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Lomefloxacin versus amoxicillin in the treatment of acute exacerbations of chronic bronchitis: An Italian multicenter study
Lomefloxacin Versus Amoxicillin in the Treatment of Acute Exacerbations of Chronic Bronchitis: An Italian Multicenter Study CARLO
GRASSI,
M.D.,
Pawa, CARLO
ALBERA,
M.D.,
ERNESTO
POZZI,M.D.,
Nine centers in Italy participated in a worldwide, multicenter study comparing the effectiveness and safety of lomefloxacin and amoxicillin in patients with acute exacerbations of chronic bronchitis caused mainly by gramnegative pathogens. The 157 enrolled patients received either 400 mg lomefloxacin once daily tn = 78) or 500 mg amoxicillin every 8 hours (n = 79) for 7-10 days. A total of 131 patients were evaluable for bacteriologic efficacy and 154 for clinical efficacy. At 2-4 days after the conclusion of treatment, the bacterial eradication rate was 84.8% for lomefloxacin-treated patients and 64.6% for amoxicillin-treated patients (p = 0.0065); the clinical success rate (cure plus improvement) for lomefloxacin was 94.7% and for amoxicillin was 83.3% (p = 0.0212). The reinfection rate was lower in the lomefloxacin group than in the amoxicillin group (3.0% vs 13.8%, p = 0.0382). Both drug regimens were well tolerated. Once-a-day treatment with 400 mg lomefloxacin was more effective than 500 mg amoxicillin three times daily for the treatment of acute exacerbations of chronic bronchitis caused by gram-negative pathogens.
From the Institute of Respiratory Diseases, University of Pavia (C.G.); Clinical and Biologrcal Sciences Department, Pulmonary Branch, University of Turin (C.A., E.P.). Turin, Italy. Requests for reprints should be addressed to Ernest0 Pow M.D., Unwersity of Turin, Clinical and Biologrcal Sciences Department, Pulmonary Branch, c/o S. Luigr Gonzaga Hospital, Regione Gonzole 10, 10043 Orbassano (Torino), Italy.
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atients with chronic bronchitis have increased bronchial mucus secretions [l,Z] and may also have bronchial obstruction (chronic obstructive bronchitis) [1,2]. These conditions frequently impair local defense mechanisms, leading to the development of lower respiratory tract infections, usually known as acute infectious exacerbations of chronic bronchitis [3]. Although Streptococcus pneumoniae is one of the bacterial strains most frequently involved in acute exacerbations of chronic bronchitis [4], Haemophilus influenzae is the etiologically involved pathogen in ZO-25% of exacerbations [41; approximately 50% of H. influenxae strains are p-lactam resistant [5]. In elderly patients, in hospital-acquired infections, and in patients with other diseases (diabetes, cardiovascular diseases, urinary tract diseases, etc.) gram-negative bacteria, such as Pseudomonas aeruginosa and Enterobacteriaceae, are involved [6]. The latter and an increased number of gram-positive, plactamase producing strains are involved in the most difficult cases of acute infectious exacerbation of chronic bronchitis. Antibiotics employed in lower respiratory tract infections must be effective against these bacteria and must reach high concentrations in bronchial secretions. Amoxicillin is used for the treatment of lower respiratory tract infections, because of its good pharmacokinetic profile and safety [7]. Lomefloxacin is a new difluorinated quinolone antimicrobial agent that has demonstrated a broad antibacterial spectrum in vitro and in vivo, showing activity similar to ofloxacin and norfloxacin [&lo]. The minimum inhibitory concentration of lomefloxacin against 90% (MI&J of the members of the family Enterobacteriaceae, P. aeruginosa, and staphylococci is 0.25-4 pg/mL [&lo]. A total of 90% of Neisseria spp. and H. injluenxae are susceptible to drug concentrations ~0.06 pg/mL [8lo], whereas the MICgO for streptococci (S. pneumoniae, Streptococcus pyogenes, and enterococci) is 6.25-8 pg/mL, so they are entirely or intermediately susceptible to lomefloxacin [S-111. Lomefloxacin, orally administered, is rapidly and virtually completely absorbed and undergoes minimal metabolism [12-151. Peak serum concentrations (approximately 3.0-4.0 pg/mL following a 400
April 6, 1992
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mg oral dose) are attained about l-2 hours after oral administration [12,13], with an elimination half-life of about 7-8 hours [12,131 and a bioavailability of about 98% [ 12,131; bronchial mucosa levels are approximately 2.1 times higher than those in blood [14,15]. The once-daily 400 mg regimen provides 24-hour sputum concentrations in excess of the MICW ranges (pg/mL) for common gram-negative respiratory pathogens such as Legionella spp. (0.06-0.25), H. influenxae (0.06-0.5), Moraxella catarrhalis (0.25) and Klebsiella pneurnoniae (0.25-2) [16]. In Japanese Phase II clinical studies on human infections caused by the previously mentioned bacterial strains, satisfactory clinical and bacteriologic responses were observed in most patients with respiratory tract infections; adverse events, such as gastric pain or heartburn, diarrhea, vertigo, drowsiness, or sleeplessness were observed in only a few patients [17-231. Both the benefits of lomefloxacin, when compared to other available quinolone antimicrobial agents (i.e., metabolism-resistant structure, resultant long half-life, and desirable pharmacokinetic profile) and the results obtained from clinical trials in Japan (i.e., the promising efficacy and safety profiles) have suggested lomefloxacin’s usefulness in treatment of chronic bronchitis exacerbations. The aim of this study was to evaluate the effectiveness and safety of lomefloxacin (400 mg orally once daily) and amoxicillin (500 mg orally every 8 hours) in the treatment of acute exacerbations of chronic bronchitis caused by gram-negative pathogens.
PATIENTSAND METHODS Investigators at nine centers in Italy participated in a comparative study of lomefloxacin and amoxicillin in patients with acute bacterial exacerbations of chronic bronchitis. Chronic bronchitis was defined as excessive tracheobronchial mucus production for at least 3 months of the year for more than two consecutive years [1,21. An acute exacerbation was defined as one or more of the following: an increase in sputum production; an increase in the purulence of the sputum (indicated by changes in the color or tenacity; body temperature >38”C). The acute exacerbation was confirmed by Gram stain and culture of the sputum showing predominantly gram-negative pathogens. Isolated pathogens were required to be susceptible to both study drugs. Patients with susceptible gram-positive pathogens could remain in the study pending satisfactory clinical response. Patients were excluded from the study if they were pregnant or nursing, terminally ill or immunocompromised, had a concomitant infection or septi4A404S
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cemia, convulsive disorders or significant abnormality of renal or hepatic function, had taken an antacid 48 hours before starting or during lomefloxacin treatment, if there was a clinical history of quinolone or p-la&am hypersensitivity, or if they were being simultaneously treated with fenbufen. Chest X-rays were performed to ensure that patients did not have acute pneumonitis. All patients provided informed consent. Patients were randomly assigned to treatment groups using a computer-generated randomization schedule. After a patient had been evaluated by an investigator to ensure that eligibility criteria had been met, prepackaged medications were issued by a third party to maintain investigator blinding. Patients in the lomefloxacin group took 400 mg of lomefloxacin (two 200 mg capsules) once daily. Patients in the amoxicillin group took one 500 mg capsule of amoxicillin every 8 hours. Patients were evaluated 48 hours before the initiation of treatment (visit l), after 2-4 days of treatment (visit 2) and 2-4 days after the end of treatment (visit 3). The initial evaluation consisted of medical history and physical examination, clinical laboratory tests, and microbiologic evaluation of the sputum. At visit 1 the investigator classified the acute exacerbation episode as “mild” (causing no limitation of usual activities), “moderate” (causing some limitation of usual activities), or “severe” (causing inability to carry out usual activities). Clinical evaluation was repeated at visits 2 and 3, and microbiologic evaluation and clinical laboratory tests at visit 3. Clinical laboratory tests included blood cell count, sedimentation rate, prothrombin time, partial thromboplastin time, blood urea, creatinine, transaminases, alkaline phosphatase, total bilirubin, total protein and protein electrophoresis, potassium, sodium, chloride, urinalysis, and pregnancy test (for potentially childbearing females). Microbiologic evaluation consisted of Gram stain and quantitative culture and susceptibility testing of a sputum specimen. Clinical results at visit 3 were reported as “cure” (disappearance of all baseline signs and symptoms), “improvement” (remission without complete disappearance of signs and symptoms), “failure” (no remission), or “nonevaluable” (loss of data, dropout patient, etc.). Both cure and improvement were considered clinical “success.” Microbiologic results were categorized as “eradication” (initial pathogen eradicated at 2-4 days post-therapy with no other pathogen isolated), “failure” (initial pathogen not eradicated), “reinfection” (initial pathogen eradicated with a different pathogen isolated 2-4 days after therapy), or “nonevaluable” (loss of data, dropout patient, etc.).
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At visit 3 investigators reported an assessment of the overall effectiveness by considering clinical and microbiologic evaluations, safety and tolerance. Overall effectiveness was categorized as “excellent, ” “good, ” “fair,” or “poor.” Adverse events were recorded and evaluated for their relationship to drug administration. Data were analyzed using Fisher’s exact test and the chi-square test.
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TABLE I Patient Characteristics I Lomefloxacin
(n = 78)
I Sex Male Female
A total of 157 patients were enrolled and randomized to treatment groups: 78 patients received 400 mg lomefloxacin once daily, and ‘79 received 500 mg amoxicillin every 8 hours. Both groups of patients were well matched in terms of age (mean +- standard deviation; lomefloxacin 59.9 k 8.3 years, amoxicillin 59.3 +- 10.4 years), sex, and severity of presenting signs and symptoms (Table I). In the lomefloxacin group the mean length of drug therapy was 8.8 + 1.5 days, in the amoxicillin group 8.4 2 1.7 days. A total of 154 patients completed the study, ‘76 of 78 in the lomefloxacin group and 78 of 79 in the amoxicillin group; 131 were evaluable for bacteriologic effectiveness, 154 for clinical effectiveness, and 157 for overall effectiveness. A total of 81 pathogen strains were initially isolated from the 78 patients in the lomefloxacin group (Table II), with the most frequently isolated being P. aerugiwsa (34.5%), H. influenxae (19.8%), and K. pneumoniae (14.8%). In the amoxicillin group 80
17(x8%)
62(78.5%) 17(21.5%)
60.32 a.3 57.1k 7.7 59.9i a.3
59.62 14.3 59.32 10.4
13(16.6%) 49(62.8%) 16(20.6%)
15(la.g%j 56(70.9%) a (10.2%)
61 (78.2%)
Agiteean 2 SD) Female Total Seve[;ty of presenting signs and symptoms
RESULTS
Moderate Severe
Amoxicillin (n = 79)
59.2 2 9.2
pathogen strains were isolated from 79 patients, most frequently H. influenxae (26.3%), Escherichia coli (15%), P. aeruginosa (12.5%), M. catarrhalis (lo%), Acinetobacter spp. (lo%), and K. pneumoniae (7.5%). At 2-4 days after the end of treatment, 67 of 81 (82.7%) pathogens in the lomefloxacin group were eradicated, 8 (9.9%) persisted, and 6 (7.4%) were not evaluable. Of 80 pathogens isolated in the amoxicillin-treated patients, 59 (73.7%) were eradicated, 15 (18.8%) persisted, and 6 (7.5%) were not evaluable. Bacteriologic outcome, by pathogen, in both lomefloxacin and amoxicillin treatment groups, is detailed in Table II. Bacteriologic and clinical effectiveness, in Tables III and IV, reflect the number
TABLE II Bacteriologic
Outcome by Pathogen
Treatment Pathogen Lomefloxacin Pseudomonas aeruginosa Haemophilos mfluenzae K/ebs/e//apneumomae Enterobacter sp. Streptococcus pyogenes Proteus sp. Eschenchia COB Moraxella catarrhals Actnetobacter sp. Other Total
Amoxicillin Haemophilus mfluenzae Eschewhia CO/I Pseudomonas aeruginosa Acnetobacter sp. Moraxella catarfbak Klebsleilapneumoniae Proteus sp.
Enterobactersp. Streptococcus pyofenes Other Total
Baseline n (%)
Eradication n (%I
Failure nW
Nonevaluable n
28 (34.5%) 16(19.8%) 12(14.8%) 4 (4.9%) 5 (6.2%) 4 (4.9%] 2 (2.5%) 2 (2.5%) 2 (2.5%) 6 (7.4%) a1(100%)
21(75.0%) 14(87.5%) 11(91.6%) 3 (75.0%) 5 (loo%) 2 (50.0%) 2 (100%) 2(1oo%) 2 (100%) 5 (83.3%) 67(82.7%)
6 (21.4%) 0 : 125.0%) 0 1(25.0%) 0 0 0 0 a (9.9%)
1 2 1 0 0 1 0 0 0 1 6
21(26.3%)
18(85.7%) IO(83.3%) 4 (40.0%) 7(87.5%) 6 (75.0%) 4 (66.7%) 3 (15.0%) 2 (66.7%) 1 (100%) 4 (57.1%) 59(73.7%)
I (4.8%) 2 (16.7%) 5 (50.0%) 1 (12.5%) 1(12.5%) 2 (33.3%) 1 (25.0%) 1 (33.3%) 0 1(14.2X) 15(18.8%)
2 0 1 0 1 0 0 0 0 2 6
12 (15.0%)
10(12.5%) 8 (10.0%)
a (10.0%) 6 (7.5%) 4 (5.0%) 3 (3.7%) 1 (1.2%) 7 (8.8%) a0(100%)
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initially infected with Pseudomonas sp. was subsequently found to have Haemophilus sp. Bacteriologic Efficacy (Visit 3) The clinical success rate 2-4 days after treatment (total patients either cured or improved) was 94.7% Eradication* Failure No. Evaluable Reinfection Patients n (%I n (%I n (%I for lomefloxacin and 83.3% for amoxicillin (p = 56(84.8%) 2 (3.0%) 8 (12.1%) 0.0212). Overall effectiveness 2-4 days after treatLomefloxacin Amoxlcillin it 42 (646%) 9 (13.8%) 14(21.5%) ment is shown in Table V. Categorizing as positive *Chi-square = 6.080846: df = 1; p = 0.01366; Rsher's exact test, p = 0.006501. results both excellent and good, and as negative both fair and poor, significantly better results were noted for patients treated with lomefloxacin than of patients considered evaluable, which was depenfor those receiving amoxicillin (87.2% vs 72.1%; p = dent on availability of data and protocol compliance. 0.0077). The bacterial eradication rate 2-4 days after the Both therapeutic regimens employed in this conclusion of treatment in evaluable patients was study were well tolerated. No clinically significant 84.8% in lomefloxacin-treated patients and 64.6% in modification of vital sign data or laboratory values amoxicillin-treated patients (p = 0.0065). was observed in either group. No adverse event The incidence of reinfection after eradication of was considered unexpected or severe in either the baseline’ pathogen was significantly higher in treatment group. The adverse event rate was 4% in amoxicillin group (9 of 65 evaluable patients; 13.8%) lomefloxacin-treated patients and 5% in amoxicillinthan in lomefloxacin group (2 of 66,3%, p = 0.0382). treated patients. Adverse events related to the Among lomefloxacin-treated patients, one initially study drug occurred in two lomefloxacin-treated infected with Pseudomonas sp. was found after patients (both reported heartburn) and in three treatment to be infected with Achromobacter sp., amoxicillin-treated patients (two nausea, one skin and one patient with Staphylococcus aureus was rash). subsequently infected with Acinetobacter anitratus. Of the amoxicillin-treated patients, _COMMENT three had E. coli eradicated; one was reinfected with Enterobacter cloacae and two with K. pneuThis multicenter trial showed that lomefloxacin moniae. Two patients had A. anitratus eradicated; has excellent clinical effectiveness and a good tolerone was reinfected with Pseudomonas sp. and one ability profile in patients with acute exacerbations with both Pseudomonas sp. and Enterobacter sp. of chronic bronchitis. The bacteriologic and clinical One patient with E. cloacae was reinfected with effectiveness rates for lomefloxacin (400 mg once Klebsiella sp. and one patient with Acinetobacter daily) were significantly higher than those obcalcoaceticus was reinfected with Klebsiella oxy- served for amoxicillin (500 mg every 8 hours). toca. A patient initially infected with Proteus miraThe distribution of isolated pathogens in the two bilis was reinfected with K. pneumoniae and one treatment groups was slightly different and may TABLE III
TABLE IV Clinical Efficacy (Visit 3) No. Evaluable Patients Lomefloxactn _ Amoxicillin
Cure nW
Improvement n (%I
55(72.4%) 36(46.1%)
E
Success* n (SC)
17(22.3%) 29(37.2%)
72(94.7%) 65(83.3%)
Failure n (%I
4 (5.3%) 13(16.7%)
Chi-square = 4.00218; df = 1; p = 0.04544; hsher's exact test, p = 0.02127.
TABLE V Overall Efficacy (Visit 3) Positive* No. Patients
Excellent nW
Good n (%I
78 79
Amoxlclllln Lomefloxacin
Negative
28(54.4%) 43 (35.9%)
*Chi-square = 5.740512; df = 1; p = 0.01657; Fisher's exact test, p = 0.007723.
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Fair nW
13 5(16.5%) (6.4%)
Poor n t-1
38 (10.1%) (3.8%)
Nonevaluable n 61
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have affected statistical evaluation of bacteriologic results. On the other hand, pathogens from lomefloxacin-treated patients were usually gramnegative strains that are generally considered more difficult to treat. Although this study was designed to expect gram-negative pathogens, five strains of S. pyogenes (all eradicated) were included in the lomefloxacin group and two strains of S. pyogenes (both eradicated) were found in the amoxicillin group. In the lomefloxacin-treated group the overall bacteriologic eradication rate was high (84.8%), as were eradication rates for pathogens more frequently involved in acute exacerbations of chronic bronchitis: 87.5% of H. influenxae, 91.6% of K. pneumoniae, and 75% of P. aeruginosa were eradicated. Once-daily oral therapy with lomefloxacin may be considered an effective and well-tolerated therapeutic regimen for the treatment of acute exacerbations of chronic bronchitis caused by gramnegative bacteria.
PARTICIPATINGINVESTIGATORS AND CENTERS Prof. Ernesto Pozzi, Cattedra di Fislopatologia Respiratoria, Ospedale S. Luigi Gonzaga, Tonno: Prof. Albert0 Elsetti, Clinlca Tisologica dell’Universit8, Ospedale Forlontnl, Roma; Prof. Ernest0 Catena. 1st ClinIca Tislologica e Malattie Apparato RespIratorlo, Ospedale V. Monaldi, Napoli; Prof. Adalberto Ciaccia, Div. di Pneumonologfa e Malattie Apparato Respiratorio, Pspedale E. Boeri Tresigallo, Ferrara; Prof. Francesco Ginesu, 1st Tlstologica e Malattie Apparato Respiratorio, Ospedale A. Conti, Sassan; Prof. Carlo Grassi, 1st Tisiologica e Malattie Apparato Respiratono, Policlinico S. Mattea, Pavla; Prof. Giuseppe Gunella, Cattedra di Fislopatologla Resplratona, Policlinico S. Orsola, Bologna; Prof. Antonino Mistretta, lnstituto di Malattie dell’Apparato Respiratorio, Universita di Catania, Catania; Prof. Dana Olivleri, Clinica Tisiologlca e Malathe Apparato Respiratorio, Ospedaie Rasori, Parma.
REFERENCES 1. Amencan Thoraclc Society. Statement by committee on diagnostic standards for nontuberculous respiratory disease. Definition and classification of chronic bronchitis, asthma and pulmonary emphysema. Am Rev Respir Dis 1962; 85: 762. 2. Medical Research Council Committee on Aetiology of Chronic Bronchitis. Definition and classification of chronic bronchitis for clmlcal and epidemiological purposes. Lancet 1965; I: 775. 3. Reynolds HY. Host defense Impairment that may lead to respiratory infections. Clin Chest Med 1387; 8: 339-58.
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ET AL
4. Grassi C, Muiesan G. Terapla pneumologica. Florence: USES publlcabon, 1987; 387. 5. Stratton CW, Hawley HB, Horsman TA, et al. Haemophilus influenzae pneumonia In adults: report of five cases caused by ampicillin-resistant strains. Am Rev Respir Dis 1980; 121: 595-8. 6. Gardner P, Arnow PM. Hospital acquired infections. In: Braunwald E, lsselbacher Kl, Petersdorf RG, Wilson JD, Marbn JB, Fauci AS, eds. Harrison’s Principles of Internal Medicme, 1 lth ed. New York: McGraw-Hill, 1987; 470-4. 7. Bergogne-Berezin E, Lambert-Zechowsky N, Morel C. Pharmacocinebque des anbbiotiques dans les secretion bronchiques. Nouv Presse Med 19n; 6: 3584. 8. Hirose T, Okezaki E, Kato H, Ito Y, lnoue M, Mitsuhashi S In vitro and In vivo achvity of NY-198, a new difluorinated quinolone. Anhmlcrob Agents Chemother 1987; 31: 854-9. 9. Chin N-X, Novelli A, Neu HC. In vitro activity of lomefloxactn (SC-47111; NY-198), a difluoroquinolone 3-carboxyllc acid, compared with those of other quinolones. Anbmicrob Agents Chemother 1988; 32: 656-62. 10. Wise R, Andrews JM, Ashby JP, Matthews RS. In vitro activity of lomefloxacin a new quinolone antimicrobial agent, in comparison with those of other agents. Antimicrob Agents Chemother 1988; 32: 617-22. 11. Fernandes PB. Mode of action, and in vitro and in vivo activities of the fluoroqulnolones. J Clin Pharmacol 1988; 28: 156-68. 12. Morrison PJ, Mant TGK, Norman GT, Robinson J, Kunka RL. Pharmacokinetics and tolerance of lomefloxacin after sequentially increasing oral doses. Antimicrob Agents Chemother 1988; 32: 1503-7. 13. Kavi J, Stone J, Andrews JM, Ashby JP, Wise R. Tissue penetration and pharmacokinetics of lomefloxacin following multiple doses. Eur J Clin Microbial Infect Dis 1989; 8: 168-70. 14. Baldwin DR, Honeybourne D, Andrews JM, Ashby JP, Wise R. Concentrations of oral lomefloxacin In serum and bronchial mucosa. Antimicrob Agents Chemother 1990; 34: 1017-g. 15. Stone JW, Andrews JM, Ashby JP, Griggs D, Wise R. Pharmacokinetics and t&sue penetration of orally administered lomefloxacin. Antimicrob Agents Chemother 1988; 32: 1508-10. 16 Kovarik JM, Smith J, Sips DJ, et a/. Steady-state pharmacokinetics and sputum penetration of lomefloxacin in chronic bronchitis patients [Abstract 1005]. 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, October 1990, Atlanta,; 253. 17. Anouma S, Tokue Y, Kitamura N, et al. Laboratory study of NY-198 and clinical evaluahon in respiratory tract infections. Chemotherapy 1988; 36 (Suppl 2): 48694. 18. Honda K, Kubo C, Nagano H. NY-198 in respiratory tract infections. Chemotherapy 1988; 36 (Suppl 2): 727-31. 19. Ida S, Shindoh Y, Takashima T. Clinical trial of NY-198 In patients with respiratory tract infections. Chemotherapy 1988; 36 (Suppl 2): 480-5. 20. Kaij M, Saito A, Shimada I, et a/. Uimcal studies on NY-198. Chemotherapy 1988; 36 (Suppl 2): 513-26. 21. Kawai S, Kawaira M., Oshitani H, Kobayashi H. NY-198 in respiratory tract infection. Chemotherapy 1988; 36 (Suppl 2): 549-53. 22. Kurasawa T; Kuze F, Kato M, et a/. NY-198 in the treatment of respiratory infections. Chemotherapy 1988; 36 (Suppl 2): 652-7. 23. Matsushima T, lkeda H, Adachi M, et al. Clinical study of NY-198 in pulmonary Infections. Chemotherapy 1988; 36 (Suppl 2): 690-5.
April 6, 1992
The American Journal of Medicine
Volume 92 (suppl 4A)
4A-107s
GRASSI,
M.D.,
Pawa, CARLO
ALBERA,
M.D.,
ERNESTO
POZZI,M.D.,
Nine centers in Italy participated in a worldwide, multicenter study comparing the effectiveness and safety of lomefloxacin and amoxicillin in patients with acute exacerbations of chronic bronchitis caused mainly by gramnegative pathogens. The 157 enrolled patients received either 400 mg lomefloxacin once daily tn = 78) or 500 mg amoxicillin every 8 hours (n = 79) for 7-10 days. A total of 131 patients were evaluable for bacteriologic efficacy and 154 for clinical efficacy. At 2-4 days after the conclusion of treatment, the bacterial eradication rate was 84.8% for lomefloxacin-treated patients and 64.6% for amoxicillin-treated patients (p = 0.0065); the clinical success rate (cure plus improvement) for lomefloxacin was 94.7% and for amoxicillin was 83.3% (p = 0.0212). The reinfection rate was lower in the lomefloxacin group than in the amoxicillin group (3.0% vs 13.8%, p = 0.0382). Both drug regimens were well tolerated. Once-a-day treatment with 400 mg lomefloxacin was more effective than 500 mg amoxicillin three times daily for the treatment of acute exacerbations of chronic bronchitis caused by gram-negative pathogens.
From the Institute of Respiratory Diseases, University of Pavia (C.G.); Clinical and Biologrcal Sciences Department, Pulmonary Branch, University of Turin (C.A., E.P.). Turin, Italy. Requests for reprints should be addressed to Ernest0 Pow M.D., Unwersity of Turin, Clinical and Biologrcal Sciences Department, Pulmonary Branch, c/o S. Luigr Gonzaga Hospital, Regione Gonzole 10, 10043 Orbassano (Torino), Italy.
win,
/[a/y
P
atients with chronic bronchitis have increased bronchial mucus secretions [l,Z] and may also have bronchial obstruction (chronic obstructive bronchitis) [1,2]. These conditions frequently impair local defense mechanisms, leading to the development of lower respiratory tract infections, usually known as acute infectious exacerbations of chronic bronchitis [3]. Although Streptococcus pneumoniae is one of the bacterial strains most frequently involved in acute exacerbations of chronic bronchitis [4], Haemophilus influenzae is the etiologically involved pathogen in ZO-25% of exacerbations [41; approximately 50% of H. influenxae strains are p-lactam resistant [5]. In elderly patients, in hospital-acquired infections, and in patients with other diseases (diabetes, cardiovascular diseases, urinary tract diseases, etc.) gram-negative bacteria, such as Pseudomonas aeruginosa and Enterobacteriaceae, are involved [6]. The latter and an increased number of gram-positive, plactamase producing strains are involved in the most difficult cases of acute infectious exacerbation of chronic bronchitis. Antibiotics employed in lower respiratory tract infections must be effective against these bacteria and must reach high concentrations in bronchial secretions. Amoxicillin is used for the treatment of lower respiratory tract infections, because of its good pharmacokinetic profile and safety [7]. Lomefloxacin is a new difluorinated quinolone antimicrobial agent that has demonstrated a broad antibacterial spectrum in vitro and in vivo, showing activity similar to ofloxacin and norfloxacin [&lo]. The minimum inhibitory concentration of lomefloxacin against 90% (MI&J of the members of the family Enterobacteriaceae, P. aeruginosa, and staphylococci is 0.25-4 pg/mL [&lo]. A total of 90% of Neisseria spp. and H. injluenxae are susceptible to drug concentrations ~0.06 pg/mL [8lo], whereas the MICgO for streptococci (S. pneumoniae, Streptococcus pyogenes, and enterococci) is 6.25-8 pg/mL, so they are entirely or intermediately susceptible to lomefloxacin [S-111. Lomefloxacin, orally administered, is rapidly and virtually completely absorbed and undergoes minimal metabolism [12-151. Peak serum concentrations (approximately 3.0-4.0 pg/mL following a 400
April 6, 1992
The American Journal of Medicine
Volume 92 (suppl 4A)
4A-103s
SYMPOSIUM
ON ONCE-A.DAY QUINOLONE
I GRAS!3 ET AL
mg oral dose) are attained about l-2 hours after oral administration [12,13], with an elimination half-life of about 7-8 hours [12,131 and a bioavailability of about 98% [ 12,131; bronchial mucosa levels are approximately 2.1 times higher than those in blood [14,15]. The once-daily 400 mg regimen provides 24-hour sputum concentrations in excess of the MICW ranges (pg/mL) for common gram-negative respiratory pathogens such as Legionella spp. (0.06-0.25), H. influenxae (0.06-0.5), Moraxella catarrhalis (0.25) and Klebsiella pneurnoniae (0.25-2) [16]. In Japanese Phase II clinical studies on human infections caused by the previously mentioned bacterial strains, satisfactory clinical and bacteriologic responses were observed in most patients with respiratory tract infections; adverse events, such as gastric pain or heartburn, diarrhea, vertigo, drowsiness, or sleeplessness were observed in only a few patients [17-231. Both the benefits of lomefloxacin, when compared to other available quinolone antimicrobial agents (i.e., metabolism-resistant structure, resultant long half-life, and desirable pharmacokinetic profile) and the results obtained from clinical trials in Japan (i.e., the promising efficacy and safety profiles) have suggested lomefloxacin’s usefulness in treatment of chronic bronchitis exacerbations. The aim of this study was to evaluate the effectiveness and safety of lomefloxacin (400 mg orally once daily) and amoxicillin (500 mg orally every 8 hours) in the treatment of acute exacerbations of chronic bronchitis caused by gram-negative pathogens.
PATIENTSAND METHODS Investigators at nine centers in Italy participated in a comparative study of lomefloxacin and amoxicillin in patients with acute bacterial exacerbations of chronic bronchitis. Chronic bronchitis was defined as excessive tracheobronchial mucus production for at least 3 months of the year for more than two consecutive years [1,21. An acute exacerbation was defined as one or more of the following: an increase in sputum production; an increase in the purulence of the sputum (indicated by changes in the color or tenacity; body temperature >38”C). The acute exacerbation was confirmed by Gram stain and culture of the sputum showing predominantly gram-negative pathogens. Isolated pathogens were required to be susceptible to both study drugs. Patients with susceptible gram-positive pathogens could remain in the study pending satisfactory clinical response. Patients were excluded from the study if they were pregnant or nursing, terminally ill or immunocompromised, had a concomitant infection or septi4A404S
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cemia, convulsive disorders or significant abnormality of renal or hepatic function, had taken an antacid 48 hours before starting or during lomefloxacin treatment, if there was a clinical history of quinolone or p-la&am hypersensitivity, or if they were being simultaneously treated with fenbufen. Chest X-rays were performed to ensure that patients did not have acute pneumonitis. All patients provided informed consent. Patients were randomly assigned to treatment groups using a computer-generated randomization schedule. After a patient had been evaluated by an investigator to ensure that eligibility criteria had been met, prepackaged medications were issued by a third party to maintain investigator blinding. Patients in the lomefloxacin group took 400 mg of lomefloxacin (two 200 mg capsules) once daily. Patients in the amoxicillin group took one 500 mg capsule of amoxicillin every 8 hours. Patients were evaluated 48 hours before the initiation of treatment (visit l), after 2-4 days of treatment (visit 2) and 2-4 days after the end of treatment (visit 3). The initial evaluation consisted of medical history and physical examination, clinical laboratory tests, and microbiologic evaluation of the sputum. At visit 1 the investigator classified the acute exacerbation episode as “mild” (causing no limitation of usual activities), “moderate” (causing some limitation of usual activities), or “severe” (causing inability to carry out usual activities). Clinical evaluation was repeated at visits 2 and 3, and microbiologic evaluation and clinical laboratory tests at visit 3. Clinical laboratory tests included blood cell count, sedimentation rate, prothrombin time, partial thromboplastin time, blood urea, creatinine, transaminases, alkaline phosphatase, total bilirubin, total protein and protein electrophoresis, potassium, sodium, chloride, urinalysis, and pregnancy test (for potentially childbearing females). Microbiologic evaluation consisted of Gram stain and quantitative culture and susceptibility testing of a sputum specimen. Clinical results at visit 3 were reported as “cure” (disappearance of all baseline signs and symptoms), “improvement” (remission without complete disappearance of signs and symptoms), “failure” (no remission), or “nonevaluable” (loss of data, dropout patient, etc.). Both cure and improvement were considered clinical “success.” Microbiologic results were categorized as “eradication” (initial pathogen eradicated at 2-4 days post-therapy with no other pathogen isolated), “failure” (initial pathogen not eradicated), “reinfection” (initial pathogen eradicated with a different pathogen isolated 2-4 days after therapy), or “nonevaluable” (loss of data, dropout patient, etc.).
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At visit 3 investigators reported an assessment of the overall effectiveness by considering clinical and microbiologic evaluations, safety and tolerance. Overall effectiveness was categorized as “excellent, ” “good, ” “fair,” or “poor.” Adverse events were recorded and evaluated for their relationship to drug administration. Data were analyzed using Fisher’s exact test and the chi-square test.
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TABLE I Patient Characteristics I Lomefloxacin
(n = 78)
I Sex Male Female
A total of 157 patients were enrolled and randomized to treatment groups: 78 patients received 400 mg lomefloxacin once daily, and ‘79 received 500 mg amoxicillin every 8 hours. Both groups of patients were well matched in terms of age (mean +- standard deviation; lomefloxacin 59.9 k 8.3 years, amoxicillin 59.3 +- 10.4 years), sex, and severity of presenting signs and symptoms (Table I). In the lomefloxacin group the mean length of drug therapy was 8.8 + 1.5 days, in the amoxicillin group 8.4 2 1.7 days. A total of 154 patients completed the study, ‘76 of 78 in the lomefloxacin group and 78 of 79 in the amoxicillin group; 131 were evaluable for bacteriologic effectiveness, 154 for clinical effectiveness, and 157 for overall effectiveness. A total of 81 pathogen strains were initially isolated from the 78 patients in the lomefloxacin group (Table II), with the most frequently isolated being P. aerugiwsa (34.5%), H. influenxae (19.8%), and K. pneumoniae (14.8%). In the amoxicillin group 80
17(x8%)
62(78.5%) 17(21.5%)
60.32 a.3 57.1k 7.7 59.9i a.3
59.62 14.3 59.32 10.4
13(16.6%) 49(62.8%) 16(20.6%)
15(la.g%j 56(70.9%) a (10.2%)
61 (78.2%)
Agiteean 2 SD) Female Total Seve[;ty of presenting signs and symptoms
RESULTS
Moderate Severe
Amoxicillin (n = 79)
59.2 2 9.2
pathogen strains were isolated from 79 patients, most frequently H. influenxae (26.3%), Escherichia coli (15%), P. aeruginosa (12.5%), M. catarrhalis (lo%), Acinetobacter spp. (lo%), and K. pneumoniae (7.5%). At 2-4 days after the end of treatment, 67 of 81 (82.7%) pathogens in the lomefloxacin group were eradicated, 8 (9.9%) persisted, and 6 (7.4%) were not evaluable. Of 80 pathogens isolated in the amoxicillin-treated patients, 59 (73.7%) were eradicated, 15 (18.8%) persisted, and 6 (7.5%) were not evaluable. Bacteriologic outcome, by pathogen, in both lomefloxacin and amoxicillin treatment groups, is detailed in Table II. Bacteriologic and clinical effectiveness, in Tables III and IV, reflect the number
TABLE II Bacteriologic
Outcome by Pathogen
Treatment Pathogen Lomefloxacin Pseudomonas aeruginosa Haemophilos mfluenzae K/ebs/e//apneumomae Enterobacter sp. Streptococcus pyogenes Proteus sp. Eschenchia COB Moraxella catarrhals Actnetobacter sp. Other Total
Amoxicillin Haemophilus mfluenzae Eschewhia CO/I Pseudomonas aeruginosa Acnetobacter sp. Moraxella catarfbak Klebsleilapneumoniae Proteus sp.
Enterobactersp. Streptococcus pyofenes Other Total
Baseline n (%)
Eradication n (%I
Failure nW
Nonevaluable n
28 (34.5%) 16(19.8%) 12(14.8%) 4 (4.9%) 5 (6.2%) 4 (4.9%] 2 (2.5%) 2 (2.5%) 2 (2.5%) 6 (7.4%) a1(100%)
21(75.0%) 14(87.5%) 11(91.6%) 3 (75.0%) 5 (loo%) 2 (50.0%) 2 (100%) 2(1oo%) 2 (100%) 5 (83.3%) 67(82.7%)
6 (21.4%) 0 : 125.0%) 0 1(25.0%) 0 0 0 0 a (9.9%)
1 2 1 0 0 1 0 0 0 1 6
21(26.3%)
18(85.7%) IO(83.3%) 4 (40.0%) 7(87.5%) 6 (75.0%) 4 (66.7%) 3 (15.0%) 2 (66.7%) 1 (100%) 4 (57.1%) 59(73.7%)
I (4.8%) 2 (16.7%) 5 (50.0%) 1 (12.5%) 1(12.5%) 2 (33.3%) 1 (25.0%) 1 (33.3%) 0 1(14.2X) 15(18.8%)
2 0 1 0 1 0 0 0 0 2 6
12 (15.0%)
10(12.5%) 8 (10.0%)
a (10.0%) 6 (7.5%) 4 (5.0%) 3 (3.7%) 1 (1.2%) 7 (8.8%) a0(100%)
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initially infected with Pseudomonas sp. was subsequently found to have Haemophilus sp. Bacteriologic Efficacy (Visit 3) The clinical success rate 2-4 days after treatment (total patients either cured or improved) was 94.7% Eradication* Failure No. Evaluable Reinfection Patients n (%I n (%I n (%I for lomefloxacin and 83.3% for amoxicillin (p = 56(84.8%) 2 (3.0%) 8 (12.1%) 0.0212). Overall effectiveness 2-4 days after treatLomefloxacin Amoxlcillin it 42 (646%) 9 (13.8%) 14(21.5%) ment is shown in Table V. Categorizing as positive *Chi-square = 6.080846: df = 1; p = 0.01366; Rsher's exact test, p = 0.006501. results both excellent and good, and as negative both fair and poor, significantly better results were noted for patients treated with lomefloxacin than of patients considered evaluable, which was depenfor those receiving amoxicillin (87.2% vs 72.1%; p = dent on availability of data and protocol compliance. 0.0077). The bacterial eradication rate 2-4 days after the Both therapeutic regimens employed in this conclusion of treatment in evaluable patients was study were well tolerated. No clinically significant 84.8% in lomefloxacin-treated patients and 64.6% in modification of vital sign data or laboratory values amoxicillin-treated patients (p = 0.0065). was observed in either group. No adverse event The incidence of reinfection after eradication of was considered unexpected or severe in either the baseline’ pathogen was significantly higher in treatment group. The adverse event rate was 4% in amoxicillin group (9 of 65 evaluable patients; 13.8%) lomefloxacin-treated patients and 5% in amoxicillinthan in lomefloxacin group (2 of 66,3%, p = 0.0382). treated patients. Adverse events related to the Among lomefloxacin-treated patients, one initially study drug occurred in two lomefloxacin-treated infected with Pseudomonas sp. was found after patients (both reported heartburn) and in three treatment to be infected with Achromobacter sp., amoxicillin-treated patients (two nausea, one skin and one patient with Staphylococcus aureus was rash). subsequently infected with Acinetobacter anitratus. Of the amoxicillin-treated patients, _COMMENT three had E. coli eradicated; one was reinfected with Enterobacter cloacae and two with K. pneuThis multicenter trial showed that lomefloxacin moniae. Two patients had A. anitratus eradicated; has excellent clinical effectiveness and a good tolerone was reinfected with Pseudomonas sp. and one ability profile in patients with acute exacerbations with both Pseudomonas sp. and Enterobacter sp. of chronic bronchitis. The bacteriologic and clinical One patient with E. cloacae was reinfected with effectiveness rates for lomefloxacin (400 mg once Klebsiella sp. and one patient with Acinetobacter daily) were significantly higher than those obcalcoaceticus was reinfected with Klebsiella oxy- served for amoxicillin (500 mg every 8 hours). toca. A patient initially infected with Proteus miraThe distribution of isolated pathogens in the two bilis was reinfected with K. pneumoniae and one treatment groups was slightly different and may TABLE III
TABLE IV Clinical Efficacy (Visit 3) No. Evaluable Patients Lomefloxactn _ Amoxicillin
Cure nW
Improvement n (%I
55(72.4%) 36(46.1%)
E
Success* n (SC)
17(22.3%) 29(37.2%)
72(94.7%) 65(83.3%)
Failure n (%I
4 (5.3%) 13(16.7%)
Chi-square = 4.00218; df = 1; p = 0.04544; hsher's exact test, p = 0.02127.
TABLE V Overall Efficacy (Visit 3) Positive* No. Patients
Excellent nW
Good n (%I
78 79
Amoxlclllln Lomefloxacin
Negative
28(54.4%) 43 (35.9%)
*Chi-square = 5.740512; df = 1; p = 0.01657; Fisher's exact test, p = 0.007723.
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Fair nW
13 5(16.5%) (6.4%)
Poor n t-1
38 (10.1%) (3.8%)
Nonevaluable n 61
SYMPOSIUM
have affected statistical evaluation of bacteriologic results. On the other hand, pathogens from lomefloxacin-treated patients were usually gramnegative strains that are generally considered more difficult to treat. Although this study was designed to expect gram-negative pathogens, five strains of S. pyogenes (all eradicated) were included in the lomefloxacin group and two strains of S. pyogenes (both eradicated) were found in the amoxicillin group. In the lomefloxacin-treated group the overall bacteriologic eradication rate was high (84.8%), as were eradication rates for pathogens more frequently involved in acute exacerbations of chronic bronchitis: 87.5% of H. influenxae, 91.6% of K. pneumoniae, and 75% of P. aeruginosa were eradicated. Once-daily oral therapy with lomefloxacin may be considered an effective and well-tolerated therapeutic regimen for the treatment of acute exacerbations of chronic bronchitis caused by gramnegative bacteria.
PARTICIPATINGINVESTIGATORS AND CENTERS Prof. Ernesto Pozzi, Cattedra di Fislopatologia Respiratoria, Ospedale S. Luigi Gonzaga, Tonno: Prof. Albert0 Elsetti, Clinlca Tisologica dell’Universit8, Ospedale Forlontnl, Roma; Prof. Ernest0 Catena. 1st ClinIca Tislologica e Malattie Apparato RespIratorlo, Ospedale V. Monaldi, Napoli; Prof. Adalberto Ciaccia, Div. di Pneumonologfa e Malattie Apparato Respiratorio, Pspedale E. Boeri Tresigallo, Ferrara; Prof. Francesco Ginesu, 1st Tlstologica e Malattie Apparato Respiratorio, Ospedale A. Conti, Sassan; Prof. Carlo Grassi, 1st Tisiologica e Malattie Apparato Respiratono, Policlinico S. Mattea, Pavla; Prof. Giuseppe Gunella, Cattedra di Fislopatologla Resplratona, Policlinico S. Orsola, Bologna; Prof. Antonino Mistretta, lnstituto di Malattie dell’Apparato Respiratorio, Universita di Catania, Catania; Prof. Dana Olivleri, Clinica Tisiologlca e Malathe Apparato Respiratorio, Ospedaie Rasori, Parma.
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4. Grassi C, Muiesan G. Terapla pneumologica. Florence: USES publlcabon, 1987; 387. 5. Stratton CW, Hawley HB, Horsman TA, et al. Haemophilus influenzae pneumonia In adults: report of five cases caused by ampicillin-resistant strains. Am Rev Respir Dis 1980; 121: 595-8. 6. Gardner P, Arnow PM. Hospital acquired infections. In: Braunwald E, lsselbacher Kl, Petersdorf RG, Wilson JD, Marbn JB, Fauci AS, eds. Harrison’s Principles of Internal Medicme, 1 lth ed. New York: McGraw-Hill, 1987; 470-4. 7. Bergogne-Berezin E, Lambert-Zechowsky N, Morel C. Pharmacocinebque des anbbiotiques dans les secretion bronchiques. Nouv Presse Med 19n; 6: 3584. 8. Hirose T, Okezaki E, Kato H, Ito Y, lnoue M, Mitsuhashi S In vitro and In vivo achvity of NY-198, a new difluorinated quinolone. Anhmlcrob Agents Chemother 1987; 31: 854-9. 9. Chin N-X, Novelli A, Neu HC. In vitro activity of lomefloxactn (SC-47111; NY-198), a difluoroquinolone 3-carboxyllc acid, compared with those of other quinolones. Anbmicrob Agents Chemother 1988; 32: 656-62. 10. Wise R, Andrews JM, Ashby JP, Matthews RS. In vitro activity of lomefloxacin a new quinolone antimicrobial agent, in comparison with those of other agents. Antimicrob Agents Chemother 1988; 32: 617-22. 11. Fernandes PB. Mode of action, and in vitro and in vivo activities of the fluoroqulnolones. J Clin Pharmacol 1988; 28: 156-68. 12. Morrison PJ, Mant TGK, Norman GT, Robinson J, Kunka RL. Pharmacokinetics and tolerance of lomefloxacin after sequentially increasing oral doses. Antimicrob Agents Chemother 1988; 32: 1503-7. 13. Kavi J, Stone J, Andrews JM, Ashby JP, Wise R. Tissue penetration and pharmacokinetics of lomefloxacin following multiple doses. Eur J Clin Microbial Infect Dis 1989; 8: 168-70. 14. Baldwin DR, Honeybourne D, Andrews JM, Ashby JP, Wise R. Concentrations of oral lomefloxacin In serum and bronchial mucosa. Antimicrob Agents Chemother 1990; 34: 1017-g. 15. Stone JW, Andrews JM, Ashby JP, Griggs D, Wise R. Pharmacokinetics and t&sue penetration of orally administered lomefloxacin. Antimicrob Agents Chemother 1988; 32: 1508-10. 16 Kovarik JM, Smith J, Sips DJ, et a/. Steady-state pharmacokinetics and sputum penetration of lomefloxacin in chronic bronchitis patients [Abstract 1005]. 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, October 1990, Atlanta,; 253. 17. Anouma S, Tokue Y, Kitamura N, et al. Laboratory study of NY-198 and clinical evaluahon in respiratory tract infections. Chemotherapy 1988; 36 (Suppl 2): 48694. 18. Honda K, Kubo C, Nagano H. NY-198 in respiratory tract infections. Chemotherapy 1988; 36 (Suppl 2): 727-31. 19. Ida S, Shindoh Y, Takashima T. Clinical trial of NY-198 In patients with respiratory tract infections. Chemotherapy 1988; 36 (Suppl 2): 480-5. 20. Kaij M, Saito A, Shimada I, et a/. Uimcal studies on NY-198. Chemotherapy 1988; 36 (Suppl 2): 513-26. 21. Kawai S, Kawaira M., Oshitani H, Kobayashi H. NY-198 in respiratory tract infection. Chemotherapy 1988; 36 (Suppl 2): 549-53. 22. Kurasawa T; Kuze F, Kato M, et a/. NY-198 in the treatment of respiratory infections. Chemotherapy 1988; 36 (Suppl 2): 652-7. 23. Matsushima T, lkeda H, Adachi M, et al. Clinical study of NY-198 in pulmonary Infections. Chemotherapy 1988; 36 (Suppl 2): 690-5.
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