DIAG. MICROBIOL.INFECT. DIS. 1990;13:143-148
143
Prospective Randomized Study Comparing the Efficacy and Safety of Ciprofloxacin with Cefaclor in the Treatment of Patients with Purulent Bronchitis Ronald W. Quenzer, Robin L. Davis, and Mary M. Neidhart
We compared safety and efficacy of ciprofloxacin and cefaclor in the treatment of patients with purulent bronchitis. Fiftyfive patients were randomized prospectively to receive ciprofloxacin with a dose of 500 mg orally twice daily or cefaclor 250 mg over 8 hr for 5 days or longer. Patient groups did not differ with respect to age, duration of illness, severity of infection, or number of other concomitant disease states. A significantly larger number of patients in the ciprofloxacin group had poor health status (39.3% vs 7.4% for the ciprofloxacin and
cefaclor groups, respectively, p = 0.02). The response to therapy did not differ between groups. Infection was completely resolved in 71.4% vs 66.7% and markedly improved in 7.1% and 11.1% for the ciprofloxacin and cefaclor groups, respectively. The response to therapy and adverse reaction rate did not differ between groups. Seven patients treated with ciprofloxacin and five patients treated with cefaclor developed adverse reactions. We conclude that ciprofloxacin is a useful agent for the treatment of purulent bronchitis.
INTRODUCTION
trum of activity against most aerobic Gram-negative bacilli and Gram-positive cocci supports many useful indications, including the treatment of certain lower respiratory tract infections. Antimicrobial agents must achieve adequate concentrations in lung tissue and respiratory secretions to have efficacy in treating pneumonia and purulent bacterial bronchitis, respectively (Bergogne-Berezin, 1983). Ciprofloxacin concentrates well in the lungs. A single oral dose of 500 mg produces levels of 0.50.8 ~g/ml in bronchial secretions (Bergogne-Berezin et al., 1986). Higher levels of ciprofloxacin would be anticipated after drug accumulation from multiple doses. The concentrations in the lung are well above the minimum inhibitory concentration (MIC) for most Gram-negative and many Gram-positive respiratory pathogens. Although Streptococcus pneumoniae may be only moderately susceptible to ciprofloxacin in vitro (MIC > 0.5-2.0 ~g/ml), nearly all of the other bacterial respiratory pathogens (e.g., Haemophilus influenzae, Klebsiella sp., Enterobacter sp., and Pseudomonas aeruginosa) are usually exquisitely sensitive to ciproflox-
The fluoroquinolones are the newest class of bactericidal agents with a unique mechanism of inhibiting the bacterial DNA gyrase and thus preventing DNA replication (Shea and Pernet, 1985). The fluoroquinolones are well absorbed and therefore can be administered orally. Because their half-lives are 4-5 hr, these agents have an advantage over many other antibiotics of less frequent administration (usually twice a day) and predictably better compliance (Crump et al., 1983; Wise et al., 1986 and 1988). Similar to beta-lactamase drugs, this class of agents has very few side effects (Arcieri et al., 1987). The broad specFrom the Department of Medicine and the College of Pharmacy, University of New MexicoMedical Center, University Hospital, Albuquerque, New Mexico. Address reprint requests to: Dr. R. W. Quenzer, General Medicine Division, Department of Medicine, University Hospital, 2211 Lomas NE, Albuquerque, NM 87131. ReceivedJanuary 10, 1990; revised and accepted January 12, 1990. © 1990Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York, NY 10010 0732-8893/90/$3.50
144
acin (Appelbaum et al., 1986; Auckenthaler et al., 1986). This agent may also have clinical efficacy against Mycoplasma pneumoniae (Furneri et al., 1988) and Legionella pneumophila (Saravolatz et al., 1988), but more in vitro and in vivo studies are needed. In this study we compared ciprofloxacin at a dose of 500 mg orally twice daily to 250 mg of cefaclor orally every 8 hr in the treatment of bacterial bronchitis caused by susceptible organisms.
R.W. Quenzer et al.
Clinical Evaluation
Patients over 18 years of age with mild to moderate respiratory tract infections were eligible for enrollment in the study. A medical history was obtained and a physical examination was performed on each subject to establish the diagnosis of infection prior to enrollment. Infection was documented by a sputum culture or Gram's stain positive for the presence of significant numbers of bacteria or by an increase in one of the following signs or symptoms: cough, sputum production, purulent sputum or the presence of chest congestion, fever, chills, or pleuritic chest pain. Patients with a history of allergy to carboxyquinolone antibiotics or cephalosporins, renal impairment (creatinine > 2.0 mg/dl or creatinine clearance < 50 ml/1.73 m2), pregnant women, nursing mothers, patients with infections requiring therapy or a concomitant antibiotic with a spectrum similar to the study drugs were excluded from the study.
The severity of infection, general health status, antibiotic efficacy, and toxicity were evaluated by the blinded physician investigator. Prior to therapy, all patients were interviewed, a physical examination was completed, and the following tests were performed: complete blood count, blood chemistries, urinalysis, and chest x-ray. Patients were seen and evaluated at least every 3 to 4 days during therapy. Sputum cultures were repeated if a productive cough persisted. Hematology, chemistry tests, and urinalysis were performed weekly during therapy. At the end of therapy, a physical examination and all laboratory tests were repeated. Drug effectiveness was determined by the blinded evaluator based on the clinical response of the patient and the bacterial response of the infecting organism. Clinical response was categorized as complete resolution (disappearance of all signs and symptoms of infection), marked improvement (marked or moderate reduction in the severity and/or number of the signs and symptoms of infection), slight improvement (slight reduction in the severity and/or number of the signs and symptoms of infection), and failure (insufficient lessening of the signs and symptoms of infection to qualify as improvement). Bacteriological response was categorized as eradication, marked reduction (reduction to a clinically insignificant number of organisms), eradication with recurrence (eradication of organisms at the end of therapy with reappearance at follow-up), eradication with reinfection by n e w organism(s), and persistence.
Drug Therapy
Statistical Analysis
After giving written informed consent, patients were randomly assigned to receive 500 mg ciprofloxacin every 12 hr or 250 mg cefaclor every 8 hr. The morning dose of ciprofloxacin was taken before breakfast, and the evening dose was taken at least 2 hr before eating. Therapy was continued for 5 days or longer if deemed necessary by the evaluating physician.
Categorical data were evaluated using chi-square analysis with Yates' correction. The duration of symptoms prior to treatment, duration of therapy, and number of concomitant medications were considered nonparametric variables and were analyzed with the Mann-Whitney test. All comparisons were made with two-tailed tests, at a significance level of 0.05 (Zar, 1984).
Microbiological Evaluation
RESULTS
A sputum sample was collected after deep coughing for Gram's stain and culture within 48 hr prior to antibiotic therapy and every 3-4 days during therapy or as often as indicated based on the clinical course of the patient's respiratory infection. Antibiotic susceptibility was tested by the standard antibiotic disk technique according to the modified Kirby-Bauer procedure (Bauer et al., 1966; NCCLS, 1979 and 1983).
A total of 59 patients, 16 men and 43 women, completed the study. Fifty-five patients were evaluated for clinical and microbiologic responses (Table 1). Patients ranged in age from 19 to 87 years. Fifty-six of the patients had community-acquired infections. The mean duration of illness prior to initiating antibiotic treatment was 15.7 and 13.6 days in the ciprofloxacin and cefaclor groups, respectively. Previous antibiotic treatment for the current episode of
METHODS Patients
Ciprofloxacin in P u r u l e n t Bronchitis
TABLE 1.
145
Patient D e m o g r a p h i c s (mean ___ SD)
Characteristics Patients evaluated Age (years) Sex Male Female Duration of illness Hospital acquired Community acquired Previous antibiotic Clinical status (%) Poor health Other diseases Infection Mild Moderate Severe Sputum culture results (%) Pathogens(s) isolated Microorganism S. pneumoniae Staphylococcus aureus H. influenzae H. parainfluenzae B. catarrhalis P. aeruginosa P. stutzeri Enterobacter aerogenes
Ciprofloxacin Group
Cefaclor Group
28 48.4 -+ 20.0
27 42.4 _+ 16.6
5 23 15.7 _+ 34.3 2 26 9
11 16 13.6 -+ 18.2 1 26 6
11 (39.3) 20 (71.4)
2 (7.4) 16 (59.3)
0.02 NS
3 (10.7) 20 (71.4) 5 (17.9)
4 (14.8) 20 (74.1) 3 (11.1)
NS NS NS
9 (32.1)
10 (37.0)
2 (7.1) 1 (3.6) 1 (3.6) 3 (10.7) 1 (3.6) 2 (7.1) 0 (0) 1 (3.6)
4 (14.8) 1 (3.7) 2 (7.4) 2 (7.4) 3 (11.1) 0 (0) 1 (3.7) 0 (0)
bronchitis h a d failed in nine (32.1%) of the patients treated with ciprofloxacin a n d six (22.2%) treated with cefaclor, but n o n e of these patients had received an antibiotic within 5 days of initiating the study drug. There was no significant difference in the clinical status data (Table 1), with the exception that the general health status was w o r s e (fair or poor) in 11 (39.3%) of the ciprofloxacin-treated group, w h e r e a s only 2 (7.4%) of the cefaclor-treated patients (p = 0.02) had p o o r general health. Seven (25.0%) patients in the ciprofloxacin g r o u p required o x y g e n s u p p l e m e n t a t i o n c o m p a r e d to one (3.7%) in the cefaclor grouts. The bac; eria isolated from the initial s p u t u m are listed in Table 1. Respiratory p a t h o g e n s were identified in - 3 5 % of the patients in each g r o u p , w h e r e a s bacteria representing usual oropharyngeal flora were the only isolates from - 6 5 % of patients in each group. Eight percent of the ciprofloxacin-treated patients and 77% of the cefaclor-treated patients had bacterial bronchitis associated with G r a m - n e g a t i v e pathogens. Streptococcus pneumoniae was isolated from the sputum of two ciprofloxacin- and four cefaclor-treated patients, and there w e r e no failures in either group.
TABLE 2.
p
Bacterial a n d Clinical O u t c o m e s (%)
Evaluation
Ciprofloxacin
Cefaclor
p
Treatment days (mean) Clinical results Resolution Improved + + + Improved + Failure Bacteriologic results Eradication Persistence Indeterminate a
13.0 -+ 4.0
12.7 _+ 3.8
NS
(71.4) (7.1) (14.2) (7.1)
18 (66.7) 3 (11.1) 6 (22.2) 0 (0)
NS NS NS NS
7 (25.0) 1 (3.6) 20 (71.4)
8 (29.6) 0 (0) 19 (70.4)
NS NS NS
20 2 4 2
aProductive cough resolved with therapy. Bacterial a n d clinical o u t c o m e s are listed in Table 2. The m e a n duration of t h e r a p y a n d p e r c e n t of patients that h a d complete or m a r k e d i m p r o v e m e n t were not different b e t w e e n t r e a t m e n t groups. The m e a n n u m b e r of t r e a t m e n t days was - 13 in each group. Of the ciprofloxacin-treated patients, 22 (78.5%) s h o w e d complete or m a r k e d clinical imp r o v e m e n t c o m p a r e d to 21 (77.8%) of the cefaclor-
146
R.W. Quenzer et al.
TABLE 3.
Adverse Drug Effects
Reactions Diarrhea Lightheadedness Vertigo Nausea Vomiting Back pain Rash Hallucinations Abdominal pain
Ciprofloxacin (%) 2 1 1 1 0 1 1 1 1
(7.1) (3.6) (3.6) (3.6) (0) (3.6) (3.6) (3.6) (3.6)
Cefaclor (%) I 1 0 2 1 0 0 0 0
(3.7) (3.7) (0) (7.4)
(3.7) (0) (0) (0) (0)
treated patients. Two patients randomized to the ciprofloxacin group failed therapy. The respiratory pathogen(s) was eradicated in all but one patient, who had persistence of a susceptible P. aeruginosa in her sputum culture despite an improved clinical response while on ciprofloxacin. All 59 patients were evaluated for adverse drug reactions (Table 3). Seven (25.0%) patients treated with ciprofloxacin and five (18.5%) patients treated with cefaclor developed side effects (p = NS). Ciprofloxacin had to be discontinued in two patients due to adverse reactions. One patient developed a generalized urticarial exanthem after 6 days of therapy, and the second patient required evaluation for an acute confusionaI and hallucinatory episode lasting 6 hr after taking two doses of ciprofloxacin. She gave a history of consuming a quart of iced tea and 2-3 caffeinated soft drinks but no coffee each day. She recovered without sequalae after the incident.
COMMENTS The results of this prospective, controlled, blinded, parallel study suggest that ciprofloxacin is as effective as a second-generation cephalosporin (cefaclor) in treating purulent bronchitis. Cure or partial cure was achieved in nearly 80% of patients treated with either drug, which is comparable to other published studies with ciprofloxacin, penicillins, and cephalosporins (Ramirez et al., 1985; Davies et al., 1986a; Ernst et al., 1986; Hoogkamp-Korstanje et al., 1986; Fass, 1987; Kobayashi, 1987; Wollschlager et al., 1987; Shah, 1988). Because an acute exacerbation of chronic bronchitis is a clinical diagnosis difficult to confirm bacteriologically in m a n y patients, one should be cautious not to overemphasize the microbiologic data from the sputum samples as indicators of response to therapy. The serum elimination half-life of 3.9 hr for ciprofloxacin ( C r u m p e t al., 1983; Wise et al., 1986 and 1988) permits a dosing schedule of every 12 hr, which is commensurate with good patient compliance. Cip-
rofloxacin concentrates well in respiratory secretions. After a 500-rag oral dose, the mean peak bronchial concentration is 0.5-9.8 ~g/ml (Bergogne-Berezin et al., 1986) whereas a 1000-rag dose produces mean peak concentrations to 2.3 ~,g/ml (Davies et al., 1986b). These are concentrations appreciably above the MIC for most respiratory pathogens. Candidates for an oral antibiotic regimen should present with an increase in cough and sputum production, purulent changes in the expectorated respiratory secretions, chest congestion and dyspnea, pleuritic chest pains, fever or chilis, and a chest roentgenogram showing no acute changes or infiltrates. Some individuals with pneumonia may also be treated adequately with oral antibiotics. Bacteria most often associated with acute and chronic purulent bronchitis are S. pneumoniae, H. influenzae, H. parainfluenzae, Branhamella catarrhalis, and several enteric Gram-negative bacilli (e.g., Escherichia coli, Klebsiella pneumoniae ) (Chodosh, 1987). Although purulent bronchitis is generally a community-acquired infection, resistant Gram-negative bacilli are frequently isolated from these patients (Ruskin and Sattler, 1988). These organisms are consistently more susceptible to ciprofloxacin than to beta-lactam drugs such as cephradine or cefaclor. Although most strains of P. aeruginosa are susceptible to ciprofloxacin (MIC 0.06-1.0 ~g/ml) (Appelbaum et al., 1986; Auckenthaler et al., 1986), the MICs predictably increase during treatment in patients with serious Pseudomonas infections, and this decrease in ciprofloxacin susceptibility has been correlated with clinical and/or bacteriologic failure in P. aeruginosa bronchopulmonary infections and in cystic fibrosis patients (Goldfarb et al., 1987; Hodson et al., 1987; Parry, 1988). Not all investigators have reported these unfavorable results. Scully et al. found that even though P. aeruginosa persist in the sputum of patients with cystic fibrosis, clinical improvement may be noted in up to 80% (1986). Because Gram's stains are not frequently interpretable and cultures are not frequently obtainable or reliable, the initial therapy is usually begun with empirical broad-spectrum antibiotics such as amoxicillin, first- or second-generation oral cephalospotins (e. g., cephalexin, cefaclor, cefuroxime axetil), or trimethoprirn/sulfamethoxazole. Ciprofloxacin should be considered in patients allergic to one of these antibiotics or in individuals who fail to respond to initial therapy and in patients who present with nursing home or hospital-acquired bronchopulmonary infections. The major predisposing factors for Gram-negative bacillary purulent bronchitis are (1) recent antibiotic exposure, (2) moderate-to-severe general disability, (3) residence in a nursing home, (4) hospitalization, and (5) chronic lung disease. Ciprofloxacin is highly active against a broad spectrum
Ciprofloxacin in Purulent Bronchitis
of aerobic respiratory pathogens with MICs generally < 0.5 ~g/ml for Haemophilus sp., Branhamella catarrhalis, and most Enterobacteriaceae (Chin and Neu, 1984; Reeves et al., 1984; Sanders et al., 1987). Ciprofloxacin has an incidence of adverse effects comparable to that of the cephalosporins. The adverse reaction rate for ciprofloxacin and other quinolones is assessed to be 4.0-8.0% (Halkin, 1988). The higher rates in our subjects of 25% and 18% for ciprofloxacin and cefaclor, respectively, may reflect closer surveillance and a truer rate of mild, tolerable side effects. Quinolones have been reported to cause adverse central nervous system (CNS) manifestations (Boerema et al., 1985; Fass, 1987). One of our patients w h o regularly consumed a large amount of caffeinated beverages developed an episode of confusion and hallucinations after her second dose of ciprofloxacin. These symptoms resolved completely after about 6 hr. Such CNS reactions are certainly very rare but may be more prevalent in the elderly on a variety of medications or in patients taking caffeinated beverages, theophylline, or related methylxanthine compounds.
147
Quinolones can reduce the clearance of the methylxanthines theophylline and caffeine (Hino et al., 1988; Lode et al., 1988; Davis et al., 1989). This may result in toxic serum theophylline concentrations. Theophylline levels were monitored in all six of our patients w h o were receiving theophylline medications and ciprofloxacin without experiencing theophylline concentrations in the toxic range. In summary, ciprofloxacin is bactericidal, very effective against a broad spectrum of Gram-positive and Gram-negative bacteria, less expensive to use than parenteral agents, and acceptably free of adverse effects. In situations in which more resistant Gram-negative bacteria may be the etiologic organism, ciprofloxacin should be considered for therapy in bronchopulmonary infections. This clinical comparative study, as well as others, supports this position.
This work was supported, in part, by a grant from Miles Inc., Pharmaceutical Division, West Haven, Connecticut.
REFERENCES Appelbaum PC, Spangler SK, Sollenberger L (1986) Susceptibility of non-fermentative gram-negative bacteria to ciprofloxacin, norfloxacin, amifloxacin, pefloxacin and cefpirome. J Antimicrob Chemother 18:675-679. Arcieri G, Griffith E, Gruenwaldt G, Heya A, O'Brien B, Becker N, August R (1987) Ciprofloxacin: an update on clinical experience. Am J Med 82(suppl 4A): 381-386. Auckenthaler R, Michea-Hamzehpour M, Pechere JC (1986) In vitro activity of newer quinolones against aerobic bacteria. J Antimicrob Chemother 17(suppl B):29-39. Bauer AW, Kirby WMM, Sherris JC, Turck M (1966) Antibiotic susceptibility testing by a standardized disk method. Am J Clin Pathol 45:493-496. Bergogne-Berezin E (1983) Pharmacokinetics of antibiotics in respiratory secretions. In Respiratory Infections: Diagnosis and Management. Ed. T Pennington. New York: Raven, pp 461-479. Bergogne-Berezin E, Berthelot G, Even P, Stern M, Reynaud P (1986) Penetration of ciprofloxacin into bronchial secretions. Eur J Clin MicrobioI 5:197-200. Boerema J, Boll B, Muytjens H, Branolte J (1985) Efficacy and safety of ciprofloxacin (Bay 0 9867) in the treatment of patients with complicated urinary tract infections. J Antimicrob Chemother 16:211-217. Chin N-X, Neu HC (1984) Ciprofloxacin, a quinolone carboxylic acid compound active against aerobic and anaerobic bacteria. Antimicrob Agents Chemother 25:319326. Chodosh S (1987) Acute bacterial exacerbations in bronchitis and asthma. Am J Med 82(suppl 4A):154-163. Crump B, Wise R, Dent J (1983) Pharmacokinetics and tissue penetration of ciprofloxacin. Antimicrob Agents Chemother 24:784-786. Davies BI, Maesen FP, Baur C (1986a) Ciprofloxacin in the
treatment of acute exacerbations of chronic bronchitis. Eur J Clin Microbiol 5:226-231. Davies BI, Maesen FP, Teengs JP, Baur C (1986b) The quinolones in chronic bronchitis. Pharm Weekbl (Sci) 8:53-59. Davis RL, Kelly HW, Quenzer RW, Standefer J, Steinberg B, Gallegos J (1989) Effect of norfloxacin on theophylline metabolism. Antimicrob Agents Chemother 33:212214. Ernst JA, Sy ER, Colon-Lucca H, Sandhu H, Rallos T, Lorian V (1986) Ciprofloxacin in the treatment of pneumonia. Antimicrob Agents Chemother 29:1088-1089. Fass RJ (1987) Efficacy and safety of oral ciprofloxacin in the treatment of serious respiratory infections. Am J Med 82(suppl 4A):202-207. Furneri PM, Tempera G, Caccamo F, Speciale AM (1988) In vitro activity of ciprofloxacin against clinical isolates and standard strains of mycoplasmas and chlamydiae. Rev Infect Dis 10(suppl 1):55-56. Goldfarb J, Stern RC, Reed MD, Yamashita TS, Myers CM, Blumer JL (1987) Ciprofloxacin monotherapy for acute pulmonary exacerbations of cystic fibrosis. Am J Med 82(suppl 4A):174-179. Halkin H (1988) Adverse effects of the fluoroquinolones. Rev Infect Dis 10(suppl 1):258-261. Hino J, Kawane H, Soejima R (1988) Effects of new quinolones on serum concentrations of theophylline in healthy volunteers. Rev Infect Dis 10(suppl 1):140. Hodson ME, Roberts CM, Butland RJA, Smith MJ, Batten JC (1987) Oral ciprofloxacin compared with conventional intravenous treatment for Pseudomonas aeruginosa infection in adults with cystic fibrosis. Lancet 1:235-237. Hoogkamp-Korstanje JAA, Klein SJ (1986) Ciprofloxacin
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in acute exacerbations of chronic bronchitis. J Antimicrob Chemother 18:407-413. Kobayashi H (1987) Clinical efficacy of ciprofloxacin in the treatment of patients with respiratory tract infections in Japan. Am ] Med 82(suppl 4A):169-173. Lode H (1988) Drug interactions with quinolones. Rev Infect Dis 10(suppl 1):132-136. National Committee for Clinical Laboratory Standards (NCCLS) (1979; second supplement 1981). Standards for antimicrobial disk susceptibility tests: M2A2S2. Villanova, PA: NCCLS. National Committee for Clinical Laboratory Standards (NCCLS) (1983) Tentative standard: methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically-M7T. Villanova, PA: NCCLS. Parry MF (1988) Efficacy of oral ciprofloxacin for the treatment of infections due to Pseudomonas aeruginosa (Abstr). Rev Infect Dis 10(suppl 10):68-69. Ramirez CA, Bran JL, Mejia CR, Garcia JF (1985) Open, prospective study of the clinical efficacy of ciprofloxacin. Antimicrob Agents Chemother 28:128-132. Reeves DS, Bywater MJ, Holt HA, White LO (1984) Invitro studies with ciprofloxacin, a new 4-quinolone compound. J Antimicrob Chemother 13:333-346. Ruskin J, Sattler F (1988) In vitro activity of ciprofloxacin and new beta-lactam antibiotics against multiply resistant gram-negative bacilli from community hospitals (Abstr). Rev Infect Dis 10(suppl 1):36. Sanders CC, Sanders WE Jr, Goering RV (1987) Overview
R.W. Q u e n z e r et al.
of preclinical studies with ciprofloxacin. Am J Med 82($4A):2-11. Saravolatz L, Pohlod D, Havlichek D, Jimenez-Lucho V (1988) Effect of quinolones, erythromycin, and rifampin on the extra- and intracellular growth of Legionella pneumophila. Rev Infect Dis 10(suppl 1):53. Scully BE, Neu HC, Parry MF, Mandell W (1986) Oral ciprofloxacin therapy of infections due to Pseudomonas aeruginosa. Lancet 1:819-822. Shah PM (1988) Analysis of multicenter clinical study of ciprofloxacin (Abstr). Rev Infect Dis 10(suppl 1):127-128. Shen LL, Pernet AG (1985) Mechanism of inhibition of DNA gyrase by analogues of nalidixic acid: the target of the drugs is DNA. Proc Natl Acad Sci USA 82:307311. Wise R, Lister D, McNulty CAM, Griggs D, Andrews JM (1986) The comparative pharmacokinetics of five quinolones. J Antimicrob Chemother 18(suppl D):71-81. Wise R, Griggs D, Andrews JM (1988) Pharmacokinetics of the quinolones in volunteers: a proposed dosing schedule. Rev Infect Dis 10(suppl 1):83-89. Wollschlager CM, Raoof S, Khan F, Guarneri JJ, LaBombardi V, Afzal Q (1987) Controlled, comparative study of ciprofloxacin versus ampicillin in treatment of bacterial respiratory tract infections. Am J Med 82(suppl 4A):164-168. Zar JH (1984) BiostatisticaI Analysis, 2nd ed. Englewood Cliffs, NJ: Prentice-Hall.
143
Prospective Randomized Study Comparing the Efficacy and Safety of Ciprofloxacin with Cefaclor in the Treatment of Patients with Purulent Bronchitis Ronald W. Quenzer, Robin L. Davis, and Mary M. Neidhart
We compared safety and efficacy of ciprofloxacin and cefaclor in the treatment of patients with purulent bronchitis. Fiftyfive patients were randomized prospectively to receive ciprofloxacin with a dose of 500 mg orally twice daily or cefaclor 250 mg over 8 hr for 5 days or longer. Patient groups did not differ with respect to age, duration of illness, severity of infection, or number of other concomitant disease states. A significantly larger number of patients in the ciprofloxacin group had poor health status (39.3% vs 7.4% for the ciprofloxacin and
cefaclor groups, respectively, p = 0.02). The response to therapy did not differ between groups. Infection was completely resolved in 71.4% vs 66.7% and markedly improved in 7.1% and 11.1% for the ciprofloxacin and cefaclor groups, respectively. The response to therapy and adverse reaction rate did not differ between groups. Seven patients treated with ciprofloxacin and five patients treated with cefaclor developed adverse reactions. We conclude that ciprofloxacin is a useful agent for the treatment of purulent bronchitis.
INTRODUCTION
trum of activity against most aerobic Gram-negative bacilli and Gram-positive cocci supports many useful indications, including the treatment of certain lower respiratory tract infections. Antimicrobial agents must achieve adequate concentrations in lung tissue and respiratory secretions to have efficacy in treating pneumonia and purulent bacterial bronchitis, respectively (Bergogne-Berezin, 1983). Ciprofloxacin concentrates well in the lungs. A single oral dose of 500 mg produces levels of 0.50.8 ~g/ml in bronchial secretions (Bergogne-Berezin et al., 1986). Higher levels of ciprofloxacin would be anticipated after drug accumulation from multiple doses. The concentrations in the lung are well above the minimum inhibitory concentration (MIC) for most Gram-negative and many Gram-positive respiratory pathogens. Although Streptococcus pneumoniae may be only moderately susceptible to ciprofloxacin in vitro (MIC > 0.5-2.0 ~g/ml), nearly all of the other bacterial respiratory pathogens (e.g., Haemophilus influenzae, Klebsiella sp., Enterobacter sp., and Pseudomonas aeruginosa) are usually exquisitely sensitive to ciproflox-
The fluoroquinolones are the newest class of bactericidal agents with a unique mechanism of inhibiting the bacterial DNA gyrase and thus preventing DNA replication (Shea and Pernet, 1985). The fluoroquinolones are well absorbed and therefore can be administered orally. Because their half-lives are 4-5 hr, these agents have an advantage over many other antibiotics of less frequent administration (usually twice a day) and predictably better compliance (Crump et al., 1983; Wise et al., 1986 and 1988). Similar to beta-lactamase drugs, this class of agents has very few side effects (Arcieri et al., 1987). The broad specFrom the Department of Medicine and the College of Pharmacy, University of New MexicoMedical Center, University Hospital, Albuquerque, New Mexico. Address reprint requests to: Dr. R. W. Quenzer, General Medicine Division, Department of Medicine, University Hospital, 2211 Lomas NE, Albuquerque, NM 87131. ReceivedJanuary 10, 1990; revised and accepted January 12, 1990. © 1990Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York, NY 10010 0732-8893/90/$3.50
144
acin (Appelbaum et al., 1986; Auckenthaler et al., 1986). This agent may also have clinical efficacy against Mycoplasma pneumoniae (Furneri et al., 1988) and Legionella pneumophila (Saravolatz et al., 1988), but more in vitro and in vivo studies are needed. In this study we compared ciprofloxacin at a dose of 500 mg orally twice daily to 250 mg of cefaclor orally every 8 hr in the treatment of bacterial bronchitis caused by susceptible organisms.
R.W. Quenzer et al.
Clinical Evaluation
Patients over 18 years of age with mild to moderate respiratory tract infections were eligible for enrollment in the study. A medical history was obtained and a physical examination was performed on each subject to establish the diagnosis of infection prior to enrollment. Infection was documented by a sputum culture or Gram's stain positive for the presence of significant numbers of bacteria or by an increase in one of the following signs or symptoms: cough, sputum production, purulent sputum or the presence of chest congestion, fever, chills, or pleuritic chest pain. Patients with a history of allergy to carboxyquinolone antibiotics or cephalosporins, renal impairment (creatinine > 2.0 mg/dl or creatinine clearance < 50 ml/1.73 m2), pregnant women, nursing mothers, patients with infections requiring therapy or a concomitant antibiotic with a spectrum similar to the study drugs were excluded from the study.
The severity of infection, general health status, antibiotic efficacy, and toxicity were evaluated by the blinded physician investigator. Prior to therapy, all patients were interviewed, a physical examination was completed, and the following tests were performed: complete blood count, blood chemistries, urinalysis, and chest x-ray. Patients were seen and evaluated at least every 3 to 4 days during therapy. Sputum cultures were repeated if a productive cough persisted. Hematology, chemistry tests, and urinalysis were performed weekly during therapy. At the end of therapy, a physical examination and all laboratory tests were repeated. Drug effectiveness was determined by the blinded evaluator based on the clinical response of the patient and the bacterial response of the infecting organism. Clinical response was categorized as complete resolution (disappearance of all signs and symptoms of infection), marked improvement (marked or moderate reduction in the severity and/or number of the signs and symptoms of infection), slight improvement (slight reduction in the severity and/or number of the signs and symptoms of infection), and failure (insufficient lessening of the signs and symptoms of infection to qualify as improvement). Bacteriological response was categorized as eradication, marked reduction (reduction to a clinically insignificant number of organisms), eradication with recurrence (eradication of organisms at the end of therapy with reappearance at follow-up), eradication with reinfection by n e w organism(s), and persistence.
Drug Therapy
Statistical Analysis
After giving written informed consent, patients were randomly assigned to receive 500 mg ciprofloxacin every 12 hr or 250 mg cefaclor every 8 hr. The morning dose of ciprofloxacin was taken before breakfast, and the evening dose was taken at least 2 hr before eating. Therapy was continued for 5 days or longer if deemed necessary by the evaluating physician.
Categorical data were evaluated using chi-square analysis with Yates' correction. The duration of symptoms prior to treatment, duration of therapy, and number of concomitant medications were considered nonparametric variables and were analyzed with the Mann-Whitney test. All comparisons were made with two-tailed tests, at a significance level of 0.05 (Zar, 1984).
Microbiological Evaluation
RESULTS
A sputum sample was collected after deep coughing for Gram's stain and culture within 48 hr prior to antibiotic therapy and every 3-4 days during therapy or as often as indicated based on the clinical course of the patient's respiratory infection. Antibiotic susceptibility was tested by the standard antibiotic disk technique according to the modified Kirby-Bauer procedure (Bauer et al., 1966; NCCLS, 1979 and 1983).
A total of 59 patients, 16 men and 43 women, completed the study. Fifty-five patients were evaluated for clinical and microbiologic responses (Table 1). Patients ranged in age from 19 to 87 years. Fifty-six of the patients had community-acquired infections. The mean duration of illness prior to initiating antibiotic treatment was 15.7 and 13.6 days in the ciprofloxacin and cefaclor groups, respectively. Previous antibiotic treatment for the current episode of
METHODS Patients
Ciprofloxacin in P u r u l e n t Bronchitis
TABLE 1.
145
Patient D e m o g r a p h i c s (mean ___ SD)
Characteristics Patients evaluated Age (years) Sex Male Female Duration of illness Hospital acquired Community acquired Previous antibiotic Clinical status (%) Poor health Other diseases Infection Mild Moderate Severe Sputum culture results (%) Pathogens(s) isolated Microorganism S. pneumoniae Staphylococcus aureus H. influenzae H. parainfluenzae B. catarrhalis P. aeruginosa P. stutzeri Enterobacter aerogenes
Ciprofloxacin Group
Cefaclor Group
28 48.4 -+ 20.0
27 42.4 _+ 16.6
5 23 15.7 _+ 34.3 2 26 9
11 16 13.6 -+ 18.2 1 26 6
11 (39.3) 20 (71.4)
2 (7.4) 16 (59.3)
0.02 NS
3 (10.7) 20 (71.4) 5 (17.9)
4 (14.8) 20 (74.1) 3 (11.1)
NS NS NS
9 (32.1)
10 (37.0)
2 (7.1) 1 (3.6) 1 (3.6) 3 (10.7) 1 (3.6) 2 (7.1) 0 (0) 1 (3.6)
4 (14.8) 1 (3.7) 2 (7.4) 2 (7.4) 3 (11.1) 0 (0) 1 (3.7) 0 (0)
bronchitis h a d failed in nine (32.1%) of the patients treated with ciprofloxacin a n d six (22.2%) treated with cefaclor, but n o n e of these patients had received an antibiotic within 5 days of initiating the study drug. There was no significant difference in the clinical status data (Table 1), with the exception that the general health status was w o r s e (fair or poor) in 11 (39.3%) of the ciprofloxacin-treated group, w h e r e a s only 2 (7.4%) of the cefaclor-treated patients (p = 0.02) had p o o r general health. Seven (25.0%) patients in the ciprofloxacin g r o u p required o x y g e n s u p p l e m e n t a t i o n c o m p a r e d to one (3.7%) in the cefaclor grouts. The bac; eria isolated from the initial s p u t u m are listed in Table 1. Respiratory p a t h o g e n s were identified in - 3 5 % of the patients in each g r o u p , w h e r e a s bacteria representing usual oropharyngeal flora were the only isolates from - 6 5 % of patients in each group. Eight percent of the ciprofloxacin-treated patients and 77% of the cefaclor-treated patients had bacterial bronchitis associated with G r a m - n e g a t i v e pathogens. Streptococcus pneumoniae was isolated from the sputum of two ciprofloxacin- and four cefaclor-treated patients, and there w e r e no failures in either group.
TABLE 2.
p
Bacterial a n d Clinical O u t c o m e s (%)
Evaluation
Ciprofloxacin
Cefaclor
p
Treatment days (mean) Clinical results Resolution Improved + + + Improved + Failure Bacteriologic results Eradication Persistence Indeterminate a
13.0 -+ 4.0
12.7 _+ 3.8
NS
(71.4) (7.1) (14.2) (7.1)
18 (66.7) 3 (11.1) 6 (22.2) 0 (0)
NS NS NS NS
7 (25.0) 1 (3.6) 20 (71.4)
8 (29.6) 0 (0) 19 (70.4)
NS NS NS
20 2 4 2
aProductive cough resolved with therapy. Bacterial a n d clinical o u t c o m e s are listed in Table 2. The m e a n duration of t h e r a p y a n d p e r c e n t of patients that h a d complete or m a r k e d i m p r o v e m e n t were not different b e t w e e n t r e a t m e n t groups. The m e a n n u m b e r of t r e a t m e n t days was - 13 in each group. Of the ciprofloxacin-treated patients, 22 (78.5%) s h o w e d complete or m a r k e d clinical imp r o v e m e n t c o m p a r e d to 21 (77.8%) of the cefaclor-
146
R.W. Quenzer et al.
TABLE 3.
Adverse Drug Effects
Reactions Diarrhea Lightheadedness Vertigo Nausea Vomiting Back pain Rash Hallucinations Abdominal pain
Ciprofloxacin (%) 2 1 1 1 0 1 1 1 1
(7.1) (3.6) (3.6) (3.6) (0) (3.6) (3.6) (3.6) (3.6)
Cefaclor (%) I 1 0 2 1 0 0 0 0
(3.7) (3.7) (0) (7.4)
(3.7) (0) (0) (0) (0)
treated patients. Two patients randomized to the ciprofloxacin group failed therapy. The respiratory pathogen(s) was eradicated in all but one patient, who had persistence of a susceptible P. aeruginosa in her sputum culture despite an improved clinical response while on ciprofloxacin. All 59 patients were evaluated for adverse drug reactions (Table 3). Seven (25.0%) patients treated with ciprofloxacin and five (18.5%) patients treated with cefaclor developed side effects (p = NS). Ciprofloxacin had to be discontinued in two patients due to adverse reactions. One patient developed a generalized urticarial exanthem after 6 days of therapy, and the second patient required evaluation for an acute confusionaI and hallucinatory episode lasting 6 hr after taking two doses of ciprofloxacin. She gave a history of consuming a quart of iced tea and 2-3 caffeinated soft drinks but no coffee each day. She recovered without sequalae after the incident.
COMMENTS The results of this prospective, controlled, blinded, parallel study suggest that ciprofloxacin is as effective as a second-generation cephalosporin (cefaclor) in treating purulent bronchitis. Cure or partial cure was achieved in nearly 80% of patients treated with either drug, which is comparable to other published studies with ciprofloxacin, penicillins, and cephalosporins (Ramirez et al., 1985; Davies et al., 1986a; Ernst et al., 1986; Hoogkamp-Korstanje et al., 1986; Fass, 1987; Kobayashi, 1987; Wollschlager et al., 1987; Shah, 1988). Because an acute exacerbation of chronic bronchitis is a clinical diagnosis difficult to confirm bacteriologically in m a n y patients, one should be cautious not to overemphasize the microbiologic data from the sputum samples as indicators of response to therapy. The serum elimination half-life of 3.9 hr for ciprofloxacin ( C r u m p e t al., 1983; Wise et al., 1986 and 1988) permits a dosing schedule of every 12 hr, which is commensurate with good patient compliance. Cip-
rofloxacin concentrates well in respiratory secretions. After a 500-rag oral dose, the mean peak bronchial concentration is 0.5-9.8 ~g/ml (Bergogne-Berezin et al., 1986) whereas a 1000-rag dose produces mean peak concentrations to 2.3 ~,g/ml (Davies et al., 1986b). These are concentrations appreciably above the MIC for most respiratory pathogens. Candidates for an oral antibiotic regimen should present with an increase in cough and sputum production, purulent changes in the expectorated respiratory secretions, chest congestion and dyspnea, pleuritic chest pains, fever or chilis, and a chest roentgenogram showing no acute changes or infiltrates. Some individuals with pneumonia may also be treated adequately with oral antibiotics. Bacteria most often associated with acute and chronic purulent bronchitis are S. pneumoniae, H. influenzae, H. parainfluenzae, Branhamella catarrhalis, and several enteric Gram-negative bacilli (e.g., Escherichia coli, Klebsiella pneumoniae ) (Chodosh, 1987). Although purulent bronchitis is generally a community-acquired infection, resistant Gram-negative bacilli are frequently isolated from these patients (Ruskin and Sattler, 1988). These organisms are consistently more susceptible to ciprofloxacin than to beta-lactam drugs such as cephradine or cefaclor. Although most strains of P. aeruginosa are susceptible to ciprofloxacin (MIC 0.06-1.0 ~g/ml) (Appelbaum et al., 1986; Auckenthaler et al., 1986), the MICs predictably increase during treatment in patients with serious Pseudomonas infections, and this decrease in ciprofloxacin susceptibility has been correlated with clinical and/or bacteriologic failure in P. aeruginosa bronchopulmonary infections and in cystic fibrosis patients (Goldfarb et al., 1987; Hodson et al., 1987; Parry, 1988). Not all investigators have reported these unfavorable results. Scully et al. found that even though P. aeruginosa persist in the sputum of patients with cystic fibrosis, clinical improvement may be noted in up to 80% (1986). Because Gram's stains are not frequently interpretable and cultures are not frequently obtainable or reliable, the initial therapy is usually begun with empirical broad-spectrum antibiotics such as amoxicillin, first- or second-generation oral cephalospotins (e. g., cephalexin, cefaclor, cefuroxime axetil), or trimethoprirn/sulfamethoxazole. Ciprofloxacin should be considered in patients allergic to one of these antibiotics or in individuals who fail to respond to initial therapy and in patients who present with nursing home or hospital-acquired bronchopulmonary infections. The major predisposing factors for Gram-negative bacillary purulent bronchitis are (1) recent antibiotic exposure, (2) moderate-to-severe general disability, (3) residence in a nursing home, (4) hospitalization, and (5) chronic lung disease. Ciprofloxacin is highly active against a broad spectrum
Ciprofloxacin in Purulent Bronchitis
of aerobic respiratory pathogens with MICs generally < 0.5 ~g/ml for Haemophilus sp., Branhamella catarrhalis, and most Enterobacteriaceae (Chin and Neu, 1984; Reeves et al., 1984; Sanders et al., 1987). Ciprofloxacin has an incidence of adverse effects comparable to that of the cephalosporins. The adverse reaction rate for ciprofloxacin and other quinolones is assessed to be 4.0-8.0% (Halkin, 1988). The higher rates in our subjects of 25% and 18% for ciprofloxacin and cefaclor, respectively, may reflect closer surveillance and a truer rate of mild, tolerable side effects. Quinolones have been reported to cause adverse central nervous system (CNS) manifestations (Boerema et al., 1985; Fass, 1987). One of our patients w h o regularly consumed a large amount of caffeinated beverages developed an episode of confusion and hallucinations after her second dose of ciprofloxacin. These symptoms resolved completely after about 6 hr. Such CNS reactions are certainly very rare but may be more prevalent in the elderly on a variety of medications or in patients taking caffeinated beverages, theophylline, or related methylxanthine compounds.
147
Quinolones can reduce the clearance of the methylxanthines theophylline and caffeine (Hino et al., 1988; Lode et al., 1988; Davis et al., 1989). This may result in toxic serum theophylline concentrations. Theophylline levels were monitored in all six of our patients w h o were receiving theophylline medications and ciprofloxacin without experiencing theophylline concentrations in the toxic range. In summary, ciprofloxacin is bactericidal, very effective against a broad spectrum of Gram-positive and Gram-negative bacteria, less expensive to use than parenteral agents, and acceptably free of adverse effects. In situations in which more resistant Gram-negative bacteria may be the etiologic organism, ciprofloxacin should be considered for therapy in bronchopulmonary infections. This clinical comparative study, as well as others, supports this position.
This work was supported, in part, by a grant from Miles Inc., Pharmaceutical Division, West Haven, Connecticut.
REFERENCES Appelbaum PC, Spangler SK, Sollenberger L (1986) Susceptibility of non-fermentative gram-negative bacteria to ciprofloxacin, norfloxacin, amifloxacin, pefloxacin and cefpirome. J Antimicrob Chemother 18:675-679. Arcieri G, Griffith E, Gruenwaldt G, Heya A, O'Brien B, Becker N, August R (1987) Ciprofloxacin: an update on clinical experience. Am J Med 82(suppl 4A): 381-386. Auckenthaler R, Michea-Hamzehpour M, Pechere JC (1986) In vitro activity of newer quinolones against aerobic bacteria. J Antimicrob Chemother 17(suppl B):29-39. Bauer AW, Kirby WMM, Sherris JC, Turck M (1966) Antibiotic susceptibility testing by a standardized disk method. Am J Clin Pathol 45:493-496. Bergogne-Berezin E (1983) Pharmacokinetics of antibiotics in respiratory secretions. In Respiratory Infections: Diagnosis and Management. Ed. T Pennington. New York: Raven, pp 461-479. Bergogne-Berezin E, Berthelot G, Even P, Stern M, Reynaud P (1986) Penetration of ciprofloxacin into bronchial secretions. Eur J Clin MicrobioI 5:197-200. Boerema J, Boll B, Muytjens H, Branolte J (1985) Efficacy and safety of ciprofloxacin (Bay 0 9867) in the treatment of patients with complicated urinary tract infections. J Antimicrob Chemother 16:211-217. Chin N-X, Neu HC (1984) Ciprofloxacin, a quinolone carboxylic acid compound active against aerobic and anaerobic bacteria. Antimicrob Agents Chemother 25:319326. Chodosh S (1987) Acute bacterial exacerbations in bronchitis and asthma. Am J Med 82(suppl 4A):154-163. Crump B, Wise R, Dent J (1983) Pharmacokinetics and tissue penetration of ciprofloxacin. Antimicrob Agents Chemother 24:784-786. Davies BI, Maesen FP, Baur C (1986a) Ciprofloxacin in the
treatment of acute exacerbations of chronic bronchitis. Eur J Clin Microbiol 5:226-231. Davies BI, Maesen FP, Teengs JP, Baur C (1986b) The quinolones in chronic bronchitis. Pharm Weekbl (Sci) 8:53-59. Davis RL, Kelly HW, Quenzer RW, Standefer J, Steinberg B, Gallegos J (1989) Effect of norfloxacin on theophylline metabolism. Antimicrob Agents Chemother 33:212214. Ernst JA, Sy ER, Colon-Lucca H, Sandhu H, Rallos T, Lorian V (1986) Ciprofloxacin in the treatment of pneumonia. Antimicrob Agents Chemother 29:1088-1089. Fass RJ (1987) Efficacy and safety of oral ciprofloxacin in the treatment of serious respiratory infections. Am J Med 82(suppl 4A):202-207. Furneri PM, Tempera G, Caccamo F, Speciale AM (1988) In vitro activity of ciprofloxacin against clinical isolates and standard strains of mycoplasmas and chlamydiae. Rev Infect Dis 10(suppl 1):55-56. Goldfarb J, Stern RC, Reed MD, Yamashita TS, Myers CM, Blumer JL (1987) Ciprofloxacin monotherapy for acute pulmonary exacerbations of cystic fibrosis. Am J Med 82(suppl 4A):174-179. Halkin H (1988) Adverse effects of the fluoroquinolones. Rev Infect Dis 10(suppl 1):258-261. Hino J, Kawane H, Soejima R (1988) Effects of new quinolones on serum concentrations of theophylline in healthy volunteers. Rev Infect Dis 10(suppl 1):140. Hodson ME, Roberts CM, Butland RJA, Smith MJ, Batten JC (1987) Oral ciprofloxacin compared with conventional intravenous treatment for Pseudomonas aeruginosa infection in adults with cystic fibrosis. Lancet 1:235-237. Hoogkamp-Korstanje JAA, Klein SJ (1986) Ciprofloxacin
148
in acute exacerbations of chronic bronchitis. J Antimicrob Chemother 18:407-413. Kobayashi H (1987) Clinical efficacy of ciprofloxacin in the treatment of patients with respiratory tract infections in Japan. Am ] Med 82(suppl 4A):169-173. Lode H (1988) Drug interactions with quinolones. Rev Infect Dis 10(suppl 1):132-136. National Committee for Clinical Laboratory Standards (NCCLS) (1979; second supplement 1981). Standards for antimicrobial disk susceptibility tests: M2A2S2. Villanova, PA: NCCLS. National Committee for Clinical Laboratory Standards (NCCLS) (1983) Tentative standard: methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically-M7T. Villanova, PA: NCCLS. Parry MF (1988) Efficacy of oral ciprofloxacin for the treatment of infections due to Pseudomonas aeruginosa (Abstr). Rev Infect Dis 10(suppl 10):68-69. Ramirez CA, Bran JL, Mejia CR, Garcia JF (1985) Open, prospective study of the clinical efficacy of ciprofloxacin. Antimicrob Agents Chemother 28:128-132. Reeves DS, Bywater MJ, Holt HA, White LO (1984) Invitro studies with ciprofloxacin, a new 4-quinolone compound. J Antimicrob Chemother 13:333-346. Ruskin J, Sattler F (1988) In vitro activity of ciprofloxacin and new beta-lactam antibiotics against multiply resistant gram-negative bacilli from community hospitals (Abstr). Rev Infect Dis 10(suppl 1):36. Sanders CC, Sanders WE Jr, Goering RV (1987) Overview
R.W. Q u e n z e r et al.
of preclinical studies with ciprofloxacin. Am J Med 82($4A):2-11. Saravolatz L, Pohlod D, Havlichek D, Jimenez-Lucho V (1988) Effect of quinolones, erythromycin, and rifampin on the extra- and intracellular growth of Legionella pneumophila. Rev Infect Dis 10(suppl 1):53. Scully BE, Neu HC, Parry MF, Mandell W (1986) Oral ciprofloxacin therapy of infections due to Pseudomonas aeruginosa. Lancet 1:819-822. Shah PM (1988) Analysis of multicenter clinical study of ciprofloxacin (Abstr). Rev Infect Dis 10(suppl 1):127-128. Shen LL, Pernet AG (1985) Mechanism of inhibition of DNA gyrase by analogues of nalidixic acid: the target of the drugs is DNA. Proc Natl Acad Sci USA 82:307311. Wise R, Lister D, McNulty CAM, Griggs D, Andrews JM (1986) The comparative pharmacokinetics of five quinolones. J Antimicrob Chemother 18(suppl D):71-81. Wise R, Griggs D, Andrews JM (1988) Pharmacokinetics of the quinolones in volunteers: a proposed dosing schedule. Rev Infect Dis 10(suppl 1):83-89. Wollschlager CM, Raoof S, Khan F, Guarneri JJ, LaBombardi V, Afzal Q (1987) Controlled, comparative study of ciprofloxacin versus ampicillin in treatment of bacterial respiratory tract infections. Am J Med 82(suppl 4A):164-168. Zar JH (1984) BiostatisticaI Analysis, 2nd ed. Englewood Cliffs, NJ: Prentice-Hall.
