Twocases of Severe Bronchiectasis Successfully Treated With

CASE REPORT

TwoCases of Severe Bronchiectasis Successfully Treated with a Prolonged Course of Trimethoprim/Sulfamethoxazole Takayuki Honda, Muneharu Hayasaka*, Tsutomu Hachiya*, Keishi Kubo*, Tsutomu Katsuyama and Atsuo Nagata**

Twopatients with severe bronchiectasis, one patient without other disease and the other with hyper IgE syndrome, were successfully treated with long-term therapy with low doses oftrimethoprim and sulfamethoxazole (TMP-SMZ).Recurrent respiratory infections with productive cough and high fever were resistant to various antibiotics and often disturbed the patients' activities in daily life. However, they showed marked improvement following TMP-SMZtherapy, which was started for methicillin-resistant Staphylococcus aureus (MRSA)infection. MRSAdisappeared some months later, but Pseudomonas aeruginosa appeared again in the sputum. Both patients, however, have remained free from symptomsfor over one year. (Internal Medicine 35: 979-983, 1996) Key words: hyper IgE syndrome, lower respiratory infection, methicillin-resistant Staphylococcus aureus, Pseudomonasaeruginosa

Introduction toms which disturbed his activity in daily life. Hemophilis influenzae and/or Pseudomonas aeruginosa (P. aeruginosa) It has been reported that trimethoprim-sulfamethoxazole were isolated from his sputum. He had received many different (TMP-SMZ) is effective for short-term and long-term use in the antibiotics including ampicillin, piperacillin sodium, treatment of chronic respiratory infections (1, 2). Recently, sultamicillin tosilate, cefazolin sodium, cefotiam hexetil hy- however, TMP-SMZhas not been considered the drug of first drochloride, cefteram pivoxil, clindamycin, ciprofloxacin hy- choice for various bacterial infections due to its side effects and drochloride and ofloxacin. They were sensitive to at least one because of the development of new antibiotics. Wedescribe antibiotic. However,other antibiotics were tried due to repeated here two cases with severe bronchiectasis successfully treated fever. Analysis of his blood showed slight leukocytosis (5,000- with a long-term course of TMP-SMZ. 1 0,800). Erythrocyte sedimentation rate (ESR) had increased to 30-60 mm/h and CRP was 2+ to 4+. Arterial blood gas analysis on November 1 1, 1989, showed hypoxemia (PaO2, 56.8 Torr, Case Report PaCO2, 40.7 Torr; pH 7.410). Various oral antibiotics taken in Case 1 (Fig. 1) rotation were effective only temporarily, and high fever often A 53-year-old male had an operation for chronic sinuitis appeared. Long-term use of erythromycin was added to his when he was 17 years old. He remained well withouthistory of treatment regimen, but the symptoms remained. Methicillin- pulmonary tuberculosis until 48 years of age, when he noted resistant Staphylococcus aureus (MRSA)was isolated from his susceptibility to colds. He visited ourhospital on November12, sputum in May 1 992, and treatment with 6 tablets ofTMP-SMZ 1988, with chief complaints of high fever and productive daily (one tablet included 40 mg ofTMP and 200 mg ofSMZ), cough. A chest roentgenogramshowedreticulonodular shadow to which MRSAwas sensitive, was begun in combination with and bronchial wall thickening in both lung fields and infiltration ciprofloxacin hydrochloride and minocycline. He showed in the right upper field. He was admitted with a diagnosis of marked improvementand becameasymptomatic within several bronchiectasis with acute pneumonia. In the following three days. Heremained free from lower respiratory tract symptoms years, he was again admitted several times for the same symp- after cession of antibiotics other than TMP-SMZ.MRSAdisap-

From the Department of Laboratory Medicine and *First Department of Internal Medicine, Shinshu University Hospital, Matsumoto and **SuwaRed Cross Hospital,Suwa Received for publication February 23, 1996; Accepted for publication September 17, 1996 Reprint requests should be addressed to Dr. Takayuki Honda, the Department of Laboratory Medicine, Shinshu University School of Medicine, 3-1-1 , Asahi, Matsumoto390

Internal Medicine Vol. 35, No. 12 (December 1996) 979 Honda et al

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Figure 1. Clinical course of Case 1. peared and only normal habitants were isolated from sputum within a few months. P. aeruginosa, however, appeared again in the sputumwithout exacerbation of the respiratory symptoms. The dose of TMP-SMXwas reduced to 3 tablets/day in December 1992. ESR and CRP fell within the respective normal ranges. Arterial blood gas analysis also improved (PaO2, 77.2 Torr; PaCO2 46.2 Torr; pH 7.390). When TMP-SMZ was reduced to one tablet/day in June 1993, his temperature rose to 38.5°C with an increase of white blood cells and elevation of CRPand ESR, although a chest roentgenogram did not show new consolidation (Fig. 2). The dose of TMP-SMZwas increased to 2 tablets/day and his temperature was reduced. He then continued to take the same dose daily for one year, and no side effects were observed. Whenthe dose of TMP-SMZwas again reduced gradually and stopped in June 1994, he noted fever and an increase in productive cough. TMP-SMZtherapy was restarted and the symptomsdisappeared immediately. He has remainedfree from symptomson a regimenof one tablet of TMP-SMZper day without adverse reactions to date. Case 2 (Fig. 3) Figure2. A chest roentgenogram of case 1 showing A 34-year-old female had suffered from abscesses on vari- bronchial thickening with reticulonodular shadow. ous regions of her body without pain. She was diagnosed as having hyper IgE syndrome with a serum IgE level of over 10,000 lU/ml when she was 13 years old. She had an operation for a peritoneal abscess at the age of 17 years. She was also

980 Internal Medicine Vol. 35, No. 12 (December 1996) TMP/SMZTherapy for Bronchiectasis

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Figure 3. Clinical course of Case 2. admitted for treatment of myelitis of the right femur and an abscess on the upperpharynx at20 and 30 years old. From1989, whenshe was 30 years old, she often cameto our hospital with respiratory infection and high fever. She was diagnosed as having bronchiectasis and was treated with various antibiotics. She had no history of chronic sinuitis or pulmonary tuberculosis. A chestroentgenogram (Fig. 3) and CT scans showed cystic lesions and bronchial thickening in the right upper lobe and bronchial thickening in both lower lobes. These respiratory symptoms often disturbed her activity in daily life and she was admitted several times over the following years. Methicillin- sensitive Staphylocossus aureus (MSSA)and P. aeruginosa were isolated from sputum. In 1991, MRSAwas first detected in sputum and TMP-SMZwas added to the other antibiotics in her treatment regimen. After initiation of TMP-SMZtreatment, the symptomsof respiratory infection were reduced. The dose of TMP-SMZwas reduced and stopped because we had no experience regarding its long-term use and the available drug information emphasized its side effects. On February 9, 1993, she again visited our hospital with fever and productive cough, Figure4. A chest roentgenogram of case 2 showing and she was treated with oral cephalosporin notTMP-SMZ.She patchy infiltration shadows in both lung fields with bronchial developed the above symptomsand then dyspnea appeared thickening predominantly in the right upper field. within three days. Chest roentgenogram showed patchy infiltration shadows in both lung fields (Fig. 4) and MRSAwas isolated from blood. She was diagnosed with adult respiratory distress and 2 tablets/day have been continued as a prophylaxis against syndrome accompanied by MRSAsepsis, which was causedby further infections. P. aeruginosa was often isolated from spu- MRSApneumonia. She recovered after intensive treatment tum, although she has remained free from symptoms of respi- with vancomycin, habekacin, minomycin and TMP-SMZto ratory infection. The level of serum IgE gradually fell to 2,000 which MRSAis sensitive. Subsequently, TMP-SMZwas used IU/ml. at a dose of 4 tablets/day without other antibiotics for one year

Internal Medicine Vol. 35, No. 12 (December 1996) 981 Honda et al

cases were reported in Swedenbetween 1976 and 1985. The Discussion motality rate for patients with bicytopenia was reported as 6%, and 52%for those with tricytopenia (1 1). Most patients Anumber of studies have shown that TMP-SMZis an with blood dyscrasias showed improvement when TMP-SMZ effective agent for treatment of respiratory tract infections (2- therapy was stopped or folic acid treatment started (13). 4). TMP-SMZis not, however, considered the drug of first It is difficult to determine the appropriate dose ofTMP-SMZ choice, because many other antibiotics have been developed for individual patients. For simultaneous primary prophylaxis and used for various bacterial infections. of Pneumocystis carinii pneumonia and toxoplasmosis in pa- Most Staphylococcus aureus strains, regardless of methicil- tients infected with HIV, TMP-SMZadministered three times lin susceptibility, have shown susceptibility to TMP-SMZ.The per week(160 mg-800mgorally twice a day) is an effective and Japan Cooperative Clinical Study Group reported that therapy well-tolerated regimen ( 14), and for the prevention of sponta- with TMP-SMZwas effective in 86 of 109 patients with neous bacterial peritonitis in patients with cirrhosis, one dou- Staphylococcus aureus infection (5). However, resistance to ble-strength TMP-SMZtablet daily, five times a week (Monday TMP-SMZin staphylococci may be rising; it has been reported through Friday), was efficacious, safe, and cost effective (15). that 60% ofMRSAstrains and 15% ofMSSAwere resistant to The present two cases have remained free from the symptoms TMP-SMZ(6). In the present two cases, TMP-SMZwas used and signs of respiratory tract infections following commence- for the treatment of MRSAinfection, and MRSAdisappeared. ment of treatment with TMP-SMZ. P. aeruginosa appeared again in the sputum some months later. The Japanese drug directions say that TMP-SMZmust be The rate of respiratory infections, however, wasapparently used only when other antibiotics are not effective. However, the reduced in both patients, and the white blood cell count, ESR incidence offetal hematological toxicity (especially tricytopenia) and CRPfell to within the respective normal ranges. After is very low. Most patients who present with blood dyscrasias cessation of TMP-SMZtherapy respiratory infections recurred are over 65 years old, and symptoms appear within several in both patients. TMP-SMZtherapy was restarted, and they weeks from the initiation of TMP-SMZtherapy. If clinicians have remained free of respiratory tract symptomsand signs on are aware of the above side effects and use this drug, TMP- low-dose TMP-SMZtreatment for over one year. The benefi- SMZseems to be safe and effective for patients suffering from cial effects of TMP-SMZare clinically apparent in these two repeated high fever and productive cough resistant to various patients with severe bronchiectasis, whose disease could not be antibiotics. controlled with other antibiotics. However, the doses of TMP- SMZused here were low, and P. aeruginosa, which appeared References after the use ofTMP-SMZ,did not showsusceptibility to TMP- SMZ.It is supposed that TMP-SMZhas effects on the respira- 1) Kanaghinis T, Jordanoglou J, Gardikas C. Trimethoprim- sulphamethoxazole in intestinal and lung infections. Chemotherapy 18: tory infection other than its bactericidal action. 184, 1973. There were somereports in the 1970's and 1980's thatTMP- 2) Hughes DTD, Russell NJ. The use oftrimethoprim-sulfamethoxazole in SMZis effective for long-term use in the treatment of chronic the treatment of chest infections. Rev Infect Dis 4: 528, 1982. bronchitis and cystic fibrosis (2, 3). More recently, there have 3) Hughes DTD, Pines A, Percival A, Stille W. Round table discussion- treatment of lower respiratory tract infections with co-trimoxazole. J also been several reports concerning long-term (over a year) Antimicrob Chemother 5: 207, 1979. TMP-SMZregimens for various diseases, and no severe side 4) De Simone C, Di Fabio S, Moretti S, Tzantzoglou S, Trinchieri V, effects were observed (3, 7-9). Long-term therapy with TMP- Gargiulo M.Open randomized controlled parallel study of ofloxacin SMZseems to be safe and effective, although the length of the versus trimethoprim-sulfamethoxazole treatment of lower respiratory period it maybe used without adverse side effects has not been tract and urinary infections. Chemotherapy 37 Supple 1 : 39, 1991. determined. 5) The Japan Cooperative Clinical Study Group. Trimethoprim- It was reported that a patient with hyper IgE syndrome sulfamethoxazole in the treatment of bacterial infections: report of clinical trials in Japan. J Infect Dis 128: S629, 1973. showed evident clinical improvement and a decrease in serum 6) Markowitz N, Quinn EL, Saravolatz LD. Trimethoprim-Sulfamethoxazole IgE level following TMP-SMZtreatment (9, 10). It is thought comparedwith vancomycinfor the treatment of Staphylococcus aureus that TMP-SMZimproves the function of polymorphonuclear infection. Ann Intern Med117: 390, 1992. leukocytes in addition to having a bacterial effects, although the 7) McRaeD, Buchanan G. Long-term sulfamethoxazole-trimethoprim in Wegener's granulomatosis. Arch Otolaryngol Head Neck Surg 119: 1 03, mechanismof this effect remains unclear (9). 1993. Severe adverse reactions to TMP-SMZdo not occur as often 8) Pacht ER. Mycobacteriumfortuitum lung abscess: Resolution with pro- as expected. Most patients in earlier studies were elderly (mean longed trimethoprim/sulfamethoxazole therapy. AmRev Respir Dis 141 : age 81 years) and female, and they developed hematological 1599, 1990. toxicity within a few weeks of initiation of TMP-SMZtreat- 9) Hattori K, Hasui M, Masuda K, Masuda M, Ogino H, Kobayashi Y. ment (ll, 12). TMP is considered a selective inhibitor of Successful trimethoprim-sulfamethoxazole therapy in a patient with hyperimmunoglobulin E syndrome. Acta Paediatr 82: 324, 1993. dihydrofolate reductase in bacteria but not in humans. How- 10) Sanal O, Gocmen A, Tezcan I, Ersoy F, Adalioglu G. Hyper IgE ever, minor effects on folate metabolism and somedegree of syndrome: a case report. Turk J Pediatr 32: 273, 1990. blood dyscrasias were observed in humans (13); its incidence, 1 1) Keisu M, Wiholm BE, Palmblad J. Trimethoprim-sulphamethoxazole- 2.6 per million at defined daily doses, was not high and 154 associated blood dyscrasias. Ten years' experience of the Swedish

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spontaneous reporting system. J Intern Med 228: 353, 1990. Podzamczer D, Salazar A, Jimenez J, et al. Intermittent trimethoprim- Malnick SDH, Atali M, Israeli E, Abend Y, Geltner D. Trimethoprim/ sulfamethoxazole comparedwith dapsone-pyrimethamine for the simul- sulfamethoxazole-induced rash, fever, abnormal liver function tests, taneous primary prophylaxis Of pneumocystis pneumonia and toxoplas- leukopenia, and thrombocytopenia. Ann Pharmacother 27: 1 139, 1993. mosis in patient infected with HIV. Ann Intern Med 122: 755, 1995. Jenkins GC, Hughes DTA, Hall PC. A haematological study of patients Singh N, Gayowski T, Yu VL, Wagener MM. Trimethoprim- receiving long-term treatment with trimethoprim and sulphonamide. J sulfamethoxazole for the prevention of spontaneous bacterial peritonitis Clin Pathol 23: 329, 1970. in cirrhosis: a randomised trial. Ann Intern Med 122: 595, 1995.

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