Journal of Antimicrobial Chemotherapy (1990) 26, Suppl. B, 103-110

Pefloxacin in lower respiratory tract infections C. GrassP, E. Catena6, G. de Iola', F. Ginesu', M. Gori', M. Lucchini', P. Mangfarotti', E. Micfflo*, M. Onoscurf' and O. Orlandl'

To determine the efficacy and safety of pefloxacin in the treatment of lower respiratory tract infections, a multicentre trial involving four departments of respiratory diseases was performed. One hundred and eight patients were admitted to the study: most of them were affected with exacerbations of chronic bronchitis or with pneumonia complicating lung cancer. Isolation and identification of responsible microorganisms from bronchial secretions was possible in 78 patients. Seven patients were withdrawn, one for worsening of the underlying disease and six for early side-effects. Thus, of 108 patients recruited, 101 completed the course of therapy (pefloxacin 400 mg bd for 5—14 days) and could be submitted to final evaluation. Of these 43 (42-6%) were cured and 48 (47-5%) showed improvement. Eradication of responsible microorganisms was achieved in 70 (90-9%) of 77 patients microbiologically evaluated. Side-effects of moderate severity were observed in 12 patients (gastrointestinal disturbances in 11 and dyspnoea in one); these did not necessitate discontinuation of therapy.

Introduction An increasing number of lower respiratory tract infections, including exacerbations of chronic bronchitis, particularly if they occur in a hospital setting, are caused by multiresistant bacteria. New fluoroquinolones are a valid alternative to /J-lactam antibiotics in the treatment of this kind of disease (Montay et al., 1984; Maesen et al., 1987; Martin et al., 1988). Among new fluoroquinolones, pefloxacin shows a very interesting profile: broad spectrum of activity, including Enterobacteriaceae, staphylococci (including methicillin-resistant strains), Pseudomonas aeruginosa, Haemophilus influenzae, Branhamella catarrhalis (King & Phillips, 1986; Verbist, 1986; Yourassowsky et al., 1986; Gonzales & Kenwood, 1989; Periti & Novelli, 1989); almost complete gastrointestinal absorption with bioequivalence between oral and iv administration (Fourtillan, 1986; Frydman et al., 1986; Periti & Novelli, 1989); and good distribution in tissues and body fluids, including the lower respiratory tract. After oral administration, 800 mg pefloxacin achieves in bronchial secretions concentrations of 7-6-25 mg/1, slightly higher than 103 0305-7453/90/26B103 + 08 $02.00/0

© 1990 The British Society for Antimicrobial Chemotherapy

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"Istituto di Tisiologia e Malattie dett'Apparato Respiratorio, Universita di Pavia; Istituto di Tisiologia e Malattie dell'Apparato Respiratorio, 7° Facolta di Medicina e Chirurgia, Universita di Napoli; 'Istituto di Tisiologia e Malattie dell'Apparato Respiratorio, Universita di Sassari; 'Divisione Pneumologica, Ospedale Orbassano, Torino; 'Direzione Medica, Rhdne-Poulenc Pharma Italia SpA, Italy



C. Grass* et al.

plasma levels and much higher than the MIC*, of susceptible bacteria (Montay, Gueffon & Rouquet, 1984; Morel et al., 1984; Fourtillan, 1986; Periti & NoveUi, 1989). A multicentre trial was performed in Italy to evaluate the efficacy and the safety of pefloxacin in the treatment of lower respiratory tract infections requiring hospitalization. Methods

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Four departments of respiratory disease participated in the trial: Istituto di Tisiologia e Malattie dell'Apparato Respiratorio, Universita di Pavia; Istituto di Tisiologia e Malattie dell'Apparato Respiratorio, 1° Facolta di Medicina e Chirurgia, Universita di Napoli; Istituto di Tisiologia e Malattie dell'Apparato Respiratorio, Universita di Sassari; III Divisione Pneumologica, Ospedale Orbassano, Torino. Male or female inpatients, at least 18 years of age, were recruited if the following criteria were fulfilled. The patients had an acute bacterial respiratory infection (pneumonia, infectious exacerbation of chronic bronchitis, etc.) demonstrated by one or more of the following symptoms: increase in sputum production; temperature of 38°C or greater, increase in purulence of sputum as suggested by change in colour or consistency. The initial diagnosis of acute respiratory infection was confirmed by appropriate Gram-stain findings in sputum or bronchial aspirate and/or isolation in culture of one or more respiratory pathogens. Sputum specimens were considered adequate for culture when < 10 squamous epithelial cells and > 25 polymorphonuclear leucocytes per high power field were present. Patients who started the therapy before bacteriological results were obtained, or in whom inadequate bacteriological examination precluded confirmation of the diagnosis, continued the treatment if the clinical condition showed some improvement within the first three days of therapy. The following conditions excluded patients from the study: hypersensitivity to quinolones; severe renal impairment (serum creatinine > 1-5 mg/lOOml); severe liver impairment; severe haematological disorders; pregnancy or lactation; infection by pefloxacin-resistant pathogens; significant immunocompromise or underlying disease that might preclude evaluation of the therapeutic response; administration of other antibiotics within 48 h before pefloxacin administration or sputum examination. Pefloxacin (Pefiacin, Rhone-Poulenc Pharma Italia SpA) was administered at a dosage of 400 mg every 12 h, orally or intravenously. Treatment was begun immediately, before sensitivity results on isolated strains were known; in fact, all significant isolates proved to be sensitive. Clinical outcomes were defined as follows: cure, disappearance of all baseline signs and symptoms relevant to the acute episode; improvement, remission but not complete disappearance of baseline signs and symptoms; failure, no remission of baseline signs and symptoms. Microbiological examination of bronchial secretions was performed before and at the end of the treatment. Susceptibility of pathogens to pefloxacin was evaluated by a disc-diffusion method (Bauer et al., 1969); the disc content was 5/ig. Bacteriological outcomes were defined as follows: eradication, initial pathogen eradicated at 2-4 days post-therapy, with no other pathogen isolated; reinfection, initial pathogen eradicated but a different pathogen isolated 2-4 days post-therapy; failure, initial pathogen not eradicated.

Lower respiratory tract infections


Standard laboratory tests, including blood count and plasma levels of glucose, urea, creatinine, transaminases and alkaline phosphatase were performed before and after the treatment to evaluate the biological safety of pefloxacin. Results

Table L Characteristics of patients and diagnosis Patients enrolled: 108 Withdrawn: 7 Patients evaluated for efficacy. 101 Age (years): range 17-85 median 66 mean 63-8 ± 13-5 Sex: 83M18F Diagnosis: exacerbations of chronic bronchitis acute bronchitis bronchopneumonia or pneumonia pneumonia and pleurisy

83 3 14 1

Tabk II. Underlying diseases in patients treated with pefloxacin COPD* COPD and bronchiectasis COPD and diabetes COPD and cardiac failure COPD and lung neoplasm COPD, bronchiectasis and diabetes COPD and leukaemia Pulmonary fibrosis Lung neoplasm Diabetes Silicosis None •Chronic obstructive pulmonary disease.

57 13 6 3 3 2 1 4 3 1 1 7

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One hundred and eight patients, aged more than 18 years, affected by acute infection of the lower respiratory tract or relapse of chronic bronchitis were enrolled. Seven patients (6-5%) were withdrawn, one for worsening of the underlying disease and six for early side-effects (four gastrointestinal disturbances, one urticaria, one CNS disturbance). Therefore 101 patients, 83 men and 18 women, aged 17-85 years (median 66), completed therapy and could be analysed for efficacy. Eighty-six patients were affected by bronchitis (three acute bronchitis and 83 exacerbation of chronic bronchitis) and 15 by bronchopneumonia, lobar pneumonia or pneumonia with pleurisy (Table I). Only seven patients (6-9%) had no underlying disease (Table II). Most patients


C. Grand et aL Table HL Microbiological data. Causative organisms isolated from bronchial secretions before therapy 26 2 1 10 9 3 2 2

Gram-positive Staph. aureus Streptococcus spp.

IS 1

Mixed flora Staph. aureus + Streptococcus spp. Ps. aeruginosa+ Achromobacter spp. Ps. aeruginosa+ K. pneumoniae Acin. calcoaceticus+K. pneumoniae Ps. aeruginosa-^ Staph. aureus Esch. coli + Staph. aureus

1 1 1 1 2 1

Total number of Gram-negative strains Total number of Gram-positive strains

64 21



suffered from chronic obstructive pulmonary disease. Consequently, concomitant symptomatic therapy was given to 95 patients (94%). Results for microbiological examination of bronchial secretions were evaluable in 77 patients. The initial examination was performed on sputum in 61 cases and on bronchial aspirate in 16 cases. The bacteria isolated from sputum or bronchial aspirate before treatment are reported in Table HI. Gram-negative bacteria, most frequently

Table IV. Dosage regimen of pefloxacin No. of patients Daily dosage (mg)


Route of administration oral iv iv-oral Duration of treatment (days)

Overall range Mean ± S.D (days)

101 (100%) 73 (72-3%) 24 (23-7%) 4 (40%)

5-7 8-10 11-14 5-14 9-1 ±1-9

25 (24-8%) 50 (49-5%) 26 (25-7%)

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Gram-negative Ps. aeruginosa Acinetobacter calcoaceticus H. influenzae Escherichia coli K. pneumoniae Serratia marcescens Enterobacter aerogenes Proteus mirabilis

Lower respiratory tract infections


Table V. Clinical efficacy of pefloxacin No. of patients Clinical outcome cure improvement no clinical modification, or worsening

43 (42-6%) 48 (47-5%) 10 (9-9%) 91/101 (90-1%)

Overall positive outcomes Mycotic colonization

70/77 (90-9%) 2

70 (90-9%) 7(9-1%) 1

Pseudomonas aeruginosa, were isolated in about 50% of cases, while Gram-positive bacteria, most frequently Staph. aureus, were obtained from 23%. All significant isolates were sensitive to pefloxacin. Twenty-three patients, in whom bacteriological evaluation was not possible before treatment, were judged by clinical criteria only. Seventy-three patients (72-3%) received pefloxacin orally, 24 (23-7%) by iv injection and four were treated at first by the iv and later by the oral route (Table IV). Positive clinical outcomes were obtained in 91 patients (901%); 43 achieved cure and 48 improvement, while the clinical condition was unmodified or worsened in ten patients (9-9%) (Table V). In seventy (90-9%) of the 77 patients microbiologically evaluated, no micro-organism was isolated from sputum cultures after treatment. One patient not submitted to final bacteriological assessment was not evaluated. Seventy-six (89-4%) of the 85 strains isolated before the treatment were eradicated (Table VI); five Ps. aeruginosa, one Klebsiella pneumoniae and three Staph. aureus were still present in the bronchial secretions after treatment (Table VI). Six of the seven

Table VI. Microbiological response Micro-organism Ps. aeruginosa Esch. coli K. pneumoniae Other Enterobacteriaceae H. influenzae Acin. calcoaceticus Staph. aureus Streptococcus spp. Achromobacter spp. Total

No. of isolates

No. of eradications

30 11 11

25 11 10

7 1 3 19 2 1 85

7 1 3 16 2 1 76


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Overall positive outcomes Microbiological outcome eradication no eradication not evaluable

C. Grass! et al.


Table VII. Adverse effects probably or possibly related to pefloxacin treatment Total patients treated: 108 Side effects

No. withdrawn

15(13-9%) 1

4 1

1 1 18 (16-7%)

1 0 6 (5-6%)

multimicrobial infections were completely eradicated by pefloxacin. Candida was isolated from sputum in two patients at the end of treatment; since there were no clinical signs of infection this growth was considered as colonization. Eighteen (16-7%) of the 108 enrolled patients showed side effects, but in only ten patients were they probably attributable to pefloxacin (Table VII). Six patients were withdrawn because of adverse reactions at the very beginning of therapy (Table VIII), as mentioned above, while only one was withdrawn for worsening of the underlying disease. One patient showed mild transient dyspnoea, but did not need the interruption of the therapy. All patients with side effects were concomitantly treated with other nonantibiotic drugs (Table IX).

Table Vm. Side effects and combined therapy Side effect

Patient's age

Gastric distress Gastric distress Gastric distress Gastric distress Gastric distress Gastric distress Gastric distress Gastric distress Gastric distress Nausea Nausea Nausea Gastric distress-vomiting Gastric distress-vomiting Abdominal pain

55 50 62 47 67 77 79 84 70 70 64 49 66 25 70

Urticaria Dizziness, headache and confusional state Dyspnoea

60 81 58

Concomitant non antibiotic treatment bromexine aminophylline, bromexine aminophylline, bromexine aminophylline, acetylcysteine theopbylline, acetylcysteine theophylline, bromexine, famotidine theophylline, bromexine theophylline, bromexine theophylline, bromexine aminophylline aminophylline, salbutamol, betamethasone aminophylline, salbutamol, ipratropium aminophylline, ambroxol, diuretics bromexine aminophylline, methylprednisolone, furosemide aminophylline, clonidine, nifedipine aminophylline, methyldigoxin, furosemide aminophylline, methylprednisolone

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Gastro-intestinal disturbances Urticaria Dizziness, headache and confusional state Dyspnoea Total

No. of patients

Lower respiratory tract Infections



References Bauer, A. W., Kirby, W. M. M., Sherris, J. C. & Turck, M. (1969). Antibiotics susceptibility testing by a standardized single disc method. American Journal of Clinical Pathology 45, 493-6. Fourtillan, J. B. (1986). Comportement pharmacocinetique de la pefloxacine chez 1'homme. Revue MeaHcale Interne 7, 185-95. Frydman, A. M., Le Roux, Y., Lcfebvre, M. A., Djebbar, F., Fourtillan, J. B. & Gaillot, J. (1986). Pharmacokinetics of pefloxacin after repeated intravenous and oral administration (400 mg b.i.d.) in young healthy volunteers. Journal of Antimicrobial Chemotherapy 17, Suppl. B, 65-79. Gonzales, J. P. & Kenwood, J. M. (1989). Pefloxacin. A review of its antibacterial activity, pharmacokinetic properties and therapeutic use. Drugs 37, 628-68. Hooper, D. C. & Wolfson, J. S. (1989). Adverse effects of quinolone antimicrobial agents. In Quinolone Antimicrobial Agents (Wolfson, J. S. & Hooper, D. C , Eds), pp. 249-72. American Society of Microbiology, Washington, DC. King, A. & Phillips, I. (1986). The comparative in-vitro activity of pefloxacin. Journal of Antimicrobial Chemotherapy 17, Suppl. B, 1-10.

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The results of this trial allow us to conclude that pefloxarin was effective in the treatment of bacterial infections of the lower respiratory tract. Over 90% of patients showed cure or improvement of the acute infective episode. The good clinical outcomes were confirmed by micro-biological assessment; the pathogens were eradicated in 90% of cases, above all when Gram-negative organisms were responsible for the infection. It should be noted that 25 (83-8%) of 30 isolated Ps. aeruginosa strains were eradicated, usually by oral treatment only. Side effects in patients who completed the treatment were mainly mild gastrointestinal disturbances, which resolved spontaneously during therapy or soon after. All patients showing side effects were treated with one or more non-antibiotic drugs, many of which could produce the same effects. It has to be pointed out that 56% of the patients were aged over 65 years, and elderly subjects are known to show generally a decreased tolerance to drugs. Pefloxacin safety was confirmed by the lack of pathological modifications of laboratory values. It should be noted that in this study many patients were treated with theophylline or aminophylline as bronchodilator therapy, mainly when underlying chronic obstructive bronchopulmonary disease was present. It is known that fluoroquinolones may impair hepatic theophylline metabolism (Hooper & Wolfson, 1989) and therefore an increased blood level of theophylline may cause some side effects, i.e. nausea, vomiting, and CNS disturbances. In this trial only five of 76 patients to which theophylline or aminophylline was administered showed mild and transient nausea, vomiting or headache and dizziness. None of these patients was withdrawn from the investigation. These results seem to confirm that the effect of fluoroquinolones, except enoxacin, on theophylline metabolism is of uncertain clinical importance (Smith, 1987); nevertheless it could be useful to monitor theophylline plasma levels in patients taking fluoroquinolones concurrently with theophylline in order to prevent possible side effects. Thus, pefloxacin seems to be effective and safe in the treatment of lower respiratory tract infections caused by Gram-negative bacteria. Moreover, results showed that pefloxacin is also effective in infections caused by Gram-positive bacteria, including Staph. aureus and sometimes Streptococcus pyogenes.


C Grassi et al

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Maescn, F. P. V., Davics, B. I., Geraedts, W. H. & Baur, C. (1987). The use of quinolones in respiratory tract infections. Drugs 34, Suppl. 1, 74-9. Martin, C , Gouin, F., Fourrier, F., Junginger, W. & Prieur, B. L. (1988). Pefloxacin in the treatment of nosocomial lower respiratory tract infections in intensive care patients. Journal of Antimicrobial Chemotherapy 21, 795-9. Montay, G., Gueffon, Y. & Rouquet, F. (1984). Absorption, distribution, metabolic fate and elimination of pefloxacin mesylate in mice, rats, monkeys and humans. Antimicrobial Agents and Chemotherapy IS, 463-72. Morel, C , Vergnaud, M., Langeard, V. & Benard, Y. (1984). Pefloxacine: diffusion dans le mucus bronchique. Pathologie Biologic 32, 516-9. Periti, P. & Novelli, A. (1989). Pefloxacina. Chemioterapia e farmacologia clinica. Farmaci e Terapia 6, Suppl. 3, 5-55. Smith, C. R. (1987). The adverse effects of fluoroquinoloncs. Journal of Antimicrobial Chemotherapy 19, 709-12. Verbist, L., (1986). In-vitro activity of pefloxacin against micro-organisms multiply resistant to /J-lactam antibiotics and aminoglycosides. Journal of Antimicrobial Chemotherapy 17, Suppl. B, 11-7. Yourassowsky, E., Van der Linden, M. P., Crokaert, F. & Glupczynsky, Y. (1986). In vitro activity of pefloxacin compared to other antibiotics. Journal of Antimicrobial Chemotherapy 17, Suppl. B, 19-28.

Pefloxacin in lower respiratory tract infections.

To determine the efficacy and safety of pefloxacin in the treatment of lower respiratory tract infections, a multicentre trial involving four departme...
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