Efficacy of Temafloxacin Versus Ciprofloxacin or Amoxicillin for Lower Respiratory Tract Infections in Smokers and the Elderly PETER

G.

DAVEY, M.D.,

Dundee, Scofland, UK

The purpose of this study was to determine the effects of smoking history and age on the efficacy and safety of temafloxacin versus ciprofloxacin or amoxicillin in patients with lower respiratory tract infections (LRTIs). Data were pooled from six clinical trials designed to evaluate the efficacy and safety of temafloxacin in bacterial infections of the lower respiratory tract. Patients were selected for this analysis based on smoking history (n = 256) and age (~65 years of age [n = 3281). Results in the smoker and elderly subgroups were compared between treatment groups and with those in nonsmoker and nonelderly subgroups. Temafloxacin 300 mg or 600 mg b.i.d., ciprofloxacin 500 mg or 750 mg b.i.d., or amoxicillin 500 mg t.i.d. was administered orally for 7-14 days. Patients were assessed at enrollment, on study days 3-7, 24-72 hours post-treatment, and at 5-9 days post-treatment. Temafloxacin and the reference drugs demonstrated comparable clinical efficacy for treatment of LRTI in smokers (93.7% and 92.5%, respectively) and the elderly (94.6% and 89.3%, respectively). However, eradication of baseline pathogens in individual patients was significantly more common after temafloxacin therapy than that following treatment with the reference drugs in both smokers (99.2% versus 91.2%, p = 0.006) and elderly patients (97.5% versus 91.5%, p = 0.028). Overall, eradication rates for pretreatment pathogens were also significantly higher in smokers (99.3% versus 91.8%, p = 0.006) and in the elderly (97.8% versus 92.3%, p = 0.027). Neither age nor smoking status had a consistent effect on the rate of premature discontinuation of study drugs. Adverse events occurred at a similar rate between treatment groups in the el-

From the Department of Pharmacology and Clrnrcal Pharmacology, Nrnewells Hospital and Medical School, Universrty of Dundee, Dundee, Scotland, UK. Reprint requests should be addressed to Peter G. Davey, M.D.: Depariment of Pharmacology and Clinrcal Pharmacology, Ninewells Hosprtal and Medical School, University of Dundee, Dundee DDl 9SY, Scotland, UK.

December

derly and in the smokers. Temafloxacin appears to be a promising alternative to therapy with either ciprofloxacin or amoxicillin in the treatment of respiratory infections in high-risk patients, smokers, and the elderly.

L

ower respiratory tract infections (LRTIs), such as pneumonia and acute infective exacerbations of chronic bronchitis, are important causes of morbidity and mortality. Despite advances in antimicrobial and supportive therapy, the mortality from pneumonia has remained unchanged over the past 25 years; reported mortality rates are in the range of 6-33% [1,2]. Known risk factors for the development of LRTI include advancing age, a history of cigarette smoking, and other factors that interfere with normal host defense mechanisms [3,4]. These same factors may be associated with an increased mortality. For example, Burrows et al [51 found a lo-year mortality rate of 60% among patients with established chronic obstructive pulmonary disease (COPD) and a smoking history (mean 51.4 pack-years), whereas lo-year mortality in asthmatic patients was only 15% (mean 17.6 pack-years). (“Pack-years” = no. of packs/day x no. of years smoked at that rate.) In another series, Marrie and coworkers [4] studied 719 patients with community-acquired pneumonia and found age to be a significant predictor of mortality. These data support the need to evaluate the efficacy and safety of antimicrobial agents against LRTIs in smokers and in the elderly, in addition to general population studies. Temafloxacin is a new oral fluoroquinolone that is effective against the gram-negative and grampositive organisms that commonly cause community-acquired LRTIs. The drug has been evaluated in a series of randomized, double-blind multicenter trials; full reports of several have been published elsewhere [6-81. This article reports the results of one noncomparative trial, trials comparing different doses of temafloxacin, and three trials comparing temafloxacin with ciprofloxacin or amoxicillin. Smokers and elderly (aged 265 years) patients who were enrolled in the trials were evaluated indepen30. 1991

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SYMPOSIUMON FLUOROQUINOLONES / DAVEY TABLE I Number of Smokers and Elderly Patients Enrolled in Clinical Trials Evaluating the Efficacy of Temafloxacin Number of Patients Smokers Protocol

Treatment Regimen

ML%137 M88-169

Temafloxacin 300 mg b.i.d. Temafloxacin 300, mg b.i.d. versus temafloxacin 600 mg b.i.d. Temafloxaw 300 mg b.i.d. versus iemafloxacin 600 mg b.i.d. Temafloxacin 600 mg b.i.d. versus ciprofloxacin 500 mg b.i.d. Temafloxacin 600 mg b.i.d. versus ciprofloxacin 750 mg b.i.d. Temafloxacin 600 mg b.i.d. versus amoxlcillin 500 mg t.1.d.

M88-178 M88-201 M88-236 M88-277

Evaluable

Total

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Enrolled

54

64

13

13

21

24

1

7

00

0

40

141

53

133

143

206

161

225

34

137

39

183

256

528

328

629

Patient Population Patients were selected for analysis from among those enrolled in six clinical trials evaluating the efficacy and safety of temafloxacin in ambulatory adult patients (218 years of age) with LRTIs (Table I). The studies were approved by the institutional review boards of each participating center. Written informed consent was obtained from each patient before enrollment in any study. No patient participated in more than one trial. Patients were selected for inclusion in the trials on the basis of the following criteria: (a) acute bacterial exacerbation of chronic bronchitis, (b) asthmatic bronchitis, (c) infected bronchiectasis, or (d) uncomplicated bacterial pneumonia. LRTI was confirmed by a Gram stain of spontaneously expectorated sputum (invasive techniques for culture specimen collection in one study) obtained within 48 hours before enrollment, and patients were enrolled only if the pretreatment pathogens were sensitive to the study drugs. Female patients were enrolled only if they were postmenopausal, surgically sterilized, or not pregnant and using birth control. Exclusion criteria at entry were the following: (a) seizure disorder, (b) severe or complicated respiratory infection that required parenteral antibiotic therapy, (c) leukopenia (~1,500 cells/mm3), (d) renal impairment (creatinine ~20% above normal), (e) hypersensitivity to quinolones, or Q concurrent antimicrobial therapy or infection. All evaluable patients enrolled in each of the six trials were reviewed, and the outcomes of their treatment analyzed if they met one of the following 30, 1991

Evaluable

24

PATIENTSAND METHODS

December

Enrolled

19

dently, and the outcome of therapy was analyzed to determine the effects of these risk factors on efficacy and safety of these antimicrobial agents.

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Elderly

criteria: (a) they were smokers or (b) were aged 165 years. Patients who met the criteria for both the smoker and elderly subgroups were included in the analysis for both subgroups. Patients were considered nonevaluable if any of the following occurred: clinically significant abnormal pretreatment laboratory findings, inability to identify a pathogen or ,identification of a pathogen resistant to the study drugs, or patient request for withdrawal. Treatment Study drugs were prepared in identical capsule form. In the comparative studies, patients were randomly assigned in a double-blind protocol (except one study) to receive either temafloxacin 600 mg or the comparative regimen. Doses were administered by mouth b.i.d. (temafloxacin or ciprofloxatin) or t.i.d. (amoxicillin) for 7-14 days. Clinical Assessment Clinical status was assessed 48 hours before therapy, days 3-7 during therapy, and at 24-48 hours and 5-9 days after treatment. The following assessments were performed: medical history; complete physical examination; documentation of signs and symptoms of infection (cough severity, sputum volume and appearance, dyspnea, fever, and chills); hematology; urinalysis; and serum chemistry analysis. A chest x-ray was obtained for all patients before beginning therapy and, for patients with pneumonia, at follow-up 5-9 days after treatment. Clinical outcome was based on signs and symptoms of LRTI and classified as cure (resolution of signs and symptoms to preinfection levels), improvement (reduction in severity or number of signs and symptoms without complete resolution), failure (continuation of signs and symptoms at levels equal to or greater than preinfection levels), or 91 (suppl

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relapse (reduction of signs and symptoms to preinfection levels at the 24-72-hour post-treatment evaluation followed by an increase in signs and symptoms at the 5-g-day post-treatment evaluation).

ON FLUOROQUINOLONES/DAVEY

exact test. Binomial 95% confidence intervals (CIs) using normal approximation were computed for the differences among treatment groups by the method of Gardner and Altman [9]. RESULTS

Bacteriologic

Assessment

Specimens for bacteriologic assessment included either spontaneously expectorated sputum (considered acceptable for culture if there were ~10 squamous epithelial cells and >25 leukocytes per low-power optical field) or bronchopulmonary secretions (obtained by transtracheal aspiration or bronchoscopy). Bacteriologic assessment included bacterial culture and identification of all pathogens by standard techniques. Susceptibility breakpoints for temafloxacin were defined as an inhibition zone diameter of ~20 mm or a minimum inhibitory concentration (MIC) of 52pgimL. Bacteriologic outcome of pretreatment pathogens was classified as eradication (absence of the original pathogen or no sputum production) or failure (original pathogen present in immediate post-treatment culture or at the time of discontinuation of study drug therapy). Safety Assessment

Patients were closely monitored for clinical adverse events. Adverse events were recorded for all patients exposed to temafloxacin or reference drugs. For the purpose of this report, adverse events that were experienced by 1% or more of the patients were summarized according to age and smoking status. Data Analysis

The patient sample size for each study was determined assuming a 50% evaluability rate. Patients were randomly assigned to treatment groups using a master randomization schedule. Patient evaluability was assessed under blinded conditions. In order to be considered evaluable, patients were required to have a pretreatment sputum sample from which a pathogen susceptible to the study drugs had been isolated. In addition, in order to be classified as a treatment failure, a patient had to receive at least 3 consecutive days of the study drug, and evaluation as a treatment success required at least 5 consecutive days of therapy. Evaluable patients received no other antimicrobial therapy from 1 week before treatment until the end of the post-treatment evaluation period. Analyses were performed using SAS procedures (SAS Institute, Cary, North Carolina). All statistical tests were two-tailed; those with p-values of 50.05 were considered statistically significant. All efficacy variables were analyzed using Fisher’s December

Of the 1,209 evaluable patients enrolled in the six studies, 528 were smokers, and 629 were ~65 years of age. In the group of smokers, 342 were male and 186 were female. In the elderly group, 395 were male and 234 were female. No statistically significant differences between the treatment groups emerged with regard to clinical response (smokers, p = 0.798; elderly, p = 0.115; Table II). However, the 95% CI for the differences in clinical success in the elderly are from 1.1% in favor of the comparator to 11.9% in favor of temafloxacin. Statistically, these results have failed to disprove the null hypothesis, but they show that there is a 95% chance that a repeat study of the same size would show a difference in clinical success in the elderly in favor of temafloxaein of up to 11.9%. Temafloxacin therapy resulted in significantly higher bacteriologic Cure rates in individual patients in both smokers (95% CI for difference, 2.3-13.7%, p = 0.006) and the elderly (95% CI for difference, 0.4-11.6%, p = 0.028) when compared with the reference drugs (Table II). The most frequent pathogens isolated from pretreatment cultures were Haemophilus influenxae, StreptococcuS pneumoniae, Mol*axella catavhalis, H. parainfuenxae, Staphylococcus aweus, and Esche~ichia coli (Table III). There was a signifi-

cant difference in bacterial eradication rates between temafloxacin-treated and reference drugtreated patients in both the smokers (99.3% vs 91.8%, p = 0.006) and elderly (97.8% vs 92.3%, p = 0.027). Furthermore, a significant difference was demonstrated in the subset of infections caused by S. pneumoniae, 96.7% versus 84.4% (p = 0.03) for temafloxacin and reference agents, respectively. Clinical cure rates in nonsmokers (n = 525) and nonelderly patients (18-64 years of age; n = 457) were similar to those found in smokers and the elderly subgroups. Bacteriologic cure rates were not statistically different between temafloxacinand reference drug-treated patients in nonsmoker and nonelderly subgroups. No consistent trends emerged relating premature termination of treatment to either smoking or age. Adverse events occurred at a similar rate (p = 0.855) among elderly patients who received temafloxacin 600 mg b.i.d. compared with those who received reference agents (Table IV). The highest incidences and most frequent adverse events involved the gastrointestinal tract (for example, nausea, dyspepsia, diarrhea). Likewise, no 30, 1991

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SYMPOSIUMON FLUOROQUINOLONES / DAVEY TABLE II Analysis of Clinical Success and Patient Bacteriologic Cure Rates Treatment Group

Success Rate (%)

Difference Between Rates

LCI

UCI

p Value

Clinical Success Rates Temafloxacin* Smokers Nonsmokers Elderly Nonelderly Smokers Temafloxacin* Reference drugs Elderly Temafloxacin* Reference drugs

119/127(93.7)‘ 2561278 192.1) 159/168(94.6) 216/237(91.1)

1.6

-3.7

6.9

3.5

-1.5

8.5

1191127 (93.7) 99/107(92.5)

1.2

-5.4

7.7

1591168 194.6) 1081121 (89.3)

5.3

-1.1

11.9

1211122 (99.2) 2561268 (95.5) 157/161(97.5)

3.7

0.7

6.6

2201229 (96.1)

1.4

1211122 (99.2) 931102(91.2)

8.0

2.3

13.7

0.006

1571161 197.5) 1081118 (91.5)

6.0

0.4

11.6

0.028

0.798

0.115

Patient Bacteriologic Cure Rates Ternafloxacin* Smokers Nonsmokers Elderly Nonelderly Smokers Temafloxacin* Reference drugs Elderly Temafloxacin* Reference drugs :I = lower confidence interval; emafloxacln 600 tng b.i.d.

UCI = upper confidence

-2.0

4.9

interval.

TABLE Ill

TABLE IV

Bacteriologic Smokers*

Response by Pathogen in the Elderly and in

Summary of Most Frequent Adverse Events* by Treatment Group Among Elderly Patients

Number of Pathogens Eradicated/Total (%) Pathogen

Temafloxacint

Haemophi/usinfluenzae Streptococcuspneumoniae Moraxeila catarrhalis Haemophilusparainfiuenzae Staphylococcusaureus Eschenchiacob

Temafloxacin (n = 328)

Reference Drug

1421144 (98.6)

59161(96.7/t 67167 (100) 818 (100) 515 (100) 515 (100)

1131115(98.3 54164 (84.4) 1 23123 (100)

13114(92.9) 6/6 (100) 515 (100)

‘athogens are arranged in order of frequency, emafloxacin 600 mg b.i.d. , = 0.03.

significant differences were observed between treatment groups among smokers, either overall or by adverse event.

Adverse Event Asthenla Constipation Diarrhea Dizziness Dyspepsia Flatulence Headache Insomnia Liver function abnormalrty Monilta (oral) Nauseaivomrting Nausea Nervousness Pruritus Rash Somnolence Vomiting

Number i 7 If 6 : ;

2; i : 4

Reference Drugs (n = 256) %

Number

%

0.6 0.9

i

1.2 1.2

?,I

4.9 3.4 1.8 2.1 0.3 1.5 2.7 1.5 6.4 0.6 0.9 2.1 1.5 1.2

10 ! i ! ; 20 ; 2 :

3”:; 3.5 2.3

1.6

1.6 1.6 0.4 1.2 7.8 1.2 1.2 0.8 0.4 0.8

21% of patients

COMMENT LRTIs are seen commonly in clinical practice and are often caused by pathogens that are commensals of the upper respiratory tract. In healthy individuals, normal defense mechanisms such as ciliary action, sputum viscoelasticity, and cell-mediated immunity are generally successful in controlling dissemination of pathogens [lo]. However, disruption of these defense mechanisms can lead to increased frequency and severity of infection. Both advancing age and a history of smoking are wellknown risk factors in patients with LRTIs. 6A-104s

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Advances in medical care and improvements in life-style have resulted in a ldnger life expectancy. Because of the aging of the population, a greater number of individuals will be at higher risk for morbidity and mortality due to LRTIs. The risk is even greater in patients housed in group-home environments (for example, nursing homes) and in those who are debilitated [4]. Importantly, debilitation has been found to alter the range of pathogens isolated in elderly patients and to increase the risk of 91 (suppl

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developing infection due to gram-negative organisms [ll]. Cigarette smoking may impair normal host defense mechanisms and cause irritation and inflammation of the airway mucosa [lo]. Airway injury creates an environment that is conducive to bacterial spread and further damage to the epithelial surface [12]. This may lead to increased long-term mortality as reported by Burrows and colleagues in their epidemiologic study [51. Because advancing age and smoking history are risk factors for LRTIs, it is essential that the outcome of antimicrobial safety and efficacy trials be evaluated in these subgroups. Six trials that evaluated the safety and efficacy of temafloxacin, a new fluoroquinolone antimicrobial, were analyzed for outcome in smokers and in the elderly. This analysis revealed that clinical cure rates were similar in smokers and in elderly patients who were treated with temafloxacin or with the reference drugs, ciprofloxacin or amoxicillin. In the elderly, however, the 95% CI for the difference in clinical success are from 11.9% in favor of temafloxacin to 1.1% in favor of the reference agents. Moreover, patient bacteriologic cure rates and pathogen eradication rates were significantly higher in smokers and elderly patients who received temafloxacin compared with those who received a reference drug. The improved bacteriologic response rate observed following temafloxacin therapy may have been due to its greater efficacy in eradicating S. pneumoniae compared with the reference drugs ciprofloxacin and amoxicillin (temafloxacin 96.7% vs reference drugs 84.4%, p = 0.03). Temafloxatin was equal in effectiveness to the reference drugs in eradicating other susceptible primary respiratory tract pathogens such as H. influenxae and M. catawhalis.

There was no consistent effect of age or smoking on premature termination of therapy that would explain the observed differences in bacterial eradication rates by temafloxacin compared with the reference drugs. Both treatment regimens were well tolerated.

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ON FLUOROQUlNOLONES/DAVEY

CONCLUSION The results of these studies indicate that temafloxacin therapy of LRTI produces short-term clinical results that are similar to ciprofloxacin or amoxicillin. However, in smokers and in the elderly, patient bacterial cure rates and bacterial eradication rates after temafloxacin therapy were significantly higher than after treatment with the reference drugs, largely due to differences in eradication of the pneumococcus. These results may have implications for the long-term morbidity of LRTI in these groups, and this possibility merits further study.

ACKNOWLEDGMENT These studies were supported by a grant from Abbott Laboratories, lllinors. Acknowledgment is made to the investigators who participated clrnical trials.

Abbott Park, in these six

REFERENCES 1. Dorca J, Bacterial respiratory infections and pneumonia. Curr Opin Infect Dis 1990; 3: 176-80. 2. Venkatesan P, Macfarlane JT. Epidemiology pathogenesis, and preventron of pneumonra. Curr Open Infect Diseases 1991; 4: 14559. 3. Donowitr GR, Mandell GL. Acute pneumonra. In: Mandell GL, Douglas RG Jr., Bennett JE, eds. Prrnciples and Practice of lnfectrous Diseases, 3rd ed. New York, New York: Churchill LivIngstone, 1990: 540-55. 4. Marrie TJ, Durant H, Yates L. Community-acqurred pneumonra requiring hosprtalrzation: 5-year prospective study. Rev Infect Dis 1989; 11: 586-99. 5. Burrows B, Bloom JW, Traver GA, Cline MG. The course and prognoses of different forms of chronic airways obstructron in a sample from the general population. N Engl J Med 1987; 317: 1309-14. 6. Lindsay GH. Safety and efficacy of temafloxacrn versus ccprofloxacin in lower respiratory tract Infections: a randomized, double-blind trral. J Antimicrob Chemother 1991; in press. 7. Chodosh S. Temafloxacin compared with ciprofloxacin in mrld to moderate lower resprratory tract infections in ambulatory patrents: a multicenter. double-blrnd, randomized study. Chest 1991; in press. 8. Carbon C, Leophonte P. Petitpretz P, Chauvin JP. Harebroucq J. A multicenter, randomized, double-blind comparison of temafloxacin and amoxicillrn in hosprtalrzed adults with community-acquired pneumonia. Antimrcrob Agents Chemother 1991; in press. 9. Gardner MJ, Altman DG. Calculabng confidence intervals for proporbons and their differences. In: Gardner MJ, Altman DG, eds. Statistrcs with Confidence. Len don, UK: British Medical Journal Publicatrons, 1989: 28-33. 10. Wrlson R. lnfectrons of the airways. Current Opin Infect Dis 1991; 4: 166-75. 11. Venkatesan P, Gladman J, Macfarlane JT, et al A hospital study of community acqurred pneumonia in the elderly. Thorax 1990; 45: 254-8. 12. Ramphal R, Small PM, Shands JW, Fischlschweiger W, Small PA Jr. Adherence of Pseudomonasaeruginosa to tracheal cells injured by influenza infection or by endotracheal intubation. Infect lmmun 1980; 27: 614-9.

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