The main finding of our meta-analysis is that the so-called respiratory fluoroquinolones did not prove superior to β-lactams for the treatment of acute bacterial sinusitis in terms of the primary effectiveness outcome (clinical success [clinical cure or improvement]) or the primary safety outcome (total adverse events). However, in some of the secondary analyses, treatment outcomes were better among patients who received a respiratory fluoroquinolone than among those given a β-lactam antibiotic, specifically in the comparison of clinically evaluable populations (patients fulfilling the criteria for clinical evaluation), in the sensitivity analysis limited to blinded randomized controlled trials, and in terms of bacteriologic success (eradication or presumed eradication of the pathogens isolated before treatment). Yet patients who received a respiratory fluoroquinolone did not have greater clinical success than those given amoxicillin–clavulanate, nor did they have fewer relapses than patients given a β-lactam antibiotic. Furthermore, in the sensitivity analysis limited to blinded randomized controlled trials, the fluoroquinolone group had more total adverse events than the β-lactam group. Still, among all the relevant studies included in our meta-analysis, treatment with fluoroquinolones resulted in fewer severe adverse events.
The aforementioned associations did not change substantially when we included randomized controlled trials comparing any fluoroquinolone with a β-lactam antibiotic in the analysis. However, ciprofloxacin and sparfloxacin, the fluoroquinolones used in these additional studies, are not regarded as being as potent against S. pneumoniae
, in microbiologic terms, as the newer fluoroquinolones,32
and they are not currently recommended for the treatment of acute bacterial sinusitis.7
Nonetheless, both were approved by the US Food and Drug Administration for this indication, although sparfloxacin was withdrawn from the US market in 2001. Despite their inferior bacteriologic activity, our inclusion of ciprofloxacin and sparfloxacin in this meta-analysis may be meaningful, given that these 2 agents share certain pharmacokinetic properties with the newer respiratory fluoroquinolones, specifically with regard to drug penetration into the sinus mucosa.33–35
In addition, from a safety standpoint, most of the adverse events observed with fluoroquinolones are thought to be related to a class effect rather than an agent-specific effect.36
In the remainder of this discussion, we focus on the respiratory fluoroquinolones, although many of the issues addressed may also be relevant to the comparison of all fluoroquinolones with β-lactam antibiotics.
Although fluoroquinolones were comparable to β-lactam antibiotics in terms of the effectiveness outcomes of this meta-analysis when the intention-to-treat population was examined, analysis of the clinically evaluable population showed a marginal advantage in favour of fluoroquinolone treatment. This apparent disparity can be explained by the fact that the intention-to-treat analysis generally provides a more conservative estimate of treatment effect. Moreover, data for the outcome of clinical success in the intention-to-treat population were available for only 5 of the 11 included randomized controlled trials. However, the value of the intention-to-treat analysis is that it respects the random assignment of patients to study treatments and precludes bias in the selection of patients for evaluation, which is particularly important in nonblinded trials. In addition, the nature of the intention-to-treat analysis relates more closely to therapeutic decision-making in clinical practice.
In addition to the overall rate of resolution of symptoms in cases of acute bacterial sinusitis, the rapidity of symptom resolution is also important, because this condition adversely affects quality of life3
and is associated with substantial loss of productivity and associated sick leave expenditures in the workplace.37
We therefore performed a subanalysis assessing clinical effectiveness within 3 weeks after the start of treatment, which showed a marginal benefit of fluoroquinolones over β-lactams.
Some factors might blunt the demonstration of true differences between treatments in trials of acute bacterial sinusitis. The most important such factor is the expected enrolment of many patients with self-limiting viral disease, despite the use of clinical or radiologic diagnostic inclusion criteria.7,38–40
In fact, in this meta-analysis, the pooled percentage of patients with bacteriologically documented disease in the trials in which relevant studies were performed was 54%. Additional factors that may confound the assessment of effectiveness of the studied treatments include the potential for sinusitis-like symptoms to persist despite bacteriologic cure7,38,39
and the likelihood of unbalanced use of symptom-relief medications among different treatment groups.41
In this regard, the greater bacteriologic success exhibited with respiratory fluoroquinolones relative to β-lactams may be important. Still, the analysis of clinical success may be the best indicator of routine clinical practice.
Among the 5779 patients enrolled in the trials included in this meta-analysis, no serious complications of sinusitis, such as orbital or intracranial spread, were reported. Although serious complications of sinusitis are rare among patients who receive appropriate treatment,13
the lack of such complications in the populations evaluated in this meta-analysis could be attributed to the fact that patients with a greater likelihood of a complicated course of disease (e.g., those with a history of chronic sinusitis or recurrent acute sinusitis) were excluded from a considerable number of the trials,21,25,26,28–30,34
even though they are frequently encountered in routine clinical practice. In addition, in all but one of the included studies,25
the duration of follow-up was limited to no more than 1 month after the end of therapy, which may have been inadequate for accurate estimation of the rates of recurrence and progression to chronic sinusitis.
From a safety standpoint, the primary analysis, which included all 11 studies, showed that the treatments were comparable in terms of total adverse events recorded. Most of the reported adverse events involved the gastrointestinal tract, with diarrhea being more frequent in the β-lactam group and nausea more frequent in the fluoroquinolones group. In the analysis of adverse events, significant statistical heterogeneity between trials was observed. This can be attributed to the findings of one trial, which had a lower rate of adverse events in the fluoroquinolone group,27
whereas the other trials had an opposing trend. When we omitted the one trial in a post hoc exploratory analysis, we found that adverse events were significantly more common among patients given a respiratory fluoroquinolone (fixed-effects model for 5 trials with a total of 2133 patients, OR 1.35, 95% CI 1.13–1.62) or any fluoroquinolone (fixed-effects model for 8 trials with a total of 4419 patients, OR 1.26, 95% CI 1.10–1.44) rather than a β-lactam antibiotic. In addition, in the sensitivity analysis limited to blinded randomized controlled trials, a higher rate of adverse events was associated with fluoroquinolone use than with β-lactam use. Notably, in a prior meta-analysis concerning treatment of skin and soft-tissue infections in 4352 patients, the use of fluoroquinolones was associated with significantly more adverse events than β-lactam use was.42
Nevertheless, adverse events characterized as severe were significantly less frequent among patients given a fluoroquinolone than among those given a β-lactam antibiotic. No cases of major arrhythmia, hepatitis, seizure or severe phototoxicity reaction, all of which are potentially serious adverse events associated with the use of some fluoroquinolones,36
were recorded among patients included in this meta-analysis. However, the absence of these adverse events could be partly attributed to the exclusion from clinical trials of patients who are prone to experience a serious adverse event associated with the study drugs. In fact, in 4 of the 11 trials included in this meta-analysis, patients were excluded if they had a history of seizure disorder,27
or a prolonged QRS interval.25,28
Moreover, some serious adverse events may be so rare that they will be identified only in large-scale postmarketing surveillance programs. This was the case for gatifloxacin, which has been withdrawn from the market because of its association with disturbances in glucose control. This drug was studied in only one of the trials included in our meta-analysis, and no adverse event of this type was reported among the 290 patients in the gatifloxacin group in that trial.24
Issues relating to bacterial drug resistance are also important in the choice of antimicrobial therapy. In fact, the major “respiratory” pathogens (S
) have acquired resistance to multiple antibiotics, to various degrees.8
Of great concern is the increased prevalence of S
with reduced susceptibility to penicillin and, in parallel, increased resistance to other classes of antimicrobial agents.43
Although pneumococcal resistance to penicillin is relative and can be overcome with high-dose amoxicillin therapy in patients with sinusitis,44
the respiratory fluoroquinolones constitute a valuable therapeutic option.45
However, indiscriminate fluoroquinolone use may promote fluoroquinolone resistance in S
, which is often associated with multiple-drug resistance.46
Our meta-analysis had certain potential limitations. First, as in most meta-analyses of this kind, there was some variability in the characteristics of the included studies, relating chiefly to inclusion and evaluation criteria and the time of determination of the outcomes. Even so, for most of the analyses, the data retrieved did not exhibit significant heterogeneity. In addition, most of the included randomized controlled trials had some methodologic shortcomings. Moreover, the majority of the included trials, including all 5 of the nonblinded studies, were supported by pharmaceutical companies associated with the fluoroquinolone agents tested, a factor that may have generated bias in the assessment of outcomes. In this regard, the findings in the analysis of the blinded randomized controlled trials should be underscored.
Despite these limitations, the value of this meta-analysis lies in its combination of data from several randomized controlled trials, based on a non-inferiority design, which resulted in demonstration of differences in some aspects of the effectiveness and safety of the treatments. Most of the differences observed were of marginal statistical significance, and a randomized controlled trial of a very large sample would be required to manifest these differences.47
In conclusion, we found that respiratory fluoroquinolones were comparable to β-lactams for the treatment of acute bacterial sinusitis, in terms of the primary effectiveness outcome (clinical cure and improvement) and the primary safety outcome (total adverse events) examined. However, a propensity for more adverse events in association with fluoroquinolone use was observed in sensitivity and exploratory analyses. Thus, the use of respiratory fluoroquinolones as first-line therapy in the vast majority of patients with bacterial sinusitis, in whom the condition often has a benign clinical course, is not supported by the available evidence. The finding that presumed bacteriologic success was superior among fluoroquinolone-treated patients suggests that use of a respiratory fluoroquinolone may be considered in cases where β-lactam treatment has failed, particularly if the risk of infection with drug-resistant pathogens is a consideration.
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