H. Feist

Sequential Therapy with I. V. and Oral Ofloxacin in Lower Respiratory Tract Infections: A Comparative Study Summary: The results of an open randomised trial comparing the efficacy of parenteral and oral ofloxacin with that of amoxycillin clavulanate are reported. Of 121 patients enrolled, 92 were clinically evaluable, of whom 59 were treated with ofloxacin and 33 with amoxycillin clavulanate. In the ofloxacin group all patients improved clinically, while in the amoxycillin clavulanate group 94% improved and 6% were clinical failures. In the ofloxacin group 95% showed satisfactory bacteriological response, while in the amoxicillin clavulanate group the bacteriological response was judged satisfactory in 82% of the patients. Seven percent of the patients had mild side effects (headache, nausea, vomiting and skin rashes). All of these side effects disappeared after treatment. We conclude that ofloxacin is a safe and effective drug in oral and parenteral forms for the treatment of lower respiratory tract infections.

Zusammenfassung: Sequentialtherapie L v. und oral mit Ofloxacin bei tiefen Atemwegsinfektionen. Vergleichsstudie. In einer offenen, randomisierten Studie wurde die Wirksamkeit einer parenteral begonnenen und oral fortgesetzten Therapie mit Ofloxacin und Amoxicillin-Clavulansiure verglichen. Die klinische Auswertung war bei 92 von 121 Patienten m6glich, davon wurden 59 mit Ofloxacin und 33 mit dem Vergleichspriparat behandelt. Eine klinische Besserung war bei allen mit Ofloxacin behandelten Patienten und in 94% der mit Amoxicillin-Clavulans/iure behandelten Patienten zu verzeichnen, bei einer Versagerquote von 6%. Befriedigende bakteriologische Ergebnisse wurden in der Ofloxacin-Gruppe in 95% und in der Vergleichsgruppe in 82% der F i l e festgestellt. Leichte Nebenwirkungen wie Kopfschmerzen, Ubelkeit, Erbrechen und Exantheme traten bei insgesamt 7% der Patienten auf und verschwanden nach der Behandlung. In oraler wie in parenteraler Form erwies sich Ofloxacin als sicheres und wirksames Antibiotikum ffir die Behandlung tiefer Atemwegsinfektionen.

Introduction Ofloxacin is a quinolone antibiotic with good antibacterial activity against a broad spectrum of gram-positive and gram-negative bacteria, as well as Mycoplasma and Chlamydia species. In this study we examined the clinical and bacteriological efficacy as well as the safety of ofloxacin in hospitalised patients with lower respiratory tract infections [1, 2].

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Table 1: Dosage of treatment in the ofloxacin-treated group (clinically evaluable patients).


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13 13

41 41

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2 2

3 3

56 3 59

Materials and Methods The study design was a randomised trial comparing parenteral and oral ofloxacin versus amoxycillin clavulanate. Patients were excluded from the study if they had a history of hypersensitivity to quinolones or a comparative drug. They were also excluded if they were pregnant or breast feeding, if they had participated in another clinical trial in the eight weeks prior to the study, or if they suffered from serious hepatic disease or a rapidly progressing fatal disease. The following criteria were used for clinical evaluation: the patient had received treatment for at least three l days, the presence of purulent sputum, pathological auscultatory findings and a body temperature I>38° C. A patient was considered to be bacteriologically evaluable if a causative pathogen could be isolated from an appropriate source within the last 48 h before the start of the study. The causative pathogen had to be sensitive to both ofloxacin and amoxycillin clavulanate. A follow-up culture was obtained on the last day of treatment as well as on the tenth day after treatment had been stopped. Both drugs were administered intravenously for at least three days and then given orally for four to seven days. Ofloxacin was given in a dosage of 200 mg intravenously twice a day before moving on to oral treatment. Thirteen patients did not receive oral ofloxacin therapy. Of those receiving oral therapy, the dosage was 200 mg either twice a day, three times a day or four times a day (Table 1). The comparative drug, amoxycillin clavulanate, was administered intravenously to most control patients in a dosage of 2,200 mg twice a day. However, there were some patients who received 2,200 mg of this drug three times a day, or 2,400 mg three times a day. They then received 625 mg of antibiotic orally, either three times a day in the majority of patients, or in the case of a few, two or four times a day (Table 2). Clinically, treatment was judged to be a success or the patient was judged to have improved if the clinical symptoms disappeared or improved markedly. A bacteriological success was defined as occurring in those cases in which the sputum cultures obtained after treatment showed no significant pathogens. A range of laboratory investigations were performed before, during and after treatment, Chest X-rays were taken before treatment and, if necessary, after treatment. Dr. med. H. Feist, PulmologischesZentrum der Stadt Wien, II. Interne Lungenabteilung, Sanatoriumstr. 2, A-1145 Wien, Austria.

Infection 19 (1991) Suppl. 7 © MMV Medizin Verlag GmbH Mfinchen, Mfinchen 1991

H. Feist: Intravenous and Oral Ofloxacin in L R T I

Table 2: Dosage of treatment in the amoxycillin/clavulanatetreated group (clinically evaluable patients).

2 x 2,200 3 x 2,400 3 x 2,200

Total patients

5 1 1 7

1 1

16 1 1 18

6 1 7

28 2 3 33

Table 5: Clinical response on completion of therapy.

Satisfactory Improved No change


16 43 59

27 73 100

10 21 2 33

30 64 6 100

Table 6: Organisms isolated prior to commencement of therapy in bacteriologically evaluable patients.

Results Of 121 patients enrolled in the study, 92 were clinically evaluable and 37 bacteriologically evaluable. Table 3 reports the demographic characteristics of the clinically evaluable patients and shows that both groups were well matched for age or body mass index, measured by kg/cm 2. Most patients presented with exacerbations of chronic bronchitis. The clinical features that most of the clinically evaluable patients had prior to therapy were purulent sputum, fever and rales (Table 4). Clinically, all patients in the ofloxacin group showed an improvement, that is, were judged to be a success. No subjects receiving ofloxacin experienced deterioration or no change in their symptoms. This compared to 94% of subjects in the amoxycillin clavulanate group showing either satisfactory change or improvement. Two of the 33 subjects (6%) in the amoxycillin clavulanate group showed no change (Table 5). Of 37 bacteriologically evaluable patients, 45 organisms could be cultured before treatment, 26 in the ofloxacin group and 19 in the amoxycillin clavulanate group. The most frequent bacteria were Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and Escherichia coli (Table 6). The organisms were isolated predominantly from sputum. Bronchial lavage produced the organism in one case from each drug group, and in two

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3 2 -

Klebsiella spp. Proteus vulgaris Proteus mirabilis

Haemophilus influenzae Pseudomonas aeruginosa Pseudornonas fluorescens

Staphylococcus aureus Streptococcus pneumoniae Total organisms


1 2 1

4 4 1




2 I


2 1



1 1 I 8




1 8

1 1 2 16



patients in the amoxycillin clavulanate group the causative organism was identified in bronchial secretions. The bacteriological response was judged satisfactory in 95% of the patients treated with ofloxacin and in 82% of the patients treated with amoxyciUin clavulanate (Table 7). In the ofloxacin group, one patient developed a superinfection with Pseudomonas aeruginosa, while of the three patients judged bacteriological failures in the amoxycillin clavulanate group, two had persisting H. influenzae strains and one a persisting E. coli. However, all patients showed clinical improvement.

Table 3: Demographic characteristics of clinically evaluable patients.

Ofloxacin Ofloxacin Amoxycillin/clavulanate Amoxycillin/clavulanate


(39) (20) (19) (14)

64 64 63 61

23 23 33 27

89 81 83 83

23.32 22.57 21.51 23.16

16.90 16.26 18.42 18.96

30.86 28.65 26.81 31.14

BMI = body mass index (kg/cmZ).

Table 4: Clinical features prior to therapy in clinically evaluable patients.

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I Purulent sputum

Fever Rales

9 4 8

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49 4 26

58 8 34

Infection 19 (1991) Suppl. 7 © MMV Medizin Verlag GmbH Mtinchen, Mtinchen 1991

6 5 5

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23 3 17


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29 8 22

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H. Feist: Intravenous and Oral Ofloxacin in LRTI Table 7: Bacteriological response in 37 evaluable patients.

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Satisfactory Unsatisfactory Total patients

19 1 20

95 5 100

14 3 17

82 18 100

33 4 37

89 11 100

treatment with ofloxacin. In regard to superinfections, only one patient had a superinfection With P. aeruginosa, but the clinical outcome was satisfactory. We conclude that ofloxacin is a safe and effective drug in both oral and parenteral forms for the treatment of lower respiratory tract infections. Discussion

Collins: You mentioned that patients in the study received at least three days of parenteral therapy before commencing oral treatment. However, some patients received more than this, or only received parenteral administration with no subsequent oral administration. Cardiovascular diseases 16 25 5 17 What were the criteria that were used to determine how Diabetes 7 11 6 21 long these patients were treated parenterally? Hepatic disorders 8 13 2 7 Feist: Approximately 90% of clinically evaluable patients Lung diseases 9 14 3 10 received three days of parenteral administration of either Malignancies 4 6 2 7 drug, while 10% received four or five days of such therapy. Compromised defence system 15 23 9 31 Others 5 8 2 7 This was decided by chance alone - it was not a decision of Total 64 100 29 100 ours, but from before we started the treatment. Collins: Looking at the oral therapy then, was there a total treatment period of a certain number of days? That is, if someone received three days of intravenous therapy, did they then receive a set number of days of oral therapy, and Adverse Reactions those who, say, received four days of intravenous Four patients, about 7%, treated with ofloxacin had mild treatment, did they then receive one day less of adverse effects. Nausea and vomiting occurred in one subsequent oral therapy? patient on the first day of therapy, while two patients Feist: No, this was not the case. All patients received at developed rashes within two days of the onset of least seven days of antimicrobial therapy, but this was not treatment. One patient developed hypotension on the a set treatment period. The longest time for which a third day of treatment and one developed mild headache patient received treatment was ten days. This depended on the second day of therapy. All of these side effects were upon the clinical decision of when we judged it to be mild, with no subjects requiring to be withdrawn from the acceptable to stop the treatment. study. Following the termination of therapy, all side Collins: Was there then any difference in treatment effects disappeared. period between the ofloxacin and amoxycillin-clavulanate None of the laboratory parameters showed any significant groups? changes in either of the study groups. There were two Feist: No, there was no difference found. deaths in the amoxycillin clavulanate group, one due to Solberg: I am very impressed by one speaker after another a bronchial carcinoma and one to respiratory failure. informing us that they get bacteriological cure rates of Table 8 lists the concomitant diseases found in the 100% or very close to this. Therefore, I would like to ask clinically evaluable patients. whatkind of culture technique or samples you obtained in your study? And also, how many days after the treatment had been stopped were the samples taken for Conclusion bacteriological evaluation? Was it perhaps the day after, This prospective, comparative, randomised open trial or the same day? demonstrated that ofloxacin and amoxycillin clavulanate Feist: There are many comments I need to make in reply had similar clinical and bacteriological efficacy in patients to this. The first point is that there were only 20 ofloxacinwith lower respiratory tract infections [3, 4]. Both drugs treated patients who were bacteriologically evaluable in were also safe when administered in oral and parenteral our study. Therefore, the results are from a relatively forms. There were no severe adverse reactions reported in small population and this needs to be remembered when looking at the results. In this group of 20 there was only the study population. Several investigators have reported the persistence of one bacteriological failure. We also need to remember superinfection with the pathogen Streptococcus that all subjects who were found to harbour resistant pneumoniae in studies of all quinolone derivatives. strains of bacteria before the trial were excluded from the However, in this study no patient showed persistence of S. study. Therefore, of course our results are going to be pneumoniae or superinfection with this pathogen after better than you would have expected under normal Table 8: Concomitant disease in clinically evaluable patients.


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Infection 19 (1991) Suppl. 7 © MMV Medizin Verlag GmbH Miinchen, M~inchen 1991

H. Feist: Intravenous and Oral Ofloxacin in LRTI conditions. The third point is that the bacteriological examination of the sputum was done very carefully. Cytological investigation of the sample was done first, and only if the sample could be proven to originate from the bronchial system and not the throat was it included. Bacteriological investigation was then done, and this was often when the leucocyte count was very high, and many of the causative bacteria identified were found in these leucocytes. And my fourth comment relates to your final question. The bacteriological assessment was done at the end of the treatment and also ten days later. I must admit we were a little impressed that even ten days after the end of treatment, we had so few relapses. We did expect more relapses than the one we found, because of our past experience with chronic obstructive patients who have recurrent infections. Solberg: Yes, I really am convinced that you have good control of your data. Andriole: I think the key is the follow-up period. We all have the same trouble trying to do cultures on patients who may not be bringing up sputum at the time that we see them, and the ten-day follow-up period used in your study, a very reasonable length of time, without relapse, is good evidence that something happened that was beneficial for the patient. Questioner: I have been very interested in the question of the once a day dosing schedule and the oral administration of these agents. Have you done any cost analysis, because in my country, as in most, cost is a very important

component. So when you compared these different regimens, did you actually do any costing studies, as this is an extremely important issue in Third World countries? Feist: In this study we did not do any testing of the once a day dose, and we have not compared the costs of the two treatment regimens studied. Questioner: This is perhaps a comment and also relates to the last paper presented, as well as to this one. In the real world, when you are on the ward, it is more often that you don't know the cause of the infection and indeed the laboratory never tells you. Have you any experience of treating all patients that are hospitalised with pneumonia using this combination? That is, not just treating the ones, which I suspect are quite a small number, that have proven bacteriological findings. Feist: Most of our patients in the study were suffering from exacerbations of chronic bronchitis and not from pneumonia. When we have a patient presenting with an acute exacerbation of chronic bronchitis and we have not identified any pathogens, we normally start treatment with amoxycillin, tetracycline or macrolides. And then only in a case of treatment failure do we try more aggressively to get a bacteriological diagnosis, performing more bacteriological sputum investigations or bronchoscopy or possibly other investigations if necessary. Then we try to treat after obtaining this result. If we can not get a definite result, we believe our second choice of therapy could be the quinolones.


exacerbations of chronic bronchitis. Rev. Infect. Dis. 11 (Suppl. 5) (1985) 197. 3. Grassi, C., Grassi, G.G., Mangiarotti, P.: Clinical efficacy of ofloxacin in lower respiratory tract infections. Drugs 34 (Suppl. I) (1987) 80-82. 4. Havard, C.W.H., Fernando, A., Brumfitt, W., Hamilton-Miller, J. M.T.: A pilot study of "Augrnentin" in lower respiratory tract infections: pharmacokinetic and clinical results. Br. J. Dis. Chest 76 (1982) 255-260.

1. Davies, B.I., Maesen, F. P. V., Teengs, P.J., Baur, C.: Neue orale Chinolon-Verbindungen bei chronischer Bronchitis. Infection 14 (Suppl. 1) (1986) $73-$78. 2. Gascon, F. S. Chavarri, M. V., Hernandez, J., Gomez,d. G., Sanehez, A.C., Santesteban, J.: Evaluation of ofloxacin in the treatment of

Infection 19 (1991) Suppl. 7 © MMV Medizin Vertag GmbH Miinchen, Miinchen 1991

S 383

Sequential therapy with i.v. and oral ofloxacin in lower respiratory tract infections: a comparative study.

The results of an open randomised trial comparing the efficacy of parenteral and oral ofloxacin with that of amoxycillin clavulanate are reported. Of ...
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