Review
Antimicrobial selection for community-acquired lower respiratory tract infections in the 21st century: a review of gemifloxacin

https://doi.org/10.1016/j.ijantimicag.2004.02.017Get rights and content

Abstract

Community-acquired lower respiratory tract infections (LRTIs) are more prevalent in the elderly than in children and younger adults and form a significant proportion of all consultations and hospital admissions in this older age group. Furthermore, in a world of increasing life expectancy the trend seems unlikely to be reversed. Antimicrobial treatment of community-acquired pneumonia (CAP) must cover Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis, and in many circumstances should also cover the intracellular (atypical) pathogens. In contrast, acute exacerbations of chronic bronchitis (AECB) are mainly associated with H. influenzae and S. pneumoniae and not with atypical bacteria: in severe cases, other Gram-negative bacteria may be involved. Frequently in LRTIs, the aetiology of the infection cannot be identified from the laboratory specimens and treatment has to be empirical. In such situations it is important to not only to use an antibiotic that covers all likely organisms, but also one that has good activity against these organisms given the local resistance patterns. Gemifloxacin is a new quinolone antibiotic that targets pneumococcal DNA gyrase and topoisomerase IV and is highly active against S. pneumoniae including penicillin-, macrolide- and many ciprofloxacin-resistant strains, as well as H. influenzae and the atypical pathogens. In clinical trials in CAP and AECB, gemifloxacin has been shown to be as effective a range of comparators and demonstrated an adverse event profile that was in line with the comparator agents. In one long-term study in AECB significantly more patients receiving gemifloxacin than clarithromycin remained free of recurrence after 26 weeks. The improved potency, broad spectrum of activity and proven clinical and bacteriological efficacy and safety profile should make it a useful agent in the 21st century battle against community-acquired LRTIs.

Introduction

Community-acquired lower respiratory tract infections (LRTIs) account for a substantial proportion of hospital admissions and antibiotic prescriptions. In addition, LRTIs figure significantly in the mortality statistics; data from the Center for Disease Control and Prevention show that in the United States in 2000, there were in excess of 120,000 deaths from chronic lower respiratory disease and over 65,000 deaths from pneumonia (and influenza) [1], making them the fourth and seventh leading cause of death respectively. A study of chronic obstructive pulmonary disease (COPD) in the United States found that in 2000, COPD was responsible for 8 million physician office and hospital outpatient visits, 1.5 million emergency department visits and 726,000 hospitalisations [2]. This study also reported a large increase in the annual death rate among women, having risen from 20 per 100,000 in 1980, to 57 per 100,000 in 2000 whereas, although the death rate among men was higher, the increase from 73 to 83 per 100,000 over the same period was more modest. Pneumonia accounted for 1.3 million hospital admissions in 2000, with almost 60% being in patients aged 65 years and over [3]. The prevalence of lower respiratory tract infections therefore imposes a significant clinical and financial burden on healthcare authorities [4], [5]. As life expectancy in the United States is now at an all-time high of 76.9 years (74.1 years for men and 79.5 years for women) [1] and, as both pneumonia and chronic bronchitis/COPD are far more prevalent in the elderly, this burden is unlikely to be reduced in the foreseeable future and may indeed become greater.

Antimicrobial resistance has changed significantly over the last four decades, from the early identification of isolates of Streptococcus pneumoniae with reduced susceptibility to penicillin [6], [7], [8] to multi-drug-resistant isolates [9], [10]. Beta-lactamase production is commonly encountered in Haemophilus influenzae and is the rule in Moraxella catarrhalis. Selection of initial antimicrobial treatment for LRTIs continues to be problematic world-wide. Initial antimicrobial therapy is normally given empirically, before the bacterial cause of the infection can be determined in the laboratory and in many cases treatment is empirical throughout owing to lack of reliable microbiological data. For each type of LRTI, an understanding of the likely pathogens and resistance patterns is helpful in guiding antibiotic choice and a detailed knowledge of the local susceptibility of the potential pathogens would ensure a more appropriate choice of the antimicrobial agent (or agents) to be used and the optimum dose.

Section snippets

Community-acquired pneumonia

Most studies of the aetiology of community-acquired pneumonia (CAP) have found S. pneumoniae to be the major pathogen, followed by H. influenzae; however, the proportions of S. pneumoniae and other pathogens vary considerably between studies, as shown in Table 1 [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21]. Our ability to identify the infectious cause in all cases of CAP remains compromised as in 20–70% of hospitalised patients, no infectious agent is found from blood or

Evolution and spectrum of activity

Since the introduction of ciprofloxacin in the 1980s, there have been continual additions to the family of quinolone antimicrobials. Each new quinolone was developed to improve upon what was already available, and the key objective was to increase the activity against Gram-positive pathogens, particularly S. pneumoniae. This development and improvement of activity against Gram-positive species led to the grouping of quinolones into generations of compounds with similar spectra of activity.

Mechanism of action of gemifloxacin

Gemifloxacin is a fluoronaphthyridone member of the quinolone class of antibacterial agents. It has a broad spectrum of activity and possesses a strong affinity for pneumococcal topoisomerase IV, which is likely to be responsible for its potent in vitro activity against S. pneumoniae [52]. Furthermore, gemifloxacin has the ability to inhibit both DNA gyrase and DNA topoisomerase IV enzyme systems at therapeutically relevant drug levels in S. pneumoniae, so that single mutations in parC or gyrA

Gemifloxacin in community-acquired pneumonia: clinical experience

Overall, the spectrum of activity of the newer quinolones such as gemifloxacin provides cover against all major bacteria that cause CAP including the atypical organisms. Six clinical studies of gemifloxacin have been performed in CAP: Study 185: a randomised, open-label comparison with sequential iv ceftriaxone/oral cefuroxime (with or without additional macrolide) [90]; Study 049: a randomized, double-blind comparison with trovafloxacin [91]; Study 061: a non-comparative, open-label study in

Adverse event profile from clinical trial program

In clinical studies, gemifloxacin demonstrated an adverse event profile that is comparable with other routinely used antimicrobial agents. The US prescribing information for gemifloxacin lists the most commonly reported drug-related adverse events as diarrhoea (3.6%), rash (2.8%) and nausea (2.7%) and these percentages correspond well with those found in the published CAP and AECB studies: diarrhoea (3.3 and 3.8%), rash (4.4 and 0.7%) and nausea (0.7 and 2.9%) (Table 10) [90], [91], [95], [96],

Conclusion

The nature of antimicrobial resistance means that treatment guidelines are ever changing; agents that were effective 10 years ago may well be less than optimal therapy in 2004. Not only is time an important factor in the fight against infection, but geographical location is crucial too. We know only too well that certain parts of the world and even certain regions and cities can have levels of resistance that can render standard national treatment guidelines useless. There is concern that the

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