JAC Clinical and economic considerations in the treatment of acute exacerbations of chronic bronchitis

Journal of Antimicrobial Chemotherapy (1999) 43, Suppl. A, 107–113 JAC Clinical and economic considerations in the treatment of acute exacerbations ...
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Journal of Antimicrobial Chemotherapy (1999) 43, Suppl. A, 107–113

JAC

Clinical and economic considerations in the treatment of acute exacerbations of chronic bronchitis Christopher J. Destache*, Naresh Dewan, Walter J. O’Donohue, J. Clayton Campbell and Vito A. Angelillo Schools of Pharmacy & Allied Health Professions and Medicine, Creighton University, Omaha, NE, USA Limited data exist to guide physicians in the cost-effective treatment of acute exacerbation of chronic bronchitis (AECB). Therefore, the main objective of this study was to determine the antimicrobial efficacy and related costs for patients with AECB. A retrospective review of 60 outpatient medical records with a diagnosis of chronic obstructive pulmonary disease (COPD) and chronic bronchitis episodes from a pulmonary clinic of a teaching institution was undertaken. The participating patients had a total of 224 episodes of AECB requiring antibiotic treatment. Before review, empirical antibiotic choices were divided into first-line (amoxycillin, co-trimoxazole, tetracyclines, erythromycin), second-line (cephradine, cefuroxime, cefaclor, cefprozil) and third-line (co-amoxiclav, azithromycin, ciprofloxacin) agents. Patients receiving first-line agents failed significantly more frequently than third-line agents (19% vs 7%, P < 0.05). Additionally, patients prescribed first-line agents were hospitalized significantly more often for AECB within 2 weeks of outpatient treatment as compared with patients prescribed third-line agents (18.0% vs 5.3% third-line agents; P < 0.02). Time between subsequent AECB episodes requiring treatment was significantly longer for patients receiving third-line agents compared with first-line and second-line agents (P < 0.005). Pharmacy costs were lowest with first-line agents (first-line US$10.30 6 8.76; second-line US$24.45 6 25.65; third-line US$45.40 6 11.11; P < 0.0001), but third-line agents showed a trend towards lower mean total costs of AECB treatment (first-line US$942 6 2173; second-line, US$563 6 2296; third-line, US$542 6 1946). The use of third-line antimicrobials, co-amoxiclav, ciprofloxacin or azithromycin, significantly reduced the failure rate and need for hospitalization, prolonged the time between AECB episodes, and showed a lower total cost for the management of AECB. Prospective studies are needed to confirm these findings.

Introduction Respiratory tract infections (RTI) are the commonest type of infectious disease presenting to primary care physicians in the USA, and it is estimated that as many as 15–21% of adults have been diagnosed with chronic bronchitis.1 Chronic bronchial disease pre-disposes patients to more frequent and progressively more severe episodes of acute infection and is responsible for approximately 10% of hospital admissions. 2 On presentation, the aetiology of lower RTI often remains unknown. This may result from use of antibiotics before presentation, lack of good quality sputum specimens, low sensitivity of sputum cultures or difficulty in recognizing atypical pathogens. Even when

organisms are isolated from patients with AECB, it is often difficult to distinguish between true pathogens and colonizing flora. Recently, our understanding of the bacterial aetiologies of lower RTI has increased. A number of pressures have driven the need to know the causes of AECB, including an increase in the number of older patients, greater use of immunosuppressive drugs, resistance to various antibiotics and the financial constraints of streamlined antibiotic prescribing. Respiratory tract organisms which are considered pathogenic include Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pneumoniae; in more severely ill patients Haemophilus parainfluenzae, Pseudomonas aeruginosa and members of the Entero-

* Corresponding address: Creighton University School of Pharmacy and AHP, Criss III Rm 369, 2500 California Plaza, Omaha, NE 68178, USA. Tel: 11-402-280-4744; Fax: 11-402-280-1268; E-mail: [email protected]

107 © 1999 The British Society for Antimicrobial Chemotherapy

C. J. Destache et al. bacteriaceae family are often implicated.3 Atypical pathogens, including Mycoplasma pneumoniae, Legionella pneu mophila and Chlamydia pneumoniae, may also play a role.3 A number of events are responsible for the development of chronic bronchitis and subsequent infections. Irritating substances inhaled into the respiratory tract may compromise the normal secretory function of the bronchial mucosa. Individuals with chronic bronchitis have thickened bronchial walls, hypertrophy of the mucus glands and dilated mucus gland ducts.4 These changes precipitate increased secretions in the peripheral airways with subsequent blockage of the small airways. Ultimately, all of these events lead to alterations of the epithelium with chronic inflammation, scarring and weakening of the bronchial walls. Because specimens may be unavailable for culture, or inadequate, empirical antibiotic therapy is generally indicated. Traditionally, antibiotics have included penicillin G, amoxycillin and co-trimoxazole. These agents may often be inappropriate due to limited spectrum in vitro, need for frequent dosing, poor tolerance and compliance and the development of bacterial resistance.5,6 Newer agents including fluoroquinolones, macrolides and azalides may prove more valuable in some circumstances.7–9 The aim of the current study was to determine retrospectively the relative efficacy and cost implications of patients receiving therapy for AECB. A second goal of this study was to define optimal antibiotic choices for the treatment of AECB and the costs associated with treatment.

Materials and methods Patient data were obtained retrospectively from the medical records in the Pulmonary Department of Creighton University School of Medicine between January 1990 and January 1994. Three antibiotic groups were selected for comparison before collection and review of data and were categorized as first-, second- or third-line agents based on the consensus of resident pulmonologists. The residents were asked, ‘what antibiotic would you choose to treat a patient with chronic bronchitis on their initial presentation, on their second presentation and on a subsequent presentation, if each episode was separated by 2–4 weeks?’ The information from these three treatment groups was compared as follows: first-line agents (amoxycillin, tetracyclines, erythromycin), second-line agents (cephradine, cefuroxime, cefaclor, cefprozil) and third-line agents (coamoxiclav, azithromycin, ciprofloxacin). Patients older than 36 years of age, identified from the medical records of the Pulmonary Department of Creighton University School Medicine, were eligible for the study if they had a mild-to-moderate acute infection and a diagnosis of chronic bronchitis documented in the medical record. Chronic bronchitis was defined as a condition associated with excessive tracheo-bronchial mucus

production for at least 3 months of the year for >2 years. Patients were enrolled if they had an acute exacerbation defined by any one or more of the following signs or symptoms: increased cough and sputum production; change in colour or tenacity of sputum suggesting increased purulence; decreased breath sounds or wheezing; dyspnoea (.22 breaths/min); or fever .388C; or having been prescribed an antibiotic for their pulmonary exacerbation. Patients may also have had one or more of the following risk factors: pre-existing chronic illness, such as chronic obstructive pulmonary disease (COPD); diabetes mellitus; cardiovascular disease with hypertension, coronary artery disease or congestive heart failure; cerebrovascular disease; or excessive alcohol use with evidence of physical sequelae. While bacterial infection was highly suspected in each of the patients, the presence of bacteria was not always proven by culture. Any case without a clear diagnosis of an AECB, but with signs and symptoms of a pulmonary infection documented in the medical record, were discussed with a pulmonologist to determine the potential for enrolment. Patients were excluded if they had any of the following: radiographic evidence of pneumonia; documented AIDS by the Centers for Disease Control and Prevention criteria; unstable angina or New York Heart Association Class IV congestive heart failure; radiographic, clinical or laboratory data suggestive of atypical pathogens (e.g. Chlamydia, Myco plasma or Legionella spp.); Pneumocystis carinii pneumonia; tuberculosis; post-obstructive pneumonia; pulmonary cancer, lymphomas and/or leukaemia; or ongoing peritoneal or haemodialysis. All study variables were gathered retrospectively from the medical records. Spirometry, when available, was used to assess the severity of pulmonary function impairment and to determine if functional impairment correlated with the number of AECB episodes. Failure rate was determined by recording the number of patients who failed to respond to initial antibiotics and who required further antibiotics within 2 weeks. The time to the next acute exacerbation episode was compared among patients who were prescribed first-, second- or third-line agents. Finally, the hospitalization rate was determined by recording the number of patients who failed to respond within 2 weeks of initial outpatient AECB treatment, and who required admission to the hospital. Hospital charges were gathered from the Business Office of St Joseph Hospital. Hospital costs were compared and analysed. Total charges of treating chronic bronchitis were compared among the three antibiotic groups. Charges for treatment of chronic bronchitis were calculated by adding all charges for laboratory work, radiology, physician office visits and prescriptions for each episode. Charge data for each patient admitted to the hospital for treatment of AECB were added to the database. Charges were corrected to 1994 charges by the new price value (NPV) from the formula NPV 5 total charges/(1 1 R)n, where R is the

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Ciprofloxacin for acute exacerbations of chronic bronchitis annual averaged consumer price index and n is the number of years until 1994. Direct charges were compared among the three groups of treatment. Data on demography, efficacy and rate of seeking medical care were compared among the three groups of patients. Statistical analysis included analysis of variance (ANOVA) with severity of disease as assessed by pulmonary function tests (PFTs) or spirometry as a covariate. Rates of hospital admission and antibiotic failure were compared among the three groups of patients using x2 analysis. Time between AECB episodes and duration of antibiotic therapy were each compared using ANOVA. Non-parametric tests (Mann–Whitney U-tests) were used if data were not normally distributed.

Results

failed antimicrobial therapy within 2 weeks of initiation. Among these 34 failures, 19 patients received first-line, 11 patients received second-line and four patients received third-line agents. There was a significant difference in failure rate between first-line and third-line agents (P , 0.05; Figure). A total of 20 of 34 (58.8%) patients failed on their first or second office visit for AECB. Twenty-six of 34 (76%) patients were hospitalized within 2 weeks of therapy for AECB. Of those who were hospitalized, 18 had received first-line, five had received second-line and three had received third-line agents. A significant difference was found between patients hospitalized after receiving firstline and third-line agents (P , 0.02). Differences between first-line and second-line agents approached statistical significance ( P , 0.054). Among 18 patients hospitalized after receiving first-line agents, 15 (83%) had received amoxycillin or co-trimoxazole. Additionally, six patients were hospitalized 3 weeks after the office visit and prescription for AECB. The duration of antibiotic therapy for an AECB episode was significantly different (P , 0.02) among the three treatment groups (Table II). No significant differences in infection rates among the study groups were demonstrated

Of the 285 patient medical records retrospectively reviewed in this study, a total of 60 patients met the inclusion and exclusion criteria. The majority of exclusions resulted from the presence of pneumonia or bronchial carcinoma. The 60 evaluable patients had 224 documented episodes of AECB (mean 3.73 episodes/patient) between January 1990 and January 1994. All patients had their medical care provided by one of the clinic’s pulmonologists and all had COPD. Antibiotic choices and the number of AECB episodes were divided into three groups: first-line agents (amoxycillin (n 5 44), co-trimoxazole (n 5 45), erythromycin (n 5 8) and tetracyclines (n 5 3)); secondline agents (cephradine (n 5 3), cefaclor (n 5 39), cefprozil (n 5 2) and cefuroxime (n 5 23)); and third-line agents (co-amoxiclav (n 5 15), azithromycin (n 5 22) and ciprofloxacin (n 5 20)). The mean age (6S.D.) of the patients selected into this study was 58.3 6 31.1 years. There were 28 males and 32 females in the study population. Vital signs, pulmonary function tests and spirometry were not statistically significantly different among the antibiotic groups (Table I). Due to the low number of respiratory function tests conducted on the 60 patients a stratification of antibiotics based on pulmonary function could not be performed. Figure. Failure rates for patients treated with different antibiotic A total of 34 of 224 (15.2%) treated episodes of AECB categories. Table I. Baseline medical characteristics

Variable

‘First-line’ agents (n 5 100)

‘Second-line’ agents ‘Third-line’ agents (n 5 67) (n 5 57)

Maximum temperature (°C) Respiratory rate (breaths/min) Heart rate (beats/min) (no. of patients) FEV1 FEV1%a (no. of patients)

37.4 6 0.7 24.4 6 5 98.7 6 16 (20) 1.27 6 0.73 50 6 24 (26)

37.5 6 0.8 24.3 6 6 80.0 6 39 (7) 1.35 6 1.11 48 6 24 (12)

a

FEV1 as percentage of predicted values.

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37.5 6 0.6 23.8 6 5 100.2 6 15 (8) 1.71 6 1.06 59 6 21 (9)

C. J. Destache et al. Table II. Main study findings Variable Days of therapya Time between AECB (weeks)b Cost of AECB episode (US$) Pharmacy costs (1994 AWP)c a

‘First-line’ agents

‘Second-line’ agents

‘Third-line’ agents

8.9 6 3.3 17.1 6 22.0 942 6 2173 10.3 6 8.76

8.3 6 2.3 22.7 6 30.0 563 6 2296 24.45 6 25.65

7.5 6 2.5 34.3 6 35.5 542 6 1946 45.40 6 11.11

P , 0.02, b P , 0.005; c P , 0.0001 (all values calculated as ‘first’ vs ‘second’ vs ‘third’ via one-way ANOVA).

for patients who were current smokers, received home oxygen therapy or were taking concomitant oral corticosteroid therapy (data not shown). Forty-five of 60 (75%) patients who were prescribed first-line or second-line agents for their initial episode of AECB in this study had a subsequent exacerbation of AECB. Of these 45 patients, 37 (82%) were prescribed another first-line or second-line agent for the second AECB episode. Among 30 patients who had more than two episodes of AECB, 21 (70%) again received either a firstline agent or a second-line agent on the third office visit. Study results were also stratified into patients requiring fewer than four office visits and those necessitating four or more office visits for management of the first AECB episode. A total of 134 of 224 (59.8%) office visits were from patients requiring four office visits. Fewer patients with more than four AECB office visits were hospitalized (12 of 134 (8.9%)) compared with those with fewer than four office visits (13 of 90 (14.4%); P 5 0.13). Patients who had more than four office visits for the first AECB episode returned to the office for further AECB treatment significantly sooner than those patients with fewer than four office visits (18.0 6 24.2 weeks vs 28.0 6 31.4 weeks; P , 0.01). The amount of time between acute exacerbations and costs associated with treatment of AECB were recorded for the three treatment groups (Table II). A significant difference among the three antibiotic groups was observed for the time between acute exacerbations. The mean time until the next AECB treatment was significantly different among the three antibiotic groups: first-line agents, 17.1 6 22.0 weeks; second-line agents, 22.7 6 30.0 weeks; and third-line agents, 34.3 6 35.5 weeks (P , 0.005). Mean pharmacy costs of the therapy of AECB were lowest with first-line agents, although costs were each significantly different among the three antibiotic groups (first-line, US$10.30; second-line, US$24.45; third-line, US$45.40; P , 0.0001; Table II). Total charges associated with treatment of AECB included office charges, radiology charges, antibiotic costs and hospitalization charges. Average total charges associated with AECB treatment for each of the antibiotic groups were as follows: first-line, US$942 6 2173; second-line, US$563 6 2296; third-line, US$542 6 1946 (P . 0.05 (first- vs third-line)). Total costs associated

with hospitalization for AECB were also calculated and were not statistically significantly different among the three antibiotic groups: first-line, US$993 6 2671; second-line, US$605 6 3857; third-line, US$500 6 2135 (P . 0.05).

Discussion The findings of this retrospective study demonstrate some consequences of the management of patients with AECB. Notably, the time between episodes of AECB requiring treatment was significantly longer for patients receiving third-line agents. Secondly, persons receiving first-line agents required hospitalization significantly more often than those given the typically more expensive second- and third-line agents. These trends should be of interest to (i) managed-care decision-makers who are involved in the formulary selection process; (ii) pulmonary physicians in their attempt to optimize antibiotic usage; and (iii) to the patient with AECB since treatment of these episodes is necessary to minimize work disability and to permit continuance of normal activities, to reduce hospitalization for more intensive therapy and to prevent further clinical deterioration from bronchitis to pneumonia. The results of stratifying patients with AECB by number of office visits are also of interest. It is possible that patients who required more than four office visits for recurrent or non-resolving episodes may have been treated with second- and third-line agents more frequently and, therefore, required hospitalization less often. Alternatively, patients who return to the office more often for AECB treatment may have more severe COPD and so may return to the office sooner than other, less severely ill, patients in the hope of obtaining early therapy and thus preventing further sequelae and hospitalization. However, data on the severity of illness were not gathered consistently enough to make any firm conclusions concerning these possibilities. The reduction in hospitalization rate with second-line and third-line agents when compared with first-line agents could have potential impact on the mortality of patients with COPD. In a recent study of 458 patients with COPD who required admission to hospital for AECB, mortality was 13% after a median length of stay of 10 days; mortality

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Ciprofloxacin for acute exacerbations of chronic bronchitis at 180 days was 35%.10 The severity of ventilator-related impairment of lung function in patients with COPD is strongly related to death both from obstructive lung disease and from all causes. The presence of chronic mucus hypersecretion is an additional risk factor for death from obstructive lung disease in patients with reduced lung function.11 Moreover, patients who experience frequent episodes of AECB are at risk for accelerated loss of lung function and effective antibiotic therapy may slow this decline.12 The use of second- or third-line antibiotics in the outpatient setting could decrease the number of hospitalizations and the degenerative disease process, and thus prolong the survival of patients with COPD. Several placebo-controlled studies have documented the benefit of antibiotics for the treatment of AECB.13–21 Indeed, a recent meta-analysis documented statistically significant improvements in outcome measurements for COPD patients treated with antibiotics.22 The majority of the reviewed clinical trials were performed as early as 1957, with only one of the trials conducted within the last 3 years. These studies used a variety of antibiotics, including tetracyclines, ampicillin or amoxycillin, chloramphenicol and co-trimoxazole. Only the trial with chloramphenicol demonstrated results that favoured placebo. Based on these findings, it might be assumed that the use of antimicrobial therapy in the treatment of AECB significantly improves outcome compared with placebo. However, the above trials were short-term studies that did not uniformly confirm a bacterial aetiology. To date, a longitudinal study to determine the most appropriate therapeutic regimen for the management of AECB has not been published. Anthonisen and co-workers17 prospectively compared antibiotic therapy with placebo for acute exacerbations and monitored the outcome of patients for 21 days. The results demonstrated a failure rate of 18.0% with placebo and 9.9% with antibiotic therapy. The results of the present study demonstrated a failure rate within 14 days of 19% of ‘first-line’ agents (amoxycillin, co-trimoxazole and erythromycin) and 7% for ‘third-line’ agents (co-amoxiclav, azithromycin and ciprofloxacin). The high failure rate with first-line agents correlates well with a recent report of increasing antibiotic resistance.23 Our study has several limitations. The retrospective study design did not permit accurate determination of patient compliance with the antibiotic therapy. If a significant number of patients were non-compliant, the incidence of return office visits with a relapse of AECB may have been influenced. Antibiotics that are given four times daily have been shown to have a higher rate of non-compliance than antibiotics given twice or once daily.24 The frequency of administration of first-, second- or third-line agents was not significantly different and we assumed that if patients were non-compliant, this non-compliance would affect all three treatment groups in a similar way. The nature of this study did not allow us to gather spirometry measurements to assess progression of each

exacerbation. In fact, only a small number of patients had spirometry measurements performed during the study period. Finally, due to the study design, we assumed that patients would return to their pulmonary physician for treatment of AECB. While this may have occurred in the majority of patients, there is no assurance that some patients did not see another internal medicine or family practice physician and receive subsequent antibiotic prescriptions. More longitudinal studies are needed before ‘third-line’ antimicrobial agents can be concluded to significantly reduce the number of AECB episodes per year. The use of antimicrobial therapy for treatment of AECB continues to be debated. The belief that AECB should be initially treated aggressively with bronchodilators and mucolytics has some experimental merit.25,26 In chronic bronchitis, the bronchial cilia are debilitated secondary to long-term smoking and other insults. Bacteria then colonize the damaged bronchial mucosa as a result of the inability to eradicate organisms from the bronchi. Alternatively, respiratory viruses may play a role in AECB.27 Antimicrobial therapy does benefit many patients with AECB. The placebo-controlled study by Anthonisen and co-workers 17 implied that chronic bronchitis patients with increased dyspnoea and sputum production, as well as purulent sputum, should benefit from antimicrobial therapy.17 A more recent study by Ball et al.28 suggested that most patients with chronic bronchitis will spontaneously recover from their exacerbation, including bacterial infections, unless they have coexistent cardiopulmonary disease and a history of at least three exacerbations per year. Thus, defining the specific subgroup that deserves antimicrobial treatment still requires more study. Our use of economic values in determining costs to a patient associated with treating AECB, are specific to our geographic region within the USA. Nonetheless, these costs included all aspects of care associated with the management of AECB, such as fees for office visits, radiology charges for chest X-rays, antibiotic costs and the substantial charges for hospitalization and resultant care. These data were then normalized to 1994 charges using a standard economic formula. Conceivably, this study may have underestimated the total costs of AECB therapy. For example, if patients underwent an outpatient procedure (i.e. bronchoscopy), this was not included in the total charges. However, gathering this type of information in a retrospective study design would be extremely difficult. Blackhouse et al.29 recently demonstrated that the use of healthcare resources is similar whether using an expensive or inexpensive antibiotic for the management of patients with AECB. However, due to greater success with the newer antimicrobials, the more expensive agent was determined to be more cost-effective overall.29 In order to streamline physicians’ use of antibiotics for both economic and patient benefits, patients can be stratified according to their disease severity, history of infective exacerbations and underlying pathology. It

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C. J. Destache et al. makes little sense to prescribe the same or another first-line agent following an initial therapeutic failure. Indeed, the above criteria should assist in the selection of the empirical therapy. In addition to these clinical and historical criteria, local antibiotic susceptibility data for the common suspected respiratory tract pathogens should help guide therapy. The Infectious Diseases Society of America/ FDA guidelines,30 as well as the Canadian chronic bronchitis recommendations,31 for the management of respiratory tract infections are useful towards this end. Based on the data collected in this study, the use of coamoxiclav, azithromycin or ciprofloxacin for the treatment of AECB resulted in significantly fewer physician office visits and appeared to prevent hospitalizations when compared with first- or second-line antimicrobial therapy. Whether there is any difference between these agents remains to be evaluated longitudinally. Additionally, the repetitive nature of returning to the office for AECB may assist in identifying patients who require the more expensive ‘third-line’ antimicrobial therapy in order to prevent AECB-related hospital admissions and progression of their disease.

Acknowledgements This work was supported by a research grant from Bayer Corporation, Pharmaceutical Division, West Haven, CT, USA. We thank Adrienne L. Block, Jonathan D. Harris and Teresa Tartaglione, for editorial contributions. This paper was presented, in part, at the International Assembly of Chest Physicians, New Orleans, LA, November 3, 1994.

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