Journal of Antimicrobial Chemotherapy (1990) 26, Suppl. D, 83-91
A comparative study of ofloxacin and amoxycillin/clavulanate in hospitalized patients with lower respiratory tract infections
"Pulmologisches Zentrum der Stadt Wien, II. Interne Lungenabteilung, Sanatoriumstrqfie 2, A-1145 Vienna; bPatholog.-bakteriolog. Institut des Psychiatrischen Krankenhauses der Stadt Wien, Sanatoriumstrafie 1, A-1145 Vienna, Austria We conducted an open randomized trial to compare the efficacy of parenteral and oral ofloxacin with that of amoxycillin/clavulanate. A total of 121 patients was studied; 92 were clinically evaluable. Of these, 59 patients were treated with ofloxacin and 33 with the comparator drug. Patients were given the drugs intravenously for a minimum of three days followed by oral preparations for the next seven to ten days. Ofloxacin was usually administered as a 200 mg dose bd. In the ofloxacin treated group all patients showed clinical improvement. In the comparator group 94% improved clinically (either a complete or partial response), while 6% were clinical failures. Of the bacteriologically evaluable patients 19 of 20 showed a satisfactory bacteriological response in the ofloxacin treated group, while in the comparator group the bacteriological response was judged satisfactory in 14 of 17 patients. A small proportion of patients (7%) treated with ofloxacin suffered mild adverse effects (nausea, vomiting, headache, hypotension and rash). On the whole, ofloxacin was well tolerated by our patients. The two deaths that occurred were in the comparator group. We conclude that ofloxacin in both oral and parenteral forms is an effective and safe drug in the treatment of lower respiratory tract infections.
Introduction Ofloxacin is a quinolone antibiotic which possesses good antibacterial activity against a broad-spectrum of Gram-positive and Gram-negative bacteria and also Mycoplasma and Chlamydia spp. (Sato et al., 1982; Osada & Ogawa, 1983; Bailey el al., 1984). Ofloxacin has been used extensively in the past in the treatment of lower respiratory tract infections (Grassi, Grassi & Mangiarotti, 1987; Saito et al., 1987). The combination of amoxycillin and the /Mactamase inhibitor clavulanic acid (Augmentin) has also been studied in a large number of patients with lower respiratory tract infections (Havard et al., 1982; Maesen, Davies & Baur, 1987). Maesen et al. (1987); reported excellent or good clinical response in 80% of patients at the end of ten days therapy. This study examines the clinical and bacteriological efficacy and safety of oral and parenteral ofloxacin in comparison with amoxycillin/clavulanate in hospitalized patients with lower respiratory tract infections. 83 O3O5-7453/9O/26DO83 + O9 $02.00/0
© 1990 The British Society for Antimicrobial Chemotherapy
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Rumi Khajotia", Markus Drlicek* and Norbert Vetter*
84
R. Khajotia et aL Patients and methods
Table I. Dosage of treatment in the ofloxacin treated group (clinically evaluable patients) Dosage iv (mg) of ofloxacin 2x200 3x200 Total patients
No oral treatment
2x200
13
41
Dosage oral (mg) 3x200 4x200 2
— -i
13
41
2
3
Total patients 56 3 59
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Patients with a minimum age of 18 years, suffering from lower respiratory tract infections were included in the study. Patients were excluded from the study if they had a history of hypersensitivity to quinolones, if they were pregnant or were breast feeding, if they had participated in another clinical trial in the eight weeks prior to study entry or if they suffered from serious hepatic disease or a rapidly progressing fatal disease. The patients were considered evaluable for clinical and/or bacteriological efficacy if the following criteria were met. The criteria for clinical evaluation were: treatment for at least three days; presence of purulent sputum, pathological auscultatory findings, or a body temperature greater than or equal to 38°C; a causative pathogen in the pretreatment culture sensitive to the treatment drug (ofloxacin or the comparator drug). If antimicrobial therapy had been given in the 72 h prior to study entry, the patient was only considered evaluable for clinical efficacy if this had proved ineffective. A positive pretreatment culture was not mandatory for clinical evaluability. For a patient to be considered bacteriologically evaluable the following prerequisites were essential: treatment for at least three days; no other concomitant antimicrobial drug; a causative pathogen isolated before the start of the study from an appropriate source (sputum, tracheal secretions, bronchoscopic lavage etc.) that was sensitive to both ofloxacin and the comparator drug; a follow-up culture obtained between the last day of treatment and the tenth day thereafter. Each drug was administered intravenously for at least the first three days. The patient was given oral therapy upon evidence of improvement in the general condition. The treatment was continued for seven to ten days or three days beyond the disappearance of clinical symptoms. Ofloxacin was usually administered as a 200 mg dose, bd. Eight patients had an alteration of their daily dose (three patients received 3 x 200 mg intravenous therapy per day, two patients received 3 x 200 mg oral therapy per day, and three patients received 4 x 200 mg oral therapy/day). Thirteen patients received intravenous medication throughout the duration of therapy (Table I). Amoxycillin/clavulanate was administered intravenously in a dose of either 2 x 2200, 2 x 2400 or 3 x 2200 mg/day. The oral therapy was administered as either 2 x 625, 3 x 625 or 4 x 625 mg/day. Seven patients received intravenous medication with the comparator drug throughout the course of therapy (Table II). The clinical status of each patient was assessed before commencement of therapy and until the end of the study. In addition to daily monitoring of manifestations of respiratory infection such as cough, sputum, evidence of lung parenchymal involvement and body temperature, relevant changes in vital parameters were also recorded.
Lower respiratory tract infections
85
Table IL Dosage in the amoxycillin/clavulanate treated group (clinically evaluable patients) Dosage iv (mg) of comparative drug
5 1 1 7
Dosage oral (mg) 2 x 625 3 x 625 4 x 625 1 — — 1
16 1 1 18
6 — 1 7
Total patients 28 2 3 33
The clinical response was assessed as 'satisfactory' if all symptoms present before initiation of treatment had subsided at the follow-up examination and the signs of consolidation on chest X-ray had resolved or had at least considerably improved. The clinical response was considered 'improved', if the clinical signs and/or symptoms improved but at least one symptom of infection still persisted. The response was judged 'unsatisfactory' if the symptoms relating to the infection remained unchanged or worsened. Samples for microbiological examination were obtained before and after treatment, and, if necessary, during treatment. Post-treatment specimens were obtained 24-48 h after the end of treatment if sputum was available. Organisms were classified according to the Systemized Nomenclature of Medicine (College of American Pathologists, 1984). The bacteriological response was considered 'satisfactory' if the post-treatment cultures showed no significant pathogen. The response was judged 'unsatisfactory' if the causative pathogen was still present in the post-treatment culture, or if the causative pathogen had been eradicated but a new pathogen was present, and there was clinical evidence of a new infection (reinfection). If more than one pathogen was isolated, only those which were judged responsible for the infection, were considered for bacteriological evaluation. A range of laboratory investigations (haematologjcal, blood chemistry, urinalysis) were performed before, during and after treatment. Laboratory values were classified as normal or abnormal according to the ranges in SI Units in Medicine (Lippert & Lehmann, 1978). Chest X-rays were taken before treatment and, if there was evidence of parenchymal involvement, the X-rays were repeated at the end of treatment. Additional X-rays were performed as required. Throughout the study, tolerance of the drug was regularly assessed and any local or general adverse reactions reported by the patient were documented. The patient's blood pressure was monitored and recorded at intervals before, during and after infusion of ofloxacin. Results A total of 121 patients was enrolled between October 1986 and August 1988. Of these, 92 patients were clinically evaluable. Of the 92 evaluable patients, 59 received therapy with ofloxacin and 33 with the comparator drug, based on a 2:1 randomization code (two patients on ofloxacin: one patient on the comparative drug). Of the 92 patients 58 (63%) were male and 34 (37%) were female. All patients were of European descent. The median ages in the ofloxacin treated patients were 64 for both males and females, while in the comparator group the medians were 63 and 61 respectively. The
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2x2200 2 x 2400 3 x 2200 Total patients
No oral treatment
86
R. Khajotia et al Table III. Demographic characteristics of clinically evaluable patients Sex (n)
Age median
Age min.
Age max.
BMI median
BMI min.
BMI max.
M (39) F (20) M (19) F (14)
64 64 63 61
23 23 33 27
89 81 83 83
23-32 22-57 21-51 2316
16-90 16-26 18-42 18-96
30-86 28-65 26-81 3114
Treatment Ofloxacin Ofloxacin Amoxycillin/clavulanate Amoxycillin/clavulanate
patients in both groups were comparable regarding weight and height as reflected by body mass index (Table HI). Clinical features In our study population there was a preponderance of patients with lower respiratory tract infections (LRTT) without parenchymal involvement (83%) compared with 17% with parenchymal involvement. However, the two treatment groups were comparable in this respect, with 50/59 (85%) of patients treated with ofloxacin and 26/33 (79%) of those treated with the comparator drug showing no evidence of parenchymal involvement. The median duration of infection before the start of treatment was ten days in the ofloxacin treated group, and 13 days in the comparator group. Purulent sputum was the predominant symptom before treatment in both groups of patients, with 58 patients (98%) in the ofloxacin group and 29 patients (88%) in the comparator group suffering from this symptom. Coarse mid-inspiratory rales was the predominant sign prior to therapy in 34 patients (58%) in the ofloxacin group, and in 22 patients (67%) in the comparator group (Table IV). Sixteen patients (27%) treated with ofloxacin showed a satisfactory clinical response, while 43 patients (73%) improved. No patient was judged a clinical failure on treatment with ofloxacin. Ten patients (30%) treated with the comparator drug showed a satisfactory response, while 21 patients (64%) improved. One patient (3%) showed no change in the clinical condition and was assessed as an 'unsatisfactory' response, while one patient showed clinical deterioration on the comparator drug and was subsequently switched to ofloxacin on day 8 of therapy. The result was a complete remission (Table V). Two deaths occurred, both in patients treated with the comparator drug, but neither of these patients was considered evaluable. Table IV. Clinical features prior to therapy (clinically evaluable patients) Ofloxacin group Amoxycillin/clavulanate group with without with without parenchymal parenchymal Total parenchyma! parenchymal Total involvement involvement symptoms involvement involvement symptoms Purulent sputum Fever Rales
9 4 8
49 4 26
58 8 34
6 5 5
23 3 17
29 8 22
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BMI, Body mass index (kg/cm3).
Lower respiratory tract infections
87
Table V. Clinical response on completion of therapy Ofloxacin no. %
Satisfactory Improved No change Total
16 43 — 59
27 73 — 100
Amoxycdllin/clavulanate no. % 10 21 2 33
30 64 6 100
Bacteriological results Of the 92 clinically evaluable patients, only 37 satisfied the criteria for bacteriological evaluability. Of these, 20 patients were in the ofloxacin treated group while 17 were treated with the comparator drug. In the ofloxacin group, 26 organisms were isolated while 19 organisms were isolated in the comparator group prior to commencement of therapy (Table VI). For bacteriological evaluability each organism had to be susceptible to both ofloxacin and the comparator drug. The most common pathogen to be isolated in the bacteriologically evaluable patients was Streptococcus pneumoniae, followed by Haemophilus influenzae (Table VI). These two organisms were also the most common pathogens to be found in the clinically evaluable patients. Sputum was the most common source for isolation of pathogens followed by bronchial secretions and bronchoalveolar lavage (Table VII). TaWe VI. Organisms isolated prior to commencement of therapy (bacteriologically evaluable patients) Organism Branhamella catarrhalis Esch. coli Enterobacter cloacae Klebsiella sp. Proteus vulgaris Pr. mirabilis H. influenzae Ps. aeruginosa Ps. fluorescent Staphylococcus aweus Str. pneumoniae Total organisms
Ofloxacin 3 2 — 1 2 1 6 1 1 1 8 26
Amoxycillin/clavulanate Total organisms 1 2 1 — — — 6 — — 1 8 19
4 4 1 1 2 1 12 1 1 2 16 45
Table VII. Source from which organisms were isolated (bacteriologically evaluable patients) Source Sputum Bronchial lavage Bronchial secretion Total organisms
Ofloxacin
Amoxycillin/clavulanate
Total organisms
25 1 — 26
16 1 2 19
41 2 2 45
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Result
88
R. Kbajotia tf a£
Bacteriological response on completion of therapy
Concomitant disease Concomitant disease was reported in both groups of patients, 64 concomitant diseases being present in the 59 patients on ofloxacin, and 29 concomitant diseases in the 33 patients on the comparator drug. The most frequent diseases in the ofloxacin group were cardiovascular disorders (25%), while 31% of patients in the comparator group suffered from compromised defence systems (Table IX). Overall, 42 of 59 patients in the ofloxacin group, and 18 of 33 in the comparator group suffered from concomitant illnesses. As a result, a wide variety of concomitant medication was taken by patients in both groups. Fifty three of 59 patients in the ofloxacin group and 28 of 33 in the comparator group took concomitant medication with most patients taking medication for cardiovascular diseases (55% in the ofloxacin group and 54% in the comparator group).
Table VUL Bacteriological response Bacteriological result
Ofloxacin % no.
Satisfactory Unsatisfactory Total patients
19 1 20
Amoxycillin/clavulanate no. % 14 3 17
95
5 100
Total patients no. % 33 4 37
82 18 100
89 11 100
Table IX. Concomitant diseases (clinically evaluable patients) Disease
Ofloxacin no, %
Cardiovascular diseases Diabetes Hepatic disorders Lung diseases Malignancies Compromised defence system Others Total
16 7 8 9 4 15 5 64
25 11 13 14 6 23 8 100
Amoxycillin/clavulanate no. % 5 6 2 3 2 9 2 29
17 21 7 10 7 31 7 100
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The bacteriological response was termed 'satisfactory' in 95% of bacteriologically evaluable patients treated with ofloxacin, while in the comparator group the response was 'satisfactory' in 82% of patients (Table VHI). Of the three patients showing an 'unsatisfactory' bacteriological response in the comparator group two had persisting H. influenzae strains while one had a persisting Escherichia coli. However, all three patients showed clinical improvement. In the ofloxacin group one patient developed superinfection with Pseudomonas aeruginosa and the bacteriological response was termed 'unsatisfactory' in this patient. However, the patient showed clinical improvement.
Lower respiratory tract infections
89
Duration of therapy The median duration of treatment in our patients was seven days in the ofloxacin group and eight days in the comparator group. Most of our patients were treated intravenously for the first three days followed by oral medication for the next four to seven days. However, 13 patients (22%) in the ofloxacin group and seven patients (21%) in the comparator group received no oral medication and were on intravenous therapy throughout.
Four patients (7%) treated with intravenous ofloxacin had mild adverse effects. Nausea and vomiting occurred in one patient on day 1 of therapy, while two patients developed rashes within two days of onset of treatment. One patient developed hypotension (greater than 20% of baseline value) on the third day of therapy and one developed mild headache on the second day of therapy. However, all these disappeared on termination of therapy. One patient developed moderately severe phlebitis, on the second day of therapy. The patient subsequently recovered on discontinuation of the drug. Laboratory parameters remained essentially unchanged in comparison to pre-treatment values, in both groups of patients. Mortality Two deaths occurred, both in the amoxycillin/clavulanate group. One patient died of cor pulmonale and respiratory failure. This patient also had bronchiolo-alveolar cell carcinoma. The immediate cause of death in the other patient was severe bilateral bronchopneumonia unresponsive to therapy. This patient also had a bronchogenic carcinoma. Discussion Fluoroquinolones have a broad spectrum of activity against both Gram-positive and Gram-negative organisms. A number of trials utilizing fluoroquinolones in the treatment of respiratory tract infections have been carried out, but most of these studies have been non comparative (Gleadhill, Ferguson & Lowry, 1986; Magnani et al., 1986). We compared the efficacy (clinical and bacteriological) and safety of oral and parenteral forms of ofloxacin with that of amoxycillin/clavulanate. Of the 59 patients treated with ofloxacin, there was a complete resolution of clinical signs and symptoms in 16 patients while the remaining 43 patients showed improvement in most of their clinical symptoms and signs. No patient was judged to be a clinical failure. These results are similar to those of other investigators (Grassi et al., 1987; Saito et al., 1987; Gascon et al., 1989), who reported a 94% clinical response in patients who had an acute infective exacerbation of chronic bronchitis treated with ofloxacin. In the group of 33 patients treated with amoxycillin/clavulanate, ten showed complete clinical cure, while 21 patients showed considerable improvement of their clinical status. However, two patients in this group proved to be clinical failures, one of whom was subsequently switched over to ofloxacin, after which he improved.
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Adverse reactions
90
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References Bailey, J. M. G., Heppelston, C. & Richmond S. J. (1984). Comparison of the in vitro activities of ofloxacin and tetracycline against Chlamydia trachomatis as assessed by indirect immunofluorescence. Antimicrobial Agents and Chemotherapy 26, 13-6. College of American Pathologists (1984). Microglossary for Surgical Pathology. Systemized Nomenclature of Medicine (SNOMED), 2nd edn. Davies, B. I., Maesen, F. P. V., Teengs, P. J. & Baur, C. (1986). Neue orale ChinolonVerbindungen bei chronischer Bronchitis. Infection 14, Suppl. 1, S73-8. Gascon, F. S., Chavarri, M. V., Hernandez, J., Gomez, J. G., Sanchez, A. C , Santesteban, J. et al. (1989). Evaluation of ofloxacin in the treatment of exacerbations of chronic bronchitis. Reviews of Infectious Diseases 11, Suppl. 5, 197. Gleadhill, I. C , Ferguson, W. P. & Lowry, R. C. (1986). Efficacy and safety of ciprofloxacin in patients with respiratory infections in comparison with amoxycillin. Journal of Antimicrobial Chemotherapy 18, Suppl. D, 133-8. Grassi, C , Grassi, G. G. & Mangiarotti, P. (1987). Clinical efficacy of ofloxacin in lower respiratory tract infections. Drugs 34, Suppl. 1, 80-2. Havard, C. W. H., Fernando, A., Brumfitt, W. & Hamilton-Miller, J. M. T. (1982). A pilot study of 'Augmenlin' in lower respiratory tract infections: pharmacokinetic and clinical results. British Journal of Diseases of the Chest 76, 255-60. Kemmerich, B. & Lode, H. (1989). Rational use of new antibiotics in respiratory infections. In Respiratory Infections: Diagnosis and Management, 2nd edn (Pennington, J. E., Ed.), pp. 648-52. Raven Press, New York. Lippert, H. & Lehman, H. P. (1978). An Introduction to the International System of Units with
Downloaded from http://jac.oxfordjournals.org/ at University of California, San Francisco on November 26, 2014
Ofloxacin is known to have good cnteral absorption, a half-life between 4 and 8 h, and a large volume of distribution, suggesting good intracellular penetration (Kemmerich & Lode, 1989). Of the bacteriologically evaluable patients treated with ofloxacin, 95% showed a satisfactory bacteriological response with post-treatment sputum cultures sterile, while 5% of patients showed an unsatisfactory response with post-treatment cultures showing persistence of pathogens or evidence of reinfection (Gascon et al., 1989). In comparison, 82% of bacteriologically evaluable patients treated with amoycillin/ clavulanate acid showed a satisfactory bacteriological response while 18% were bacteriological failures. Several investigators have reported the persistence of Streptococcus pnewnoniae or superinfection with this pathogen in studies of all quinolone derivatives (Davies et al., 1986). However, in our study, patients showed no persistence of Str. pnewnoniae or superinfection with this pathogen after treatment with ofloxacin. Only one patient showed superinfection with Ps. aeruginosa, but the clinical outcome was satisfactory. Moreover, ofloxacin was also well tolerated with only four patients having mild adverse effects such as nausea, vomiting, headache, hypotension and rash, all of which resolved on termination of therapy. However, one patient developed phlebitis of moderate severity, but which resolved on discontinuation of ofloxacin. Changes in laboratory parameters which could be attributed to therapy were not documented in either group of patients. In conclusion, this prospective, comparative, randomized, open trial showed that ofloxacin and amoxycillin/clavulanate had similar clinical efficacy, with most patients showing considerable clinical improvement. Both drugs were also safe when administered in oral and parenteral forms with no severe adverse reactions being reported in our study population.
Lows' respiratory tract Infections
91
102271
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Conversion Tables and Normal Ranges. SI Units in Medicine. Urban & Schwarzenberg, Munich. Maesen, F. P. V., Davies, B. I. & Baur, C. (1987). Amoxycillin/clavulanate in acute purulent exacerbations of chronic bronchitis. Journal of Antimicrobial Chemotherapy 19, 373-83. Magnani, C , Fregni, S., Valli, G., Cosentina, R. & Bisetti, A. (1986). Comparative clinical study of dprofloxacin and cotrimoxazole in respiratory tract infections. In Proceedings of the 1st International Ciprofloxacin Workshop, pp. 260-4. Excerpta Medica, Amsterdam. Osada, Y. & Ogawa, H. (1983). Antimycoplasmal activity of ofloxadn (DL-8280). Antimicrobial Agents and Chemotherapy 23, 509-11. Saito^A., Katsu, M., Saito, A. & Sojeima, R. (1987). Ofloxacin in respiratory tract infections. Drugs 34, Suppl. 1, 83-9. Sato, K., Matsuura, Y., Inove, M., Une, T., Osada, Y., Ogawa, H. et al. (1982). In vitro and in vivo activity of DL-8280, a new oxazine derivative. Antimicrobial Agents and Chemotherapy 22,548-53.
A comparative study of ofloxacin and amoxycillin/clavulanate in hospitalized patients with lower respiratory tract infections
"Pulmologisches Zentrum der Stadt Wien, II. Interne Lungenabteilung, Sanatoriumstrqfie 2, A-1145 Vienna; bPatholog.-bakteriolog. Institut des Psychiatrischen Krankenhauses der Stadt Wien, Sanatoriumstrafie 1, A-1145 Vienna, Austria We conducted an open randomized trial to compare the efficacy of parenteral and oral ofloxacin with that of amoxycillin/clavulanate. A total of 121 patients was studied; 92 were clinically evaluable. Of these, 59 patients were treated with ofloxacin and 33 with the comparator drug. Patients were given the drugs intravenously for a minimum of three days followed by oral preparations for the next seven to ten days. Ofloxacin was usually administered as a 200 mg dose bd. In the ofloxacin treated group all patients showed clinical improvement. In the comparator group 94% improved clinically (either a complete or partial response), while 6% were clinical failures. Of the bacteriologically evaluable patients 19 of 20 showed a satisfactory bacteriological response in the ofloxacin treated group, while in the comparator group the bacteriological response was judged satisfactory in 14 of 17 patients. A small proportion of patients (7%) treated with ofloxacin suffered mild adverse effects (nausea, vomiting, headache, hypotension and rash). On the whole, ofloxacin was well tolerated by our patients. The two deaths that occurred were in the comparator group. We conclude that ofloxacin in both oral and parenteral forms is an effective and safe drug in the treatment of lower respiratory tract infections.
Introduction Ofloxacin is a quinolone antibiotic which possesses good antibacterial activity against a broad-spectrum of Gram-positive and Gram-negative bacteria and also Mycoplasma and Chlamydia spp. (Sato et al., 1982; Osada & Ogawa, 1983; Bailey el al., 1984). Ofloxacin has been used extensively in the past in the treatment of lower respiratory tract infections (Grassi, Grassi & Mangiarotti, 1987; Saito et al., 1987). The combination of amoxycillin and the /Mactamase inhibitor clavulanic acid (Augmentin) has also been studied in a large number of patients with lower respiratory tract infections (Havard et al., 1982; Maesen, Davies & Baur, 1987). Maesen et al. (1987); reported excellent or good clinical response in 80% of patients at the end of ten days therapy. This study examines the clinical and bacteriological efficacy and safety of oral and parenteral ofloxacin in comparison with amoxycillin/clavulanate in hospitalized patients with lower respiratory tract infections. 83 O3O5-7453/9O/26DO83 + O9 $02.00/0
© 1990 The British Society for Antimicrobial Chemotherapy
Downloaded from http://jac.oxfordjournals.org/ at University of California, San Francisco on November 26, 2014
Rumi Khajotia", Markus Drlicek* and Norbert Vetter*
84
R. Khajotia et aL Patients and methods
Table I. Dosage of treatment in the ofloxacin treated group (clinically evaluable patients) Dosage iv (mg) of ofloxacin 2x200 3x200 Total patients
No oral treatment
2x200
13
41
Dosage oral (mg) 3x200 4x200 2
— -i
13
41
2
3
Total patients 56 3 59
Downloaded from http://jac.oxfordjournals.org/ at University of California, San Francisco on November 26, 2014
Patients with a minimum age of 18 years, suffering from lower respiratory tract infections were included in the study. Patients were excluded from the study if they had a history of hypersensitivity to quinolones, if they were pregnant or were breast feeding, if they had participated in another clinical trial in the eight weeks prior to study entry or if they suffered from serious hepatic disease or a rapidly progressing fatal disease. The patients were considered evaluable for clinical and/or bacteriological efficacy if the following criteria were met. The criteria for clinical evaluation were: treatment for at least three days; presence of purulent sputum, pathological auscultatory findings, or a body temperature greater than or equal to 38°C; a causative pathogen in the pretreatment culture sensitive to the treatment drug (ofloxacin or the comparator drug). If antimicrobial therapy had been given in the 72 h prior to study entry, the patient was only considered evaluable for clinical efficacy if this had proved ineffective. A positive pretreatment culture was not mandatory for clinical evaluability. For a patient to be considered bacteriologically evaluable the following prerequisites were essential: treatment for at least three days; no other concomitant antimicrobial drug; a causative pathogen isolated before the start of the study from an appropriate source (sputum, tracheal secretions, bronchoscopic lavage etc.) that was sensitive to both ofloxacin and the comparator drug; a follow-up culture obtained between the last day of treatment and the tenth day thereafter. Each drug was administered intravenously for at least the first three days. The patient was given oral therapy upon evidence of improvement in the general condition. The treatment was continued for seven to ten days or three days beyond the disappearance of clinical symptoms. Ofloxacin was usually administered as a 200 mg dose, bd. Eight patients had an alteration of their daily dose (three patients received 3 x 200 mg intravenous therapy per day, two patients received 3 x 200 mg oral therapy per day, and three patients received 4 x 200 mg oral therapy/day). Thirteen patients received intravenous medication throughout the duration of therapy (Table I). Amoxycillin/clavulanate was administered intravenously in a dose of either 2 x 2200, 2 x 2400 or 3 x 2200 mg/day. The oral therapy was administered as either 2 x 625, 3 x 625 or 4 x 625 mg/day. Seven patients received intravenous medication with the comparator drug throughout the course of therapy (Table II). The clinical status of each patient was assessed before commencement of therapy and until the end of the study. In addition to daily monitoring of manifestations of respiratory infection such as cough, sputum, evidence of lung parenchymal involvement and body temperature, relevant changes in vital parameters were also recorded.
Lower respiratory tract infections
85
Table IL Dosage in the amoxycillin/clavulanate treated group (clinically evaluable patients) Dosage iv (mg) of comparative drug
5 1 1 7
Dosage oral (mg) 2 x 625 3 x 625 4 x 625 1 — — 1
16 1 1 18
6 — 1 7
Total patients 28 2 3 33
The clinical response was assessed as 'satisfactory' if all symptoms present before initiation of treatment had subsided at the follow-up examination and the signs of consolidation on chest X-ray had resolved or had at least considerably improved. The clinical response was considered 'improved', if the clinical signs and/or symptoms improved but at least one symptom of infection still persisted. The response was judged 'unsatisfactory' if the symptoms relating to the infection remained unchanged or worsened. Samples for microbiological examination were obtained before and after treatment, and, if necessary, during treatment. Post-treatment specimens were obtained 24-48 h after the end of treatment if sputum was available. Organisms were classified according to the Systemized Nomenclature of Medicine (College of American Pathologists, 1984). The bacteriological response was considered 'satisfactory' if the post-treatment cultures showed no significant pathogen. The response was judged 'unsatisfactory' if the causative pathogen was still present in the post-treatment culture, or if the causative pathogen had been eradicated but a new pathogen was present, and there was clinical evidence of a new infection (reinfection). If more than one pathogen was isolated, only those which were judged responsible for the infection, were considered for bacteriological evaluation. A range of laboratory investigations (haematologjcal, blood chemistry, urinalysis) were performed before, during and after treatment. Laboratory values were classified as normal or abnormal according to the ranges in SI Units in Medicine (Lippert & Lehmann, 1978). Chest X-rays were taken before treatment and, if there was evidence of parenchymal involvement, the X-rays were repeated at the end of treatment. Additional X-rays were performed as required. Throughout the study, tolerance of the drug was regularly assessed and any local or general adverse reactions reported by the patient were documented. The patient's blood pressure was monitored and recorded at intervals before, during and after infusion of ofloxacin. Results A total of 121 patients was enrolled between October 1986 and August 1988. Of these, 92 patients were clinically evaluable. Of the 92 evaluable patients, 59 received therapy with ofloxacin and 33 with the comparator drug, based on a 2:1 randomization code (two patients on ofloxacin: one patient on the comparative drug). Of the 92 patients 58 (63%) were male and 34 (37%) were female. All patients were of European descent. The median ages in the ofloxacin treated patients were 64 for both males and females, while in the comparator group the medians were 63 and 61 respectively. The
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2x2200 2 x 2400 3 x 2200 Total patients
No oral treatment
86
R. Khajotia et al Table III. Demographic characteristics of clinically evaluable patients Sex (n)
Age median
Age min.
Age max.
BMI median
BMI min.
BMI max.
M (39) F (20) M (19) F (14)
64 64 63 61
23 23 33 27
89 81 83 83
23-32 22-57 21-51 2316
16-90 16-26 18-42 18-96
30-86 28-65 26-81 3114
Treatment Ofloxacin Ofloxacin Amoxycillin/clavulanate Amoxycillin/clavulanate
patients in both groups were comparable regarding weight and height as reflected by body mass index (Table HI). Clinical features In our study population there was a preponderance of patients with lower respiratory tract infections (LRTT) without parenchymal involvement (83%) compared with 17% with parenchymal involvement. However, the two treatment groups were comparable in this respect, with 50/59 (85%) of patients treated with ofloxacin and 26/33 (79%) of those treated with the comparator drug showing no evidence of parenchymal involvement. The median duration of infection before the start of treatment was ten days in the ofloxacin treated group, and 13 days in the comparator group. Purulent sputum was the predominant symptom before treatment in both groups of patients, with 58 patients (98%) in the ofloxacin group and 29 patients (88%) in the comparator group suffering from this symptom. Coarse mid-inspiratory rales was the predominant sign prior to therapy in 34 patients (58%) in the ofloxacin group, and in 22 patients (67%) in the comparator group (Table IV). Sixteen patients (27%) treated with ofloxacin showed a satisfactory clinical response, while 43 patients (73%) improved. No patient was judged a clinical failure on treatment with ofloxacin. Ten patients (30%) treated with the comparator drug showed a satisfactory response, while 21 patients (64%) improved. One patient (3%) showed no change in the clinical condition and was assessed as an 'unsatisfactory' response, while one patient showed clinical deterioration on the comparator drug and was subsequently switched to ofloxacin on day 8 of therapy. The result was a complete remission (Table V). Two deaths occurred, both in patients treated with the comparator drug, but neither of these patients was considered evaluable. Table IV. Clinical features prior to therapy (clinically evaluable patients) Ofloxacin group Amoxycillin/clavulanate group with without with without parenchymal parenchymal Total parenchyma! parenchymal Total involvement involvement symptoms involvement involvement symptoms Purulent sputum Fever Rales
9 4 8
49 4 26
58 8 34
6 5 5
23 3 17
29 8 22
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BMI, Body mass index (kg/cm3).
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Table V. Clinical response on completion of therapy Ofloxacin no. %
Satisfactory Improved No change Total
16 43 — 59
27 73 — 100
Amoxycdllin/clavulanate no. % 10 21 2 33
30 64 6 100
Bacteriological results Of the 92 clinically evaluable patients, only 37 satisfied the criteria for bacteriological evaluability. Of these, 20 patients were in the ofloxacin treated group while 17 were treated with the comparator drug. In the ofloxacin group, 26 organisms were isolated while 19 organisms were isolated in the comparator group prior to commencement of therapy (Table VI). For bacteriological evaluability each organism had to be susceptible to both ofloxacin and the comparator drug. The most common pathogen to be isolated in the bacteriologically evaluable patients was Streptococcus pneumoniae, followed by Haemophilus influenzae (Table VI). These two organisms were also the most common pathogens to be found in the clinically evaluable patients. Sputum was the most common source for isolation of pathogens followed by bronchial secretions and bronchoalveolar lavage (Table VII). TaWe VI. Organisms isolated prior to commencement of therapy (bacteriologically evaluable patients) Organism Branhamella catarrhalis Esch. coli Enterobacter cloacae Klebsiella sp. Proteus vulgaris Pr. mirabilis H. influenzae Ps. aeruginosa Ps. fluorescent Staphylococcus aweus Str. pneumoniae Total organisms
Ofloxacin 3 2 — 1 2 1 6 1 1 1 8 26
Amoxycillin/clavulanate Total organisms 1 2 1 — — — 6 — — 1 8 19
4 4 1 1 2 1 12 1 1 2 16 45
Table VII. Source from which organisms were isolated (bacteriologically evaluable patients) Source Sputum Bronchial lavage Bronchial secretion Total organisms
Ofloxacin
Amoxycillin/clavulanate
Total organisms
25 1 — 26
16 1 2 19
41 2 2 45
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Bacteriological response on completion of therapy
Concomitant disease Concomitant disease was reported in both groups of patients, 64 concomitant diseases being present in the 59 patients on ofloxacin, and 29 concomitant diseases in the 33 patients on the comparator drug. The most frequent diseases in the ofloxacin group were cardiovascular disorders (25%), while 31% of patients in the comparator group suffered from compromised defence systems (Table IX). Overall, 42 of 59 patients in the ofloxacin group, and 18 of 33 in the comparator group suffered from concomitant illnesses. As a result, a wide variety of concomitant medication was taken by patients in both groups. Fifty three of 59 patients in the ofloxacin group and 28 of 33 in the comparator group took concomitant medication with most patients taking medication for cardiovascular diseases (55% in the ofloxacin group and 54% in the comparator group).
Table VUL Bacteriological response Bacteriological result
Ofloxacin % no.
Satisfactory Unsatisfactory Total patients
19 1 20
Amoxycillin/clavulanate no. % 14 3 17
95
5 100
Total patients no. % 33 4 37
82 18 100
89 11 100
Table IX. Concomitant diseases (clinically evaluable patients) Disease
Ofloxacin no, %
Cardiovascular diseases Diabetes Hepatic disorders Lung diseases Malignancies Compromised defence system Others Total
16 7 8 9 4 15 5 64
25 11 13 14 6 23 8 100
Amoxycillin/clavulanate no. % 5 6 2 3 2 9 2 29
17 21 7 10 7 31 7 100
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The bacteriological response was termed 'satisfactory' in 95% of bacteriologically evaluable patients treated with ofloxacin, while in the comparator group the response was 'satisfactory' in 82% of patients (Table VHI). Of the three patients showing an 'unsatisfactory' bacteriological response in the comparator group two had persisting H. influenzae strains while one had a persisting Escherichia coli. However, all three patients showed clinical improvement. In the ofloxacin group one patient developed superinfection with Pseudomonas aeruginosa and the bacteriological response was termed 'unsatisfactory' in this patient. However, the patient showed clinical improvement.
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Duration of therapy The median duration of treatment in our patients was seven days in the ofloxacin group and eight days in the comparator group. Most of our patients were treated intravenously for the first three days followed by oral medication for the next four to seven days. However, 13 patients (22%) in the ofloxacin group and seven patients (21%) in the comparator group received no oral medication and were on intravenous therapy throughout.
Four patients (7%) treated with intravenous ofloxacin had mild adverse effects. Nausea and vomiting occurred in one patient on day 1 of therapy, while two patients developed rashes within two days of onset of treatment. One patient developed hypotension (greater than 20% of baseline value) on the third day of therapy and one developed mild headache on the second day of therapy. However, all these disappeared on termination of therapy. One patient developed moderately severe phlebitis, on the second day of therapy. The patient subsequently recovered on discontinuation of the drug. Laboratory parameters remained essentially unchanged in comparison to pre-treatment values, in both groups of patients. Mortality Two deaths occurred, both in the amoxycillin/clavulanate group. One patient died of cor pulmonale and respiratory failure. This patient also had bronchiolo-alveolar cell carcinoma. The immediate cause of death in the other patient was severe bilateral bronchopneumonia unresponsive to therapy. This patient also had a bronchogenic carcinoma. Discussion Fluoroquinolones have a broad spectrum of activity against both Gram-positive and Gram-negative organisms. A number of trials utilizing fluoroquinolones in the treatment of respiratory tract infections have been carried out, but most of these studies have been non comparative (Gleadhill, Ferguson & Lowry, 1986; Magnani et al., 1986). We compared the efficacy (clinical and bacteriological) and safety of oral and parenteral forms of ofloxacin with that of amoxycillin/clavulanate. Of the 59 patients treated with ofloxacin, there was a complete resolution of clinical signs and symptoms in 16 patients while the remaining 43 patients showed improvement in most of their clinical symptoms and signs. No patient was judged to be a clinical failure. These results are similar to those of other investigators (Grassi et al., 1987; Saito et al., 1987; Gascon et al., 1989), who reported a 94% clinical response in patients who had an acute infective exacerbation of chronic bronchitis treated with ofloxacin. In the group of 33 patients treated with amoxycillin/clavulanate, ten showed complete clinical cure, while 21 patients showed considerable improvement of their clinical status. However, two patients in this group proved to be clinical failures, one of whom was subsequently switched over to ofloxacin, after which he improved.
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References Bailey, J. M. G., Heppelston, C. & Richmond S. J. (1984). Comparison of the in vitro activities of ofloxacin and tetracycline against Chlamydia trachomatis as assessed by indirect immunofluorescence. Antimicrobial Agents and Chemotherapy 26, 13-6. College of American Pathologists (1984). Microglossary for Surgical Pathology. Systemized Nomenclature of Medicine (SNOMED), 2nd edn. Davies, B. I., Maesen, F. P. V., Teengs, P. J. & Baur, C. (1986). Neue orale ChinolonVerbindungen bei chronischer Bronchitis. Infection 14, Suppl. 1, S73-8. Gascon, F. S., Chavarri, M. V., Hernandez, J., Gomez, J. G., Sanchez, A. C , Santesteban, J. et al. (1989). Evaluation of ofloxacin in the treatment of exacerbations of chronic bronchitis. Reviews of Infectious Diseases 11, Suppl. 5, 197. Gleadhill, I. C , Ferguson, W. P. & Lowry, R. C. (1986). Efficacy and safety of ciprofloxacin in patients with respiratory infections in comparison with amoxycillin. Journal of Antimicrobial Chemotherapy 18, Suppl. D, 133-8. Grassi, C , Grassi, G. G. & Mangiarotti, P. (1987). Clinical efficacy of ofloxacin in lower respiratory tract infections. Drugs 34, Suppl. 1, 80-2. Havard, C. W. H., Fernando, A., Brumfitt, W. & Hamilton-Miller, J. M. T. (1982). A pilot study of 'Augmenlin' in lower respiratory tract infections: pharmacokinetic and clinical results. British Journal of Diseases of the Chest 76, 255-60. Kemmerich, B. & Lode, H. (1989). Rational use of new antibiotics in respiratory infections. In Respiratory Infections: Diagnosis and Management, 2nd edn (Pennington, J. E., Ed.), pp. 648-52. Raven Press, New York. Lippert, H. & Lehman, H. P. (1978). An Introduction to the International System of Units with
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Ofloxacin is known to have good cnteral absorption, a half-life between 4 and 8 h, and a large volume of distribution, suggesting good intracellular penetration (Kemmerich & Lode, 1989). Of the bacteriologically evaluable patients treated with ofloxacin, 95% showed a satisfactory bacteriological response with post-treatment sputum cultures sterile, while 5% of patients showed an unsatisfactory response with post-treatment cultures showing persistence of pathogens or evidence of reinfection (Gascon et al., 1989). In comparison, 82% of bacteriologically evaluable patients treated with amoycillin/ clavulanate acid showed a satisfactory bacteriological response while 18% were bacteriological failures. Several investigators have reported the persistence of Streptococcus pnewnoniae or superinfection with this pathogen in studies of all quinolone derivatives (Davies et al., 1986). However, in our study, patients showed no persistence of Str. pnewnoniae or superinfection with this pathogen after treatment with ofloxacin. Only one patient showed superinfection with Ps. aeruginosa, but the clinical outcome was satisfactory. Moreover, ofloxacin was also well tolerated with only four patients having mild adverse effects such as nausea, vomiting, headache, hypotension and rash, all of which resolved on termination of therapy. However, one patient developed phlebitis of moderate severity, but which resolved on discontinuation of ofloxacin. Changes in laboratory parameters which could be attributed to therapy were not documented in either group of patients. In conclusion, this prospective, comparative, randomized, open trial showed that ofloxacin and amoxycillin/clavulanate had similar clinical efficacy, with most patients showing considerable clinical improvement. Both drugs were also safe when administered in oral and parenteral forms with no severe adverse reactions being reported in our study population.
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Conversion Tables and Normal Ranges. SI Units in Medicine. Urban & Schwarzenberg, Munich. Maesen, F. P. V., Davies, B. I. & Baur, C. (1987). Amoxycillin/clavulanate in acute purulent exacerbations of chronic bronchitis. Journal of Antimicrobial Chemotherapy 19, 373-83. Magnani, C , Fregni, S., Valli, G., Cosentina, R. & Bisetti, A. (1986). Comparative clinical study of dprofloxacin and cotrimoxazole in respiratory tract infections. In Proceedings of the 1st International Ciprofloxacin Workshop, pp. 260-4. Excerpta Medica, Amsterdam. Osada, Y. & Ogawa, H. (1983). Antimycoplasmal activity of ofloxadn (DL-8280). Antimicrobial Agents and Chemotherapy 23, 509-11. Saito^A., Katsu, M., Saito, A. & Sojeima, R. (1987). Ofloxacin in respiratory tract infections. Drugs 34, Suppl. 1, 83-9. Sato, K., Matsuura, Y., Inove, M., Une, T., Osada, Y., Ogawa, H. et al. (1982). In vitro and in vivo activity of DL-8280, a new oxazine derivative. Antimicrobial Agents and Chemotherapy 22,548-53.
