Treatment of Chlamydial Infections: 2014 Update

Home , Chlamydia pneumoniae, Chlamydia trachomatis, Chlamydophila

Review Treatment of chlamydial infections: 2014 update

† Stephan A Kohlhoff & Margaret R Hammerschlag † 1. Introduction SUNY Downstate Medical Center, Division of Pediatric Infectious Diseases, Department of Pediatrics, Brooklyn, NY, USA 2. Antimicrobial susceptibility of Chlamydia spp. Introduction: Chlamydiae are obligate intracellular bacterial pathogens 3. Treatment of genital whose entry into mucosal epithelial cells is required for intracellular survival C. trachomatis infections in and subsequent growth. The life cycle of Chlamydia spp. and the ability to adults and adolescents cause persistent, often subclinical infection, has major ramifications for diag- 4. Treatment of acute respiratory nosis and treatment of Chlamydia trachomatis and C. pneumoniae infections C. pneumoniae infection in humans. Areas covered: 5. Expert opinion This paper reviews the current literature on the antimicrobial susceptibilities and treatment of genital infections due to C. trachomatis and respiratory infections due to C. pneumoniae published since 2011. Expert opinion: Chlamydiae are susceptible to antibiotics that interfere with DNA and protein synthesis, including tetracyclines, macrolides and quinolones, which are the compounds that have been most extensively studied and used for treatment of human infection. Since our original review was published in 2011, there have been some major advances in diagnostic tests for C. trachomatis and the introduction of the first FDA-approved test for the detection of C. pneumoniae in respiratory samples. However, the options for treating chlamydial infections have largely remained the same. There are a small number of new drugs currently in preclinical development and early clinical trials that may have a role in the treatment of chlamydial

For personal use only. infections.

Keywords: antibiotics, Chlamydia pneumoniae, Chlamydia trachomatis, Chlamydiae

Expert Opin. Pharmacother. (2015) 16(2):205-212

1. Introduction

Chlamydiae are obligate intracellular bacterial pathogens whose entry into mucosal epithelial cells is required for intracellular survival and subsequent growth. Chlamydiae cause a variety of diseases in animal species at virtually all phylo- genic levels, from amphibians and reptiles to birds and mammals. The chlamyd- Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Sanofi Synthelabo on 01/23/15 ial species that most frequently cause disease in humans are Chlamydia trachomatis and C. pneumoniae. C. trachomatis is a major cause of sexually transmitted infections including non-gonococcal urethritis (NGU) and epididymitis in men, cervicitis and pelvic inflammatory disease in women, and conjunctivitis and pneumonia in infants born to women with active genital infection [1,2]. C. pneumoniae is primarily a respiratory pathogen and is a frequent cause of community- acquired pneumonia (CAP) in adults and children [3]. The organism has also been implicated as an infectious trigger in asthma [2,3]. The majority of C. trachomatis and C. pneumoniae infections are asymptomatic and frequently of long duration. This topic was last reviewed in Expert Opinion in Pharmacotherapy in 2011 [4]. The present review covers advances in the management of infections due to C. trachomatis and C. pneumoniae published since 2011.

Table 1. MIC of selected antimicrobial agents against Article highlights. Chlamydia trachomatis and C. pneumoniae. . Chlamydiae are susceptible to antibiotics that interfere with DNA and protein synthesis, including Antimicrobial C. trachomatis C. pneumoniae tetracyclines, macrolides and quinolones. . Since 2011, there have been major advances in FDA-approved drugs diagnostic tests for Chlamydia trachomatis and the Doxycycline 0.031 -- 0.25 0.015 -- 0.5 introduction of the first FDA-approved test for the Tigecycline 0.03 -- 0.125 0.125 -- 0.25 detection of C. pneumoniae in respiratory samples. Erythromycin 0.016 -- 2 0.015 -- 0.25 . The options for treating C. trachomatis and Azithromycin 0.6 -- 2 0.05 -- 0.25 C. pneumoniae infections are largely the same as Clarithromycin 0.015 -- 0.125 0.004 -- 0.125 they were in 2011. Clindamycin 2 -- 16 -- . Azithromycin remains the drug of choice for Ciprofloxacin 0.5 -- 21-- 4 uncomplicated C. trachomatis genital infection Levofloxacin 0.12 -- 0.5 0.25 -- 1 and trachoma. Moxifloxacin 0.5 -- 1 0.125 -- 1 . In vitro antibiotic resistance in Chlamydia spp. is very Rifampin 0.005 -- 0.25 0.0075 -- 0.03 rare and does not appear to affect microbiologic Trimethoprim ‡ 128 ‡ 128 efficacy in vivo. Sulfamethoxazole 0.5 -- 4 ‡ 500 . There several new drugs currently in preclinical Gentamicin 500 500 development and early clinical trials, including Vancomycin 1000 1000 solithromycin and a novel nonquinolone DNA gyrase Investigational drugs inhibitor (AZD 0914) that may have a role in the Solithromycin (CEM-101) 0.125 -- 0.5 0.25 -- 1 treatment of chlamydial infections. Sitafloxacin 0.031 -- 0.063 0.031 -- 0.125 Nemonoxacin 0.03 -- 0.125 0.03 -- 0.125 -- -- This box summarizes key points contained in the article. Delafloxacin 0.06 0.125 AZD0914 0.06 -- 0.5 0.25 -- 1 Rifalazil 0.00125 -- 0.0025 0.00125

µ 2. Antimicrobial susceptibility of Chlamydia MIC range ( g/ml). Data taken from [3,4,11-13,25-28,36,37]. spp.

The biology of Chlamydiae was reviewed in detail by Hammers- AZD0914 (AstraZeneca) is a member of a new class of anti- bacterials which incorporates a novel spiropyrimidinetrione chlag and Kohlhoff in 2011 [4]. Chlamydiae are susceptible to a that also targets DNA gyrase/topoisomerase IV through novel

For personal use only. wide variety of antibiotics that interfere with DNA and protein synthesis, including tetracyclines, macrolides, quinolones, rifa- mode of inhibition [9]. AZD0914 has potent in vitro antibac- mycins and clindamycin (Table 1). Although there are no stan- terial activity against fluoroquinolone-resistant and multi- dardized methods for in vitro susceptibility testing of drug resistant MRSA, Streptococcus pneumoniae and Neisseria gonorrhoeae [9,10]. Preliminary data have also demonstrated Chlamydia spp., results have been largely consistent [5-7]. Chlamydia spp. are resistant to trimethoprim, aminoglycosides good activity against C. trachomatis and C. pneumoniae [11]. and glycopeptides. C. trachomatis is sensitive to sulfonamides In addition, there are two quinolones, nemonoxacin and dela- but C. pneumoniae and C. psittaci are resistant. Genomic analysis floxacin which are being fast-tracked by the FDA for treat- has revealed that C. trachomatis and C. pneumoniae encode for ment of gonorrhea. These compounds also retain activity proteins forming a nearly complete pathway for the synthesis against quinolone-resistant N. gonorrhoeae and are active of peptidoglycan, including three penicillin-binding proteins, against Chlamydia spp [12,13]. Both are currently in Phase III thus penicillin and amoxicillin have been found to have some clinical trials for treatment of gonococcal infection. Solithro- Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Sanofi Synthelabo on 01/23/15 activity in vitro, this has been called the chlamydial paradox or mycin (CEM-101) is a ketolide antibiotic that is currently in Phase III clinical trials for treatment of CAP. It has good anomaly [8]. Amoxicillin has been recommended as an alternative regimen for treating C. trachomatis infection in pregnant in vitro activity against both C. trachomatis and C. pneumoniae women and has been found to be as effective and better tolerated [4], but the efficacy against CAP due to C. pneumoniae is not being assessed in these treatment studies. than erythromycin [1]. The intracellular location of Chlamydia spp. requires that antimicrobial agents need to achieve adequate intracellular 2.1 Antibiotic resistance in C. trachomatis and penetration and concentration to be effective. Efficacy is gen- C. pneumoniae erally defined by a MIC of 1 µg/ml or less, but an antibiotic Although resistance to quinolones and rifamycins can be with an MIC of 0.1 µg/ml may not necessarily have greater induced in C. trachomatis and C. pneumoniae in vitro by serial microbiologic efficacy in vivo than one with an MIC of passage in subinhibitory concentrations of antibiotics [14-16], 1 µg/ml [4]. antibiotic resistance in both species appears to be very rare There are several new antibiotics with anti-chlamydial in vivo. The number of passages needed to select for resistant activity that are currently in early clinical development. mutants varied by species, strain and antibiotic. The role of

206 Expert Opin. Pharmacother. (2015) 16(2) Treatment of chlamydial infections: 2014 update

antimicrobial resistance in treatment failures or persistent adults with CAP [3]. Most patients improved clinically despite infection is not clear. The potential of the organism to persistence of the organism. Persistence did not appear to be develop antimicrobial resistance in vivo has not been well secondary to the development of antibiotic resistance, as the studied, mostly limited to a few case reports that suggested MICs of the isolates obtained after treatment did not that resistance was a possible cause of clinical treatment fail- change [25-28]. ure; however, the possible mechanisms of resistance were not well defined [7]. 3. Treatment of genital C. trachomatis Most recurrent C. trachomatis infections result from re- infections in adults and adolescents infection from an untreated partner or new infection from a new sexual partner [17]. Studies examining the in vitro suscepti- Because of the long life cycle of C. trachomatis,48-- 72 h bilities of clinical isolates from patients with C. trachomatis depending on biovar and strain, treatment has in the past infection seen in the US and Israel in 2005 and 1995 did not required multiple dose treatment regimens. For decades, reveal any resistant organisms [18,19]. A more recent survey 7-day courses of doxycycline and erythromycin were standard from Croatia, which has the highest consumption of azithro- treatment [1]. The need for multiple dose regimens has raised mycin in Europe, did not find any resistance to azithromycin concerns about the impact on compliance. The introduction or doxycycline in 24 recent clinical urogenital isolates of C. tra- of azithromycin with its long half-life in tissue has allowed chomatis [20]. The MICs for azithromycin and doxycycline for single-dose treatment of genital C. trachomatis infec- ranged from 0.064 to 0.125 µg/ml and 0.016 -- 0.064 µg/ml, tions [1]. Currently, the centers for disease control and respectively. Two large surveys of C. trachomatis isolates from prevention (CDC) recommends either single dose azithromy- patients with trachoma did not detect development of macro- cin or 7-day course of doxycycline as first-line regimens for lide resistance after biannual communitywide distributions of the treatment of uncomplicated genital C. trachomatis infec- azithromycin for control of trachoma [21,22]. In 2009, tion in adolescent and adult men and women [1]. Alternative Hong et al. [21] investigated the susceptibilities of C. trachomatis regimens include 7-day course of erythromycin base or ethyl- isolates 18 months after four biannual community-wide antibi- succinate. Erythromycin is has a higher rate of gastrointestinal otic distributions in Ethiopia. These distributions involved side effects than either azithromycin or doxycycline, which hundreds of individuals ‡ 1 year of age receiving a single dose may contribute to lower efficacy seen in a number of studies. azithromycin, 20 mg/kg in children or 1 g in adults twice a Levofloxacin and ofloxacin are also listed as alternatives treat- year, which could conceivably provide selective pressure which ment regimens; however, they are more expensive and require might enable expansion of resistant clones of C. trachomatis. multiple dosing which offers no advantages over the first-line

For personal use only. The investigators found no significant differences in in vitro recommendations. These recommendations have not changed susceptibilities of C. trachomatis isolates from these patients since 1993. A meta-analysis of 12 randomized clinical trials, to azithromycin and doxycycline. More recently, West et al. published in 2002, comparing single dose azithromycin to a [22] reported similar findings after 3 yearly mass distributions 7-day course of doxycycline found a rate of microbiologic of azithromycin in 32 communities in Tanzania. They identi- eradication of 97% for azithromycin and 98% for doxycy- fied 30 children with trachoma who remained positive for cline [29]. Manhart et al. [30] in a study published in 2013, C. trachomatis. In vitro susceptibility testing was performed evaluating azithromycin and doxycyline for the treatment of on 15 paired C. trachomatis isolates from these children. The non-gonoccocal urethritis found that although both regimens average MIC was 0.26 µg/ml for azithromycin before, and had a similar microbiologic cure rate, it was lower than what 0.20 µg/ml after mass distribution of azithromycin. The had previously been reported. The microbiologic cure rates authors concluded that other potential causes of persistent for C. trachomatis were 86% for azithromycin and 90% for

Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Sanofi Synthelabo on 01/23/15 infection needed to be evaluated. It should be noted that the doxycycline, which were substantially lower than earlier stud- communitywide azithromycin exposure with treatment of ies. Although the authors describes various reasons why their chlamydial genital infections is significantly less than the results were different, including: it was a single site study mass treatments required for control of trachoma. and variations in duration of follow up and timing of test of In contrast, mass distribution of azithromycin for control cure specimens, the most likely explanation is that the earlier of trachoma has been associated with increased carriage of trials used culture or immunoassays to detect C. trachomatis, azithromycin-resistant fecal Escherichia coli [23] and increased whereas the current study used a nucleic acid amplification carriage of azithromycin-resistant S. pneumoniae in young test (NAAT). NAATs are significantly more sensitive than children [24]. culture for detection of C. trachomatis in urogenital speci- Similar data have been reported for treatment of C. pneu- mens. The use of less sensitive methods, including culture moniae respiratory infections. Results of several multicenter and immunoassays, may have led to overestimation of micro- treatment studies that utilized culture demonstrated biologic efficacies. Recently, Kong et al. [31] conducted 70 -- 86% efficacy of treatment with erythromycin, clarithro- another meta-analysis of trials comparing azithromycin to mycin, azithromycin, levofloxacin and moxifloxacin in eradi- doxycycline published from1990 through 2013. They found cating C. pneumoniae from the nasopharynx of children and a 3% increased efficacy overall for doxycycline compared to

Expert Opin. Pharmacother. (2015) 16(2) 207 S. A. Kohlhoff & M. R. Hammerschlag

azithromycin for the treatment of urogenital chlamydial infec- sequelae in men and women, including colorectal fistulas, tions in men and women. However, as with many meta-anal- strictures and elephantiasis. Unlike uncomplicated genital yses, the quality of the evidence varied considerably but, they infection due to trachoma biovar strains of C. trachomatis, felt that with the increasing concern about potential azithro- treatment of LGV requires a prolonged course of therapy. mycin failure, additional studies are needed. The CDC currently recommends doxycycline, 100 mg orally Efficacy of treatment regimens may also vary by anatomic twice daily for 21 days as the first-line treatment regimen [1]. site. Khosropour et al. [32], in a retrospective cohort study, Erythromycin base, 500 mg orally four times daily for compared azithromycin to doxycycline for the treatment of 21 days is the alternative regimen for use in pregnancy. rectal C. trachomatis infection in men. They found that persis- Published studies have demonstrated persistent C. tracho- tent or recurrent infection was higher among men treated matis RNA in rectal samples from patients with LGV procto- with azithromycin compared to doxycycline, 8% for azithro- colitis after 2 weeks of doxycycline, in comparison, mycin, versus 0% for doxycycline, 14 -- 30 days after treat- C. trachomatis DNA was undetectable by 7 days of treatment ment. However, it is possible that some of these men may in patients with proctitis due to trachoma biovar strains [39]. have had lymphogranuloma venereum (LGV). Although 21-day treatment with doxycycline appears to be On the other hand, as treatment with doxycycline requires very effective, there have been reports of failure, usually in a multi-dose regimen, compliance is always a concern. In men co-infected with HIV [40-42].Oudet al. [41] reported another study from the same group, the investigators docu- four patients with LGV presenting with inguinal lymphade- mented that sub-optimal adherence to doxycycline therapy nopathy, all were men who have sex with men (MSM), three was associated with microbiologic failure in men with NGU of whom were HIV positive, who failed a 3-week course of who had C. trachomatis infection [33]. Sub-optimal therapy doxycycline. The patients responded after an additional was defined as missing at least 1 dose of doxycycline in 6 -- 12 weeks of doxycycline plus aspiration of the buboes. 7 days. Approximately 28% of the men were non-adherent Vall-Mayans et al. [42] reported a 47-year-old MSM with and 20% of them had C. trachomatis detected at follow-up LGV proctitis and inguinal lymphadenopathy who in addi- compared to < 3% of men who reported being adherent. tion to 3 weeks of doxycycline, required additional treatment There have been very few studies of new antibiotics for the with 20 days of azithromycin followed by 12 days treatment of genital C. trachomatis infection and none of these of moxifloxacin. compounds are currently in clinical development in the US. Data on use of other antibiotics, including azithromycin Two relatively small studies from Japan [34,35] evaluated a and quinolones are limited to anecdotal reports, although quinolone, sitafloxacin, 100 mg twice a day for 7 days for in vitro susceptibilities against C. trachomatis suggest that Table 1 For personal use only. treatment of NGU. The microbiologic eradication rates for they would be effective ( ). Regimens of azithromycin C. trachomatis were 95.7 and 100%, in a total 69 patients used have included a single 1-g dose and 1 g weekly for with C. trachomatis infection from both studies. Detection 3 weeks [1,43]. The question of what is the optimal treatment of C. trachomatis was done by NAAT. Sitafloxacin offers no for LGV will not be resolved until we have data from advantages over levofloxacin and ofloxacin [36], which are rec- controlled trials. ommended by the CDC as alternative treatment regimens [1], especially as it requires multiple dosing which offers no advan- 4. Treatment of acute respiratory tages over doxycyline. C. pneumoniae infection Rifalazil is a long-acting rifamycin with excellent in vitro activity against both C. trachomatis and C. pneumoniae [37]. C. pneumoniae is a common cause of respiratory infections Geisler et al., recently reported the results of a Phase II dou- including CAP and is frequently described as the cause of [44-46] Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Sanofi Synthelabo on 01/23/15 ble-blind, multi-centre study comparing single dose rifalazil community outbreaks . Guidelines for the treatment of to azithromycin for the treated of uncomplicated genital CAP typically include antibiotics with activity against C. trachomatis infection in women [38]. Rifalazil was well tol- C. pneumoniae [47]. However, most studies evaluating regimens erated and efficacious. A single 25 mg dose of rifalazil was including antichlamydial agents for the empirical treatment of equivalent to 1 g of azithromycin with C. trachomatis eradica- CAP did not include sufficient numbers of patients with tion rates of 84.8 compared to 92.1% for azithromycin at the proven C. pneumoniae infection to establish that inclusion of test-of-cure visit, 22 -- 26 days after treatment. However, as such agents is essential [48,49]. Further limitations to the analysis stated above, rifalazil is no longer in clinical development in of CAP treatment studies are the lack of uniform diagnostic the US. parameters and use of serology alone for diagnosis of C. pneumoniae infection, which is at best a clinical end point, 3.1 Treatment of LGV in the majority of published pneumonia treatment studies. LGV is a systemic, invasive chlamydia infection caused by the Recently, the first FDA-approved molecular diagnostic test C. trachomatis serovars L1,L2 or L3 [1]. Most LGV infections for respiratory pathogens that includes C. pneumoniae has seen in Europe and the US have been due to L2 strains. If not become available (BioFire FilmArray Respiratory Panel) [50]. treated early and appropriately, LGV can lead to serious This may allow more widespread and standardized testing

208 Expert Opin. Pharmacother. (2015) 16(2) Treatment of chlamydial infections: 2014 update

and targeted treatment in patients with respiratory infection In conclusion, while diagnosis and treatment of docu- in the future. mented C. pneumoniae infections in asthmatics with signs Results of several multi-centre treatment studies that utilized and symptoms of an airway infection should follow the above direct detection by culture and included microbiologic end- recommendations for acute respiratory infection, the benefits points demonstrated 70 -- 86% efficacy of treatment with of using antibiotics with activity against atypical bacteria in erythromycin, clarithromycin, azithromycin, levofloxacin and asthmatics without evidence of acute infection remains con- moxifloxacin in eradicating C. pneumoniae from the nasophar- troversial. Currently, there are no indications for the treat- ynx of children and adults with CAP [25-28]. On the basis of the ment of any other chronic diseases for presumed infection few studies using microbiologic end points, the following regi- with C. pneumoniae. mens can be used for respiratory infection due to C. pneumoniae: in adults, doxycycline, 100 mg orally twice daily for 5. Expert opinion 14 -- 21 days, tetracycline, 250 mg orally 4 times daily for 14 -- 21 days, azithromycin, 1.5 g orally over 5 days, clarithro- Chlamydiae are susceptible to antibiotics that interfere with mycin, 500 mg orally, twice a day for 10 days, levofloxacin, DNA and protein synthesis, including tetracyclines, macro- 500 mg, intravenously or orally, once a day for 7 -- 14 days, lides and quinolones, which are the compounds that have or moxifloxacin, 400 mg orally, once a day for 10 days. been most extensively studied and used for treatment of For children, erythromycin suspension, 50 mg/kg/day for human infection. The recommendations for the treatment 10 -- 14 days, clarithromycin suspension, 15 mg/kg/day for of C. trachomatis and C. pneumoniae infection remain essen- 10 days, or azithromycin suspension, 10 mg/kg once on day tially the same as when we last reviewed this subject in one followed by 5 mg/kg, once daily for 4 days. Some patients 2011 [4]. Current data also confirm that antibiotic resistance may require re-treatment. essentially does not occur in C. trachomatis and does not appear to effect microbiologic efficacy in vivo. This was con- firmed with the community-wide azithromycin treatment 4.1 Treatment of C. pneumoniae in chronic disease for trachoma, where development of resistance in C. tracho- Chronic, persistent infection with C. pneumoniae has been matis isolates before and after treatment was not found [22]. implicated in the pathogenesis of several chronic diseases, ini- Similar data have reported for treatment of C. pneumoniae tially not thought to be infectious. However, studies of the infections, the MICs of isolates obtained after treatment association of C. pneumoniae and these disorders have been were the same as the isolates at baseline [25-28]. Thus, persis- hampered by difficulty in diagnosing chronic, persistent infec- tence after treatment is probably due to other factors. The tion with the organism due to a lack of standardized methods. For personal use only. lower microbiologic efficacy rates of azithromycin and doxy- This makes it very difficult to determine the efficacy of inter- cycline reported in recent studies of genital infection may be vention. Probably, the most widely accepted association is secondary to the use of more sensitive molecular diagnostic between infection with C. pneumoniae and exacerbation of tests for C. trachomatis [30,31]. asthma, which has been documented by a large number of There are few new agents under investigation that are being epidemiologic and clinical studies (reviewed in [2]). Several evaluated for treatment of C. trachomatis or C. pneumoniae studies have addressed the question whether antibiotic treat- infection. Unfortunately, two compounds that were evaluated ment of C. pneumoniae infection in asthmatics leads to in clinical trial for treatment of C. trachomatis genital infec- improvement in disease activity (reviewed in [2]). The study tion, sitafloxacin and rifalazil, are not currently in clinical design has been complicated by the fact that macrolides, qui- development in the US or Europe [34,35,38]. All existing antibi- nolones, ketolides and tetracyclines all have immunomodula- otics remain good treatment options with good safety record tory activity independent of their antimicrobial activity. Any and with no clinical demonstration of resistance. Future areas Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Sanofi Synthelabo on 01/23/15 positive treatment outcomes may therefore be due to antichla- of research include redefining the epidemiology of C. pneumo- mydial, immunomodulatory effects, or a combination of the niae infection and the development of reliable diagnostic tests two. Recently, in vitro suppression of C. pneumoniae-induced for C. pneumoniae in order to better target treatment. cytokine and IgE responses by doxycycline independent of antichlamydial activity in peripheral blood mononuclear cells Declaration of interest from subjects with asthma was demonstrated; this suggests an important role of anti-inflammatory properties for antibiotics The authors have no relevant affiliations or financial involve- used in patients with chronic respiratory symptoms [51]. Sev- ment with any organization or entity with a financial interest eral randomized controlled trials were underpowered to in or financial conflict with the subject matter or materials show a benefit of macrolide treatment in C. pneumoniae discussed in the manuscript. This includes employment, con- infected asthmatics due to low numbers of study subjects sultancies, honoraria, stock ownership or options, expert testi- with proven infection [52,53]. mony, grants or patents received or pending, or royalties.

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Affiliation † Stephan A Kohlhoff 1,2 MD & Margaret R Hammerschlag1,2 MD † Author for correspondence 1SUNY Downstate Medical Center, Division of Infectious Diseases, Department of Pediatrics, 450 Clarkson Ave., Brooklyn, NY 11203-2098, USA E-mail: [email protected] 2SUNY Downstate Medical Center, Division of Pediatric Infectious Diseases, Department of Medicine, Brooklyn, NY, USA For personal use only. Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Sanofi Synthelabo on 01/23/15

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