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Lower respiratory tract infections (LRTI) are the leading infectious cause of death in most developed countries; community acquired pneumonia (CAP) and acute exacerbations of chronic bronchitis (AECB) are responsible for the bulk of the adult morbidity. Until recently quinolone antibiotics were not recommended for the routine treatment of these infections.1-3 Neither ciprofloxacin nor ofloxacin have adequate activity againstStreptococcus pneumoniae in vitro, and life threatening invasive pneumococcal disease has been reported in patients treated for respiratory tract infections with these drugs.4-6 The development of new fluoroquinolone agents with increased activity against Gram positive organisms, combined with concerns about increasing microbial resistance to β-lactam agents, has prompted a re-evaluation of the use of quinolones in LRTI. Sparfloxacin and levofloxacin are now approved for the treatment of community acquired LRTIs in the UK (grepafloxin, which was also approved for this indication, has recently been withdrawn from the market). It is important to define the role of these drugs in the treatment of CAP and AECB.
The most common cause of CAP worldwide is S pneumoniae which accounts for 60–75% of pathogens isolated.7-9 Other less common causes includeMycoplasma pneumoniae andLegionella pneumophila. Any agent used for the empirical treatment of CAP must cover S pneumoniae, and preferably these other organisms as well, especially in severe disease. In AECB the role of bacterial pathogens is less clearly defined; Haemophilus influenzae, S pneumoniae, andMoraxella catarrhalis are most frequently associated. Several of the newer quinolones have MIC90values for S pneumoniae that are significantly lower than those reported for ofloxacin and ciprofloxacin, which suggests that they should be effective in clinical use. Clinafloxacin, sitafloxacin, and gemifloxacin have the lowest MIC90 values in vitro, followed by trovafloxacin, moxifloxacin, gatifloxacin, grepafloxacin, sparfloxacin, and levofloxacin.10-14 All have excellent in vitro activity against the other significant bacterial causes of CAP and AECB.15-18
Pneumococcal resistance to β-lactams is an increasing problem in many parts of the world, with penicillin resistant pneumococci accounting for up to 40% of isolates in Spain19 and 33% in the United States.20 In England and Wales the prevalence is lower; in the first quarter of 1999 6.5% of blood/cerebrospinal fluid isolates were reported to the Public Health Laboratory Service as showing intermediate sensitivity or resistance (D Livermore, personal communication). Pneumococcal resistance to penicillin is not specifically linked to quinolone resistance and, in general, penicillin resistant pneumococci are sensitive to the newer fluoroquinolones.11 21
Resistance to ciprofloxacin develops relatively easily in bothS pneumoniae and H influenzae, requiring only a single mutation in theparC gene.22 23 Other quinolones such as sparfloxacin and clinafloxacin require two mutations in the parC andgyrA genes.11 23 Despite this, the prevalence of S pneumoniae with decreased quinolone sensitivity has increased in parallel with increased prescription of these drugs,24 and pneumococci with decreased in vitro grepafloxacin sensitivity have been isolated from patients following treatment with this agent.25Efflux resistance has been recognised among S pneumoniae; some quinolones appear to be more susceptible to this than others.11 26 27 In the case ofH influenzae, some isolates from patients with LRTI have developed decreased susceptibility to ciprofloxacin; such isolates remain fully sensitive to clinafloxacin, trovafloxacin, and gatifloxacin but not to moxifloxacin, sparfloxacin, or grepafloxacin.11
The pharmacokinetic properties of the new quinolone agents support their use in LRTI. The drugs are extensively distributed, achieving high concentrations in lung tissues and secretions.28Those which are available in both oral and intravenous formulations, such as levofloxacin and moxifloxacin, have good absolute bioavailability, allowing early and simple change from intravenous to oral treatment. Most have relatively long terminal elimination half lives and can be administered once daily.
There are few published clinical trials assessing the efficacy of fluoroquinolones in CAP. Three studies have shown intravenous and/or oral levofloxacin to be as good as or better than comparative treatments (ceftriaxone,29 30 oral cefuroxime,29 amoxycillin/clavulanic acid31) in terms of clinical and bacteriological cure. Sparfloxacin has been compared with erythromycin,32roxithromycin,33 cefaclor,34amoxycillin,35 amoxycillin/clavulanic acid,32and amoxycillin/ofloxacin,36 again showing equivalent clinical and microbiological success rates. Single studies have shown grepafloxacin to be as effective as, and trovafloxacin significantly better than, amoxycillin (by clinical cure rate in evaluable patients) for the treatment of CAP.37 38 Most patients entered into these comparative trials had mild or moderate rather than severe pneumonia, based on accepted clinical and laboratory indicators. Few have had bacteraemic pneumococcal pneumonia, a more rigorous test of antimicrobial activity in terms of disease severity, and only a very small number of patients were infected with penicillin resistant pneumococci. In most studies the analysis was not performed on an intention-to-treat basis. Comparative clinical data on other new quinolones are limited and generally unpublished.
Levofloxacin, sparfloxacin, and grepafloxacin have been shown to be as effective clinically as comparative oral treatment (cefuroxime axetil or amoxycillin/clavulanate) for treating AECB.39-41However, most acute exacerbations of bronchitis are not due primarily to bacterial infection, and difficulty in defining the role of antibiotics in treatment has made comparative trials problematic.
Safety is paramount if quinolones are to gain wider use in the community as well as in hospital. Most adverse events reported are common to the class, but the frequency and severity varies from drug to drug. Recent reports of hepatotoxicity have led to the product licence for trovafloxacin being suspended in the UK and restricted in the USA.42 Nausea and other minor gastrointestinal problems are common with all quinolones, as are mild CNS effects such as dizziness, headache, and light headedness. These effects may be more common with grepafloxacin.43 Photosensitivity is more common and more severe with 8-halogenated quinolones such as sparfloxacin and clinafloxacin.44 Several quinolones can cause minor prolongation of the electrocardiographic QT interval (as do the macrolides); sparfloxacin has been implicated in an episode of torsades de pointes arrhythmia45 but the incidence of clinically significant ECG changes is extremely low. In comparative clinical studies the incidence of side effects in the quinolone group has not exceeded that in the comparative group and they are generally better tolerated than macrolides. Some quinolones, notably grepafloxacin, can inhibit hepatic cytochrome P450 leading to increased plasma concentrations of co-administered drugs such as theophylline.
The current guidelines of the Infectious Diseases Society of America list fluoroquinolones as a preferred option for both inpatient and outpatient management of CAP.46 The European Respiratory Society recommends them as an alternative to aminopenicillins for AECB but not for CAP (except in combination with other agents in very serious infections).47 New British guidelines are awaited. The antimicrobial spectrum and pharmacokinetic properties of these agents suggest that they are likely to be an effective treatment for respiratory infections due to penicillin resistant pneumococci and other organisms. However, clinical data are limited, particularly in severe and invasive disease. Potential compliance benefits due to once daily dosing must be weighed against increased drug cost; there is little practical evidence to support the suggestion (based on cost analysis models48) that quinolones may decrease the cost of treating CAP by reducing the need for hospital admission.
The prevalence of clinically significant pneumococcal resistance to penicillin in the UK is currently low, although it is rising. Beta-lactam antibiotics alone or in combination with a macrolide remain adequate empirical treatment for most cases of CAP. There is no compelling evidence for fluoroquinolones to become the standard first line treatment for CAP. Although there is a need for a safe and effective parenteral/oral agent for treating severe CAP in hospital, it is not yet clear if any of the currently available quinolones can fill this role. Antibiotics are usually not indicated in AECB49and there is little evidence to suggest that quinolones offer benefit over other antimicrobial treatments, although they may be used as second line drugs in a few cases where an antibiotic is appropriate.
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