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Sparfloxacin in the Treatment of Drug Resistant Tuberculosis Or Intolerance

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Sparfloxacin in the Treatment of Drug Resistant Tuberculosis Or Intolerance Copyright #ERS Journals Ltd 2001 Eur Respir J 2001; 17: 641±646 European Respiratory Journal Printed in UK ± all rights reserved ISSN 0903-1936 Spar¯oxacin in the treatment of drug resistant tuberculosis or intolerance of ®rst line therapy A. Lubasch*, R. Erbes*, H. Mauch#, H. Lode* Spar¯oxacin in the treatment of drug resistant tuberculosis or intolerance of ®rst line *Depts of Chest and Infectious Dis- therapy. A. Lubasch, R. Erbes, H. Mauch, H. Lode. #ERS Journals Ltd 2001. eases and #Microbiology, Chest Hospi- ABSTRACT: Patients with multiresistant tuberculosis TB) and patients with tal Heckeshorn, Berlin, Germany. intolerance of ®rst line antituberculosis drugs present a major treatment problem. Correspondence: A.Lubasch Spar¯oxacin is highly active against mycobacteria, but the use is restricted by side Dept of Chest and Infectious Diseases effects and the contribution to antituberculosis therapy is unclear.A prospective study Chest Hospital Heckeshorn has therefore been performed to analyse the ef®cacy and tolerability of spar¯oxacin in Zum Heckeshorn 33 cases of resistant TB or intolerance of ®rst line therapy. D-14109, Berlin Between April 1993 and April 1999, 30 TB patients 28 with pulmonary TB and two Germany with lymph node TB) were treated with combinations of spar¯oxacin and at least two Fax: 49 03080022623 other drugs at the Chest Hospital Heckeshorn, Berlin.Sixteen patients were infected by resistant mycobacteria one single drug resistance SDR), one polyresistance, and 14 Keywords: Intolerance of antitubercu- multidrug resistances MDR); 14 males age range 23±53 yrs), 2 females 68±74 yrs)). losis therapy multiresistant tuberculosis Twelve patients 11 males, one female, 27±80 yrs) had not tolerated ®rst line antituber- spar¯oxacin culosis drugs.Two additional male patients had continuous proof of Mycobacterium tuberculosis in sputum without resistance during therapy Received: August 9 1999 The duration of spar¯oxacin therapy during hospitalization ranged 2.5±4 months. Accepted after revision November 13 Twenty-®ve patients completed therapy and were cured according to this study9s 2000 de®nition.Although spar¯oxacin was generally well tolerated, ®ve mild phototoxic reactions and six moderate prolongations of the electrocardiographic QT-interval 30± 40 ms compared to baseline ¡450 ms) were registered without clinical symptoms in the patient group. In summary, spar¯oxacin proved an effective and safe alternative antituberculosis drug for complicated tuberculosis. Eur Respir J2001; 17: 641±646. The standard antituberculosis therapy in sputum spar¯oxacin in patients with MDR TB or intolerance smear positive cases is a combination of isoniazid of ®rst line antituberculosis drugs in the literature, a 7INH), rifampicin 7RMP), pyrazinamide 7PZA) and prospective study was performed to analyse spar¯ox- ethambutol 7EMB) for 2 months, followed by INH acin9s ef®cacy and tolerability in such cases. and RMP for further 4 months [1].In cases of spu- tum smear negative patients, a regimen of three drugs Material and methods 7INH, RMP and PZA for 2 months, INH and RMP for further 4 months) is recommended [1]. Spar¯oxacin The global increase of multiresistant Mycobacterium tuberculosis strains [2±7] and intolerance of ®rst line Spar¯oxacin is a highly potent ¯uoroquinolone aga- antituberculosis drugs 7INH, RMP, PZA, EMB, inst a wide range of gram-positive and gram-negative streptomycin 7SM)) [8, 9] may cause major treatment bacteria, anaerobes, Legionella spp., Mycoplasma spp., problems and necessitate modi®cation of the standard Chlamydia spp.and Mycobacteria spp., including therapy regimen. multiresistant strains [12, 15, 16].The elimination Recently developed drugs like ¯uoroquinolones show half-life 7t1/2) is approximately 15±20 h which allows suf®cient antimycobacterial activity and may play a once daily administration.Spar¯oxacin diffuses well signi®cant role in the treatment of MDR tuberculosis into tissues and respiratory tract secretion and con- 7TB) and in cases of severe intolerance of ®rst line centrates within macrophages, where mycobacteria antituberculosis medication [2, 5, 10, 11]. survive and multiply [12, 17]. Spar¯oxacin currently seems to be the most potent Spar¯oxacin is generally well tolerated.While gas- ¯uoroquinolone against M. tuberculosis, including mul- trointestinal reactions are the most frequent side effect, tiresistant strains [2, 11±14], although it may show some photosensitivity reactions and cardiovascular tolerabi- problematic side effects 7e.g.phototoxic reactions). lity 7electrocardiograph QT-interval) should be given However, as there were no reports on the use of special attention [12, 17±22].Due to its phototoxic 642 A.LUBASCH ET AL. potential, the use of spar¯oxacin should be limited to specimens were sputum.Specimens were also obtained respiratory infections with resistant organisms. via ®breoptic bronchoscopy or lymph node puncture. In this study, spar¯oxacin tablets were administered After acid-fast bacteria staining using the auramine once daily 7dosages: ¡50 kg body weight, 200 mg; 50± ¯uorescence method [26], the obtained specimens were 70 kg body weight, 300 mg; >70 kg body weight, 400 investigated by ¯uorescence microscopy.Primary cul- mg) under directly observed therapy 7DOT). tures were grown in soluble media 7Middelbrook 7H9 broth)andonLoÈwenstein-Jensen solid medium [26]. Susceptible testing was performed on LoÈwenstein- Study design Jensen solid medium by the breakpoint technique In a prospective study, the data of 30 hospitalized TB using the standard proportion method [26].Resistance patients treated with spar¯oxacin at the Chest Hospi- was diagnosed when <1% inhibition of the original tal Heckeshorn, between April 1993 and April 1999 inoculum of M. tuberculosis occurred on LoÈwenstein- were analysed.The patients were divided into three Jensen medium containing the following concentrations . -1 . -1 groups: resistant group 7n=16), intolerance group 7n= of antibiotics: INH: 0.25 mg L ;RMP:32.0mgL , . -1 . -1 . -1 12) and continuous proof group 7n=2).Patient PZA: 125 mg L ,EMB:1.0mgL , SM: 4.0 mg L , . -1 characteristics are listed in table 1. PTH: 32.0 mg L [27].The minimal inhibition con- centrations 7MICs) of all ®rst and second line anti- tuberculosis drugs and spar¯oxacin were determined De®nitions from strains resistant to ®rst line antituberculosis drugs. The breakpoints for susceptibility of spar¯oxacin were The following de®nitions were used [23]: mono or ¡1 mg.mL-1:susceptible;1±4mg.mL-1: moderately single drug resistance 7SDR): resistance to a single susceptible; and >4 mg.mL-1: resistant [12, 15]. drug; multi-drug resistant 7MDR): resistance to at Patient compliance in the continuous proof group least INH and RMP; polyresistance: resistance to more was controlled by urine tests for INH. than one drug excluding MDR. Hepatic intolerance was de®ned as an increase in liver enzymes to more than three times the normal limit during therapy and a rapid new increase in liver Follow up enzymes after re-exposure.Evidence of considerable amounts of acid-fast bacteria in sputum for over 10 Specimens were obtained weekly from patients able weeks was de®ned as continuous proof of M. tuber- to produce sputum during hospitalization.Those with culosis.Patients consuming more than 80 g of alcohol resistant tuberculosis were isolated until sputum cul- per day were de®ned as alcohol abusers.The treatment ture conversion.Weekly laboratory tests for hepatic, outcome was assessed using standard categories [24].A haematological or renal side effects were also perform- patient who had completed a full course of anti-TB ed.Chest radiographs were performed monthly until therapy with documented conversion of culture during discharge from the hospital.The chest radiographs the continuation phase was de®ned as cured. were assessed by two independent physicians 7a ra- diologist and a pulmonologist).Electrocardiography 7ECG) examinations for control of the QT-interval Diagnostics were done every two weeks, and twice weekly in cases of QT prolongation. Current standards were used in the diagnostic pro- After discharge from the hospital, patients were cedures for TB [25].The most frequently investigated treated on an outpatient basis by their pulmonologists. Table 1. ± Patient characteristics All patients Resistance group Intolerance group Continuous proof group Patients n 30 16 12 2 Mean age yrs 46.4 40.6 55 41.5 Median 7range) age yrs 41 723±80) 37.5 723±74) 60 727±80) # Sex male/female 27/3 14/2 11/1 2/0 German-born 12 2 8 2 Non-German-born 18 14 4 Relapse 17 13 4 Uni/bilateral disease 9/19 5/11 4/6 0/2 Cavitary disease 15 8 6 1 Lymph node TB 2 2 Sputum smear positive 20 11 7 2 Culture positive 29* 15* 12 2 Alcohol abuse 7 1 4 2 i.v.Drug abuse HIV positive *: one patient was treated because of progression in chest radiography and history of multidrug-resistant tuberculosis 7TB); #: only two patients 7aged 41 and 42, respectively).HIV: human immunode®ciency virus. IMPORTANCE OF SPARFLOXACIN IN ANTITUBERCULOSIS THERAPY 643 The practitioners were contacted at the end of therapy Table 3. ± Multidrug resistance 3MDR) in 14 of the to evaluate the treatment outcome. resistance group Resistance Number of patients Results 3x 3 INH+RMP+Rifa 4x 1 INH+RMP+EMB+SM Resistance group 1 INH+RMP+PZA+PAS* 1 INH+RMP+SM+Rifa The group with resistant micro bacteria 716 patients) 5x 1 INH+RMP+PZA+SM+Rifa comprised 14 non-German born males with a mean 1 INH+RMP+EMB+Rifa+SMZ age of 37 yrs 7range 23±53 yrs) and 2
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