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Antimicrobial Agents and Chemotherapy, January 2006, p. 22-33, Vol. 50, No. 1
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.1.22-33.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

MINIREVIEW

Quinolones for Treatment of Human Brucellosis: Critical Review of the Evidence from Microbiological and Clinical Studies

Matthew E. Falagas1,2,3* and Ioannis A. Bliziotis1

Alfa Institute of Biomedical Sciences (AIBS), Athens, Greece,1 Department of Medicine, Henry Dunant Hospital, Athens, Greece,2 Department of Medicine, Tufts University School of Medicine, Boston, Massachusetts3


   INTRODUCTION
Top
 Introduction
Conclusions
 References
 
Brucellosis is a zoonotic disease with worldwide distribution that is endemic in the Mediterranean region, the Middle East, Central Asia, and parts of Africa and Latin America. Worldwide, brucellosis remains a major cause of morbidity in humans and domesticated animals. In animals, bovine brucellosis, caused mainly by Brucella abortus, is still the most widespread form. In humans, ovine/caprine brucellosis caused by Brucella melitensis is by far the most common type of disease. The disease has a wide spectrum of clinical manifestations and can affect a variety of organs and systems. Localized and complicated forms of brucellosis cause important morbidity and require prolonged medical treatment. Fortunately, mortality is relatively low and is related mainly to cardiovascular and central nervous system complications of the disease.

Although several studies have been conducted over the past 2 decades, there is no conclusive evidence on the optimum antibiotic therapy for brucellosis. Disease relapse still represents one of the most important therapeutic problems. The last recommendation by the World Health Organization (WHO) for the treatment of acute brucellosis in adults was published in 1986 and suggested 600 to 900 mg rifampin and 200 mg doxycycline daily for a minimum of 6 weeks (8). Alternatively, the WHO suggested that rifampin could be replaced with 15 mg/kg of streptomycin, administered intramuscularly for only 2 weeks. However, a meta-analysis, as well as a prospective randomized trial, both performed by Solera et al., showed that the "good old" combination regimen of streptomycin with an oral tetracycline results in fewer relapses than the doxycycline-rifampin combination (57, 58). Controlled clinical trials with other antibiotics, including trimethoprim-sulfomethoxazole, new macrolides, and ß-lactams, have shown inferior results or involved too few patients for a proper evaluation. Thus, the most widely used regimens are the two aforementioned combinations that were recommended by the WHO. In addition, rifampin monotherapy is the main option for brucellosis during pregnancy, whereas its combination with trimethoprim-sulfomethoxazole is the suggested treatment for childhood brucellosis (5, 34).

Certain focal forms of brucellosis are difficult to treat, and surgery should be considered for patients with endocarditis or cerebral, epidural, splenic, or other abscesses (20, 41). Regarding medical treatment, although the antibiotics used are essentially the same, prolonged therapy, up to six or more months, may be needed for patients with osteoarticular forms of the disease, and especially spondylitis (18, 56, 65). Also, triple-antibiotic combinations were found to be of value in some case series of brucellar endocarditis, spondylitis, and meningitis (2, 41, 65). Relapse of the disease also represents a major therapeutic problem for its focal forms.

Since the mid 1980s, laboratory researchers and clinicians have performed several microbiological and clinical studies of the possible use of quinolones in the treatment of human brucellosis. The activity against intracellular bacteria (23), reduced risk of nephrotoxicity, good pharmacokinetic characteristics, and lack of a requirement for drug level monitoring represent the main advantages of using quinolones in this setting. Moreover, the need for a regimen that would eliminate disease relapse further necessitated the use of quinolones. However, there is only one brief review focusing on the issue, published in 1992 (38). This study reviewed the available in vitro and clinical data at the time and examines the rationale, as well as the outcomes, of quinolone use for brucellosis.


   DATA SOURCES AND ANALYSIS
 
We searched for microbiological and clinical studies that examined the use of quinolones for human brucellosis by making use of PubMed and the Institute of Scientific Information Web of Science database. Search keywords included brucella, brucellosis, treatment, quinolone, ciprofloxacin, clinafloxacin, difloxacin, fleroxacin, gatifloxacin, grepafloxacin, levofloxacin, lomefloxacin, moxifloxacin, norfloxacin, ofloxacin, pefloxacin, rufloxacin, sparfloxacin, temafloxacin, and trovafloxacin. We also, reviewed the references in the relevant articles. Since the primary and by far the most common pathogen causing human brucellosis is Brucella melitensis, we evaluated laboratory studies focusing on that specific pathogen. On the other hand, clinical studies were included in our review even if the diagnosis of brucellosis was established without isolation of Brucella melitensis but instead was based on serology, which cannot identify the rare cases of infection by other types of brucella. Finally, we included studies written in English, German, French, Italian, Spanish, Portuguese, or Greek.

Data were extracted from the included studies, and evidence-based recommendations were made whenever possible. The grades of recommendation used in this study are the ones proposed by the Oxford Centre for Evidence-Based Medicine (http://www.cebm.net/levels_of_evidence.asp#levels). In brief, possible grades for recommendations are the letters A to E, with grade A representing recommendations based on studies with the highest level of evidence (e.g., meta-analysis of randomized controlled trials [RCTs]), and grade E recommendations are based on studies with a low level of evidence (e.g., expert opinion).


   LABORATORY STUDIES
 
In Table 1, we present results from the laboratory studies that examined the use of various quinolones against isolates of Brucella melitensis (3, 6, 13, 15, 17, 21, 24-27, 32, 36, 39, 44-54, 62). Sparfloxacin and clinafloxacin were the quinolones with the lowest MICs among the few studies that evaluated them in comparison with other quinolones (24-26, 36, 51-54). A careful review of the studies shows that the MICs of some of the most widely used quinolones against Brucella melitensis are generally low; ofloxacin (MIC90, 0.02 to 2.5 mg/liter), ciprofloxacin (MIC90, 0.06 to 2.0 mg/liter), norfloxacin (MIC90, 0.12 to 0.5 mg/liter), levofloxacin (MIC90, 0.5 mg/liter), and moxifloxacin (MIC90, 0.5 to 1 mg/liter) achieved low MICs for the majority of isolates.


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  		TABLE 1. In vitro studies examining the use of quinolones against Brucella melitensis isolates

 
Despite these results, two studies provided important insights regarding the decreased antimicrobial activities of quinolones in an environment at pH 5, which is the pH of phagolysosomes in macrophages, where brucellae grow. According to Garcia-Rodriguez et al. (24), there was a twofold to fourfold decrease in the antimicrobial activities of quinolones at pH 5 compared to pH 7. In addition, Akova et al. (3) showed that at pH 5, only doxycycline and rifampin retain good activity against brucellae with MICs below the Clinical and Laboratory Standards Institute (formerly NCCLS) breakpoints, in contrast to other tested antibiotics, which included ciprofloxacin, ofloxacin, streptomycin, erythromycin, and azithromycin. In fact, in this study, it was shown that rifampin is the only drug with increased activity (a decreased MIC) at pH 5 compared to pH 7. Finally, it should be noted that in the study of Garcia-Rodriguez et al., all quinolones exhibited very low bactericidal activities against the 21 strains tested, regardless of pH, with a minimal bactericidal concentration at which 90% of strains are killed of ≥8 mg/liter.

In a study by Rubinstein et al. (54), various antibiotic combinations were tested against Brucella melitensis in combination studies, but none of them exhibited actual synergy. Qadri et al., in an earlier study (44), also reported the absence of synergy between quinolones and other antibiotics against Brucella melitensis. Moreover, in killing-rate studies, in the study by Rubinstein et al., it was shown that the combination of ciprofloxacin with minocycline exhibited the slowest bacterial killing, whereas combinations of streptomycin with other antibiotics achieved the fastest killing. In a study by Akova et al. (3), the combination of ofloxacin with rifampin was tested against 20 isolates at pH 7 and 5. In 17 isolates, there was antagonism, and in 3, there was indifference between the two antibiotics at pH 7, whereas at pH 5, the combination exhibited antagonism, indifference, additive effect, and synergy in 7, 8, 1, and 4 isolates, respectively; in this study, the combination of rifampin and doxycycline was found to be the most synergistic.

Qadri et al. reported rare in vitro resistance of Brucella melitensis (<2% of studied isolates) to ciprofloxacin and cross-resistance to all other tested quinolones (44, 45, 51-53). The agent PD 131628 was the only quinolone for which no cross-resistance of a ciprofloxacin-resistant strain was found in another study by Qadri et al. (50), although an increased MIC for the drug was noted against this strain. On the other hand, in two recent studies, one from Turkey (13) and one from Kuwait (21), all isolates were susceptible to ciprofloxacin, whereas 9.6% and 8% of the isolates were resistant to rifampin in vitro, respectively.


   RANDOMIZED CONTROLLED TRIALS
 
Data from seven RCTs testing monotherapy (one RCT) or combination therapy with quinolones versus standard combinations for the treatment of brucellosis (mainly doxycycline combined with rifampin) were available for evaluation (Table 2) (1, 4, 11, 29, 31, 37, 55). As shown in Table 2, these RCTs are heterogeneous in regard to the study populations, the combinations of antibiotics used and their dosages, the duration of treatment, and the periods of follow-up. Thus, the results were also considered too heterogeneous to be included in a formal meta-analysis. Nevertheless, important conclusions may be drawn from a critical review of these data. Monotherapy with ciprofloxacin results in an unacceptably high probability of relapse, as shown by Lang et al. (37). Similar high rates of relapse have also been found in two other nonrandomized prospective cohort studies that used ciprofloxacin monotherapy in a total of 30 patients (Table 3) (7, 22).


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  		TABLE 2. RCTs examining use of quinolones in treatment of human brucellosis

 

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  		TABLE 3. Retrospective and prospective (non-randomized) studies examining the use of quinolones in the treatment of human brucellosis

 
In four out of the other six RCTs, ofloxacin was the agent used in the quinolone treatment arm, in combination with rifampin. In three of these studies, the results were similar between the quinolone and the nonquinolone arms in regard to initial treatment success and probability of relapse (4, 31, 55). Also, in one of these three studies (4), although the initial treatment success was better for the nonquinolone arm (no P value was reported), the reported toxicity (mild gastrointestinal discomfort) was far more common in that treatment arm (P<0.005). On the other hand, in the one of the four studies that examined the combination of ofloxacin with rifampin, the quinolone arm was found to be inferior to four other treatment regimens in terms of initial treatment success and relapse rate (P < 0.05 in two out of four comparisons of relapse rates that we performed by the {chi}2 method), whereas no important difference was noted in toxicity (11). It should be noted, however, that in this study, only patients with spondylitis were included.

In two RCTs, ciprofloxacin was the quinolone used, combined with doxycycline (29) or rifampin (1); the results were similar between the quinolone and the nonquinolone groups. Interestingly, in the study by Kalo et al. (29), only patients with nonlocalized brucellosis were included, whereas in the second ciprofloxacin study, by Agalar et al. (1), only patients with positive blood cultures were included. Another point that deserves to be mentioned is that in two RCTs studying quinolones as part of a combination treatment regimen (in one RCT, ofloxacin [31], and in the other RCT, ciprofloxacin [1]), the quinolone combination regimen was administered for a shorter duration than the nonquinolone regimen (30 versus 45 days).


   CLINICAL STUDIES
 
Quinolones were used in various retrospective, as well as prospective (non-RCT), studies (Table 3) (7, 9, 12, 22, 33, 43, 59-61). It should be mentioned that such studies are generally more difficult to identify in searches of literature databases, because treatment is not the focus in a considerable proportion of them. Thus, there may be more published studies that we could not identify. A further point that should be made is that it is difficult to interpret and extrapolate the results from these studies, since there is wide heterogeneity in the studied populations and the methods used.

Two prospective studies by al Sibai et al. (7) and Doganay and Aygen (22) reported high probabilities of brucellosis relapse after monotherapy with ciprofloxacin (26.7% and 21.4%, respectively), whereas in a study of 22 patients treated with the same regimen, Sturniolo et al. (59) reported a relatively high rate of initial treatment failure (9.1%), but no relapses. A case series by Baykal et al. (12), in which ofloxacin was used as monotherapy, reported a probability of relapse similar to that noted with the use of the standard combination regimens (8.3%). On the other hand, in a retrospective study by Tekkok et al. (61), ofloxacin monotherapy led to a higher probability of brucellosis relapse than the combination of ofloxacin and rifampin in a small number of patients with spondylitis. A critical analysis of a large retrospective study by Aygen et al. (9) that included 480 patients with various forms of brucellosis showed that the probabilities of relapse for the various treatment regimens were 4.6% for patients who received nonquinolone regimens and 17.9% for patients who received quinolone-based regimens (21.4% for ciprofloxacin monotherapy and 14.3% for the combinations of quinolones with other antibiotics).

In three studies in which quinolones were used in patients with osteoarticular brucellosis, the results were equivocal. Pappas et al. (43) reported a series of five patients with spondylitis who were cured and had no relapse with a combination of doxycycline and ciprofloxacin for 12 weeks. On the other hand, Tekkok et al. (61) reported on 15 patients with spondylitis, 7 of whom received quinolones. The only relapse among these 15 patients occurred in a patient who received ofloxacin monotherapy. Finally, in a retrospective control study by Tasova et al. (60), which focused on 87 patients with osteoarticular brucellosis (including 12 patients with spondylitis), the results were similar for the quinolone and nonquinolone arms.

In addition to prospective and retrospective studies reporting results for series of patients with brucellosis reviewed above, there are several case reports in the literature describing some observations that may have clinical significance. Among them, two reports describe good results with the use of conservative treatment with quinolones in infective endocarditis (41, 42), whereas another report describes failure of therapy in prosthetic-valve endocarditis caused by quinolone-resistant Brucella melitensis (30). In addition, there are case reports, or reports of single cases within larger studies, that offer some data regarding the use of quinolones as alternatives to standard treatment when the latter causes toxicity to the patients (14, 16, 19). Also, successful treatment of relapse of brucellosis by the use of quinolone-based regimens, in cases where standard treatments failed, has been described (28, 43). Finally, there are promising reports regarding the use of a quinolone as the third agent in therapeutic combinations for complicated and difficult-to-treat cases of brucellosis (2, 40, 63, 64, 66).


   CRITICAL EVALUATION OF THE AVAILABLE EVIDENCE
 
The traditional combination of streptomycin with a tetracycline has been proven to be probably the best currently available therapeutic option for brucellosis, especially in cases of localized forms of the disease (57, 58). Nevertheless, relapses also occur with this regimen. In addition, streptomycin carries the toxicity profile of the aminoglycosides, which necessitates monitoring of renal function. Moreover, the fact that streptomycin is administered only intramuscularly or intravenously is yet another disadvantage of the tetracycline-streptomycin combination. On the other hand, the combination of a tetracycline with rifampin has the advantage of oral administration for both drugs, but relapse of brucellosis is more common than with the tetracycline-streptomycin combination (57, 58); in addition, toxicity is also relatively frequent with the tetracycline-rifampin combination, although not commonly serious (4, 31).

Thus, the use of a quinolone, as monotherapy or in combination with rifampin or a tetracycline, instead of the traditional combination therapy could be considered for the treatment of brucellosis if it led to better outcomes, including a lower probability of relapse, or if it had the same probability of relapse but with less toxicity than the tetracycline-streptomycin or tetracycline-rifampin combinations. Unfortunately, such a statement cannot be supported by a critical review of the literature on this issue. Specifically, the available evidence does not suggest that quinolones lead to improved outcomes. On the contrary, when quinolones are used as monotherapy, disease relapse is unacceptably high, whereas when they are used in combination with rifampin or doxycycline, relapse is, in the best case, comparable to that observed with the other regimens.

The finding of lower toxicity in the quinolone treatment arm, described by Akova et al. (4), although statistically significant, referred to less gastrointestinal discomfort, which did not necessitate discontinuation of therapy and thus could not represent a serious criterion in favor of quinolone use per se. However, the issue of the comparative toxicities of various regimens against brucellosis, including quinolones, should be further studied in a more systematic way in future RCTs.

Finally, one should not overlook the obvious increase in the cost of therapy when a quinolone is used for the treatment of patients with brucellosis. The issue of cost may have been one reason why some authors compared regimens containing quinolones with shorter duration versus traditional regimens, since a shorter-duration regimen could compensate for the increase in cost of quinolone therapy (1, 31).

Despite the above observations, quinolones may have some role in the management of brucellosis (Table 4). First, they may replace a tetracycline or rifampin whenever toxicity of one of these two agents occurs when they are administered in combination therapy. Moreover, there is a rationale, as well as some evidence, for using quinolones as part of a second-line regimen in patients who fail to respond or develop disease relapse after therapy with a nonquinolone regimen (28, 43). Also, there are anecdotal reports of promising clinical results when quinolones are used in complicated brucellosis as a third treatment agent in combination therapy.


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  		TABLE 4. Authors' evidence-based evaluation of the use of quinolones for the treatment of brucellosisa

 
The development by Brucella melitensis of resistance against treatment with quinolones is a relatively uncommon phenomenon. However, after the increase in use of quinolones during the last few decades, there has been a concurrent increase in the emergence of resistance against quinolones in a great variety of organisms (10, 35). Thus, it will not be surprising if resistance of Brucella melitensis to quinolones will increase as well in the future. It should also be noted that resistance of Brucella to rifampin may represent an issue for consideration, judging by the results of some recent in vitro studies (13, 21). As Baykam et al. have also commented (13), this fact may be linked to the increased use of rifampin in some areas due to the reemergence of tuberculosis.


   CONCLUSIONS
Top
 Introduction
 Conclusions
References
 
In conclusion, a critical review of the available literature from laboratory and clinical studies regarding quinolone use in the treatment of human brucellosis suggests that there is a lack of evidence supporting the inclusion of quinolones in the initial therapeutic regimen. First, in vitro studies showed decreased activity of quinolones at pH 5 compared to pH 7 and a lack of synergistic activity of combinations of quinolones with the older antibiotics against brucellosis. Although these two findings may be misleading, since discrepancies often exists between laboratory and clinical results, they should not be overlooked. Moreover, the available RCTs do not provide support for the use of quinolone-based combinations as a first-line therapy. However, it should be emphasized that these RCTs are heterogeneous in regard to the study populations, the combinations of antibiotics used and their dosages, the duration of treatment, and the periods of follow-up. What is more important is that all of the RCTs included only a small number of patients in each treatment arm.

Subsequently, further laboratory research may be of value, focusing on in vitro studies of combinations of various quinolones with other antibiotics, especially with tetracyclines. What may be more valuable is the design of RCTs with larger numbers of patients in order to evaluate the definitive role of quinolones in the treatment of brucellosis. However, quinolone-based treatments seem to have a role in modern clinical practice as alternatives to standard therapy for patients with relapse of brucellosis after treatment with another regimen, as well as in patients in whom toxicity has developed due to the use of some of the older agents.


   ACKNOWLEDGMENTS
 
We thank S. N. Kontadakis for his help with studies reported in Italian.


   FOOTNOTES
 
* Corresponding author. Mailing address: Alfa Institute of Biomedical Sciences (AIBS), 9 Neapoleos Street, Marousi 151 23, Greece. Phone: 30-694-611-0000. Fax: 30-210-683-9605. E-mail: matthew.falagas{at}tufts.edu. Back


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Top
 Introduction
 Conclusions
 References
 

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Antimicrobial Agents and Chemotherapy, January 2006, p. 22-33, Vol. 50, No. 1
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.1.22-33.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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