Ofloxacin Treatment of Cblamydiapneumoniae (Strain TWAR) Lower Respiratory Tract Infections BENJAMINA. LIPSKY, M.D., Seattle, Washington, KENNETH J. TACK, M.D., Raritan, New Jersey, CHOCHOU KUO, M.D., Ph.D., SAN-PIN WANG, M.D., J. THOMAS GRAYSTON, M.D., Seattle, Washington

PURPOSF~I,imlted data suggest that tetracycline or erythromycin is the antibiotic of choice for treating ChlRmydia pnellmoniae infection, but they are not always effective or well tolerated. Because the fluoroquinolone ofloxacin is effective for Cbl~mydia trachonmtis infections, we investigated its role in treating C. pneumon~e infections. PATIENTS AND METHODS: Eighty-seven patients were enrolled in a randomiT~d trial of antibiotic therapy for acute lower respiratory tract infections. The patients were randomly assigned to oral treatment with either ofloxacin (400 mg twice a day) or erythromycin (400 mg four times a day) for 10 days. Frozen acute and convalescent serologic specimens were tested for TWAR antibody by microlmmunofluorescence.Susceptibility testing of C. pneumon;Re to ofloxacin was also performed. RESULTS:Four patients who received ofloxacin were retrospectively identified as having C. pneumoni~e pneumonia (two) or bronchitis (two). Within 2 weeks of starting ofloxacin therapy, all were cured or markedly improved. The minimum inhibitory concentrations of ofloxacin for three previously isolated clinical str~in~ of C. pneumon/ae were determined to be 1.0 to 2.0/~g/ mL~ well within the achievable serum levels (3 to 5/zg/mI,) with ofloxacin therapy. CONCLUSION:Ofloxacin may be an effective alternative antibiotic treatment for C. pneumon/ae respiratory infections.

From the Department of Medicine (BAL), School of Medicine, University of Washington and Veterans Administration Medical Center, Seattle, Washington; R.W. Johnson Pharmaceutical Research Institute (KJT), Raritan, New Jersey; Department of Pathobiology (C-cK, S-pW), University of Washington, Seattle, Washington; and Department of Epidemiology (JTG), School of Public Health and Community Medicine, University of Washington, Seattle, Washington. Requestsfor reprints should be addressedto BenjaminA. Lipsky, M.D., Seattle Veterans Administration Medical Center (111M), 1660 South Columbian Way, Seattle, Washington 98108. Dr. Tack's current address: The Upjohn Company, Kalamazoo, Michigan. Manuscript submitted March 22, 1990. and accepted in revised form August 14, 1990.

722

he newly described Chlaraydia species, Chla-

T mydia pneumoniae strain TWAR, can cause

acute respiratory infections, including pneumonia and bronchitis [1-3]. Data on treatment of these infections are very limited. In vitro susceptibility testing suggests that tetracycline and erythromycin are the most active agents [4]. The clinical response to tetracycline treatment of C. pneumoniae pneumonia, however, has been somewhat variable [5], with some patients requiring retreatment. Similarly, although erythromycin is usually effective, when given in low doses or with short courses, it has frequently failed to produce a prompt resolution of symptoms [1,6]. Thus, additional antibiotics to treat these infections would be welcomed. Ofloxacin is a new fluoroquinolone that has shown excellent in vitro and clinical effectiveness against Chlamydia trachomatis and Chlamydia psittaci infections [7-10]. A phase III multicenter comparative study of ofloxacin and erythromycin for treatment of acute lower respiratory tract infections provided us the o p p o r t u n i t y to retrospectively determine the response to these antibiotics in patients found to have C. pneumoniae infections. We also tested three other clinical isolates of C. pneumoniae for their in vitro susceptibility to ofloxacin.

PATIENTS AND METHODS Between November 1986 and June 1988, adult outpatients or inpatients with signs and symptoms of acute lower respiratory tract infections underwent chest radiography and sputum Gram stain and culture. Patients who had received systemic antimicrobial therapy in the preceding week or who were so ill that they required parenteral antibiotic therapy were excluded from the study. Eligible patients with radiographic pulmonary infiltrates (pneumonia) or purulent sputum only (bronchitis) were randomized to oral treatment with either ofloxacin (400 mg twice a day) or erythromycin (400 mg four times a day) for 10 days. They were then followed for 4 to 6 weeks with cultures and radiographs obtained again as indicated. Serologic specimens obtained at enrollment, and approximately 4 weeks later, were tested for Le-

gionella pneumophila and Mycoplasma pneumoniae. Approximately 2 years later the frozen acute

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OFLOXACIN THERAPY OF C. PNEUMONIAEINFECTIONS/ LIPSKY ET AL

and convalescent specimens were thawed and at the TABLEI same time all were tested for TWAR antibody with Minimum InhibitoryConcentrations(/~g/mL) for Chlamydia the microimmunofluorescence test [1,11]. Serologic pneumoniae*of Ofloxacinand OtherAntibiotics evidence of current or recent infection was defined Viability Infectivity as a fourfold increase in antibody titer, or a titer of (First Passage) (Second Passage) 16 or greater in the IgM serum fraction and 512 or Ofloxacin 1.0-2.0 1.0-2.0 greater in the IgG fraction. Tetracycline 0.05-0.1 0.05-0.1 Susceptibility of C. pneumoniae was tested in Erythromycin 0.01-0.05 0.01-0.05 Penicillint >100 0.1-0.2 cell culture by previously published methods [4]. Ampicillin >100 0.8-1.6 Ofloxacin was tested in serial twofold dilutions. The Sulfisoxazole >400 >400 minimal inhibitory concentrations (MICs) for the TestedstrainswereTW-183,AR-39,andAR-388. Measuredin U/mL. complete inhibition of inclusion formation in the original inoculation (for viability) and for the complete inhibition of inclusion formation in the second passage (for infectivity) were determined. The patient treated with erythromycin improved and MICs were determined for three previously isolated the other was cured. C. pneumoniae strains: TW-183 (an ocular isolate from Taiwan), AR-39, and AR-388 (throat isolates Susceptibility Testing of C. pneumoniae to Ofloxacin from Seattle). The MICs of ofloxacin for the three strains of C. Two weeks after antibiotic therapy was initiated, pneumoniae, and comparable results previously patients were classified as clinically "cured" if they determined for other agents [4], are shown in Table became asymptomatic, with resolution of all abnor- I. mal findings, including radiographic infiltrates. If symptoms and signs largely but incompletely re- COMMENTS solved, the patients were classified as "improved." In the past 5 years several investigations have shown that C. pneumoniae strain T W A R causes RESULTS about 5% of cases of bronchitis and 10% of pneumonias [12]. T W A R infections are found in all age Clinical Cases Sera from 87 subjects were tested; 69 had paired groups, in ambulatory and hospitalized patients, specimens and 18 had only a single specimen. Sero- and in endemic and epidemic forms [13].In outpadiagnosis of acute C. pneumoniae infection was tients,the clinicalcharacteristicsof C. pneumoniae made in six (11.5%) of the patients for whom paired infection are of an "atypical" pneumonia, and are specimens were available. The diagnosis was based similar to those of M. pneumoniae. Although the on IgM titers of 16 or greater in three, IgG titers of infections are usually mild and sputum production 512 or greater in two, and a fourfold increase in both is variable, patients not treated with tetracycline or erythromycin may have prolonged malaise and IgM and IgG titers in one. The patients with C. pneumoniae infection were cough [12]. Because of the increasing recognition of such resfrom three different medical centers. All but one of the patients were men, and all but one were between piratory pathogens as M. pneumoniae, Legionella 60 and 70 years old. Two patients had pneumonia, species, Branhamella catarrhalis, and now C. three had an exacerbation of chronic bronchitis, pneumoniae, empiric treatment of community-acand one had acute bronchitis. All the patients had quired atypical pneumonias with erythromycin is purulent sputum, which yielded no predominant often recommended [13]. In view of the limitations respiratory pathogen(s) on culture. Results of sero- of the spectrum of erythromycin, and the gastroinlogic tests for L. pneumophila and M. pneumoniae testinal distress it may cause, alternative broadspectrum antibiotics would be useful. Ofloxacin, were negative in all patients. Four patients were randomized to treatment with which attains levels in bronchial secretions and ofloxacin (two of whom had pneumonia, and one lung tissue that equal or exceed serum concentraeach who had acute or chronic bronchitis), and two tions [14] and is active against most aerobic organreceived erythromycin (both of whom had an exac- isms, including Legionella species as well as Mycoerbation of chronic bronchitis). Among the patients plasma, Chlamydia, and Coxiella species, seems an treated with ofloxacin, within 2 weeks three had appropriate choice [7,15]. One preliminary report [7] found ofloxacin was complete resolution of all signs and symptoms, and one was markedly improved. One month after treat- clinically effective in all of 13 patients serologically ment, the radiographic pulmonary infiltrates had diagnosed as having C. psittaci pneumonia. The resolved in the two patients with pneumonia. One clinical histories of these patients were not detailed, December 1990 The American Journal of Medicine Volume 89

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OFLOXACIN THERAPY OF C. PNEUMONIAEINFECTIONS / LIPSKY ET AL

however, and they did not have culturesor serologic testsfor C. pneumoniae infection.One other report described three patients with chlamydial pneumonia,two with psittacosis,and one with C. pneumoniae infection, who were cured by ofloxacin [16]. There are few reports of the outcome of antibiotic treatment of C. pneumoniae infections.The four successfully treated patients reported herein suggest that ofloxacin may be an effectiveagent. The susceptibilitystudies show that the MICs of this drug are almost 100-foldhigher than for erythromycin,but well within the achievableserum levels(3 to 5 pg/mL) with ofloxacintherapy [17].Intracellular levelsmay, in fact,substantiallyexceed serum levels [18],and ofloxacin has been shown to inhibit growth of intracellularL. pneumophila [19]. Although penicillinand ampicillininhibitinfectivity, they fail to suppress viability,and sulfisoxazole completely failsto inhibit C. pneumoniae. Until prospective controlled studies are available, the treatment of choice for C. pneumoniae infectionsisunknown. The currentlyrecommended therapy is eithertetracyclineor erythromycin, 2 g/ day for 10 to 14 days, or I g daily for 3 weeks [5,12]. In view of its clinical efficacy in C. trachomatis infections, and the susceptibility and clinical results we have found, ofloxacin may prove to be effective in treatment of C. pneumoniae lower respiratory tract infections, thus providing a useful alternative antibiotic treatment.

ACKNOWLEDGMENT We thank Drs. Roger E. Pecoraro and Christopher Beaty for help in designing this study, and Bi-Lan Chiong for secretarial assistance.

REFERENCES 1. Grayston JT, Kuo C, Wang S, Altman J. A new Chlamydia psittaci strain, TWAR, isolated in acute respiratory tract infections. N Engl J Med 1986; 315: 161-8. 2. Grayston JT, Diwan VK, Cooney M, Wang S. Community- and hospital-ac-

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quired pneumonia associated with Chlamydia TWAR infection demonstrated serologically. Arch Intern Med 1989; 149: 169-73. 3. Grayston JT, Mordhorst C, Bruu A, Vene S, Wang S. Countrywide epidemics of Chlamydiapneumoniae, strain TWAR, in Scandinavia, 1981-1983. J Infect Dis 1989; 159: 1111-4. 4. Kuo C-C, Grayston JT. In vitro drug susceptibility of Chlamydia sp strain TWAR. Antimicrob Agents Chemother 1988; 32: 257-8. 5. Sinnott JT, Himelright I. Chlamydiaspecies strain TWAR. Infect Control Hosp Epidemiol 1989; 10: 175-7. 6. Campbell JF, Barnes RC, Kozarsky PE, Spika JS. Clinical characteristics of culture-positive pneumonia due to Chlamydiapneumoniae [Abstract 267]. In: Program and abstracts of the 29th Interscience Conference on Antimicrobial Agents and Chemotherapy. Houston: American Society of Microbiology, 1989: 145. 7. Leroy O, Sivery B, Beuscart C, Mouton Y, Du Laurier MV, Efficacy of ofloxacin as therapy for pneumonia due to Legionellasp, Mycoplasmapneumoniae, Chlamydiapsittaci, or Coxiellaburnetti[Abstract 551]. In: Program and abstracts of the 29th Interscience Conference on Antimicrobial Agents and Chemotherapy. Houston: American Society of Microbiology, 1989: 193. 8. MonkJP, Campoli-Richards DM. Ofloxacin. A review of its antibacterial activity, pharmacokinetic properties and therapeutic uses. Drugs 1987; 33: 346-91. 9. Oriel JD. Use of quinolones in chlamydial infection. Rev Infect Dis 1989; 11 (Suppl 5): $1273-6. 10. Mogabgab WJ, Holmes B, Murray M, Beville R, Lutz FB, Tack KJ. Randomized comparison of ofloxacin and doxycycline for Chlamydiaand urea plasma urethritis and cervicitis. Chemotherapy 1990; 36: 70-6. 11. Wang SP, Grayston JT. Microimmunofluorescence serological studies with the TWAR organism. In: Oriel JD, Ridgway G, Schachter J, Taylor-Robinson D, Ward M, eds. Chlamydial infections. Cambridge, England: Cambridge University Press, 1986: 329-32. 12. Grayston JT. Chlamydiapneumoniae,strain TWAR. Chest 1989; 95: 664-9. 13. Schachter J. Chlamydiapsittaci--"reemergence" of a forgotten pathogen. N Engl J Med 1986; 315: 189-91. 14. Smythe MA, Rybak MJ. Ofloxacin: a review. DICP 1989; 23: 839-46. 15. Kobayashi H. Clinical evaluation of ofloxacin in lower respiratory tract infections. Infection 1986; 14 (Suppl 4): $279-82. 16. Hayashi Y, Kato M, Ito G, et aL The clinical effectiveness of ofloxacin in the treatment of chlamydial pneumonia. Kansenshogaku Zasshi 1989; 63:1141-8. 17. Flor S, Weintraub H, Beals B, Tack K. Pharmacokinetics of ofloxacin in humans after single dose and during multiple dose administration [Abstract 483]. In: Program and abstracts of the 26th Interscience Conference on Antimicrobial Agents and Chemotherapy. New Orleans: American Society of Microbiology, 1986: 185. 18. Pascual A, Garcia I, Perea EJ, Fluorometric measurement of ofloxacin uptake by human polymorphonuclear leukocytes. Antimicrob Agents Chemother 1989; 33: 653-6. 19. Saito A, Sawatari K, Fukuda Y, etaL Susceptibility of Legionellapneumophila to ofloxacin in vitro and in experimental Legionellapneumonia in guinea pigs. Antimicrob Agents Chemother 1985; 28: 15-20.

December 1990 The American Journal of Medicine Volume 89

Ofloxacin treatment of Chlamydia pneumoniae (strain TWAR) lower respiratory tract infections.

Limited data suggest that tetracycline or erythromycin is the antibiotic of choice for treating Chlamydia pneumoniae infection, but they are not alway...
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