Fluoroquinolones in the Management of Acute Lower Respiratory Infection

Home , Clinafloxacin, Grepafloxacin, Sparfloxacin, Trovafloxacin

Thorax 2000;55:83–85 83

Occasional review Thorax: first published as 10.1136/thorax.55.1.83 on 1 January 2000. Downloaded from

The next generation: ﬂuoroquinolones in the management of acute lower respiratory infection in adults

Peter J Moss, Roger G Finch

Lower respiratory tract infections (LRTI) are ing for up to 40% of isolates in Spain19 and 33% the leading infectious cause of death in most in the United States.20 In England and Wales developed countries; community acquired the prevalence is lower; in the first quarter of pneumonia (CAP) and acute exacerbations of 1999 6.5% of blood/cerebrospinal fluid isolates chronic bronchitis (AECB) are responsible for were reported to the Public Health Laboratory the bulk of the adult morbidity. Until recently Service as showing intermediate sensitivity or quinolone antibiotics were not recommended resistance (D Livermore, personal communi- for the routine treatment of these infections.1–3 cation). Pneumococcal resistance to penicillin Neither ciprofloxacin nor ofloxacin have ad- is not specifically linked to quinolone resist- equate activity against Streptococcus pneumoniae ance and, in general, penicillin resistant in vitro, and life threatening invasive pneumo- pneumococci are sensitive to the newer coccal disease has been reported in patients fluoroquinolones.11 21 treated for respiratory tract infections with Resistance to ciprofloxacin develops rela- these drugs.4–6 The development of new fluoro- tively easily in both S pneumoniae and H influ- quinolone agents with increased activity enzae, requiring only a single mutation in the against Gram positive organisms, combined parC gene.22 23 Other quinolones such as with concerns about increasing microbial sparfloxacin and clinafloxacin require two resistance to â-lactam agents, has prompted a mutations in the parC and gyrA genes.11 23 re-evaluation of the use of quinolones in LRTI. Despite this, the prevalence of S pneumoniae Sparfloxacin and levofloxacin are now ap- with decreased quinolone sensitivity has in- http://thorax.bmj.com/ proved for the treatment of community ac- creased in parallel with increased prescription quired LRTIs in the UK (grepafloxin, which of these drugs,24 and pneumococci with was also approved for this indication, has decreased in vitro grepafloxacin sensitivity have recently been withdrawn from the market). It is been isolated from patients following treatment important to define the role of these drugs in with this agent.25 EZux resistance has been the treatment of CAP and AECB. recognised among S pneumoniae; some qui- The most common cause of CAP worldwide nolones appear to be more susceptible to this 11 26 27

is S pneumoniae which accounts for 60–75% of than others. In the case of H influenzae, on September 23, 2021 by guest. Protected copyright. pathogens isolated.7–9 Other less common some isolates from patients with LRTI have causes include Mycoplasma pneumoniae and developed decreased susceptibility to cipro- Legionella pneumophila. Any agent used for the floxacin; such isolates remain fully sensitive to empirical treatment of CAP must cover S clinafloxacin, trovafloxacin, and gatifloxacin pneumoniae, and preferably these other organ- but not to moxifloxacin, sparfloxacin, or isms as well, especially in severe disease. In grepafloxacin.11 AECB the role of bacterial pathogens is less The pharmacokinetic properties of the new clearly defined; Haemophilus influenzae, S pneu- quinolone agents support their use in LRTI. moniae, and Moraxella catarrhalis are most The drugs are extensively distributed, achiev- frequently associated. Several of the newer qui- ing high concentrations in lung tissues and 28 nolones have MIC90 values for S pneumoniae secretions. Those which are available in both that are significantly lower than those reported oral and intravenous formulations, such as Division of Infectious for ofloxacin and ciprofloxacin, which suggests levofloxacin and moxifloxacin, have good abso- Diseases and that they should be eVective in clinical use. lute bioavailability, allowing early and simple Microbiology, School Clinafloxacin, sitafloxacin, and gemifloxacin change from intravenous to oral treatment. of Clinical Laboratory have the lowest MIC90 values in vitro, followed Most have relatively long terminal elimination Sciences, University of by trovafloxacin, moxifloxacin, gatifloxacin, half lives and can be administered once daily. Nottingham, Nottingham City grepafloxacin, sparfloxacin, and levo- There are few published clinical trials 10–14 Hospital, Nottingham floxacin. All have excellent in vitro activity assessing the eYcacy of fluoroquinolones in NG5 1PB, UK against the other significant bacterial causes of CAP. Three studies have shown intravenous P J Moss CAP and AECB.15–18 and/or oral levofloxacin to be as good as or R G Finch Pneumococcal resistance to â-lactams is an better than comparative treatments 29 30 29 Correspondence to: increasing problem in many parts of the world, (ceftriaxone, oral cefuroxime, amoxycillin/ Professor R G Finch with penicillin resistant pneumococci account- clavulanic acid31) in terms of clinical and 84 Moss, Finch

bacteriological cure. Sparfloxacin has been British guidelines are awaited. The antimicro- compared with erythromycin,32 bial spectrum and pharmacokinetic properties Thorax: first published as 10.1136/thorax.55.1.83 on 1 January 2000. Downloaded from roxithromycin,33 cefaclor,34 amoxycillin,35 of these agents suggest that they are likely to be amoxycillin/clavulanic acid,32 and an eVective treatment for respiratory infections amoxycillin/ofloxacin,36 again showing equival- due to penicillin resistant pneumococci and ent clinical and microbiological success rates. other organisms. However, clinical data are Single studies have shown grepafloxacin to be limited, particularly in severe and invasive dis- as eVective as, and trovafloxacin significantly ease. Potential compliance benefits due to once better than, amoxycillin (by clinical cure rate in daily dosing must be weighed against increased evaluable patients) for the treatment of drug cost; there is little practical evidence to CAP.37 38 Most patients entered into these support the suggestion (based on cost analysis comparative trials had mild or moderate rather models48) that quinolones may decrease the than severe pneumonia, based on accepted cost of treating CAP by reducing the need for clinical and laboratory indicators. Few have hospital admission. had bacteraemic pneumococcal pneumonia, a The prevalence of clinically significant pneu- more rigorous test of antimicrobial activity in mococcal resistance to penicillin in the UK is terms of disease severity, and only a very small currently low, although it is rising. Beta-lactam number of patients were infected with penicil- antibiotics alone or in combination with a lin resistant pneumococci. In most studies the macrolide remain adequate empirical treat- analysis was not performed on an intention-to- ment for most cases of CAP. There is no com- treat basis. Comparative clinical data on other pelling evidence for fluoroquinolones to be- new quinolones are limited and generally come the standard first line treatment for CAP. unpublished. Although there is a need for a safe and effective Levofloxacin, sparfloxacin, and grepa- parenteral/oral agent for treating severe CAP in floxacin have been shown to be as eVective hospital, it is not yet clear if any of the currently clinically as comparative oral treatment (ce- available quinolones can fill this role. Antibiot- furoxime axetil or amoxycillin/clavulanate) for ics are usually not indicated in AECB49 and treating AECB.39–41 However, most acute exac- there is little evidence to suggest that quinolo- erbations of bronchitis are not due primarily to nes oVer benefit over other antimicrobial treat- bacterial infection, and diYculty in defining ments, although they may be used as second the role of antibiotics in treatment has made line drugs in a few cases where an antibiotic is comparative trials problematic. appropriate. Safety is paramount if quinolones are to gain wider use in the community as well as in hospi- 1 American Thoracic Society. Guidelines for the initial management of adults with community-acquired pneumo- tal. Most adverse events reported are common nia: diagnosis, assessment of severity and initial antimicro- to the class, but the frequency and severity bial therapy. Am Rev Respir Dis 1993;148:1418–26. 2 Mandell LA, Niederman MS. Antimicrobial treatment of varies from drug to drug. Recent reports of community acquired pneumonia in adults: a conference http://thorax.bmj.com/ hepatotoxicity have led to the product licence report. Can J Infect Dis 1993;4:25–8. 3 British Thoracic Society. Guidelines for the management of for trovafloxacin being suspended in the UK community-acquired pneumonia in adults admitted to 42 and restricted in the USA. Nausea and other hospital. Br J Hosp Med 1993;49:346–50. minor gastrointestinal problems are common 4 Frieden TR, Mangi RJ. Inappropriate use of oral ciprofloxacin. JAMA 1990;264:1438–40. with all quinolones, as are mild CNS eVects 5 Lee BL, Kimbrough RC, Jones SR, et al. Infectious compli- such as dizziness, headache, and light headed- cations with respiratory pathogens despite ciprofloxacin therapy. N Engl J Med 1991;325:520–1. ness. These eVects may be more common with 6 Korner RJ, Reeves DS, MacGowan AP. Dangers of oral grepafloxacin.43 Photosensitivity is more com- fluoroquinolone treatment in community acquired upper respiratory tract infections. BMJ 1994;308:191–2. mon and more severe with 8-halogenated 7 Fine MJ, Smith MA, Carson CA, et al. Prognosis and on September 23, 2021 by guest. Protected copyright. quinolones such as sparfloxacin and outcomes of patients with community-acquired pneumonia. JAMA 1996;275:134–41. clinafloxacin.44 Several quinolones can cause 8 Macfarlane JT. Treatment of lower respiratory tract infections. Lancet 1987;ii:1446–9. minor prolongation of the electrocardiographic 9 Sow O, Frechet M, Diallo AA, et al. Community-acquired QT interval (as do the macrolides); spar- pneumonia in adults: a study comparing clinical features and outcomes in Africa and Europe. Thorax 1996;51:385– floxacin has been implicated in an episode of 8. torsades de pointes arrhythmia45 but the 10 Langtry HD, Lamb HM. Levofloxacin. Its use in infections incidence of clinically significant ECG changes of the respiratory tract, skin, soft tissues and urinary tract. Drugs 1998;56:487–515. is extremely low. In comparative clinical studies 11 Piddock LJ, Johnson M, Ricci V, et al. Activities of new fluoroquinolones against fluoroquinolone-resistant pathogens the incidence of side eVects in the quinolone of the lower respiratory tract. Antimicrob Agents Chemother group has not exceeded that in the comparative 1998;42:2956–60. 12 Pankuch GA, Jacobs MR, Appelbaum PC. Antipneumococ- group and they are generally better tolerated cal activity of grepafloxacin compared to that of other than macrolides. Some quinolones, notably agents by time-kill methodology. Antimicrob Agents Chem- other 1998;42:1263–5. grepafloxacin, can inhibit hepatic cytochrome 13 Fuentes F, Marco F, Gimenez MJ, et al. Comparative in P450 leading to increased plasma concentra- vitro activity of gemifloxacin against Strepotococcus pneumoniae clinical isolates exhibiting high ciprofloxacin MICs tions of co-administered drugs such as theo- (abstract). 21st International Congress of Chemotherapy. phylline. 1999:P385. 14 Milatovic D, Fluit A, Schmitz F-J, et al. In vitro activity of The current guidelines of the Infectious Dis- sitafloxin and six other fluoroquinolones. Part II: Gram- eases Society of America list fluoroquinolones positive cocci (abstract). 21st International Congress of Chemotherapy. 1999:P601. as a preferred option for both inpatient and 15 Hoogkamp-Korstanje JA. In-vitro activities of ciprofloxacin, outpatient management of CAP.46 The Euro- levofloxacin, lomefloxacin, ofloxacin, pefloxacin, sparfloxacin and trovafloxacin against gram-positive and gram- pean Respiratory Society recommends them as negative pathogens from respiratory tract infections. J an alternative to aminopenicillins for AECB Antimicrob Chemother 1997;40:427–31. 16 Hoogkamp-Korstanje JA, Dirks-Go SI, Kabel P, et al.Mul- but not for CAP (except in combination with ticentre in-vitro evaluation of the susceptibility of Strepto- other agents in very serious infections).47 New coccus pneumoniae, Haemophilus influenzae and Moraxella Fluoroquinolones for acute lower respiratory infection in adults 85

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