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Efficacy and safety of single-dose 2.0 g azithromycin in the treatment of acute exacerbation of chronic obstructive pulmonary disease
J Infect Chemother (2011) 17:793–798 DOI 10.1007/s10156-011-0260-z
ORIGINAL ARTICLE
Efficacy and safety of single-dose 2.0 g azithromycin in the treatment of acute exacerbation of chronic obstructive pulmonary disease Nobuhiro Asai • Yoshihiro Ohkuni • Takuya Iwasaki • Ryo Matsunuma • Kei Nakashima • Yoshihito Otsuka • Norihiro Kaneko
Received: 16 February 2011 / Accepted: 16 May 2011 / Published online: 2 June 2011 Ó Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases 2011
Abstract To evaluate the efficacy and safety of singledose 2.0 g azithromycin (ZSR) in the treatment of acute exacerbation of chronic obstructive pulmonary disease (AE-COPD), we retrospectively reviewed all patients with AE-COPD who were treated with ZSR. In comparison with patients who received intravenous therapy for AE-COPD, the clinical cure rate, length of stay in hospital, and medical costs were evaluated. A total of 29 patients thus were eligible for this study. Clinical cure rates of ZSR and intravenous therapy for the treatment of AE-COPD were 83.3% (n = 12) and 88.2% (n = 17), respectively, between the groups (P = 1.000). No severe adverse events were found in either group. The ZSR and intravenous groups averaged 9.9 and 12.5 days of admission, respectively. Length of admission for clinical success cases was much shorter for patients who received ZSR than patients who received intravenous therapy (6.2 vs. 11.9 days, P = 0.038). Medical costs were less for the group receiving ZSR than for the intravenous therapy group. We suggest ZSR can achieve near-perfect compliance and could be one of the tools in the treatment of AE-COPD. Keywords Acute exacerbation Chronic obstructive pulmonary disease Antibiotic therapy Azithromycin Medication compliance Oral antibiotics
N. Asai (&) Y. Ohkuni T. Iwasaki R. Matsunuma K. Nakashima N. Kaneko Department of Pulmonology, Kameda Medical Center, 929 Higashi-cho, Kamogawa, Chiba 296-8602, Japan e-mail: [email protected] Y. Otsuka Department of Laboratory Medicine, Kameda Medical Center, Chiba, Japan
Introduction Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the world and is expected to become the third by the year 2020 [1–3]. Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is the major cause of the high morbidity and mortality among COPD patients, mostly caused by lower respiratory tract infections. AE-COPD can also lead to costly and clinically significant consequences. Varying among countries, nearly 41–60% of the global cost of COPD is associated with exacerbation episodes, particularly severe acute exacerbations that require hospital admission [3, 4]. Initial treatment of AE-COPD is generally empirical and should cover the common typical respiratory pathogens known to cause the disease, such as Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis. Current guidelines recommend that AE-COPD should be treated by oral or intravenous antibiotics and/or corticosteroid for 2 weeks [5]. Anthonisen et al. indicated that antibiotics are considered efficacious, compared with a placebo [6]. The efficacy and safety of some oral medications such as azithromycin 500 mg on day 1 and 250 mg per day for days 2 to 5, or oral levofloxacin 500 mg q 24 h for 7 days, in the treatment of AE-COPD have recently been reported [7–10]. Indeed, mild or moderate AE-COPD cases could be treated as outpatients using oral medications, thus reducing medical costs. However, patient compliance with prescribed therapy might be problematic. Single-dose therapy has the potential to achieve 100% patient compliance, even among the elderly. In addition, the administration of a single large dose of azithromycin as front-loading achieves more rapid bacterial eradiation and is more effective than the same dose divided over several
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days, which has previously been demonstrated. Azithromycin (ZSR) has already been approved for the treatment of acute otitis media and community-acquired pneumonia in the United States since 2008 and 2005, respectively [11]. The number of elderly patients who live independently is increasing year by year because of the aging society in Japan. Thus, it is generally thought that the reason AECOPD patients in Japan tend to be treated in hospitals, no matter how mild the disease, is because of the uncertainty for medication compliance, especially by the aged who live alone. Therefore, we need to establish an oral therapy guideline/protocol for AE-COPD that is easy to follow and is as effective as intravenous therapy. The efficacy and safety of ZSR single-dose therapy in the treatment of AE-COPD have not been reported previously, so far as we could determine by a PubMed search. This is the first study demonstrating that ZSR is not inferior to intravenous therapy in the treatment of AECOPD.
Patients and methods For the purpose of evaluating efficacy and safety of single-dose 2.0 g azithromycin (ZSR) for AE-COPD, we retrospectively reviewed all AE-COPD patients treated by ZSR between August 2009 and April 2010 at Kameda Medical Center, Japan. To compare the ZSR-treated AECOPD patients with intravenous treatment patients, the clinical cure rate, length of stay in hospital, and medical cost were evaluated. All the patients had been diagnosed as COPD based on current guidelines. The staging of COPD was classified by the Global Initiative for Chronic Obstructive Lung Disease (GOLD). The diagnosis of AECOPD was confirmed by the presence of at least two of the following criteria: increased cough, increased expectoration, or worsening of dyspnea according to the definition of AE-COPD by Anthonisen et al. [6]. The severity of AE-COPD was also categorized as severe, moderate, or mild based on the current guideline. The severity of infection was classified as severe, moderate, or mild according to the Severity Criteria of the Japanese Society of Chemotherapy. Exclusion criteria in this study were as follows: (1) severe comorbidities that interfere with the evaluation of the clinical response, or alcoholism or drug dependence; (2) hypersensitivity to macrolide; (3) a history of other antimicrobial or investigational drug therapy in the previous 4 weeks; (4) pregnancy; (5) immunosuppression; (6) necessity to be on ventilator; or (7) outpatients. We have sought and obtained approval from our institution to use patient records for this study, and the patients’ confidentiality was maintained.
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Clinical and radiologic assessments Clinical assessments were based on the signs and symptoms of AE-COPD progression that required additional antibiotics. Clinical response of the patients was classified as cure or failure. Cure was defined as the resolution of the signs and symptoms related to AE-COPD for which no additional antibiotics were deemed necessary. In addition, the chest X-ray results had to be either resolved or unchanged. Clinical failure was defined as either the persistence or worsening of signs and symptoms related to AE-COPD for which additional antibiotics were necessary, with radiologic evidence of infection progression. Bacteriological assessment At the first visit, freshly expectorated sputum specimens were obtained and sent to a central laboratory for Gram stain. Specimens with fewer than ten epithelial cells per low-power field were cultured, and isolated pathogens were tested for susceptibility to azithromycin (AZM) according to the Clinical and Laboratory Standards Institute procedures. In addition, all the subjects submitted a urine specimen for S. pneumoniae antigen testing (BINAX), and blood cultures were collected from those subjects with a positive urine antigen test. Statistical analysis Baseline demographic characteristics and clinical outcomes for the two treatment groups were compared using Fisher’s exact test. Laboratory data in these two groups were evaluated by analysis of variance (ANOVA) as appropriate. For all the analyses, P \ 0.05 was considered statistically significant.
Results A total of 29 patients were eligible for this study. There were no significant differences in clinical characteristics between the two groups (Table 1). Clinical cure rates of ZSR and those of intravenous therapy for the treatment of AE-COPD were 83.3% (n = 12) and 88.2% (n = 17), respectively, with no statistical differences between the groups (P = 1.000). In the intravenous group, ceftriaxone (CTRX) was the antibiotic most commonly administered (n = 13, 76.5%), followed by piperacillin/tazobactam (TAZ/PIPC) (n = 3, 17.6%) and ampicillin/sulbactam (SBT/ABPC) (n = 1, 5.9%). In clinical response shown by signs and symptoms such as fever, cough, sputum, and dyspnea, patients in the ZSR group became well sooner than did the intravenous group
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795
Table 1 Baseline characteristics of patients and clinical outcomes Variables
Azithromycin (ZSR) group (n = 12)
Intravenous group (n = 17)
P value
Male
11
17
0.414
Female
1
0
\65
2
0
65–75
2
6
8 20.4
11 19.9
Never smoked
0
0
Ex-smoker
12
17
Current smoker
0
0
Mild
3
3
Moderate
3
7
Severe
3
3
Very severe
1
4
Unknown
2
0
Sex
Age (years)
C75 Body mass index (BMI)
0.718
History of smoking
Severity of chronic obstructive pulmonary disease (COPD)
Severity of acute exacerbation (AE)-COPD [according to Global Initiative for Chronic Obstructive Lung Disease (GOLD)] Mild
1
3
Moderate
2
6
Severe 9 8 Severity of infection (according to the Severity Criteria of the Japanese Society of Chemotherapy) Mild
1
1
Moderate
11
16
Severe
0
0
6
9
Pneumococcal vaccination
1.00
Home oxygen therapy
6
6
0.471
Length of admission (average days)
9.9
12.5
0.419
Length of stay for cured cases (average days)
6.2
11.9
0.038
Medical cost (U.S. dollars)
8,414
10,488
0.0002
Cure
10
15
1.000
Failure
2
2
Clinical outcome
(Table 2). One patient in the intravenous group died; no patients died in the ZSR group. Diarrhea was the most common treatment-related adverse event, occurring in one patient (8.3%) and three patients (17.8%) in the ZSR and intravenous therapy groups, respectively (P = 0.622). No cases of Clostridium difficile colitis occurred in either group. Liver dysfunction, which was the second most common treatment-related adverse event, was seen in one patient (8.3%) and two patients (11.8%) in ZSR and intravenous therapy groups, respectively (P = 1.000). No other treatment-related adverse events, including abdominal pain, nausea, and vomiting, occurred in either group. No side effects sufficiently significant to stop therapy were
experienced in this study. The ZSR and intravenous group had, on average, 9.9 and 12.5 days of admission, respectively. Among the clinical success cases, patients who received ZSR had a much shorter hospital stay than did patients who received intravenous therapy (6.2 vs. 11.9 days, P = 0.038). Also, medical costs for the ZSR group were less than those for the intravenous therapy group. From 9 subjects (75%) in the ZSR group and 12 subjects (70.6%) in the intravenous group, at least one pathogen was identified at the first visit (Table 3). The proportions of subjects with single or multiple pathogens were comparable in the two groups. The most commonly isolated
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Table 2 Cure rates of symptoms related to AE-COPD in both groups on day 3 and day 10 after the initiation of treatment Day 3
Day 10
ZSR group n (%)
Intravenous group n (%)
ZSR group n (%)
Intravenous group n (%)
Fever
9/11 (81.8)
10/16 (62.5)
10/11 (90.9)
13/16 (81.3)
Cough
6/12 (50)
3/16 (18.8)
11/12 (91.7)
10/16 (62.5)
Sputum Dyspnea
6/12 (50) 8/12 (66.7)
3/16 (18.8) 9/14 (64.3)
11/12 (91.7) 12/12 (100)
12/16 (75) 12/14 (85.7)
Cure rate of each symptom that presented after initiation of treatment Table 3 Pathogens isolated at the first visit Parameter
Value for treatment group ZSR group (n = 12)
Intravenous group (n = 17)
No. (%) of subjects with pathogens
8 (66.7)
12 (70.6)
No. (%) of subjects with single pathogens
2 (16.7)
9 (52.9)
No. (%) of subjects with multiple pathogens
3 (25)
3 (17.6)
Number of isolates of Haemophilus influenzae
3
5
Moraxella catarrhalis
4
2
Streptococcus pneumoniae Staphylococcus aureus
3
2
Oxacillin susceptible
0
1
Oxacillin resistant
0
1
Pseudomonas aeruginosa
2
3
Klebsiella pneumoniae
0
1
pathogen overall was H. influenzae, followed by M. catarrhalis, S. pneumoniae, and Pseudomonas aeruginosa. None was isolated by blood cultures. Susceptibility rates for antibiotics used in both groups were 100% (n = 5) in the ZSR group and 90% (n = 10) in the intravenous group, according to the reports from our central laboratory. All five cases of S. pneumoniae were susceptible to azithromycin.
Discussion Although COPD is one of the most common diseases worldwide, the treatment of AE-COPD is still controversial. Some reports previously documented the efficacy of antibiotics in the treatment of AE-COPD [5–10]. Some regimens of oral medication, such as levofloxacin (LVFX) 500 mg/day for 7 days, garenoxacin (GRNX) 400 mg/day for 14 days, or amoxicillin 500 mg/8 h for 10 days, have previously been reported [7–10]. Although the efficacy of macrolides for prevention of acute exacerbation of chronic bronchitis and COPD has been demonstrated [12], ZSR has never been reported as an effective short-course antibiotic
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therapy in the treatment of AE-COPD that is not inferior to intravenous therapy. One possible explanation of efficacy of AZM in the treatment of AE-COPD is that AZM and other macrolides can decrease neutrophil chemotaxis and infiltration into the respiratory epithelium, downregulate adhesion molecule expression, and enhance neutrophil apoptosis [13, 14]. Patients with mild or moderate AE-COPD may be treated as outpatients by administering oral medication; however, medication compliance could be problematic without supervision. Some elderly patients in Japan live alone, and poor compliance would result in clinical failure. Previous surveys demonstrated compliance declines in terms of the frequency and duration of antibiotic therapy [15–17]. Once symptoms begin to resolve, within a few days of beginning treatment, patients often stop taking their antibiotics, thereby increasing the risk of treatment failure. Thus, the availability of single-dose antibiotic therapy may enhance compliance, thereby maximizing efficacy and minimizing the emergence of bacterial resistance. Other studies have shown that shortcourse antibiotic therapy, by improving compliance, can lead to faster resolution of symptoms, as shown in this study [18]. In addition, a meta-analysis of several studies on
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bacterial upper respiratory tract infections, including acute otitis media, acute bacterial sinusitis, and streptococcal pharyngitis, concluded that shorter courses of antibiotics have the potential to increase patient compliance with therapy, decrease adverse events by decreasing drug exposure, decrease the emergence of resistant strains, and reduce cost [19, 20]. We suggest that a single-dose antibiotic therapy achieves near-perfect compliance as well as several advantages, as follows. Short-term admission or treatment as outpatients will reduce medical costs. The medical expense for COPD will increase year by year and become a great burden in the very near future. Previous research showed that nearly 41–60% of the global cost of COPD is associated with exacerbation episodes, particularly severe acute exacerbations requiring hospital admission [3, 4]. In our study, the medical costs for the ZSR group were less than those for the intravenous group (P \ 0.001). In terms of medical economics, ZSR therapy could contribute to reducing medical expenses in the treatment of AE-COPD. One of the advantages is the lesser toxicity of singledose therapy, compared with conventional antibiotic therapies such as AZM 500 mg for 3 days or LVFX 500 mg/ day for 7 days [7–10]. ZSR therapy was well tolerated by the AE-COPD patients, including the elderly. Treatmentrelated diarrhea and liver dysfunction, seen in one patient in each group (8.3%), respectively, required no additional medication. No severe treatment-related adverse events were found in this study, as reported in previous studies for community-acquired pneumonia (CAP) and acute otitis using ZSR [11, 21]. Causative pathogens were identified in just over 50% of patients in both treatment groups, which is similar to the rates reported in other CAP or AE-COPD studies [22, 23]. No pathogens were detected in 12 of the 29 (41.4%) subjects collected, which suggests that atypical pneumonia such as that caused by Mycoplasma pneumoniae or Chlamydophila pneumoniae was related to AE-COPD. The modality of the diagnosis of atypical pneumonia is limited, and thus it is difficult to make this diagnosis in cases of AE-COPD as well. S. pneumoniae was isolated in 5 cases (17.2%) in this study, all of which were susceptible to azithromycin. In Japan, the high rate of isolated S. pneumoniae that is resistant to macrolides is problematic [24, 25]. Administering 2.0 g azithromycin as a single dose is likely to result in concentrations of azithromycin in lung tissue and fluid that would be effective against S. pneumoniae with low-level macrolide resistance [11]. A trial examining the lung pharmacokinetics of the single-dose azithromycin regimen is currently under way to provide data to support this hypothesis [11]. Two of the 12 patients were considered clinical failures in the ZSR group. P. aeruginosa was isolated from these 2
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patients. Therefore, it is reasonable to assume that ZSR was not effective. It has previously been reported that P. aeruginosa was isolated more frequently among patients with forced expiratory volume in 1 s (FEV1) \50% than among those with FEV1 C50% [23]. Thus, we recommend that single-dose azithromycin therapy could be effective for the patients with stage I or II COPD. Oral antibiotics such as moxifloxacin or azithromycin are recommended for the treatment of AE-COPD by the current guideline [5], and we believe that they are more effective than oral b-lactam/b-lactamase inhibitors. New quinolones and macrolides have been known to show rapid lung tissue penetration and bacterial eradication [7, 8, 26, 27]. Thus, by means of this mechanism, they might help prolong the time to the next acute exacerbations of chronic bronchitis and AE-COPD. Donaldson et al. reported that frequent exacerbation contributes to the rate of decline in FEV1. In the study, the decline in FEV1 of frequent exacerbators (C2.92 times per year) was significantly faster than that of infrequent exacerbators (\2.92 times per year) [28]. In addition, it has been demonstrated that mortality increases with the frequency of AE-COPD, particularly if it requires hospital admission [3]. We suggest that one of the most important factors for decreasing mortality of patients with COPD is prevention and reduction of the risk of AE-COPD. Our study has several limitations. First, this was a retrospective analysis in a very small population. Retrospective studies may be less reliable in terms of the data collected, particularly for data such as physical examination and duration of symptoms. Second, a selection bias might have occurred with the choice of ZSR therapy or intravenous therapy by the attending physicians. A prospective study is necessary, and more cases are to be expected. In conclusion, ZSR could be one of the best treatments for AE-COPD in terms of not only clinical benefits but also of medical cost. For the purpose of reducing mortality in patients with COPD, ZSR could be effective to help decrease and prevent AE-COPD. We expect a prospective study to be done concerning the treatment of AE-COPD by ZSR therapy. Acknowledgments We are grateful for the diligent and thorough critical reading of our manuscript by Mr. John Wocher, Executive Vice President and Director, International Affairs/International Patient Services, Kameda Medical Center (Japan).
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J Infect Chemother (2011) 17:793–798 15. Branthwaite A, Pechere JC. Pan-European survey of patients’ attitudes to antibiotics and antibiotic use. J Int Med Res. 1996;24:229–38. 16. Sclar DA, Tartaglione TA, Fine MJ. Overview of issues related to medical compliance with implications for the outpatient management of infectious disease. Infect Agents Dis. 1994;3:266–73. 17. Cockburn J, Gibberd RW, Reid AL, Sanson-Fisher RW. Determinants of non-compliance with short-term antibiotic regimens. BMJ. 1987;295:814–8. 18. Colcher IS, Bass JW. Penicillin treatment of streptococcal pharyngitis: a comparison of schedules and the role of specific counseling. JAMA. 1972;222:657–9. 19. Pichicero ME. Short course antibiotic in acute otitis media and sinusitis infections. J Int Med Res. 1998;17:828–33. 20. Pichicero ME. Short course antibiotic therapy for respiratory infections: a review of the evidence. Pediatr Infect Dis J. 2000;19:929–37. 21. Daniel RR. Comparison of azithromycin and co-amoxiclav in the treatment of otitis media in children. J Antimicrob Chemother 1993;31(suppl E):65–71. 22. Bernstein JM. Treatment of community-acquired pneumonia— IDSA guidelines. Chest. 1999;115:9S–13S. 23. Mandell LA. Epidemiology and etiology of community-acquired pneumonia. Infect Dis Clin N Am. 2004;18:761–76. 24. Inoue M, Farrell DJ, Kaneko K, Akizawa K, Fujita S, Kaku M, et al. Antimicrobial susceptibility of respiratory tract pathogens in Japan during PROTEKT year 1–5 (1994–2004). Microb Drug Resist. 2008;14:109–17. 25. Inoue M, Kaneko K, Akizawa K, Fujita S, Kaku M, Igari J, et al. Antimicrobial susceptibility of respiratory tract pathogens in Japan during PROTEKT years 1–3 (1999–2002). J Infect Chemother. 2006;12:9–21. 26. Miravitlles M, Espinosa C, Ferna´ndez-Laso E, Martos JA, Maldonado JA, Gallego M. Relationship between bacterial flora in sputum and functional impairment in patients with acute exacerbations of COPD. Chest. 1999;116:40–6. 27. Baldwin DR, Wise R, Andrews JW, Ashby JP, Honeybourne D. Azithromycin concentrations at the sites of pulmonary infection. Eur Respir J. 1990;3:886–90. 28. Donaldson GC, Seemungal TA, Bhowmik A, Wedzicha JA. Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease. Thorax. 2002;57:847–52.
ORIGINAL ARTICLE
Efficacy and safety of single-dose 2.0 g azithromycin in the treatment of acute exacerbation of chronic obstructive pulmonary disease Nobuhiro Asai • Yoshihiro Ohkuni • Takuya Iwasaki • Ryo Matsunuma • Kei Nakashima • Yoshihito Otsuka • Norihiro Kaneko
Received: 16 February 2011 / Accepted: 16 May 2011 / Published online: 2 June 2011 Ó Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases 2011
Abstract To evaluate the efficacy and safety of singledose 2.0 g azithromycin (ZSR) in the treatment of acute exacerbation of chronic obstructive pulmonary disease (AE-COPD), we retrospectively reviewed all patients with AE-COPD who were treated with ZSR. In comparison with patients who received intravenous therapy for AE-COPD, the clinical cure rate, length of stay in hospital, and medical costs were evaluated. A total of 29 patients thus were eligible for this study. Clinical cure rates of ZSR and intravenous therapy for the treatment of AE-COPD were 83.3% (n = 12) and 88.2% (n = 17), respectively, between the groups (P = 1.000). No severe adverse events were found in either group. The ZSR and intravenous groups averaged 9.9 and 12.5 days of admission, respectively. Length of admission for clinical success cases was much shorter for patients who received ZSR than patients who received intravenous therapy (6.2 vs. 11.9 days, P = 0.038). Medical costs were less for the group receiving ZSR than for the intravenous therapy group. We suggest ZSR can achieve near-perfect compliance and could be one of the tools in the treatment of AE-COPD. Keywords Acute exacerbation Chronic obstructive pulmonary disease Antibiotic therapy Azithromycin Medication compliance Oral antibiotics
N. Asai (&) Y. Ohkuni T. Iwasaki R. Matsunuma K. Nakashima N. Kaneko Department of Pulmonology, Kameda Medical Center, 929 Higashi-cho, Kamogawa, Chiba 296-8602, Japan e-mail: [email protected] Y. Otsuka Department of Laboratory Medicine, Kameda Medical Center, Chiba, Japan
Introduction Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the world and is expected to become the third by the year 2020 [1–3]. Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is the major cause of the high morbidity and mortality among COPD patients, mostly caused by lower respiratory tract infections. AE-COPD can also lead to costly and clinically significant consequences. Varying among countries, nearly 41–60% of the global cost of COPD is associated with exacerbation episodes, particularly severe acute exacerbations that require hospital admission [3, 4]. Initial treatment of AE-COPD is generally empirical and should cover the common typical respiratory pathogens known to cause the disease, such as Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis. Current guidelines recommend that AE-COPD should be treated by oral or intravenous antibiotics and/or corticosteroid for 2 weeks [5]. Anthonisen et al. indicated that antibiotics are considered efficacious, compared with a placebo [6]. The efficacy and safety of some oral medications such as azithromycin 500 mg on day 1 and 250 mg per day for days 2 to 5, or oral levofloxacin 500 mg q 24 h for 7 days, in the treatment of AE-COPD have recently been reported [7–10]. Indeed, mild or moderate AE-COPD cases could be treated as outpatients using oral medications, thus reducing medical costs. However, patient compliance with prescribed therapy might be problematic. Single-dose therapy has the potential to achieve 100% patient compliance, even among the elderly. In addition, the administration of a single large dose of azithromycin as front-loading achieves more rapid bacterial eradiation and is more effective than the same dose divided over several
123
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days, which has previously been demonstrated. Azithromycin (ZSR) has already been approved for the treatment of acute otitis media and community-acquired pneumonia in the United States since 2008 and 2005, respectively [11]. The number of elderly patients who live independently is increasing year by year because of the aging society in Japan. Thus, it is generally thought that the reason AECOPD patients in Japan tend to be treated in hospitals, no matter how mild the disease, is because of the uncertainty for medication compliance, especially by the aged who live alone. Therefore, we need to establish an oral therapy guideline/protocol for AE-COPD that is easy to follow and is as effective as intravenous therapy. The efficacy and safety of ZSR single-dose therapy in the treatment of AE-COPD have not been reported previously, so far as we could determine by a PubMed search. This is the first study demonstrating that ZSR is not inferior to intravenous therapy in the treatment of AECOPD.
Patients and methods For the purpose of evaluating efficacy and safety of single-dose 2.0 g azithromycin (ZSR) for AE-COPD, we retrospectively reviewed all AE-COPD patients treated by ZSR between August 2009 and April 2010 at Kameda Medical Center, Japan. To compare the ZSR-treated AECOPD patients with intravenous treatment patients, the clinical cure rate, length of stay in hospital, and medical cost were evaluated. All the patients had been diagnosed as COPD based on current guidelines. The staging of COPD was classified by the Global Initiative for Chronic Obstructive Lung Disease (GOLD). The diagnosis of AECOPD was confirmed by the presence of at least two of the following criteria: increased cough, increased expectoration, or worsening of dyspnea according to the definition of AE-COPD by Anthonisen et al. [6]. The severity of AE-COPD was also categorized as severe, moderate, or mild based on the current guideline. The severity of infection was classified as severe, moderate, or mild according to the Severity Criteria of the Japanese Society of Chemotherapy. Exclusion criteria in this study were as follows: (1) severe comorbidities that interfere with the evaluation of the clinical response, or alcoholism or drug dependence; (2) hypersensitivity to macrolide; (3) a history of other antimicrobial or investigational drug therapy in the previous 4 weeks; (4) pregnancy; (5) immunosuppression; (6) necessity to be on ventilator; or (7) outpatients. We have sought and obtained approval from our institution to use patient records for this study, and the patients’ confidentiality was maintained.
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Clinical and radiologic assessments Clinical assessments were based on the signs and symptoms of AE-COPD progression that required additional antibiotics. Clinical response of the patients was classified as cure or failure. Cure was defined as the resolution of the signs and symptoms related to AE-COPD for which no additional antibiotics were deemed necessary. In addition, the chest X-ray results had to be either resolved or unchanged. Clinical failure was defined as either the persistence or worsening of signs and symptoms related to AE-COPD for which additional antibiotics were necessary, with radiologic evidence of infection progression. Bacteriological assessment At the first visit, freshly expectorated sputum specimens were obtained and sent to a central laboratory for Gram stain. Specimens with fewer than ten epithelial cells per low-power field were cultured, and isolated pathogens were tested for susceptibility to azithromycin (AZM) according to the Clinical and Laboratory Standards Institute procedures. In addition, all the subjects submitted a urine specimen for S. pneumoniae antigen testing (BINAX), and blood cultures were collected from those subjects with a positive urine antigen test. Statistical analysis Baseline demographic characteristics and clinical outcomes for the two treatment groups were compared using Fisher’s exact test. Laboratory data in these two groups were evaluated by analysis of variance (ANOVA) as appropriate. For all the analyses, P \ 0.05 was considered statistically significant.
Results A total of 29 patients were eligible for this study. There were no significant differences in clinical characteristics between the two groups (Table 1). Clinical cure rates of ZSR and those of intravenous therapy for the treatment of AE-COPD were 83.3% (n = 12) and 88.2% (n = 17), respectively, with no statistical differences between the groups (P = 1.000). In the intravenous group, ceftriaxone (CTRX) was the antibiotic most commonly administered (n = 13, 76.5%), followed by piperacillin/tazobactam (TAZ/PIPC) (n = 3, 17.6%) and ampicillin/sulbactam (SBT/ABPC) (n = 1, 5.9%). In clinical response shown by signs and symptoms such as fever, cough, sputum, and dyspnea, patients in the ZSR group became well sooner than did the intravenous group
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Table 1 Baseline characteristics of patients and clinical outcomes Variables
Azithromycin (ZSR) group (n = 12)
Intravenous group (n = 17)
P value
Male
11
17
0.414
Female
1
0
\65
2
0
65–75
2
6
8 20.4
11 19.9
Never smoked
0
0
Ex-smoker
12
17
Current smoker
0
0
Mild
3
3
Moderate
3
7
Severe
3
3
Very severe
1
4
Unknown
2
0
Sex
Age (years)
C75 Body mass index (BMI)
0.718
History of smoking
Severity of chronic obstructive pulmonary disease (COPD)
Severity of acute exacerbation (AE)-COPD [according to Global Initiative for Chronic Obstructive Lung Disease (GOLD)] Mild
1
3
Moderate
2
6
Severe 9 8 Severity of infection (according to the Severity Criteria of the Japanese Society of Chemotherapy) Mild
1
1
Moderate
11
16
Severe
0
0
6
9
Pneumococcal vaccination
1.00
Home oxygen therapy
6
6
0.471
Length of admission (average days)
9.9
12.5
0.419
Length of stay for cured cases (average days)
6.2
11.9
0.038
Medical cost (U.S. dollars)
8,414
10,488
0.0002
Cure
10
15
1.000
Failure
2
2
Clinical outcome
(Table 2). One patient in the intravenous group died; no patients died in the ZSR group. Diarrhea was the most common treatment-related adverse event, occurring in one patient (8.3%) and three patients (17.8%) in the ZSR and intravenous therapy groups, respectively (P = 0.622). No cases of Clostridium difficile colitis occurred in either group. Liver dysfunction, which was the second most common treatment-related adverse event, was seen in one patient (8.3%) and two patients (11.8%) in ZSR and intravenous therapy groups, respectively (P = 1.000). No other treatment-related adverse events, including abdominal pain, nausea, and vomiting, occurred in either group. No side effects sufficiently significant to stop therapy were
experienced in this study. The ZSR and intravenous group had, on average, 9.9 and 12.5 days of admission, respectively. Among the clinical success cases, patients who received ZSR had a much shorter hospital stay than did patients who received intravenous therapy (6.2 vs. 11.9 days, P = 0.038). Also, medical costs for the ZSR group were less than those for the intravenous therapy group. From 9 subjects (75%) in the ZSR group and 12 subjects (70.6%) in the intravenous group, at least one pathogen was identified at the first visit (Table 3). The proportions of subjects with single or multiple pathogens were comparable in the two groups. The most commonly isolated
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Table 2 Cure rates of symptoms related to AE-COPD in both groups on day 3 and day 10 after the initiation of treatment Day 3
Day 10
ZSR group n (%)
Intravenous group n (%)
ZSR group n (%)
Intravenous group n (%)
Fever
9/11 (81.8)
10/16 (62.5)
10/11 (90.9)
13/16 (81.3)
Cough
6/12 (50)
3/16 (18.8)
11/12 (91.7)
10/16 (62.5)
Sputum Dyspnea
6/12 (50) 8/12 (66.7)
3/16 (18.8) 9/14 (64.3)
11/12 (91.7) 12/12 (100)
12/16 (75) 12/14 (85.7)
Cure rate of each symptom that presented after initiation of treatment Table 3 Pathogens isolated at the first visit Parameter
Value for treatment group ZSR group (n = 12)
Intravenous group (n = 17)
No. (%) of subjects with pathogens
8 (66.7)
12 (70.6)
No. (%) of subjects with single pathogens
2 (16.7)
9 (52.9)
No. (%) of subjects with multiple pathogens
3 (25)
3 (17.6)
Number of isolates of Haemophilus influenzae
3
5
Moraxella catarrhalis
4
2
Streptococcus pneumoniae Staphylococcus aureus
3
2
Oxacillin susceptible
0
1
Oxacillin resistant
0
1
Pseudomonas aeruginosa
2
3
Klebsiella pneumoniae
0
1
pathogen overall was H. influenzae, followed by M. catarrhalis, S. pneumoniae, and Pseudomonas aeruginosa. None was isolated by blood cultures. Susceptibility rates for antibiotics used in both groups were 100% (n = 5) in the ZSR group and 90% (n = 10) in the intravenous group, according to the reports from our central laboratory. All five cases of S. pneumoniae were susceptible to azithromycin.
Discussion Although COPD is one of the most common diseases worldwide, the treatment of AE-COPD is still controversial. Some reports previously documented the efficacy of antibiotics in the treatment of AE-COPD [5–10]. Some regimens of oral medication, such as levofloxacin (LVFX) 500 mg/day for 7 days, garenoxacin (GRNX) 400 mg/day for 14 days, or amoxicillin 500 mg/8 h for 10 days, have previously been reported [7–10]. Although the efficacy of macrolides for prevention of acute exacerbation of chronic bronchitis and COPD has been demonstrated [12], ZSR has never been reported as an effective short-course antibiotic
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therapy in the treatment of AE-COPD that is not inferior to intravenous therapy. One possible explanation of efficacy of AZM in the treatment of AE-COPD is that AZM and other macrolides can decrease neutrophil chemotaxis and infiltration into the respiratory epithelium, downregulate adhesion molecule expression, and enhance neutrophil apoptosis [13, 14]. Patients with mild or moderate AE-COPD may be treated as outpatients by administering oral medication; however, medication compliance could be problematic without supervision. Some elderly patients in Japan live alone, and poor compliance would result in clinical failure. Previous surveys demonstrated compliance declines in terms of the frequency and duration of antibiotic therapy [15–17]. Once symptoms begin to resolve, within a few days of beginning treatment, patients often stop taking their antibiotics, thereby increasing the risk of treatment failure. Thus, the availability of single-dose antibiotic therapy may enhance compliance, thereby maximizing efficacy and minimizing the emergence of bacterial resistance. Other studies have shown that shortcourse antibiotic therapy, by improving compliance, can lead to faster resolution of symptoms, as shown in this study [18]. In addition, a meta-analysis of several studies on
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bacterial upper respiratory tract infections, including acute otitis media, acute bacterial sinusitis, and streptococcal pharyngitis, concluded that shorter courses of antibiotics have the potential to increase patient compliance with therapy, decrease adverse events by decreasing drug exposure, decrease the emergence of resistant strains, and reduce cost [19, 20]. We suggest that a single-dose antibiotic therapy achieves near-perfect compliance as well as several advantages, as follows. Short-term admission or treatment as outpatients will reduce medical costs. The medical expense for COPD will increase year by year and become a great burden in the very near future. Previous research showed that nearly 41–60% of the global cost of COPD is associated with exacerbation episodes, particularly severe acute exacerbations requiring hospital admission [3, 4]. In our study, the medical costs for the ZSR group were less than those for the intravenous group (P \ 0.001). In terms of medical economics, ZSR therapy could contribute to reducing medical expenses in the treatment of AE-COPD. One of the advantages is the lesser toxicity of singledose therapy, compared with conventional antibiotic therapies such as AZM 500 mg for 3 days or LVFX 500 mg/ day for 7 days [7–10]. ZSR therapy was well tolerated by the AE-COPD patients, including the elderly. Treatmentrelated diarrhea and liver dysfunction, seen in one patient in each group (8.3%), respectively, required no additional medication. No severe treatment-related adverse events were found in this study, as reported in previous studies for community-acquired pneumonia (CAP) and acute otitis using ZSR [11, 21]. Causative pathogens were identified in just over 50% of patients in both treatment groups, which is similar to the rates reported in other CAP or AE-COPD studies [22, 23]. No pathogens were detected in 12 of the 29 (41.4%) subjects collected, which suggests that atypical pneumonia such as that caused by Mycoplasma pneumoniae or Chlamydophila pneumoniae was related to AE-COPD. The modality of the diagnosis of atypical pneumonia is limited, and thus it is difficult to make this diagnosis in cases of AE-COPD as well. S. pneumoniae was isolated in 5 cases (17.2%) in this study, all of which were susceptible to azithromycin. In Japan, the high rate of isolated S. pneumoniae that is resistant to macrolides is problematic [24, 25]. Administering 2.0 g azithromycin as a single dose is likely to result in concentrations of azithromycin in lung tissue and fluid that would be effective against S. pneumoniae with low-level macrolide resistance [11]. A trial examining the lung pharmacokinetics of the single-dose azithromycin regimen is currently under way to provide data to support this hypothesis [11]. Two of the 12 patients were considered clinical failures in the ZSR group. P. aeruginosa was isolated from these 2
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patients. Therefore, it is reasonable to assume that ZSR was not effective. It has previously been reported that P. aeruginosa was isolated more frequently among patients with forced expiratory volume in 1 s (FEV1) \50% than among those with FEV1 C50% [23]. Thus, we recommend that single-dose azithromycin therapy could be effective for the patients with stage I or II COPD. Oral antibiotics such as moxifloxacin or azithromycin are recommended for the treatment of AE-COPD by the current guideline [5], and we believe that they are more effective than oral b-lactam/b-lactamase inhibitors. New quinolones and macrolides have been known to show rapid lung tissue penetration and bacterial eradication [7, 8, 26, 27]. Thus, by means of this mechanism, they might help prolong the time to the next acute exacerbations of chronic bronchitis and AE-COPD. Donaldson et al. reported that frequent exacerbation contributes to the rate of decline in FEV1. In the study, the decline in FEV1 of frequent exacerbators (C2.92 times per year) was significantly faster than that of infrequent exacerbators (\2.92 times per year) [28]. In addition, it has been demonstrated that mortality increases with the frequency of AE-COPD, particularly if it requires hospital admission [3]. We suggest that one of the most important factors for decreasing mortality of patients with COPD is prevention and reduction of the risk of AE-COPD. Our study has several limitations. First, this was a retrospective analysis in a very small population. Retrospective studies may be less reliable in terms of the data collected, particularly for data such as physical examination and duration of symptoms. Second, a selection bias might have occurred with the choice of ZSR therapy or intravenous therapy by the attending physicians. A prospective study is necessary, and more cases are to be expected. In conclusion, ZSR could be one of the best treatments for AE-COPD in terms of not only clinical benefits but also of medical cost. For the purpose of reducing mortality in patients with COPD, ZSR could be effective to help decrease and prevent AE-COPD. We expect a prospective study to be done concerning the treatment of AE-COPD by ZSR therapy. Acknowledgments We are grateful for the diligent and thorough critical reading of our manuscript by Mr. John Wocher, Executive Vice President and Director, International Affairs/International Patient Services, Kameda Medical Center (Japan).
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