Journal of Antimicrobial Chemotherapy (1990) 26, 237-246
Temafloxacin in acute purulent exacerbations of chronic bronchitis B. I. Davits', F. P. V. Maesen*, H. L. L. Gubbeunans* and H. M. H. G. Cramers'
Temafloxacin hydrochloride, a new fluoroquinolone, was given orally in doses of 300 or 600 mg twice daily for ten days to 36 patients, all hospitalized because of severe acute purulent exacerbations of chronic bronchitis. Sputum cultures before, during and after treatment showed that the infection was eliminated in 12/18 evaluable patients given 300 mg and in 13/16 receiving the 600 mg doses. Haemophilia influenzae, Branhamella catarrhalis and Streptococcus pneumoniae were effectively eliminated, but only half the Pseudomonas aeruginosa infections were eradicated. MICs for most pathogens were 1 mg/1 or less (including the majority of the pneumococci) but the MICs for Ps. aeruginosa ranged from 0-5 to > 16 mg/1, those for 10 of the 22 strains being > 2 mg/1. Pharmacokinetic studies on serum and sputum specimens showed serum Cam, values of 3-5 and 6-0 mg/1, the sputum C _ being 2-35 and 417 mg/1 after the different doses. No interaction with concomitant theophylline could be found. Two patients complained of moderate nausea or water brash. Temafloxacin can be considered safe and effective at these dosages, but for Ps. aeruginosa infections higher dosages need to be investigated.
Introduction
Temafloxacin hydrochloride, A-62254 (the hydrochloride of Abbott 63004), is a new fluoroquinolone which has been recently developed (Hardy et al., 1987; Nye et al., 1989). Its chemical name is l-(2,4-difluorophenyl) -6fluoro-7-(3-methylpiperazin-l-yl)1, 4-dihydro-4-oxyquinoline-3 carboxylic acid hydrochloride. Preliminary studies in a wide variety of experimental animals have shown that the drug is safe, and it is well absorbed after oral administration. Studies in human volunteers given doses varying from 100 mg to 1000 mg have confirmed thesefindings,with linear pharmacokinetics in the 200 to 600 mg dose range (P. J. Carpentier, personal communication) and a rather long elimination-phase half-life. Temafloxacin is highly active against many species of bacteria (Chin et al., 1988; Barry & Jones, 1989; Nye et al., 1989), with an antibacterial activity approximating to that of ofloxacin and ciprofloxacin. In view of this we were asked to carry out a small in-vitro study on recent clinical isolates of Streptococcus pneumoniae, Haemophilus influenzae and Branhamella catarrhalis to see if there would be any ethical objections to carrying out a clinical study in patients with acute purulent exacerbations of chronic bronchitis. The local strains of H. influenzae and B. catarrhalis were highly sensitive to temafloxacin, and strains of Str. pneumoniae with MICs higher than 1 mg/1 were rare. Study of the investigator's manual and the literature published before the investigation started showed that the MICJJ and MIC,,, values for Pseudomonas aeruginosa were 237 0305-7453/90/080237+10 $02.00/0
© 1990 The British Society for Antimicrobial Chemotherapy
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Departments of "Medical Microbiology, bRespiratory Diseases and 'Biopharmacy, De Wever Ziekenhuis, 6401 CX Heerlen, The Netherlands
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B. I. Davies et aL
approximately 1 mg/1 (Hardy et al., 1987). Because of these findings we included patients with Ps. aeruginosa infections in the study, as well as those with the more conventional respiratory pathogens. The Hospital Ethical Committee examined the protocol and gave permission for the clinical study to take place. Materials and methods
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Thirty six patients, all hospitalized because of acute purulent exacerbations of chronic bronchitis serious enough to require hospital admission, gave their informed consent to participate in the study. Any patients known to be allergic to quinolones were excluded, as were any with bronchogenic carcinoma, pulmonary tuberculosis or pneumonia, any with a compromised immune status (e.g. neutropenia) and any person who had preexisting central nervous system disease which could lead to dizziness or convulsions. No other antimicrobial agents were permitted simultaneously or in the three days prior to admission, and no mineral antacids were allowed. Two different drug dosages were investigated. The manufacturer provided numbered packs of capsules and these were allocated to the patients at random according to the sequential study numbers. There was a sealed randomization list which was not opened until the study documentation was complete. Half the patients received three 100 mg temafloxacin capsules twice daily for 10 days whereas the others were given three 200 mg capsules (swallowed with water, two hours after breakfast or a light evening meal). Expectorated sputum was examined microscopically and cultured before the start of treatment, on the third treatment day and on the day after the end of treatment (study day 11). The patients remained in hospital seven days more before being discharged home and a further sputum sample was examined bacteriologically on the 17th study day. Sputum was washed by the standard Dutch method (Mulder et al., 1952; Davies & Maesen, 1983) before being cultured. Smears of the purulent material thus obtained were stained by Gram's method. On admission of the patient to hospital, sputum was sent immediately to the laboratory and the results of the urgent Gram-stained smear were telephoned directly to the ward, where a decision was made on clinical grounds whether to included the patient in the study or whether immediate empirical therapy was required. Bacteria were identified by standard methods (Cowan, 1974). Susceptibility tests were carried out by the disc-diffusion method, but agar-dilution MIC measurements were made at the end of the study. A Denley multiple inoculator was used, with an inoculum of approximately 5 x 104 organisms per point and the plates were incubated in an atmosphere containing 5% CO2 (Davies, Maesen & Brouwers, 1982). Geometric mean MIC values were calculated by means of a programmable electric calculator (Hewlett Packard HP 97). Blood samples were collected from all patients on the first treatment day for measurement of the temafloxacin concentrations. These were obtained before the first drug dose and 1,2, 3, 5, 7,9 and 11 h after it. Pooled 2 h specimens of sputum were also obtained on the first treatment day while the sputum was still purulent. These were collected over 2 h before the first drug dose, and 0-2, 2-4, 4-6, 6-8 and 10-12 h after it (immediately before the next drug dose was given). A standard agar-well diffusion method (Davies et al., 1982) was used for all the drug measurements in large assay plates (Nunc 1015) containing Isosensitest agar (Oxoid CM 471). The amount of agar used was 200 ml per plate for the serum assays and 300 ml for those on sputum. The
Temafloxadn in chronic bronchitis
239
Results
The patients investigated included 28 males (mean age 68-2 years, mean body weight 64-9 kg) and right females (mean age 606 years, mean body weight 610 kg). Analysis of the ages and weights of the two groups of 14 male patients receiving 300 mg or 600 mg . dosages showed no differences between the two series. However, the four females given 600 mg doses of temafloxadn were, on average, slightly older (65-7 compared with 55-5 years) and heavier (63-5 compared with 58-5 kg) than the four receiving 300 mg doses. The results of the sputum cultures in the entire group of 36 patients are presented in Table I, which shows clearly that most of the original infecting organisms were eliminated. Several patients yielded relatively unusual organisms in their pre-treatment sputum specimens. One patient produced Neisseria meningitidis, one Proteus mirabilis, one Staphylococcus aureus and one other yielded a Corynebacterium sp. which we were unable to identify. One patient suffered a superinfection with a strain of Str.pneumoniae resistant to temafloxadn on day 3 for which he was given bacampirillin. There were, in total, ten patients with Ps. aeruginosa infections, five in each dosage group. In the 300 mg group, three infections were eliminated and two persisted, whereas in the four evaluable patients receiving 600 mg only two of the four infections were successfully eradicated and the other two recurred after initial elimination. There
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sputum was not washed or homogenized before assay, and only purulent material was placed in the wells. The indicator strain was Escherichia coli 1341 (kindly supplied by Hoffmann La Roche, Basel) and the surfaces of the assay plates were inoculated with a 1:1000 dilution of an overnight broth cuture and allowed to dry before holes 10 mm in diameter were punched in the medium. The assays were incubated overnight at 37°C, in air. The standard solutions were prepared in sterile horse serum and covered the range 0-125-8 mg/1. Because of the differences in the depth of the medium, standard solutions were employed in every assay plate. Mean concentration-time curves were constructed for the serum and the sputum results with both drug dosages after the randomization code had been broken. The areas under the individual 0-11 h concentration-time curves were calculated by a special computer programme (Storey & Davies, 1986). Blood concentrations of theophylline were monitored before, during and after the administration of temafloxadn in the first 13 patients to receive both drugs. The pre-temafloxacin specimens were taken at 11 am two days and one day before the start, and daily measurements (always at 11 am) were continued up to the 1 lth study day unless theophylline had been stopped earlier. Fluorescence polarography was employed for the theophylline assays (TDX, Abbott Laboratories). Patients were assessed clinically each day throughout the period of hospitalization, and a special watch was kept for the occurrence of any unwanted drug reactions. Conventional biochemical and haematological testing was carried out before starting temafloxadn and these tests were repeated on study days 3 or 4 and 11. Microscopical and chemical analysis of urine was also carried out on these occasions. Clinical assessment of efficacy was carried out on study days 11 and 17, and followed the same standard protocol used in all our previous studies (Davies et al., 1978) with results bring classified as 'excellent', 'good', 'moderate' or 'poor'. Bacteriological evaluation was carried out on the same days and followed the scheme of the Working Party of the British Sodety for Antimicrobial Chemotherapy (Working Party, 1989).
240
B. I. Dairies et aL Table L Sputum culture results (36 patients) Study day
3
11
17
H. influenzae Ps. aeruginosa B. catarrhalis Str. pneumoniae Ps. aeruginosa+H. influeraae Ps. aeruginosa + Str. pneumoniae Ps. aeruginosa+B. catarrhalis H. influenzae + Str. pneumoniae B. catarrhalis+Str. pneumoniae B. catarrhalis + H. influenzae Corynebacterium spp. Streptococcus spp. H. influenzae + Str. pneumoniae+ B. catarrhalis N. meningitidis Pr. mirabilis Staph. aureus
11 6 5 — 2
3 — 1
3 — —
4 — 1
2
—
—
—
1 —
1 1
Negative culture/no sputum produced Dropped out/required otheT antibiotics
— —
30 2
25 4'
31 —
•One patient died on day 17.
were five patients with pneumococcal infections, three in the 300 mg group and two who received 600 mg doses of temafloxacin. Four patients dropped out of the study or could not be assessed for other reasons. One of them (patient 10) was infected from the outset with a temafloxacin-resistant strain of Ps. aeruginosa (MIC > 16 mg/1) and was changed over on the fourth treatment day to ceftazidime. In retrospect, she failed to fulfil the entry criterion of susceptibility of the pathogen and has been assessed as unevaluable. Another patient, who had left ventricular decompensation, refused the last four drug doses and died from heart failure on the 17th study day. He also was considered as unevaluable. Two others, one with heavily purulent sputum and persistently positive sputum cultures yielding relatively resistant Corynebacterium spp., as well as the patient described above with the pneumococcal superinfection, required additional bacampicillin and were assessed as treatment failures. The results of the MIC measurements are shown in Table II. Most of the Ps. aeruginosa isolated showed temafloxacin MICs of 0-5-4 mg/1, although neither the highly resistant strain in patient 10 (already referred to) nor the Ps. aeruginosa isolates with MICs of 8 and 16 mg/1 post-treatment (in two other patients) could be eliminated. The M I Q Q was > 16 mg/1 and the geometric mean MIC was 31 mg/1. All strains of H. influenzae and B. catarrhalis were highly susceptible, with MIC*, values of 0-06 mg/1 and geometric mean MICs of 0-035 and 0-043 mg/1,respectively,and all were effectively eradicated. Only the one highly resistant strain of Str. pneumoniae was found, the other 17 all showing MICs of 1 mg/1, or less, with a geometric mean MIC of 0-73 mg/1. A general analysis of the bacteriological efficacy results (Table HI) failed to show a difference between the patients given 300 and 600 mg doses of temafloxacin. The pharmacokinetic results (Table TV) showed obvious differences between the
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0
Temafloxadn in chronic bronchitis
241
Table IL MICs for temafloxadn (including strains from the pilot study) Numbers of strains with these MICs (mg/1): O03 (M)6 0-125 0-25 0-5 1 2 4 8 16 >16 G.M.
Organism Ps. aeruginosa (22) H. influenzae (36) B. catarrhalis (23) Str. pneumonia; (18)
— — 3 0 4 13 —
8 1
— 1 2 —
— 4 3 5 3 i — _ _ _ — 1
— 7
_ _ _ 8 — —
2
2 3* — — _
— —
— _ — 1*
3109 0035 0-043 0-733
patients receiving 300 mg doses of temafloxadn and these taking 600 mg. On doubling the dose, the serum C ^ values practically doubled, as did the areas under the 0-11 h concentration-time curves. The elimination phase half-lives varied from 9-3 h after 300 mg to 11-7 h after 600 mg doses of temafloxadn in this group of relatively elderly patients. Eleven hours after the first drug administration the serum concentrations still averaged 1-58 and 2-87 mg/1 after 300 and 600 mg temafloxadn. In general, the (?„„ was reached in just under 3 h. The mean maximum concentration in sputum was reached somewhat later (4-25-5-35 h after drug administration) and was rather lower than the C^ in serum (2-35 mg/1 compared with 3-48 mg/1 in serum after the 300 mg dose, and 4-17 mg/1 compared with 5-97 mg/1 in serum after the 600 mg dose of temafloxadn). Furthermore, the 0-11 h AUC values in sputum were only 55-62% of the corresponding values in serum. Penetration of temafloxadn from blood to sputum varied between 55-2% and 69-8%, according to the method of calculation (Table IV). The course of the serum and sputum concentration-time curves is shown graphically in Figure 1. However, the interindividual variations in concentrations were particularly marked, espedally 1, 2 and 3 h after administration of the 600 mg temafloxadn dose. Theophylline was given concomitantly to 33 of the 36 patients in the study. Two patients were treated intravenously throughout, 17 changed from iv to oral administration and 14 were only given the drug by mouth. The theophylline concentrations in
Table ED. Bacteriological assessment of 36 patients treated with temafloxadn 300 mg doses 11 17
600 mg doses 11 17
Elimination Persistence Superinfection Elimination with recurrence Elimination with reinfection Not evaluable
14 3 1 — —
12 3 1
15 1
13
2
— — 2
2 1 2
Percentage showing elimination
77-8
66-7
93-7
81-2
Study days:
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"Same strain on three occasions in one patient (patient 10). 'One patient with pneumococcal superinfection. G.M., Geometric mean MIC.
242
B. I. Davfes et aL Table TV. Phannacokinetic results with temafloxacin
300 mg dosage
600 mg dosage
3-48 (±1-15)
5-97 (±1-70) 2-89 11-7
Serum results C m (mg/1)
2-76 9-3
23-4(±8-7)
mean 0-11 h AUC (mg/l.h) range
9-7 to 41-6
42-4 (±134) 211 to 72-8
mean concentrations Sputum results C^ (mg/1)
1-58 (±08)
2-87 (±119)
2-35 (±1-34)
417 (±211) 5-35 23-4 (±9-5)
4-25
14-55 (±8-54)
mean 0-11 h AUC (mg/l.h) range mean concentrations 10-12 h after dosage (mg/1)
3-9 to 30-2
1-21 (±0-93)
13-8 to 45-4
1-99 (±219)
Penetration, blood to sputum
as based on peak: peak values
67-5% 622%
as based on AUC: AUC values
69-8% 55-2%
serum at 11 am on the two days prior to starting temafloxacin averaged 7-55 ( ± 2-45) and 7-28 ( ± 2-14) mg/1, respectively, in the 13 patients studied in detail. The mean serum theophylline concentrations actually fell when temafloxacin therapy was started, those on the first three treatment days averaging 5-98, 6-99 and 7-22 mg/1, respectively. The mean theophylline serum concentration reached its maximum on the seventh temafloxacin day (8-08, ± 3-74 mg/1). Separate analysis of the theophylline concentrations in patients given the drug intravenously and those treated orally showed only minimal differences. Temafloxacin did not lead to any accumulation of theophylline, and there was no evidence of drug interaction. The clinical results, assessed on the study days 11 and 17, showed that in both dosage groups 80-90% of the patients yielded excellent clinical results one day after the end of
4
6
S
12
Tima (h) after first drug dose
Figure 1. Scrum concentrations after 600 mg ( • ) , and 300 mg ( • ) doses, and sputum concentration* after 600 mg (O), and 300 mg ( • ) doses of temafloxacui.
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11 h after dosage (mg/1)
Temafloxadn hi chronic bronchitis
243
Table V. Clinical results with two dosages of tcmafloxacin in 36 patients
Clinical assessment Excellent Good Moderate Failure Not evaluable
14
600 mg dosage study day 11 17
4 —
13 1 — 4 —
16 — 1 — 1
11 4 1 — 2
14/18 77-8
13/18 72-2
16/17
11/16 68-8
941
the treatment course. After the follow-up week the number fell to 13 out of 18 (72-2%) in the group given 300 mg doses of temafloxacin. In the group given the higher dosage, 16 of the 17 evaluable patients yielded excellent results on study day 11 although this proportion fell to 11 out of 16 (68-8%) at the end of the follow-up week. In each of the two dosage groups of 18 patients, there were 17 who were completely free of any unwanted drug effects. One patient reported moderate nausea from day 3 onwards while receiving 300 mg doses of temafloxacin which continued for three days after the course of treatment had ended. Another patient given 600 mg doses had a moderate degree of waterbrash during the first three days of treatment, together with slight diarrhoea on the first temafloxacin day. However, the problems cleared up spontaneously. No patient felt it necessary to discontinue the temafloxacin because of any unwanted drug effects. Discussion
We have, in recent years, studied a number of the new quinolones in seriously ill patients admitted to hospital because of acute purulent exacerbations of chronic bronchitis. Enoxacin (Davies, Maesen & Teengs, 1984) produced too many adverse drug reactions, almost certainly due to interaction with theophylline (Wijnands et al., 1987), a drug that is almost universally used in these patient. Subsequent susceptibility studies with pefloxacin (Maesen, Davies & Teengs, 1985) and fleroxacin (unpublished results) have shown that some quinolones, although well tolerated and with advantageous phannacokinetic properties, are insufficiently active against Str. pneumoniae for general use in the treatment of respiratory infections. Ciprofloxacin, also studied, was the most active quinolone in vitro, but its phannacokinetic properties were inferior to other quinolones (Davies, Maesen & Baur, 1986). Furthermore, there is evidence of an interaction between ciprofloxacin and theophylline (Raoof, Wollschlager & Khan, 1987) leading to accumulation of the latter. Up to now, the only consistently effective quinolone in such acute purulent exacerbations has been ofloxacin, but only in doses as high as 800 mg (Maesen et al., 1987). A dosage schedule of 800 mg ofloxacin twice daily was successful in many patients with infections associated with Ps. aeruginosa (Meek, Maesen & Davies, 1989). For an orally administered quinolone antimicrobial agent to be reliably effective in such patients, it must be adequately absorbed from the gut, well distributed through the body (penetrating readily through the bronchial mucosa into
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Number excellent Percentage
300 mg dosage study day 11 17
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B. L Darks et aL
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the sputum), and must be highly active against the expected pathogens. In general, there is no problem with the quinolones in the eradication of H. influenzae or B. catarrhalis but it is the pneumococcal and pseudomonas infections which usually produce the difficulties (Davies & Maesen, 1986, 1987). Temafloxacin (A-62254) is one of the newer quinolones under development by Abbott Laboratories (Barry & Jones, 1989) and, in experimental mice, yields serum concentrations which are much higher than those of ciprofloxacin. Furthermore, it is more active than ciprofloxacin against Str.pneumoniae (Hardy et al., 1987; Nye et al., 1989). However, recently published in-vitro studies have shown that it is slightly less active than ciprofloxacin against Ps. aeruginosa (Barry & Jones, 1989; Nye et al., 1989) with MIQo values as high as 16 mg/1 (Barry & Jones, 1989). Studies on the pharmacokinetics of temafloxacin in healthy young volunteers (Nye et al., 1989) have revealed serum C^ values averaging 3-3 mg/1 after a 400 mg dose, with a r , ^ value of 1-5 (±0-6)h. Temafloxacin penetrated slowly into blister fluid but equilibration was reached approximately 5 h post-dose. The ratio of the blister fluid to serum AUC values was slightly less than with ofloxacin (Lockley, Wise & Dent, 1984). The pharmacokinetic results in the present study confirmed that the drug was well absorbed after oral administration and that the serum C ^ and AUCo-n values both rose in proportion to the dose given. The twice daily drug administration did not permit us to study AUC values for more than 11 h. The actual C^ and AUC values attained in the serum after 600 mg temafloxacin were practically identical with those after the same dose of ofloxacin but the elimination phase half-life after the 600 mg temafloxacin dose (roughly 11 h) was slightly longer that that of ofloxacin (± 10 h) in comparable patients (Davies et at., 1987). However, the penetration from blood to sputum was clearly less with temafloxacin as happened in the blister fluid model (Nye et al., 1989). After the 600mg dose the mean C^ in sputum was 417 (±211) mg/1, compared with the 61 mg/1 after ofloxacin, suggesting a penetration of 60-70% rather than 70-100%. The main problem in the present study was not the failure to eliminate pneumococci, which might have been predicted by relating the concentrations reached in serum and sputum (Table TV) to the rather low MICs of temafloxacin (Table II) for pneumococci. Instead, most of the difficulties occurred with Ps. aeruginosa and Table II has already shown that there was a wide spread in the MIC values between 0-5 and > 16 mg/1. There was a slight tendency for the MICs for Ps. aeruginosa to rise during treatment, which is an unfortunate property of many quinolones (Davies et al., 1986), particularly pefloxacin. This rise was mainly responsible for the persistence of some symptomatic Ps. aeruginosa infections and the recurrence of others after apparent initial eradication (Tables II and m ) . Although Ps. aeruginosa is not amongst the three most common organisms to be associated with acute purulent exacerbations of chronic bronchitis in this area, it nevertheless occurs in the fourth position, accounting for approximately 10% of isolates (Davies & Maesen, 1988). Furthermore, unlike many study protocols, we did not specifically exclude patients with Ps. aeruginosa infections unless the organism was shown to be resistant to temafloxacin (zone of inhibition of growth less than IS mm in diameter) initially. Occasional patients with purulent infections associated with Corynebacterium spp. (a highly unusual pathogen) failed to improve on temafloxacin, these strains yielding MIC values of 2-4 mg/1. We have seen such infections persist or develop in small numbers of patients in studies with ofloxacin (e.g. Meek el al., 1989). There was no evidence of any interaction with theophylline and no
Temafloxsdn in chronic bronchitis
245
sign of accumulation of the latter. The unwanted drug effects noted were mild or moderate, only two of the 36 patients having any complaints whatsoever. In conclusion, temafloxacin is a well tolerated antimicrobial agent, with pharmacokinetic and antibacterial properties making it suitable for the treatment of respiratory infections. The only caveat remains its effectiveness against Ps. aeruginosa respiratory infections, and higher drug dosages may be necessary. Further studies with the 600 mg doses are clearly needed. Acknowledgements
References . Barry, A. L. & Jones, R. N. (1989). In-vitro activities of temafloxacin, tosufloxacin (A-61827) and five other fluoroquinolone agents. Journal of Antimicrobial Chemotherapy 23, 527-35. Chin, N. X., Figueredo, V. M., Novelli, A. & Neu, H. C. (1988). In vitro activity of temafloxacin, a new difluoro quinolone antimicrobial agent. European Journal of Clinical Microbiology and Infectious Diseases 7, 58-63. Cowan, S. T. (1974). Cowan and Steel's Manual for the Identification of Medical Bacteria, 2nd edn. Cambridge University Press, London. Davies, B. I. & Maesen, F. P. V. (1983). The diagnosis and treatment of respiratory infections. In A Clinical Approach to Progress in Infectious Diseases (Brumfitt, W. & Hamilton-Miller, J. M. T., Eds), pp. 132-58. Oxford University Press, Oxford. Davies, B. I. & Maesen, F. P. V. (1986) Quinolones in chest infections. Journal of Antimicrobial Chemotherapy 18, 296-9. Davies, B. I. & Maesen, F. P. V. (1987). Respiratory infections: clinical experiences with the new quinolones. Pharmaceutisch Weekblad (Scientific Edition), Suppl. 9, S53-7. Davies, B. I. & Maesen, F. P. V. (1988). The epidemiology of respiratory tract pathogens in southern Netherlands. European Respiratory Journal 1, 415-20. Davies, B. 1., Maesen, F. P. V. & Baur, C. (1986). Ciprofloxacin in the treatment of acute exacerbations of chronic bronchitis. European Journal of Clinical Microbiology, 5, 226-31. Davies, B. I., Maesen, F. P. V., Brombacher, P. J. & Sjovall, J. (1978). Twice daily dosage of bacampicillin in chronic bronchitis. A double-blind study. Scandinavian Journal of Respiratory Diseases 59, 249-56. Davies, B. I., Maesen, F. P. V. & Brouwers, J. (1982). Cefoperazone in acute exacerbations of chronic bronchitis. Journal of Antimicrobial Chemotherapy 9, 149-55. Davies, B. I., Maesen, F. P. V., Geraedts, W. H. & Baur, C. (1987). Penetration of ofloxacin from blood to sputum. Drugs 34, Suppl. 1, 26-32. Davies, B. I., Maesen, F. P. V. & Teengs, J. P. (1984). Serum and sputum concentrations of enoxacin after single oral dosing in a clinical and bacteriological study. Journal of Antimicrobial Chemotherapy 14, Suppl. C, 83-9. Davies, B. I., Maesen, F. P. V., Teengs, J. P. & Baur, C. (1986). Neue orale Chinolon-Verbindungen bci chronischer Bronchitis. Infection 14, Suppl. 1, S73-8. Hardy, D. J., Swanson, R. N., Hensey, D. M., Ramer, N. R., Bower, R. R., Hanson, C. W. et al. (1987). Comparative antibacterial activities of temafloxacin hydrochloride (A-62254) and two reference fluoroquinolones. Antimicrobial Agents and Chemotherapy 31, 1768-74.
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We should like to acknowledge the help of Dr P. J. Carpentier of Abbott Laboratories (Chicago), and Ms A. Haydock of TIL (Medical) Ltd, Guildford, Surrey, who initiated and monitored the study and arranged the supplies of temafloxacin. The figure was drawn by Mr J. Smeets, Head of the Lung Function Department of the De Wever Hospital. The laboratory tests were coordinated by Mr J. Kliffen and Mrs M. Debije-Wolfs and the manuscript was typed by Mrs J. Winkens-Frissen and Miss M. Krutzen.
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(Received 27 November 1989; revised version accepted 2 April 1990)
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Locklcy, M. R., Wise, R. & Dent, J. (1984). The pharmacokinctics and tissue penetration of ofloxacin. Journal of Antimicrobial Chemotherapy 14, 647-52. Maesen, F. P. V., Davies, B. I., Geraedts, W. H. & Baur, C. (1987). The use of quinoloncs in respiratory tract infections. Drugs 34, Suppl. 1, 74-9. Maesen, F. P. V., Davies, B. I. & Teengs, J. P. (1985). Pefloxacin in acute exacerbations of chronic bronchitis. Journal of Antimicrobial Chemotherapy 16, 379-88. Meek, J. C. E., Maesen, F. P. V. & Davies, B. I. (1989). A prospective study of ofloxacin in acute exacerbations of chronic respiratory disease associated with Pseudomonas aeruginosa. Journal of Antimicrobial Chemotherapy 24, 447-53. Mulder, J., Goslings, W. R. O., van der Plas, M. C. & Lopes Cardozo, P. (1952). Studies on the treatment with antibacterial drugs of acute and chronic mucopurulent bronchitis caused by Haemophilus influenzae. Ada Medica Scandinavica 143, 32-49. Nye, K., Shi, Y. G., Andrews, J. M., Ashby, J. P. & Wise, R. (1989). The in-vitro activity, pharmacokinetics and tissue penetration of temafloxacin. Journal of Antimicrobial Chemotherapy 24, 415-24. Raoof, S., Wollschlager, C. & Khan, F. A. (1987). Ciprofloxacin increases serum levels of theophylline. American Journal of Medicine 82, Suppl. 4A, 115-8. Storey, B. E. & Davies, B. I. (1986). A simple computer program for calculating areas under concentration-time curves. Journal of Antimicrobial Chemotherapy 18, 281-5. Wijnands, W. J. A., Vree, T. B., Baars, A. M. & van Herwaarden, C. L. A. (1987). Steady-state kinetics of the quinolone derivatives ofloxacin, enoxacin, ciprofloxacin and pefloxacin during maintenance treatment with theophylline. Drugs 34, Suppl. 1, 159-69. Working Party (1989). The clinical evaluation of antibacterial drugs. Report of a working party of the British Society for Antimicrobial Chemotherapy. Journal of Antimicrobial Chemotherapy 23, Suppl. B, 1-42.
Temafloxacin in acute purulent exacerbations of chronic bronchitis B. I. Davits', F. P. V. Maesen*, H. L. L. Gubbeunans* and H. M. H. G. Cramers'
Temafloxacin hydrochloride, a new fluoroquinolone, was given orally in doses of 300 or 600 mg twice daily for ten days to 36 patients, all hospitalized because of severe acute purulent exacerbations of chronic bronchitis. Sputum cultures before, during and after treatment showed that the infection was eliminated in 12/18 evaluable patients given 300 mg and in 13/16 receiving the 600 mg doses. Haemophilia influenzae, Branhamella catarrhalis and Streptococcus pneumoniae were effectively eliminated, but only half the Pseudomonas aeruginosa infections were eradicated. MICs for most pathogens were 1 mg/1 or less (including the majority of the pneumococci) but the MICs for Ps. aeruginosa ranged from 0-5 to > 16 mg/1, those for 10 of the 22 strains being > 2 mg/1. Pharmacokinetic studies on serum and sputum specimens showed serum Cam, values of 3-5 and 6-0 mg/1, the sputum C _ being 2-35 and 417 mg/1 after the different doses. No interaction with concomitant theophylline could be found. Two patients complained of moderate nausea or water brash. Temafloxacin can be considered safe and effective at these dosages, but for Ps. aeruginosa infections higher dosages need to be investigated.
Introduction
Temafloxacin hydrochloride, A-62254 (the hydrochloride of Abbott 63004), is a new fluoroquinolone which has been recently developed (Hardy et al., 1987; Nye et al., 1989). Its chemical name is l-(2,4-difluorophenyl) -6fluoro-7-(3-methylpiperazin-l-yl)1, 4-dihydro-4-oxyquinoline-3 carboxylic acid hydrochloride. Preliminary studies in a wide variety of experimental animals have shown that the drug is safe, and it is well absorbed after oral administration. Studies in human volunteers given doses varying from 100 mg to 1000 mg have confirmed thesefindings,with linear pharmacokinetics in the 200 to 600 mg dose range (P. J. Carpentier, personal communication) and a rather long elimination-phase half-life. Temafloxacin is highly active against many species of bacteria (Chin et al., 1988; Barry & Jones, 1989; Nye et al., 1989), with an antibacterial activity approximating to that of ofloxacin and ciprofloxacin. In view of this we were asked to carry out a small in-vitro study on recent clinical isolates of Streptococcus pneumoniae, Haemophilus influenzae and Branhamella catarrhalis to see if there would be any ethical objections to carrying out a clinical study in patients with acute purulent exacerbations of chronic bronchitis. The local strains of H. influenzae and B. catarrhalis were highly sensitive to temafloxacin, and strains of Str. pneumoniae with MICs higher than 1 mg/1 were rare. Study of the investigator's manual and the literature published before the investigation started showed that the MICJJ and MIC,,, values for Pseudomonas aeruginosa were 237 0305-7453/90/080237+10 $02.00/0
© 1990 The British Society for Antimicrobial Chemotherapy
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Departments of "Medical Microbiology, bRespiratory Diseases and 'Biopharmacy, De Wever Ziekenhuis, 6401 CX Heerlen, The Netherlands
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approximately 1 mg/1 (Hardy et al., 1987). Because of these findings we included patients with Ps. aeruginosa infections in the study, as well as those with the more conventional respiratory pathogens. The Hospital Ethical Committee examined the protocol and gave permission for the clinical study to take place. Materials and methods
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Thirty six patients, all hospitalized because of acute purulent exacerbations of chronic bronchitis serious enough to require hospital admission, gave their informed consent to participate in the study. Any patients known to be allergic to quinolones were excluded, as were any with bronchogenic carcinoma, pulmonary tuberculosis or pneumonia, any with a compromised immune status (e.g. neutropenia) and any person who had preexisting central nervous system disease which could lead to dizziness or convulsions. No other antimicrobial agents were permitted simultaneously or in the three days prior to admission, and no mineral antacids were allowed. Two different drug dosages were investigated. The manufacturer provided numbered packs of capsules and these were allocated to the patients at random according to the sequential study numbers. There was a sealed randomization list which was not opened until the study documentation was complete. Half the patients received three 100 mg temafloxacin capsules twice daily for 10 days whereas the others were given three 200 mg capsules (swallowed with water, two hours after breakfast or a light evening meal). Expectorated sputum was examined microscopically and cultured before the start of treatment, on the third treatment day and on the day after the end of treatment (study day 11). The patients remained in hospital seven days more before being discharged home and a further sputum sample was examined bacteriologically on the 17th study day. Sputum was washed by the standard Dutch method (Mulder et al., 1952; Davies & Maesen, 1983) before being cultured. Smears of the purulent material thus obtained were stained by Gram's method. On admission of the patient to hospital, sputum was sent immediately to the laboratory and the results of the urgent Gram-stained smear were telephoned directly to the ward, where a decision was made on clinical grounds whether to included the patient in the study or whether immediate empirical therapy was required. Bacteria were identified by standard methods (Cowan, 1974). Susceptibility tests were carried out by the disc-diffusion method, but agar-dilution MIC measurements were made at the end of the study. A Denley multiple inoculator was used, with an inoculum of approximately 5 x 104 organisms per point and the plates were incubated in an atmosphere containing 5% CO2 (Davies, Maesen & Brouwers, 1982). Geometric mean MIC values were calculated by means of a programmable electric calculator (Hewlett Packard HP 97). Blood samples were collected from all patients on the first treatment day for measurement of the temafloxacin concentrations. These were obtained before the first drug dose and 1,2, 3, 5, 7,9 and 11 h after it. Pooled 2 h specimens of sputum were also obtained on the first treatment day while the sputum was still purulent. These were collected over 2 h before the first drug dose, and 0-2, 2-4, 4-6, 6-8 and 10-12 h after it (immediately before the next drug dose was given). A standard agar-well diffusion method (Davies et al., 1982) was used for all the drug measurements in large assay plates (Nunc 1015) containing Isosensitest agar (Oxoid CM 471). The amount of agar used was 200 ml per plate for the serum assays and 300 ml for those on sputum. The
Temafloxadn in chronic bronchitis
239
Results
The patients investigated included 28 males (mean age 68-2 years, mean body weight 64-9 kg) and right females (mean age 606 years, mean body weight 610 kg). Analysis of the ages and weights of the two groups of 14 male patients receiving 300 mg or 600 mg . dosages showed no differences between the two series. However, the four females given 600 mg doses of temafloxadn were, on average, slightly older (65-7 compared with 55-5 years) and heavier (63-5 compared with 58-5 kg) than the four receiving 300 mg doses. The results of the sputum cultures in the entire group of 36 patients are presented in Table I, which shows clearly that most of the original infecting organisms were eliminated. Several patients yielded relatively unusual organisms in their pre-treatment sputum specimens. One patient produced Neisseria meningitidis, one Proteus mirabilis, one Staphylococcus aureus and one other yielded a Corynebacterium sp. which we were unable to identify. One patient suffered a superinfection with a strain of Str.pneumoniae resistant to temafloxadn on day 3 for which he was given bacampirillin. There were, in total, ten patients with Ps. aeruginosa infections, five in each dosage group. In the 300 mg group, three infections were eliminated and two persisted, whereas in the four evaluable patients receiving 600 mg only two of the four infections were successfully eradicated and the other two recurred after initial elimination. There
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sputum was not washed or homogenized before assay, and only purulent material was placed in the wells. The indicator strain was Escherichia coli 1341 (kindly supplied by Hoffmann La Roche, Basel) and the surfaces of the assay plates were inoculated with a 1:1000 dilution of an overnight broth cuture and allowed to dry before holes 10 mm in diameter were punched in the medium. The assays were incubated overnight at 37°C, in air. The standard solutions were prepared in sterile horse serum and covered the range 0-125-8 mg/1. Because of the differences in the depth of the medium, standard solutions were employed in every assay plate. Mean concentration-time curves were constructed for the serum and the sputum results with both drug dosages after the randomization code had been broken. The areas under the individual 0-11 h concentration-time curves were calculated by a special computer programme (Storey & Davies, 1986). Blood concentrations of theophylline were monitored before, during and after the administration of temafloxadn in the first 13 patients to receive both drugs. The pre-temafloxacin specimens were taken at 11 am two days and one day before the start, and daily measurements (always at 11 am) were continued up to the 1 lth study day unless theophylline had been stopped earlier. Fluorescence polarography was employed for the theophylline assays (TDX, Abbott Laboratories). Patients were assessed clinically each day throughout the period of hospitalization, and a special watch was kept for the occurrence of any unwanted drug reactions. Conventional biochemical and haematological testing was carried out before starting temafloxadn and these tests were repeated on study days 3 or 4 and 11. Microscopical and chemical analysis of urine was also carried out on these occasions. Clinical assessment of efficacy was carried out on study days 11 and 17, and followed the same standard protocol used in all our previous studies (Davies et al., 1978) with results bring classified as 'excellent', 'good', 'moderate' or 'poor'. Bacteriological evaluation was carried out on the same days and followed the scheme of the Working Party of the British Sodety for Antimicrobial Chemotherapy (Working Party, 1989).
240
B. I. Dairies et aL Table L Sputum culture results (36 patients) Study day
3
11
17
H. influenzae Ps. aeruginosa B. catarrhalis Str. pneumoniae Ps. aeruginosa+H. influeraae Ps. aeruginosa + Str. pneumoniae Ps. aeruginosa+B. catarrhalis H. influenzae + Str. pneumoniae B. catarrhalis+Str. pneumoniae B. catarrhalis + H. influenzae Corynebacterium spp. Streptococcus spp. H. influenzae + Str. pneumoniae+ B. catarrhalis N. meningitidis Pr. mirabilis Staph. aureus
11 6 5 — 2
3 — 1
3 — —
4 — 1
2
—
—
—
1 —
1 1
Negative culture/no sputum produced Dropped out/required otheT antibiotics
— —
30 2
25 4'
31 —
•One patient died on day 17.
were five patients with pneumococcal infections, three in the 300 mg group and two who received 600 mg doses of temafloxacin. Four patients dropped out of the study or could not be assessed for other reasons. One of them (patient 10) was infected from the outset with a temafloxacin-resistant strain of Ps. aeruginosa (MIC > 16 mg/1) and was changed over on the fourth treatment day to ceftazidime. In retrospect, she failed to fulfil the entry criterion of susceptibility of the pathogen and has been assessed as unevaluable. Another patient, who had left ventricular decompensation, refused the last four drug doses and died from heart failure on the 17th study day. He also was considered as unevaluable. Two others, one with heavily purulent sputum and persistently positive sputum cultures yielding relatively resistant Corynebacterium spp., as well as the patient described above with the pneumococcal superinfection, required additional bacampicillin and were assessed as treatment failures. The results of the MIC measurements are shown in Table II. Most of the Ps. aeruginosa isolated showed temafloxacin MICs of 0-5-4 mg/1, although neither the highly resistant strain in patient 10 (already referred to) nor the Ps. aeruginosa isolates with MICs of 8 and 16 mg/1 post-treatment (in two other patients) could be eliminated. The M I Q Q was > 16 mg/1 and the geometric mean MIC was 31 mg/1. All strains of H. influenzae and B. catarrhalis were highly susceptible, with MIC*, values of 0-06 mg/1 and geometric mean MICs of 0-035 and 0-043 mg/1,respectively,and all were effectively eradicated. Only the one highly resistant strain of Str. pneumoniae was found, the other 17 all showing MICs of 1 mg/1, or less, with a geometric mean MIC of 0-73 mg/1. A general analysis of the bacteriological efficacy results (Table HI) failed to show a difference between the patients given 300 and 600 mg doses of temafloxacin. The pharmacokinetic results (Table TV) showed obvious differences between the
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0
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241
Table IL MICs for temafloxadn (including strains from the pilot study) Numbers of strains with these MICs (mg/1): O03 (M)6 0-125 0-25 0-5 1 2 4 8 16 >16 G.M.
Organism Ps. aeruginosa (22) H. influenzae (36) B. catarrhalis (23) Str. pneumonia; (18)
— — 3 0 4 13 —
8 1
— 1 2 —
— 4 3 5 3 i — _ _ _ — 1
— 7
_ _ _ 8 — —
2
2 3* — — _
— —
— _ — 1*
3109 0035 0-043 0-733
patients receiving 300 mg doses of temafloxadn and these taking 600 mg. On doubling the dose, the serum C ^ values practically doubled, as did the areas under the 0-11 h concentration-time curves. The elimination phase half-lives varied from 9-3 h after 300 mg to 11-7 h after 600 mg doses of temafloxadn in this group of relatively elderly patients. Eleven hours after the first drug administration the serum concentrations still averaged 1-58 and 2-87 mg/1 after 300 and 600 mg temafloxadn. In general, the (?„„ was reached in just under 3 h. The mean maximum concentration in sputum was reached somewhat later (4-25-5-35 h after drug administration) and was rather lower than the C^ in serum (2-35 mg/1 compared with 3-48 mg/1 in serum after the 300 mg dose, and 4-17 mg/1 compared with 5-97 mg/1 in serum after the 600 mg dose of temafloxadn). Furthermore, the 0-11 h AUC values in sputum were only 55-62% of the corresponding values in serum. Penetration of temafloxadn from blood to sputum varied between 55-2% and 69-8%, according to the method of calculation (Table IV). The course of the serum and sputum concentration-time curves is shown graphically in Figure 1. However, the interindividual variations in concentrations were particularly marked, espedally 1, 2 and 3 h after administration of the 600 mg temafloxadn dose. Theophylline was given concomitantly to 33 of the 36 patients in the study. Two patients were treated intravenously throughout, 17 changed from iv to oral administration and 14 were only given the drug by mouth. The theophylline concentrations in
Table ED. Bacteriological assessment of 36 patients treated with temafloxadn 300 mg doses 11 17
600 mg doses 11 17
Elimination Persistence Superinfection Elimination with recurrence Elimination with reinfection Not evaluable
14 3 1 — —
12 3 1
15 1
13
2
— — 2
2 1 2
Percentage showing elimination
77-8
66-7
93-7
81-2
Study days:
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"Same strain on three occasions in one patient (patient 10). 'One patient with pneumococcal superinfection. G.M., Geometric mean MIC.
242
B. I. Davfes et aL Table TV. Phannacokinetic results with temafloxacin
300 mg dosage
600 mg dosage
3-48 (±1-15)
5-97 (±1-70) 2-89 11-7
Serum results C m (mg/1)
2-76 9-3
23-4(±8-7)
mean 0-11 h AUC (mg/l.h) range
9-7 to 41-6
42-4 (±134) 211 to 72-8
mean concentrations Sputum results C^ (mg/1)
1-58 (±08)
2-87 (±119)
2-35 (±1-34)
417 (±211) 5-35 23-4 (±9-5)
4-25
14-55 (±8-54)
mean 0-11 h AUC (mg/l.h) range mean concentrations 10-12 h after dosage (mg/1)
3-9 to 30-2
1-21 (±0-93)
13-8 to 45-4
1-99 (±219)
Penetration, blood to sputum
as based on peak: peak values
67-5% 622%
as based on AUC: AUC values
69-8% 55-2%
serum at 11 am on the two days prior to starting temafloxacin averaged 7-55 ( ± 2-45) and 7-28 ( ± 2-14) mg/1, respectively, in the 13 patients studied in detail. The mean serum theophylline concentrations actually fell when temafloxacin therapy was started, those on the first three treatment days averaging 5-98, 6-99 and 7-22 mg/1, respectively. The mean theophylline serum concentration reached its maximum on the seventh temafloxacin day (8-08, ± 3-74 mg/1). Separate analysis of the theophylline concentrations in patients given the drug intravenously and those treated orally showed only minimal differences. Temafloxacin did not lead to any accumulation of theophylline, and there was no evidence of drug interaction. The clinical results, assessed on the study days 11 and 17, showed that in both dosage groups 80-90% of the patients yielded excellent clinical results one day after the end of
4
6
S
12
Tima (h) after first drug dose
Figure 1. Scrum concentrations after 600 mg ( • ) , and 300 mg ( • ) doses, and sputum concentration* after 600 mg (O), and 300 mg ( • ) doses of temafloxacui.
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11 h after dosage (mg/1)
Temafloxadn hi chronic bronchitis
243
Table V. Clinical results with two dosages of tcmafloxacin in 36 patients
Clinical assessment Excellent Good Moderate Failure Not evaluable
14
600 mg dosage study day 11 17
4 —
13 1 — 4 —
16 — 1 — 1
11 4 1 — 2
14/18 77-8
13/18 72-2
16/17
11/16 68-8
941
the treatment course. After the follow-up week the number fell to 13 out of 18 (72-2%) in the group given 300 mg doses of temafloxacin. In the group given the higher dosage, 16 of the 17 evaluable patients yielded excellent results on study day 11 although this proportion fell to 11 out of 16 (68-8%) at the end of the follow-up week. In each of the two dosage groups of 18 patients, there were 17 who were completely free of any unwanted drug effects. One patient reported moderate nausea from day 3 onwards while receiving 300 mg doses of temafloxacin which continued for three days after the course of treatment had ended. Another patient given 600 mg doses had a moderate degree of waterbrash during the first three days of treatment, together with slight diarrhoea on the first temafloxacin day. However, the problems cleared up spontaneously. No patient felt it necessary to discontinue the temafloxacin because of any unwanted drug effects. Discussion
We have, in recent years, studied a number of the new quinolones in seriously ill patients admitted to hospital because of acute purulent exacerbations of chronic bronchitis. Enoxacin (Davies, Maesen & Teengs, 1984) produced too many adverse drug reactions, almost certainly due to interaction with theophylline (Wijnands et al., 1987), a drug that is almost universally used in these patient. Subsequent susceptibility studies with pefloxacin (Maesen, Davies & Teengs, 1985) and fleroxacin (unpublished results) have shown that some quinolones, although well tolerated and with advantageous phannacokinetic properties, are insufficiently active against Str. pneumoniae for general use in the treatment of respiratory infections. Ciprofloxacin, also studied, was the most active quinolone in vitro, but its phannacokinetic properties were inferior to other quinolones (Davies, Maesen & Baur, 1986). Furthermore, there is evidence of an interaction between ciprofloxacin and theophylline (Raoof, Wollschlager & Khan, 1987) leading to accumulation of the latter. Up to now, the only consistently effective quinolone in such acute purulent exacerbations has been ofloxacin, but only in doses as high as 800 mg (Maesen et al., 1987). A dosage schedule of 800 mg ofloxacin twice daily was successful in many patients with infections associated with Ps. aeruginosa (Meek, Maesen & Davies, 1989). For an orally administered quinolone antimicrobial agent to be reliably effective in such patients, it must be adequately absorbed from the gut, well distributed through the body (penetrating readily through the bronchial mucosa into
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Number excellent Percentage
300 mg dosage study day 11 17
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the sputum), and must be highly active against the expected pathogens. In general, there is no problem with the quinolones in the eradication of H. influenzae or B. catarrhalis but it is the pneumococcal and pseudomonas infections which usually produce the difficulties (Davies & Maesen, 1986, 1987). Temafloxacin (A-62254) is one of the newer quinolones under development by Abbott Laboratories (Barry & Jones, 1989) and, in experimental mice, yields serum concentrations which are much higher than those of ciprofloxacin. Furthermore, it is more active than ciprofloxacin against Str.pneumoniae (Hardy et al., 1987; Nye et al., 1989). However, recently published in-vitro studies have shown that it is slightly less active than ciprofloxacin against Ps. aeruginosa (Barry & Jones, 1989; Nye et al., 1989) with MIQo values as high as 16 mg/1 (Barry & Jones, 1989). Studies on the pharmacokinetics of temafloxacin in healthy young volunteers (Nye et al., 1989) have revealed serum C^ values averaging 3-3 mg/1 after a 400 mg dose, with a r , ^ value of 1-5 (±0-6)h. Temafloxacin penetrated slowly into blister fluid but equilibration was reached approximately 5 h post-dose. The ratio of the blister fluid to serum AUC values was slightly less than with ofloxacin (Lockley, Wise & Dent, 1984). The pharmacokinetic results in the present study confirmed that the drug was well absorbed after oral administration and that the serum C ^ and AUCo-n values both rose in proportion to the dose given. The twice daily drug administration did not permit us to study AUC values for more than 11 h. The actual C^ and AUC values attained in the serum after 600 mg temafloxacin were practically identical with those after the same dose of ofloxacin but the elimination phase half-life after the 600 mg temafloxacin dose (roughly 11 h) was slightly longer that that of ofloxacin (± 10 h) in comparable patients (Davies et at., 1987). However, the penetration from blood to sputum was clearly less with temafloxacin as happened in the blister fluid model (Nye et al., 1989). After the 600mg dose the mean C^ in sputum was 417 (±211) mg/1, compared with the 61 mg/1 after ofloxacin, suggesting a penetration of 60-70% rather than 70-100%. The main problem in the present study was not the failure to eliminate pneumococci, which might have been predicted by relating the concentrations reached in serum and sputum (Table TV) to the rather low MICs of temafloxacin (Table II) for pneumococci. Instead, most of the difficulties occurred with Ps. aeruginosa and Table II has already shown that there was a wide spread in the MIC values between 0-5 and > 16 mg/1. There was a slight tendency for the MICs for Ps. aeruginosa to rise during treatment, which is an unfortunate property of many quinolones (Davies et al., 1986), particularly pefloxacin. This rise was mainly responsible for the persistence of some symptomatic Ps. aeruginosa infections and the recurrence of others after apparent initial eradication (Tables II and m ) . Although Ps. aeruginosa is not amongst the three most common organisms to be associated with acute purulent exacerbations of chronic bronchitis in this area, it nevertheless occurs in the fourth position, accounting for approximately 10% of isolates (Davies & Maesen, 1988). Furthermore, unlike many study protocols, we did not specifically exclude patients with Ps. aeruginosa infections unless the organism was shown to be resistant to temafloxacin (zone of inhibition of growth less than IS mm in diameter) initially. Occasional patients with purulent infections associated with Corynebacterium spp. (a highly unusual pathogen) failed to improve on temafloxacin, these strains yielding MIC values of 2-4 mg/1. We have seen such infections persist or develop in small numbers of patients in studies with ofloxacin (e.g. Meek el al., 1989). There was no evidence of any interaction with theophylline and no
Temafloxsdn in chronic bronchitis
245
sign of accumulation of the latter. The unwanted drug effects noted were mild or moderate, only two of the 36 patients having any complaints whatsoever. In conclusion, temafloxacin is a well tolerated antimicrobial agent, with pharmacokinetic and antibacterial properties making it suitable for the treatment of respiratory infections. The only caveat remains its effectiveness against Ps. aeruginosa respiratory infections, and higher drug dosages may be necessary. Further studies with the 600 mg doses are clearly needed. Acknowledgements
References . Barry, A. L. & Jones, R. N. (1989). In-vitro activities of temafloxacin, tosufloxacin (A-61827) and five other fluoroquinolone agents. Journal of Antimicrobial Chemotherapy 23, 527-35. Chin, N. X., Figueredo, V. M., Novelli, A. & Neu, H. C. (1988). In vitro activity of temafloxacin, a new difluoro quinolone antimicrobial agent. European Journal of Clinical Microbiology and Infectious Diseases 7, 58-63. Cowan, S. T. (1974). Cowan and Steel's Manual for the Identification of Medical Bacteria, 2nd edn. Cambridge University Press, London. Davies, B. I. & Maesen, F. P. V. (1983). The diagnosis and treatment of respiratory infections. In A Clinical Approach to Progress in Infectious Diseases (Brumfitt, W. & Hamilton-Miller, J. M. T., Eds), pp. 132-58. Oxford University Press, Oxford. Davies, B. I. & Maesen, F. P. V. (1986) Quinolones in chest infections. Journal of Antimicrobial Chemotherapy 18, 296-9. Davies, B. I. & Maesen, F. P. V. (1987). Respiratory infections: clinical experiences with the new quinolones. Pharmaceutisch Weekblad (Scientific Edition), Suppl. 9, S53-7. Davies, B. I. & Maesen, F. P. V. (1988). The epidemiology of respiratory tract pathogens in southern Netherlands. European Respiratory Journal 1, 415-20. Davies, B. 1., Maesen, F. P. V. & Baur, C. (1986). Ciprofloxacin in the treatment of acute exacerbations of chronic bronchitis. European Journal of Clinical Microbiology, 5, 226-31. Davies, B. I., Maesen, F. P. V., Brombacher, P. J. & Sjovall, J. (1978). Twice daily dosage of bacampicillin in chronic bronchitis. A double-blind study. Scandinavian Journal of Respiratory Diseases 59, 249-56. Davies, B. I., Maesen, F. P. V. & Brouwers, J. (1982). Cefoperazone in acute exacerbations of chronic bronchitis. Journal of Antimicrobial Chemotherapy 9, 149-55. Davies, B. I., Maesen, F. P. V., Geraedts, W. H. & Baur, C. (1987). Penetration of ofloxacin from blood to sputum. Drugs 34, Suppl. 1, 26-32. Davies, B. I., Maesen, F. P. V. & Teengs, J. P. (1984). Serum and sputum concentrations of enoxacin after single oral dosing in a clinical and bacteriological study. Journal of Antimicrobial Chemotherapy 14, Suppl. C, 83-9. Davies, B. I., Maesen, F. P. V., Teengs, J. P. & Baur, C. (1986). Neue orale Chinolon-Verbindungen bci chronischer Bronchitis. Infection 14, Suppl. 1, S73-8. Hardy, D. J., Swanson, R. N., Hensey, D. M., Ramer, N. R., Bower, R. R., Hanson, C. W. et al. (1987). Comparative antibacterial activities of temafloxacin hydrochloride (A-62254) and two reference fluoroquinolones. Antimicrobial Agents and Chemotherapy 31, 1768-74.
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We should like to acknowledge the help of Dr P. J. Carpentier of Abbott Laboratories (Chicago), and Ms A. Haydock of TIL (Medical) Ltd, Guildford, Surrey, who initiated and monitored the study and arranged the supplies of temafloxacin. The figure was drawn by Mr J. Smeets, Head of the Lung Function Department of the De Wever Hospital. The laboratory tests were coordinated by Mr J. Kliffen and Mrs M. Debije-Wolfs and the manuscript was typed by Mrs J. Winkens-Frissen and Miss M. Krutzen.
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(Received 27 November 1989; revised version accepted 2 April 1990)
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