Fluoroquinolones in the treatment of bronchopulmonary disease in cystic fibrosis

Abstract

Fluoroquinolones are commonly used to treat lung infections in patients with cystic fibrosis. These patients are susceptible to lung infection with common bacteria such as Staphylococcus aureus and Haemophilus influenzae, but are also prone to infection by opportunistic bacteria, including Pseudomonas aeruginosa. The good oral bioavailability and broad antimicrobial spectrum of activity, including antipseudomonal properties, make this class of antimicrobial attractive. We review the evidence assessing the use of fluoroquinolones in the context of preventing and eradicating early lung infection and in managing chronic lung infection and pulmonary exacerbations. The safety of fluoroquinolones and the use of newer agents in the class are also discussed.

Keywords

pseudomonas aeruginosa fluoroquinolones pulmonary exacerbations antibiotics cystic fibrosis bronchopulmonary disease

Introduction

Fluoroquinolones have a broad spectrum of antimicrobial activity and as a result are often used in the treatment of lung infection in the context of cystic fibrosis (CF). With antipseudomonal properties, they are commonly used in Pseudomonas aeruginosa eradication regimens, the treatment of mild exacerbations in patients chronically infected with P. aeruginosa and for the treatment of infections with other bacteria, including Stenotrophomonas maltophilia [UK Cystic Fibrosis Trust, 2009]. The mode of action of this group of antibiotics is incompletely understood, as are the mechanisms that underlie resistance to their effects. In addition, fluoroquinolones may have additional effects beyond their bactericidal properties. However, the side effect profiles of some agents in the class are extensive, highlighting the need for targeted use [Lapi et al. 2010].

Mechanism of action

Fluoroquinolones are understood to exert their effect at the nucleic acid level of bacterial topoisomerases, in particular DNA gyrase (topoisomerase II) and topoisomerase IV. These two enzymes act as ‘guardians’ over the processes of efficient DNA replication. DNA replication results from ‘unzipping’ of the linked DNA strands, thereafter each single strand is complemented by the addition of DNA bases to form two new DNA molecules. This process occurs sequentially along the DNA molecule; however, as the DNA unwinds for replication, bases along the DNA strand may mistakenly complement along the same strand, producing unwanted supercoils and interlocked DNA circles. Unchecked, these conformational changes during DNA replication would inhibit DNA replication. DNA gyrase and topoisomerase IV act to remove these structures to allow DNA replication to proceed unhindered [Bearden and Danziger, 2001]. Fluoroquinolones target these enzymes by binding to the active site of these molecules and inhibiting their action and through inhibition of DNA repair mechanisms eventually lead to cell death [Zhanel et al. 2002].

Antibiotic resistance to fluoroquinolones is understood to occur as a result of mutations in the topoisomerase genes, decreased permeability of the bacterial cell wall or the activity of efflux pumps [McDermott et al. 2003; Muller et al. 2011]. Efflux pumps act on specific substrates to remove toxins, metabolites and quorum sensing signal molecules from within the bacterial cell. Fluoroquinolones are a substrate of efflux pumps and overexpression of efflux pumps occurs in P. aeruginosa. Coadministration of levofloxacin with an efflux pump inhibitor is being developed as a strategy that may potentiate the antibacterial activity levofloxacin in vitro [Renau et al. 2002]. Clinical trials are awaited.

Pulmonary infection in CF may involve organisms growing in an anaerobic niche (e.g. within mucus plugs) and it is advantageous for an antibiotic to be active against obligate anaerobes or organisms such as P. aeruginosa, which can be facultative anaerobes. Many antibiotics have reduced activity in anaerobic conditions [Tunney et al. 2008]. However, some quinolones, such as levofloxacin, are equally active in an aerobic or anaerobic environment [King et al. 2010].

Pharmacokinetics and pharmacodynamics

It has previously been reported that the pharmacokinetics of antibiotics in patients with CF is altered compared with healthy individuals [Touw, 1998]. The same appears to hold true for fluoroquinolones in that patients with CF experiencing an exacerbation may have increased bioavailability of ciprofloxacin given orally compared with healthy volunteers (80% versus 57%). Increased clearance was also observed, suggesting that there is no need for a dose alteration [Christensson et al. 1992]. In a comparison of the pharmacokinetics of ciprofloxacin and ofloxacin, ciprofloxacin was cleared more quickly [Pedersen et al. 1987]. While studies in adults have varying results (as reviewed by Touw) [Touw, 1998], none of the differences appear to be clinically meaningful. However, there are few studies of the pharmacokinetics of fluoroquinolones in children with CF. In two separate studies, while the majority of pharmacokinetic indices were similar to those observed in adults with CF, there was a suggestion of age-related increases in drug clearance, with children eliminating the drug more quickly, and as such the authors suggested that an increase in dose in younger compared with older patients may be required [Rubio et al. 1997; Schaefer et al. 1996].

Using a population pharmacokinetic model, a 400 mg dose of ciprofloxacin twice or three times daily may be inadequate to treat an exacerbation as the area under the curve (AUC)/minimum inhibitory concentration (MIC) was suggested to be suboptimal in 70–90% of simulated patients [Montgomery et al. 2001]. Estimates of ciprofloxacin sputum penetration also vary and while it is difficult to understand the reasons for this, whether the drug level reaches the MIC appears to depend largely on the MIC of the individual organism isolated [Pedersen et al. 1987].

Pseudomonas aeruginosa prevention and eradication

Preventing infection with P. aeruginosa, or treating early infection when it does occur, is a strategy aimed at deferring chronic P. aeruginosa infection for as long as is possible so that the damage incurred as a result is reduced. While it has not been demonstrated that benefits in clinical outcomes result from such an approach, eradication regimens appear to render P. aeruginosa undetectable from respiratory secretions several months after antibiotic therapy commences [Langton-Hewer and Smyth, 2009]. Unfortunately, however, the Cochrane review examining this area had insufficient data with which to determine an optimal regimen.

A recent trial reported results that go in some way to further our understanding of how difficult it can be to prevent P. aeruginosa infection. In a 3-year blinded, randomized, controlled trial, 65 children who were P. aeruginosa negative (absence of P. aeruginosa positive cultures, serology and anti-pseudomonal antibiotics) were randomized in three age blocks (0–5 years, 6–11 years and 12–18 years) to receive either twice daily nebulized colistin with oral ciprofloxacin or dual placebo for 3-week periods every 3 months for 3 years [Tramper-Stranders et al. 2010]. Respiratory cultures (from cough swab or sputum) were taken at 3-monthly intervals along with 6-monthly lung function for those over 4 years, serum anti- Pseudomonas antibodies and annual X-ray and blood work up. Of these children, 19 met the endpoint of P. aeruginosa isolation on two occasions, 1 week apart. The median age at acquisition of P. aeruginosa was 6.8 years with no difference between the treatment and placebo groups (p = 0.101). No ciprofloxacin or colistin resistance was noted in any of the initial infecting strains. Non-fermenting Gram-negative bacteria (excluding P. aeruginosa) were cultured more frequently in the treated group, a concern as such bacteria are becoming increasingly recognized in the lung microbiome [Tunney et al. 2008]. However, it is unfortunate that the nebulized placebo contained mannitol, an agent that has recently been shown to improve lung function in CF, probably an osmotic effect improving mucociliary clearance [Aitken et al. 2012; Bilton et al. 2011]. These mannitol studies have shown no effect on quantitative or qualitative sputum microbiology, suggesting that any effect on the control group in the prophylaxis study would be minimal.

A number of studies have previously reported results of P. aeruginosa eradication regimens, many of which include ciprofloxacin (Table 1). While noting that the evidence base is weak, the UK Cystic Fibrosis Trust guidelines indicate that ciprofloxacin may be used in the treatment of early infection and its use is commonplace in this context [UK Cystic Fibrosis Trust, 2009].

Table 1.

Controlled trials of regimens for eradication of early Pseudomonas aeruginosa.

Study	Study design	Eradication regimen		Result
		Intravenous/inhaled antibiotic	Oral quinolone
Valerius et al. [1991]	Placebo-controlled trial	Colistin twice daily (3 weeks)	Ciprofloxacin (3 weeks)	14% intervention versus 58% placebo became chronically infected (p < 0.05)
Wiesemann et al. [1998]	Double-blind placebo-controlled randomized trial	Tobramycin inhalation (80mg) twice daily (1 year)	–	10/11 tobramycin PA-ve, 5/11 placebo PA-ve
Gibson et al. [2003]	Double-blind placebo-controlled randomized trial. Bronchoscopy sampling	TIS (300 mg) twice daily (28 days)	–	100% eradication (8 patients) in treatment arm compared with 1/13 in placebo arm (p < 0.001) (study stopped early)
Ratjen et al. [2010]	Open label two-arm randomized study	TIS 300 mg twice daily (28 days versus 56 days)	–	Equal rates of eradication in both arms (28 days 93% and 56 days 92%). Rates of recurrence were equal (p = 0.593).
Treggiari et al. [2011]	Randomized controlled trial	TIS 300 mg twice daily (28 days)	Ciprofloxacin 30–40 mg/kg/day (14 days)	No difference between cycled and culture-based therapy and no difference between ciprofloxacin and placebo
Treggiari et al. [2011]	TIS ± ciprofloxacin (cycled every 3 months/culture-based therapy)	TIS 300 mg twice daily (28 days)	Ciprofloxacin 30–40 mg/kg/day (14 days)

PA-ve, P. aeruginosa negative; TIS, tobramycin inhalation solution.

As can be seen from the table, tobramycin inhalation solution (TIS) alone appears to be an effective agent in eradicating early P. aeruginosa infection when given at 80 mg twice daily for a year [Ratjen et al. 2001; Wiesemann et al. 1998], or at 300 mg twice daily for 28 days [Gibson et al. 2003; Ratjen et al. 2010; Treggiari et al. 2011]. Indeed the recent the earLy inhaled tobramycin for eradication study (ELITE) trial demonstrated no additional benefit of extending the treatment course to 56 days over the standard 28 days, using the 300 mg twice daily dose [Ratjen et al. 2010]. Safety and efficacy of inhaled tobramycin has also been demonstrated in a powder formulation, with the suggested advantages of convenience and increased satisfaction. It is possible that adherence may be increased, although this has yet to be confirmed [Konstan et al. 2011].

The recent early pseudomonas infection control study (EPIC) trial, however, has cast doubt on the benefit of adding ciprofloxacin to a standard regimen of TIS [Treggiari et al. 2011]. This four-arm randomized placebo-controlled trial was designed to answer two questions: does the addition of oral ciprofloxacin to a standard regimen of TIS confer benefit, and is this treatment best given in response to a positive culture (culture based) or at regular intervals irrespective of cultures (cycled therapy)? The intention-to-treat analysis included 304 children between the ages of 1 and 12 years, 76 children randomly assigned to each arm: cycled TIS and placebo, cycled TIS and ciprofloxacin, culture-based TIS and placebo, culture-based TIS and ciprofloxacin. The cycled and culture-based therapy groups performed equally with 24 of 152 (16%) in the cycled and 26 of 152 (17%) in the culture-based group experiencing a pulmonary exacerbation (hazard ratio 0.95, p = 0.86). Similarly, 29 of 152 (19%) of those who received ciprofloxacin and 21 of 152 (14%) who received placebo experienced a pulmonary exacerbation (hazard ratio 1.45, p = 0.20). An equal proportion of patients in each group were able to clear P. aeruginosa from respiratory samples. The odds of a P. aeruginosa positive culture for the cycled versus culture-based regimens was 0.78 (p = 0.28) whereas the odds for those receiving ciprofloxacin versus lacebo was 1.10 (p = 0.67). There were no differences in the frequency of adverse events between groups except that those receiving ciprofloxacin reported more coughing. There were no differences in lung function. On the basis of this trial, it would appear that culture-based TIS alone is sufficient for the treatment of early P. aeruginosa infection.

However, consensus remains lacking, with the UK Cystic Fibrosis Trust recommending nebulized colistin and oral ciprofloxacin for 3 months as first-line therapy for the eradication of early P. aeruginosa [UK Cystic Fibrosis Trust, 2009]. The use of colistin, in preference to tobramycin, as first line is based on lower graded evidence and appears to be largely related to more experience of using colistin, as traditionally this was the only inhaled treatment licensed in the UK. It is not licensed for use in the USA. The Danish group have extensive experience of using a regimen of colistin and ciprofloxacin and have been able to document 80% of their cohort as being free of P. aeruginosa for 15 years after first infection [Hansen et al. 2008].

Currently recruiting is a trial to determine whether 10 days of intravenous ceftazidime and tobramycin and nebulized colistin is superior to 3 months of oral ciprofloxacin and nebulized colistin [International Standard Randomised Controlled Trial Number: ISRCTN02734162]. The primary endpoint is successful eradication of P. aeruginosa 3 months after treatment commences and the proportion remaining infection free for 15 months after the start of the allocated treatment.

Treatment of chronic Pseudomonas aeruginosa infection

Once chronic infection with P. aeruginosa is established, eradication is no longer possible and the focus of treatment turns to optimization of nutritional status, treatment of complications and the aggressive management of pulmonary exacerbations when they occur. Unfortunately there is no universally agreed diagnostic criteria for exacerbations and many clinical trials use ‘physician-diagnosed’ criteria. For the most part patients experiencing a pulmonary exacerbation report deterioration in sputum production, lung function and reduction in ability to attend work or school [Rosenfeld et al. 2001]. There is uncertainty regarding the underlying pathophysiology of exacerbations but some form of host-pathogen response is likely. In the context of chronic lung infection, the use of antibiotics must be balanced between the opposing pressures of aiming to reduce bacterial burden through the frequent or chronic use of antibiotics and keeping adverse effects of those antibiotics, in terms of toxicity, side effects and antimicrobial resistance to a minimum.

Clinical trials of antibiotics (Tables 2 and 3) in the context of chronic infection in CF are complicated by concern that spontaneously expectorated sputum may not reliably represent the heterogeneous pattern of lung infection in any given patient and previous attempts at quantitative microbiology may be misleading [Rogers et al. 2008]. Indeed, pulmonary exacerbations may not be preceded by an increase in sputum bacterial density [Stressmann et al. 2011]. Cautious interpretation of microbiological outcomes in trials is therefore warranted.

Table 2.

Controlled trials of maintenance therapies for chronic infection that include fluoroquinolones.

Study	Study design	Maintenance regimen		Result
		Intravenous/inhaled antibiotic	Quinolone
Jensen et al. [1987b]	Randomized double bind placebo-controlled crossover trial (cycled therapy)		14 days of treatment (cycled 3 monthly), oral ciprofloxacin 750 mg twice daily + ofloxacin 400 mg twice daily	Improved clinical score and lung function at end of 14 days of treatment in both arms (p < 0.05). Clinical score returned to baseline by 3 months
Jensen et al. [1987a]	Randomized trial (therapy cycled 3 monthly − 2 courses conventional, 2 courses quinolone − 1 ciprofloxacin, 1 ofloxacin)	Conventional – tobramycin + β lactam	Ciprofloxacin 750 mg twice daily or ofloxacin 400 mg twice daily	11/26 failed to complete, 5 of these because of little improvement on first course of quinolone. Two preferred quinolone and others had oral antibiotic for a mild exacerbation in the interim. All courses yielded improvement in FEV₁ but conventional treatment showed most improvement
Geller et al. [2011]	Randomized double-blind placebo controlled trial (maintenance therapy study)		Nebulized levofloxacin 120 mg once daily, 240 mg once daily or 240 mg once daily	FEV₁ improved with increasing dose (8.7% difference between 240 mg twice daily and placebo), and decreased in the placebo group (p = 0.003)

FEV1, forced expiratory volume in 1 s.

Table 3.

Controlled trials of fluoroquinolone-containing regimens for treatment of pulmonary exacerbations.

Study	Study design	Exacerbation regimen		Result
		Intravenous/inhaled antibiotic	Quinolone
Bosso et al. [1987]	Randomized trial (exacerbation treatment – ciprofloxacin versus tobramycin and azlocillin)	Intravenous tobramycin	Oral ciprofloxacin 750 mg twice daily	No difference between groups. More patients on ciprofloxacin completed 14-day course, 7/10 versus 5/10
Bosso et al. [1987]		Intravenous azlocillin	Oral ciprofloxacin 750 mg twice daily
Hodson et al. [1987]	Randomized trial (exacerbation study – azlocillin and gentamicin versus ciprofloxacin)	Intravenous gentamicin 80 mg	Oral ciprofloxacin 500 mg	Significant improvement in lung function from baseline in both groups. Cipro group maintained improvement at 6 weeks, but not intravenous group
Hodson et al. [1987]		Intravenous azlocillin 5 g	Oral ciprofloxacin 500 mg
Black et al. [1989]	Randomized trial (exacerbation treatment – ciprofloxacin treatment for four successive exacerbations versus alternate ciprofloxacin/intravenous azlocillin and tobramycin for 4 successive exacerbations)	Intravenous tobramycin	Oral ciprofloxacin	Interval abstract report during an ongoing trial. Equal clinical efficacy
Black et al. [1989]		Intravenous azlocillin	Oral ciprofloxacin
Bosso et al. [1989]	Randomized controlled trial (exacerbation treatment – ciprofloxacin versus tobramycin and azlocillin)	Intravenous tobramycin	Oral ciprofloxacin 750 mg twice daily	No significant difference between two arms
Bosso et al. [1989]		Intravenous azlocillin 75 mg/kg three times daily	Oral ciprofloxacin 750 mg twice daily	No significant difference between two arms
Church et al. [1997]	Randomized double-blind trial (paediatric exacerbation treatment – ciprofloxacin oral/intravenous versus intravenous ceftazidime and tobramycin)	Intravenous ceftazidime and tobramycin (10 days)	Intravenous ciprofloxacin 10 mg/kg three times daily (7 days), oral ciprofloxacin 20 mg/kg twice daily (3 days)	All patients in both arms improved compared with baseline (p < 0.001). Both arms were equivalent
Schaad et al. [1989]	Randomized trial (exacerbation treatment – aztreonam and amikacin versus ceftazidime and amikacin each followed by ciprofloxacin for 4 weeks)	Intravenous aztreonam	Oral ciprofloxacin	Improved clinical outcome from baseline but no additional improvement from end intravenous to end ciprofloxacin phase
		Intravenous amikacin
		Intravenous ceftazidime
Schaad et al. [1997]	Randomized trial (exacerbation study – initial conventional intravenous antibiotic followed by ciprofloxacin versus ciprofloxacin and amikacin inhaler)	Inhaled amikacin	Oral ciprofloxacin	After conventional intravenous therapy both arms continued to improve in ‘clinical symptoms’ although after cessation of intravenous treatment lung function gradually deteriorated in both arms

It was previously unclear whether antibiotics should be administered in a cycled fashion (elective irrespective of symptoms and cultures), in response to an increase in symptoms or indeed administered by oral, intravenous or inhalation routes. Elborn and colleagues conducted a pragmatic randomized trial (for which fluoroquinolones were an eligible therapy) to determine the optimal treatment strategy in terms of elective or symptomatic treatment [Elborn et al. 2000]. Antibiotic choice and diagnosis of an exacerbation were left to the treating centre. At the end of the 3-year trial, there were no differences between the groups in lung function, clinical or radiographic scores, anthropometric measures or bacteriology.

Maintenance treatment

The conventional aim of maintenance antibiotic treatment has been to reduce lung damage by the chronic suppression of bacteria, aiming to slow the gradual decline in lung function. Studies that have been completed (Table 2) suggest that while lung function or clinical score may be improved while receiving the antibiotic, when this is stopped the decline resumes. Concerns of inducing antibiotic resistance by such a strategy remain. However, there is a lack of consensus on the significance of antibiotic resistance as determined by antibiotic susceptibility testing, as clinical treatment success and in vitro antibiotic susceptibility appear not to be closely correlated [Fothergill et al. 2010; Hurley et al. 2012a].

Treatment of pulmonary exacerbations

Pulmonary exacerbations are independently associated with a poor outcome [de Boer et al. 2011] and so optimizing treatment of these is a priority for patients with CF. The trials involving fluoroquinolones that have reported are considered in Table 3 and a Cochrane review considering the intravenous antibiotic treatment of pulmonary exacerbations is underway [Hurley et al. 2012b]. It is important to note that many of the trials that have been completed are small and may have been underpowered to detect a small difference, should one exist. In a study directly comparing conventional intravenous ceftazidime and tobramycin with intravenous ciprofloxacin followed by oral dosing, all patients improved, compared with baseline, with no significant difference between the two groups in clinical score and lung function [Church et al. 1997]. In both arms clinical score and lung function deteriorated after end of treatment and equal numbers of patients in both arms developed a degree of antibiotic resistance. There was a 13% relapse rate (all in severely affected female white patients) in both groups.

Nebulized fluoroquinolone therapy

A Cochrane review has considered the efficacy of nebulized antibiotics and suggests that while inhaled antibiotics probably improve lung function and reduce exacerbation rate, there is currently insufficient evidence to recommend a particular drug or dose [Ryan et al. 2011]. It concluded that trials of a longer duration are required.

Since the publication of this Cochrane review, trials of nebulized levofloxacin have reported results. In a randomized, double-blind, placebo-controlled study involving 151 patients randomized to receive 120 mg daily, 240 mg daily, 240 mg twice daily or placebo for 28 days with follow up for 56 days. The primary efficacy endpoint was change in sputum density of P. aeruginosa. Secondary endpoints were change in lung function, time to administration of other antipseudomonal antibiotics and changes in symptom score [Geller et al. 2011]. Treatment commenced during a period of clinical stability. For the primary outcome, change in sputum density, this showed the largest fall from baseline at the 240 mg twice daily dose, with less significant decreases observed for the other two doses. Unfortunately no details are given of the microbiological methods used, and as previously mentioned, in the light of recent evidence questioning the aetiology of exacerbations, such endpoints should be treated with caution. Nevertheless, when considering forced expiratory volume in 1 s (FEV₁) and respiratory symptom score, patients receiving 240 mg twice daily responded with a significant improvement 8.6% above that of placebo at 28 days of the treatment phase, although this effect returned to baseline after cessation of the drug. The lower doses had a minimal effect. Two phase III trials of levofloxacin are currently underway, one placebo controlled [ClinicalTrials.gov identifier: NCT01180634], the other a comparison against tobramycin inhalation solution [ClinicalTrials.gov identifier: NCT01270347].

The side effect profile of nebulized levofloxacin appears to be good with numbers of adverse events in the treatment arms similar to those in the placebo group, except for complaints about taste, which was attributed to the study drug [Geller et al. 2011].

An inhaled preparation of ciprofloxacin [ClinicalTrials.gov identifier: NCT00645788] has recently completed a phase II randomized, double-blind, placebo-controlled study. The results are awaited.

Safety and adverse events

Adverse events reported in clinical trials may or may not be attributed to the drug regimen under investigation. Many reported adverse events relate to the disease and infection for which the antibiotic is intended to treat. In a controlled trial, both treatment groups may experience adverse events. When the rates of reported events are significantly greater in the treatment group compared with the comparator, or adverse events in the treatment group are severe (e.g. causing death or hospital admission), then this requires careful scrutiny.

Recognized side effects of fluoroquinolones, for all indications, include gastrointestinal disturbance (nausea reported in 6–10% of those receiving moxifloxacin, but less for ciprofloxacin), headache and dizziness (levofloxacin and moxifloxacin 1–5%), rash and photosensitivity (ciprofloxacin 1–5%, highest of all in the group [Lapi et al. 2010], very low for levofloxacin and not reported for moxifloxacin) and musculoskeletal effects [Zhanel et al. 2002].

With regard to cardiac toxicity, sparfloxacin and grepafloxacin have been removed from the market following concerns about QT-prolongation cardiac toxicity. The development of garenoxacin was also stopped after phase I trials. While this appears to be a class effect, the dual-elimination of most agents in the class make the risk of QT-related cardiac events unlikely, currently only levofloxacin and gatifloxacin are solely renally excreted and so may require dose adjustment in renal insufficiency. In fact the rates of QT prolongation are very low. However, it is suggested that some drugs in the class, particularly moxifloxacin and levofloxacin, are not used in combination with certain antiarrhythmics.

Less common but important adverse events of fluoroquinolones include retinal detachment (number needed to harm 2500) [Etminan et al. 2012] and a case of suicidal ideation that resolved after cessation of ciprofloxacin, after having recently received levofloxacin [Labay-Kamara et al. 2012]

There have been particular concerns of fluoroquinolone use in children after reports of drug-related arthropathy [Adefurin et al. 2011]. A prospective comparative cohort study in France recruited 276 children who were receiving a fluoroquinolone and 249 controls. A quarter of these children were younger than 2 years and a third had CF [Chalumeau et al. 2003]. Ten musculoskeletal events (10 patients) were experienced in the treatment group (perfloxacin 18.2%, ciprofloxacin 3.3%). The doses given to these patients were the same as those given to patients who did not report musculoskeletal side effects, with symptoms consisting of myalgia and arthralgias of large joints [Chalumeau et al. 2003]

However, it should be noted that often the most informative generation of safety data occurs in the postmarketing phase, in the UK facilitated by the yellow card adverse event reporting system. With this in mind, the case of trovafloxacin is apt [US Food and Drug Administration, 2009]. It was through postmarketing surveillance reports that unpredictable severe liver reactions (leading to transplant or death) were noted and the use of trovafloxacin restricted to those with limited indications.

New fluoroquinolones

There are numerous members of the quinolone family that have reached various points of development (Table 4). Many have fallen by the wayside due to side effects. While many have not been specifically evaluated in the context of infection in CF, some agents appear to show impressive levels of potency against P. aeruginosa (e.g. prulifloxacin) [Roveta et al. 2005]. Other agents appear to have specific non-antibiotic effects, such as effects on the host (moxifloxacin appears to inhibit activation of specific inflammatory mediators in CF epithelia) [Blau et al. 2007], or antivirulence effects on the pathogen (moxifloxacin may decrease adhesion and biofilm formation of Stenotrophomonas maltophilia) [Pompilio et al. 2010]. In addition, levofloxacin appears to be effective delivered in a newly developed inhalation vehicle.

Table 4.

Fluoroquinolones past, present and future.

First generation	Second generation	Third generation	Fourth generation
Nalidixic acid	Ciprofloxacin	Levofloxacin	Trovafloxacin
Cinoxacin	Norfloxacin	Sparfloxacin	Clinafloxacin
	Lomefloxacin	Grepafloxacin	Moxifloxacin
	Enoxacin	Gatifloxacin	Garenoxacin
	Ofloxacin	Gemifloxacin	Besifloxacin
	Perfloxacin	Tosufloxacin	Prulifloxacin
	Fleroxacin	Temafloxacin	Gatifloxacin
			Sitafloxacin
			Altrofloxacin

Summary

Fluoroquinolones are a useful component in the antibiotic arsenal against the wide range of pathogens that cause infection in CF. The oral administration of ciprofloxacin is particularly attractive for those experiencing a mild exacerbation of symptoms with good oral bioavailability. Newer inhaled agents are convenient to administer and may be suitable for maintenance treatment. Administration of agents in this class has been associated with improvements in lung function and clinical score. However, in the majority of these studies a sustained effect is not seen once the antibiotic course is completed. Concerns about side effects remain. The benefits in lung function and clinical scores observed in patients receiving these antibiotics must be weighed against the risks of side effects and alterations in the antibiotic sensitivity of infecting bacteria, and perhaps the increased possibility of infection with other bacteria. Long-term well conducted trials are needed to determine the optimal frequency of the use of maintenance antibiotics in this context. In addition, studies that further our understanding of the mechanisms underlying infection, pulmonary exacerbations and the relationship between the host, bacteria and antibiotics are urgently needed.

Footnotes

Funding

MNH is funded by a Wellcome Trust Clinical Research Training Fellowship (WT092295MA).

Conflict of interest statement

ARS has held positions on Advisory Committees/Boards for Vertex, Mpex Pharma and Forest Laboratories. MNH has no conflicts of interest to declare.

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