Antimicrobial Agents
The purpose of this study was to determine effect of repeated exposure to sub-inhibitory concentrations of amoxicillin/clavulanic acid on the development of resistance in Streptococcus pneumoniae. Other agents, azithromycin, cefaclor and levofloxacin, were also tested. Twenty S. pneumoniae were passaged for 9 days in the presence of sub-inhibitory concentrations of each antimicrobial agent and MICs determined by NCCLS macro-dilution method. There was a four-fold increase in amoxicillin/clavulanic acid MICs for 2 of 20 isolates. Three of 9 tested against cefaclor, 11 of 13 tested against azithromycin and 9 of 20 tested against levofloxacin showed ≥4-fold increase. Amoxicillin/clavulanic acid was the most stable of the agents tested. Cefaclor MICs were also fairly stable. Azithromycin and levofloxacin MICs were most affected.
A randomized, double-blind study comparing 5 days oral gemifloxacin with 7 days oral levofloxacin in patients with acute exacerbation of chronic bronchitis
2004, Respiratory Medicine
Objective: To demonstrate that 5 days of treatment with a new fluoroquinolone, gemifloxacin, is at least as effective as 7 days of treatment with levofloxacin in adult patients with acute exacerbation of chronic bronchitis (AECB).
Design: Randomized, double-blind, double dummy, multicentre, parallel group study
Setting: Sixty different medical centers in US, UK and Germany.
Material and methods: A total of 360 adults (>40 years of age) with AECB were randomly assigned to receive gemifloxacin 320 mg once daily for 5 days or levofloxacin 500 mg once daily for 7 days. The primary efficacy parameter was a clinical response at follow-up (Days 14–21).
Results: In total, 335/360 patients completed the study (93.1%). Seven patients receiving gemifloxacin withdrew from the study compared to 18 patients receiving levofloxacin; this difference was statistically significant (Fisher's exact test: p=0.02). In the intent-to-treat (ITT) population, the clinical success rate at follow-up (Days 14–21) was 85.2% (155/182) with gemifloxacin and 78.1% (139/178) with levofloxacin. Clinical success rate in the per-protocol (PP) population was 88.2% (134/152) with gemifloxacin and 85.1% (126/148) with levofloxacin. At long-term follow-up (Days 28–35), the clinical success rates in the PP population were 83.7% (123/147) with gemifloxacin and 78.4% (109/139) with levofloxacin. The difference in success rates was 5.26% (95% CI: −3.83, 14.34).
Conclusion: The clinical efficacy of gemifloxacin 320 mg once daily for 5 days in AECB was at least as good as levofloxacin 500 mg once daily for 7 days. Fewer withdrawals and superior clinical efficacy at long-term follow-up were also seen with gemifloxacin.
In vitro pharmacodynamic activity of gatifloxacin, gemifloxacin, moxifloxacin and levofloxacin against Streptococcus pneumoniae containing specific mutations in DNA gyrase and topoisomerase IV
2003, Diagnostic Microbiology and Infectious Disease
An in vitro pharmacodynatnic modeling apparatus (PDMA) generated specific bacterial kill profiles for single-dose regimens of gatifloxacin (GT), gemifloxacin (GM), moxifloxacin (MX) and levofloxacin (LV) against isolates of Streptococcus pneumoniae with specific QRDR profiles: SP-WT (no modifications); SP-C (changes in parC); and SP-AC (changes in both parC and gyrA). No differences in 3-log reduction time or total log reduction were observed among the four agents for SP-WT; however, LV failed to achieve a 3-log reduction in SP-C and SP-AC, and total log reduction after 12 hrs was minimal compared to the other agents. GM and MX required less time for 3-log reduction of SP-AC compared to GT, but total log reductions in SP-AC were similar among the three newer quinolone agents (GM > MX > GT). The study isolates with QRDR modifications greatly reduced LV activity. GM and MX maintained the greatest degree of activity against all study isolates and their activity was not adversely influenced by the genetic modifications in SP-C and SP-AC. The dual targeting characteristic of GM was also assessed, but did not offer significant advantages relative to MX and GT.
Chapter 19. Antibacterial treatment of community-acquired respiratory tract INFECTIONS
2003, Annual Reports in Medicinal Chemistry
This chapter discusses the antibacterial treatment of community-acquired respiratory tract infections (CARTIs). CARTIs represent one of the most globally prevalent classes of infection. Acute RTls account for approximately 75% of all antibiotic prescriptions and 20% of all medical consultations. Community-acquired upper respiratory tract infections (CAURTI) and viral RTIs are typically not life-threatening unless complicated by a coinfection or an immunocompromised host. CAURTIs respond well to front-line antibiotics such as penicillins, erythromycin, azithromycin, amoxicillin/clavulanate, or cefpodoxime. Viral RTIs are usually self-limiting and only require symptomatic support. Of greater concern are lower respiratory tract infections (LRTI) including community-acquired pneumonia (CAP) and acute exacerbations of chronic bronchitis (AECB). These LRTIs account for nearly half of all reported community-acquired infections, can be challenging to treat, place a considerable burden on the health care system, and exhibit significantly higher rates of morbidity and mortality. The chapter discusses the epidemiology and treatment of CARTIs and discusses the treatment guidelines, diagnoses, and pathogens associated with CARTIs. It also discusses the antibiotics that are used in the treatment of CARTIs.
Gemifloxacin for community-acquired pneumonia
2008, Expert Opinion on Investigational Drugs

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International Journal of Antimicrobial Agents

Abstract

Introduction

Section snippets

Methods

Results

Discussion

Acknowledgements

References (15)

Surveillance of antimicrobial resistance in Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis in the United States in 1996–1997 respiratory season

Diagnostic Microbiology and Infectious Disease

Acute otitis media: management and surveillance in an era of pneumococcal resistance—a report from the drug-resistant Streptococcus pneumoniae therapeutic working group

Pediatric Infectious Disease Journal

Relevance of pharmacokinetics and pharmacodynamics in the selection of antibiotics for respiratory tract infections

Journal of Chemotherapy

Practice guidelines for the management of community acquired pneumonia in adults

Clinical Infectious Disease

Antimicrobial treatment guidelines for acute bacterial rhinosinusitis

Otolaryngology—Head and Neck Surgery

Susceptibilities of Streptococcus pneumoniae and Haemophilus influenzae to 10 oral antimicrobial agents based on pharmacodynamic parameters: 1997 U.S. Surveillance Study

Antimicrobial Agents and Chemotherapy

Cited by (15)

Differential effect of P-gp and MRP2 on cellular translocation of gemifloxacin

Streptococcus pneumoniae in vitro development of resistance to amoxicillin/clavulanic acid, cefaclor, levofloxacin and azithromycin

A randomized, double-blind study comparing 5 days oral gemifloxacin with 7 days oral levofloxacin in patients with acute exacerbation of chronic bronchitis

In vitro pharmacodynamic activity of gatifloxacin, gemifloxacin, moxifloxacin and levofloxacin against Streptococcus pneumoniae containing specific mutations in DNA gyrase and topoisomerase IV

Chapter 19. Antibacterial treatment of community-acquired respiratory tract INFECTIONS

Gemifloxacin for community-acquired pneumonia

Original articleComparative in vitro activity of gemifloxacin to other fluoroquinolones and non-quinolone agents against Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis in the United States in 1999–2000

Abstract

Introduction

Section snippets

Methods

Results

Discussion

Acknowledgements

Diagnostic Microbiology and Infectious Disease

Acute otitis media: management and surveillance in an era of pneumococcal resistance—a report from the drug-resistant Streptococcus pneumoniae therapeutic working group

Pediatric Infectious Disease Journal

Relevance of pharmacokinetics and pharmacodynamics in the selection of antibiotics for respiratory tract infections

Journal of Chemotherapy

Practice guidelines for the management of community acquired pneumonia in adults

Clinical Infectious Disease

Antimicrobial treatment guidelines for acute bacterial rhinosinusitis

Otolaryngology—Head and Neck Surgery

Susceptibilities of Streptococcus pneumoniae and Haemophilus influenzae to 10 oral antimicrobial agents based on pharmacodynamic parameters: 1997 U.S. Surveillance Study

Antimicrobial Agents and Chemotherapy

Original article
Comparative in vitro activity of gemifloxacin to other fluoroquinolones and non-quinolone agents against Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis in the United States in 1999–2000