Value of short-course antimicrobial therapy in community-acquired pneumonia

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Antimicrobial Agents ELSEVIER

International Journal of Antimicrobial Agents 26 Suppl. 3 (2005) S148 S155 www.ischemo.org

Value of short-course antimicrobial therapy in community-acquired pneumonia Francesco Blasi*, Paolo Tarsia Institute of Respiratory Diseases, University of Milan, IRCCS Fondazione Policlinico-Mangiagalli-Regina Elena Milano, Italy

Abstract

Community-acquired pneumonia (CAP) is a major cause of morbidity and mortality worldwide. Non-compliance with therapy may be associated with deterioration in the patient' s condition, treatment failure, and increased use and cost of healthcare resources such as the requirement for additional drugs and hospital admission. Adherence to the prescribed regimen is affected by a number of variables including dosing interval, treatment duration, adverse effects, and palatability in pediatric patients. Accumulating evidence suggests that short-course antimicrobial therapy may be at least as effective as, and in some cases may be more effective than, traditional longer therapies (7-14 days) even in hospital-acquired pneumonia. Given the unique pharmacokinetic properties of azithromycim attempts have been made to condense the traditional total dose over a 3-5-day period into single-dose therapy with the aim of improving treatment compliance. The results of two phase III CAP trials indicate that a single 2.0 g dose of azithromycin microspheres is a suitable alternative to 7 days of either clarithromycin XL or levofloxacin. © 2005 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. Keywords: Short-course therapy; Azithromycin microspheres; Community-acquired pneumonia

1. Introduction

Lower respiratory tract infections (LRTIs) are a major healthcare and economic problem due to their high morbidity and to the direct and indirect costs that their management engenders. Once a diagnosis o f LRTI has been made, empirical antibiotic therapy is usually indicated. When this is the case, the first-line agent should be the narrowest spectrum antibiotic that would be expected to treat the most conm~on causative organisms, including Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and the atypical pathogens Mycoplasma pneumoniae, Chlamydia pneumoniae and Legionella spp. Atypical infections are underdiagnosed because of the lack o f a consistent and reproducible diagnostic test available to all microbiology laboratories. However, it has been reported that atypical pathogens may be responsible for approximately onequarter o f community-acquired pneumonia (CAP) cases [1]. CAP has a considerable impact on morbidity and mortality, particularly in infants and the elderly in whom the incidence is highest and vulnerability is greatest. Annually, * Corresponding author. Istituto di Tisiologia e Malattie dell' Apparato Respiratorio, UniversitA degli Studi di Milano, Pad. Sacco, Fondazione Policlinico-Mangiagalli-Regina Elena Milano, via E Sforza 35, 1-20122 Milan, Italy. Tel.: +39 02 5032 0623; fax +39 02 5032 0628. E-mail address." [email protected] (E Blasi). 0924-8579/$

2 - 3 million cases o f CAP result in ca. 10 million physician visits, 500000 hospitalizations and 45 000 deaths in the USA [2]. In Europe, the overall incidence of conmmnity-acquired LRTIs was found to be 44 cases per 1000 population per year in a single general practice. However, the incidence was two to four times higher in people aged ~>60 years compared with those aged <50 years [3]. A study in Finland o f 546 patients with CAP found that the overall incidence was 11.6 per 1000 inhabitants per year. In total, 31% were aged ~>60 years [4]. Although many antibiotics are available, mortality in hospitalized patients remains high, particularly in the intensive care unit setting. In a Finnish study, 42% o f cases o f CAP were adnfitted to hospital and the case fatality rate was 4% [4]. On average, the mortality rate in patients with CAP who have been hospitalized is - 1 2 % both in the U S A and Europe, whilst in outpatients the mortality rate is lower at - 5 % [5,6]. As expected, patients with more severe CAP have a higher mortality rate (29%). Current European and Japanese guidelines on CAP management in adults, as well as those from bodies such as the Infectious Diseases Society of America (IDSA), the American Thoracic Society (ATS) and the Centers for Disease Control (CDC), all endorse macrolides as having an important role in the treatment o f C A P [ 7 11]. This reflects the ability o f macrolides to provide coverage for

see front matter © 2005 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

K BlasL P Tarsia/International Journal of Antimicrobial Agents 26 Suppl. 3 (2005) S148 S155

the key bacterial pathogens that cause CAP, including atypical bacteria. It is suggested that macrolides may be used as monotherapy in outpatient cases of uncomplicated CAP, whereas combination therapy with a [3-1actam and an advanced macrolide (such as azithromycin) is a cornerstone of suggested treatment in hospitalized patients.

2. Short-course antimicrobial therapy for CAP The importance of patients completing their full course of antibiotic therapy is increasingly being recognized as a key requirement for appropriate antibiotic use. The US Food and Drug Adnfinistration now requires that all antibiotic labels include guidance to physicians to counsel their patients that skipping doses or not completing the full course of therapy may decrease the effectiveness of the treatment and increase the likelihood that bacteria will develop resistance [12]. In addition, shorter courses of antibiotic treatment would be likely to reduce potentially harmful effects experienced with traditionally more prolonged antimicrobial therapy. In addition to educational initiatives, other factors can positively influence patients to complete their antibiotic therapy. Completion of therapy is affected by a number of variables, including dosing interval, treatment duration, adverse effects, and palatability in pediatric patients. Adherence to once-daily regimens has been shown to be far superior to that of twice- or thrice-daily dosing schemes, and the number of patients completing therapy falls after 3-7 days of treatment [13,14]. Therefore, shortcourse antibiotic regimens, particularly those that offer once-daily dosing, can offer advantages in terms of patient completion of therapy. Studies of 3- or 5-day short-course antibiotic regimens have demonstrated that they can be as effective as longer 10-day antibiotic regimens. In a prospective, open-labeled, randomized, multicenter trial in outpatients with CAP, Rahav et al. [15] compared a 3-day course of azithromycin monotherapy with 10 days of other antibiotic monotherapies (involving either erythromycin, amoxicillin/clavulanic acid, roxithromycin, cefuroxime axetil, doxycycline or cefaclor). Treatment groups were comparable in terms of age and severity of CAR Pneumonia resolution occurred in 98.4% of patients treated with azithromycin compared with 87% treated with other antibiotics (P < 0.017). Patients receiving azithromycin recovered normal function at home and returned to work earlier than patients treated with other antibiotics (P < 0.001). No hospitalizations occurred in the azithromycin group compared with two patients in the comparison group. This resulted in a total cost per 100 patients of $28 224 in the azalide group versus $54590 in the comparison group. In a second study of 390 clinically evaluable patients with mild-to-severe CAP, patients were randomized to receive levoftoxacin 750mg per day for 5 days or levoftoxacin

S 149

500rag per day for 10 days [16]. The clinical success was 92.4% in the high-dose, short-course levoftoxacin group compared with 91.1% in the standard regimen, whereas microbiological eradication rates were 93.2% in the former and 92.4% in the latter. These data appear to indicate that the high-dose, short-course levoftoxacin regimen was at least as effective as a standard course in patients with mildto-severe CAR In addition, there is some evidence that giving a higher dose of drug over a shorter period can reduce the selection of antibiotic-resistant strains. For example, in children with respiratory tract infections, high-dose, shortcourse amoxicillin (90 mg/kg for 5 days) was associated with significantly lower penicillin-resistant S. pneumoniae carriage in follow-up nasopharyngeal specimens compared with a standard regimen (40mg/kg for 10 days) [17]. The advantage of short-course therapy has been demonstrated in ventilator-associated pneumonia: patients receiving a shorter course of antibiotic therapy had better clinical outcomes than patients receiving longer therapy, with fewer subsequent superinfections attributed to antibiotic-resistant pathogens [ 18]. Data in the literature indicate that macrolide-containing regimens have been associated with lower mortality rates and shorter lengths of hospital stay than other types of monotherapy or combination therapies in patients with CAP, including bacteremic pneumococcal pneumonia[19 23]. The nature of such a beneficial effect is still unclear and may include coverage of atypical pathogens, both as a direct cause of pneumonia and as part of a mixed infection [24]. In fact, patients with mixed pneumonia due to S. pneumoniae and C. pneumoniae in whom antinficrobial therapy was targeted only against S. pneumoniae (with a [3-1actam alone) experienced a significantly longer delay in recovery compared with patients who also received a macrolide [25, 26]. Interestingly, these benefits were evident even when compared with other agents that provide coverage against atypical pathogens such as the ftuoroquinolones. Therefore, to explain the observed benefits of macrolide-containing antibiotic regimens in CAP, additional mechanisms such as anti-inftanm~atory properties have been suggested.

3. Single-dose therapy for CAP For antibiotics with suitable pharmacokinetic characteristics, a single-dose approach offers advantages to patients by ensuring that they complete their prescribed course of therapy and receive the optimal dosage of antibiotic. Azithromycin has a half-life of ca. 60 h and concentrates within a variety of cells, including fibroblasts, epithelial cells, macrophages, monocytes and neutrophils [29,30], thus achieving high and sustained tissue concentrations particularly at sites of infection. These properties allow for shorter dosing regimens than are possible with other

E Blasi, P Tarsia/International Journal of Antimicrobial Agents 26 Suppl. 3 (2005) S148 S155

S 150

Table 1 Demographics and baseline characteristics of patients included in two comparative phase III communityacquired pneumonia studies of 2 g single-dose azithromycin microspheres

Study 1 [27]

Study II [28]

Azithromycin microspheres (n-247)

Clarithromycin XL 1.0 mg (n-252)

Azithromycin microspheres (n-211)

Levofloxacin 500 mg (n-212)

Mean age (years)

45.6

43.6

48.2

49

No. of subjects ~>65 years

33 (13.4%)

26 (10.3%)

49 (23.2%)

48 (22.6%)

Male/female

112/135

134/118

121/90

109/103

White

190

191

132

135

Black

14

15

5

3

Asian

35

34

47

48

Hispanic

6

9

2

2

Other

2

3

25

24

History of diabetes

13

11

20

27

Unilobar disease

211

219

172

181

Smoker/ex-smoker

131

139

99

100

Single-dose pre-treatment antibiotic a

20 (8%)

27 (11%)

18 (9%)

15 (7%)

Cases of pneumococcal bacteremia

0

3

0

0

Race

a

Received a single-dose pre-treatment antibiotic (as allowed by the protocol).

Table 2 Clinical and bacteriological response at test-of-cure visit (Days 14-21) of per protocol patients included in two comparative phase III community-acquired pneumonia studies of 2 g single-dose azithromycin microspheres Study I [27]

Study II [28]

Azithromycin microspheres

Clarithromycin XL 1.0 mg

95% CI

Azithromycin microspheres

Levofloxacin 500 mg95% CI

Clinical response

92.6% ( n - 202)

94.7% ( n - 209)

-6.9, 2.6

Bacteriological response

93% ( n - 100)

92.1% ( n - 127)

89.7%( n - 174)

93.7% ( n - 189)

90.1% (n-91)

92.3% ( n - 104)

Haemophilus influenzae

14/15 (93%)

23/26 (88%)

14/15 (93%)

8/8 (100%)

Moraxella catarrhalis

8/8 (100%)

3/5 (60%)

7/7 (100%)

2/2 (100%)

-9.7, 1.7

Clinical response by pathogen

Streptococcuspneumoniae

17/19 (89%)

25/27 (93%)

11/14 (79%)

10/12 (83%)

Chlamydia pneumoniae

19/21 (90%)

29/31 (94%)

18/19 (94%)

21/22 (95%)

Mycoplasma pneumoniae

25/26 (96%)

20/21 (95%)

5/7 (71%)

18/18 (100%)

CI, confidence interval.

antibiotics that have short elimination half-lives. Administration of a single, higher dose of azithromycin has been shown to achieve more rapid bacterial eradication and enhanced survival than the same dose divided over several days in pre-clinical infection models of otitis media, murine pneumonia and septicemia [31,32], suggesting that a single-dose approach may offer benefits. However, one challenge to this higher single-dose approach is the high level of gastrointestinal intolerance associated with the currently available 2.0 g dose of azithromycin inmmdiaterelease sachet formulation, which is approved for treatment of chlamydial urethritis and cervicitis [33].

A novel azithromycin microsphere formulation (recently approved as Zmax in the USA) has been developed to address the challenge of administering a higher oral dose of the drug as a single dose while maintaining tolerability. This formulation, in which azithromycin is contained within microspheres, allows for oral administration of a single 2.0 g dose while dramatically improving upon the adverse event profile of the inm~ediate-release sachet formulation. The maximum plasma concentration (Cm~x) and 24-h area under the concentratiomtime curve (AUCo_24) after a single 2.0 g dose of azithromycin microspheres are two and three times higher, respectively, than those achieved with 1.5 g

E Blasi, P Tarsia/International Journal of Antimicrobial Agents 26 Suppl. 3 (2005) S148 S155 Table 3 Susceptibility of the 56 Streptococcus pneumoniae isolates identified in the azithromycin versus clarithromycin XL study in patients with communityacquired pneumonia [27] a Susceptible

Intermediate

S 151

Table 4 Susceptibility patterns of the 28 Streptococcus pneumoniae isolates identified in the azithromycin versus levofloxacin study in patients with community-acquired pneumonia [28] a Susceptible

Resistant

Intermediate

Resistant

Penicillin

38 (68%)

16 (29%)

2 (4%)

Penicillin

19 (68%)

8 (29%)

1 (4%)

Azithromycin

49 (88%)

1 (2%)

6 (11%)

Azithromycin

21 (75%)

0

7 (25%)

Clarithromycin

50 (89%)

0

6 (11%)

Levofloxacin

28 (100%)

0

0

a

Based on the criteria of the National Committee for Clinical Laboratory Standards: penicillin, S ~<0.06 ~tg/mL, 1 - 0 . 1 2 - 1 ~tg/mL, R ~>2 ~tg/mL; azithromycin, S ~<0.5 ~tg/mL, I - 0.5 ~tg/mL, R ~>2.0 ~tg/mL; clarithromycin, S ~<0.25 ~tg/mL, I - 0.5 ~tg/mL, R ~> 1.0 ~tg/mL.

of conventional inm~ediate-release azithromycin given over either 3 days or 5 days. By 'front loading' the dose early in the course of infection, maxinmm drug exposure is achieved when bacterial burden is likely to be highest. Front loading also increases the AUCo_24/mininmm inhibitory concentration (MIC) ratio, which is the pharmacokinetic/ pharmacodynamic parameter that best predicts the efficacy of azithromycin [34]. Two phase III multinational, multicenter, double-blind, double-dunmly studies analysed the efficacy and safety of a new microsphere formulation of azithromycin in CAR In these trials, a single 2.0 g dose of azithromycin was compared with either the extended-release formulation of clarithromycin XL (ling once daily for 7 days)[27] or with levoftoxacin (500 mg once daily for 7 days) [28] in the treatment of adults with mild-to-moderate CAR In the clarithromycin XL comparator trial, eligible subjects were required to be 16 years of age or older, with cough productive of sputum and a diagnosis of pneumonia as demonstrated by two or more of the following signs or symptoms: auscultatory findings on pulmonary examination of rales and/or evidence of pulmonary consolidation; dyspnea or tachypnea; body temperature <38°C (oral); or an elevated total peripheral white blood cell count (>10 000/nml 3) or >15% immature neutrophils (bands). In addition, subjects had to have a prospectively calculated Modified Fine Risk score of ~<70 (Fine Classes I and II). In the levoftoxacin trial, subjects were aged 18 years or older with a clinical diagnosis of mild-to-moderate CAP with a Fine mortality risk class of I, II or III (i.e. a risk score of ~<90). In both studies, clinical assessments were conducted at baseline (Day 1), during treatment (Days 3-5), at the end of treatment (Days 8-11), post treatment at the test of cure (TOC) visit (Days 14-21) and at a long-term follow-up visit (Days 28-35). Clinical efficacy was assessed at the TOC visit. Subjects with a clinical response of cure at the TOC visit were assessed for relapse at the long-term follow-up visit (Days 28-35). Bacteriological response was assessed in those subjects from whom a pathogen was identified at baseline.

Based on the criteria of the National Committee for Clinical Laboratory Standards: penicillin, S ~<0.06 ~tg/mL, I - 0.12-1 ~tg/mL, R ~>2 ~tg/mL; azithromycin, S ~<0.5 ~tg/mL, I - 0.5 ~tg/mL, R ~>2.0 ~tg/mL; levofloxacin S ~<2 ~tg/mL, I - 4 ~tg/mL, R ~>8 ~tg/mL. a

Table 1 shows the demographics and baseline characteristics of the patients enrolled in the two studies. No differences in terms of either clinical response or bacteriological response were noted between azithromycin microspheres and comparators at the TOC visit (Days 14-21). Clinical and bacteriological results are reported in Table 2. Tables 3 and 4 show the susceptibility patterns of S. pneumoniae strains isolated in the two studies. Data on S. pneumoniae eradication rates and clinical response, according to bacterial susceptibility to macrolides and penicillin, were analysed in both studies (Tables 5 and 6). No clear relationship between resistance patterns and clinical and bacteriological outcomes was observed. In the two studies combined, 6 of 11 infections due to macrolide non-susceptible S. pneumoniae strains that were treated with macrolides resulted both in clinical cure and bacteriological eradication (presumed or documented). In the study comparing azithromycin microspheres with levofloxacin, all subjects treated with azithromycin microspheres were compliant with the full course of active treatment. Ten of the 212 levofloxacin-treated subjects (4.7%) did not complete the full 7-day course of active treatment. Six subjects (two azithromycin and four levofloxacin) were hospitalized for worsening pneumonia; two of the levofloxacin-treated and one of the azithromycin-treated subjects ultimately died of causes other than pneumonia. The safety and tolerability of this novel azithromycin fornmlation were excellent. The majority of all reported adverse events were mild or moderate in severity. For azithromycin microspheres, most adverse events occurred on the day of administration and resolved within 2 days. There were no clinically significant changes in clinical laboratory parameters. In the study comparing azithromycin microspheres and clarithromycin XL, there were five deaths, all of which were in the clarithromycin XL arm. None of the deaths were attributed to study therapy or progression of CAR Table 7 shows the adverse reactions recorded in the two studies. In both studies, the azithromycin group showed a greater number of diarrhea and loose stools adverse events. In most cases the effect was limited to the day of therapy

S 152

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E BlasL P. Tarsia/International Journal of Antimicrobial Agents 26 Suppl. 3 (2005) S148 S155

Table 7 Adverse events of patients included in two phase III comparative studies of 2 g single-dose azithromycin microspheres in the treatment of communityacquired pneumonia Study I [27] Azithromycin microspheres (n - 247)

Study II [28]

Clarithromycin XL 1.0 mg (n - 252)

Azithromycin microspheres (n-211)

Levofloxacin 500 mg (n-212)

Diarrhea/loose stools

30 (12.1%)

19 (7.5%)

27 (12.8%)

11 (5.2%)

Nausea

9 (3.6%)

8 (3.2%)

3 (1.4%)

2 (0.9%)

Abdominal pain

9 (3.6%)

3 (1.2%)

4 (1.9%)

2 (0.9%)

Rash

3 (1.2%)

1 (0.4%)

1 (0.5%)

0

Taste perversion

3 (1.2%)

9 (3.6%)

0

1 (0.5%)

Vomiting

2 (0.8%)

2 (0.8%)

4 (1.9%)

2 (0.9%)

or the following day. Two azithromycin-treated subjects and one clarithromycin-treated subject were hospitalized for worsening of pneumonia. Owing to the single-dose nature of the regimen, all azithromycin-treated patients completed the treatment course, whereas 15 of 254 subjects (5.9%) randomized to the clarithromycin XL arm did not complete the entire 7-day course of active treatment.

4. Conclusions

As recently sunmlarized by File [35], the basic rationale behind short-course antibiotic treatment in CAP is to 'hit hard and stop early' . There is now accunmlating evidence that this approach may offer real benefits. Studies have shown that short-course 3- or 5-day antibiotic regimens are as effective as longer 10-day regimens in the treatment of mildto-moderate CAR However, the azithromycin microsphere formulation offers equivalent efficacy versus comparator regimens, with the additional benefit of ensuring that patients complete their prescribed course of therapy. Failure to complete therapy may be associated with deterioration in the patient' s condition, treatment failure, and increased use and cost ofhealthcare resources such as the requirement for additional drugs and hospital admission. Failure to complete therapy may also increase the likelihood that bacteria will develop resistance [12,36]. Another compliance-related advantage of single-dose therapy is the potential for use as directly-observed therapy (DOT). The use of a DOT approach to pneumonia is certainly interesting and may be valuable in the clinic or emergency department where compliance may be in doubt or barriers to filling prescriptions may exist. The results of controlled trials in CAP demonstrated that a single dose of azithromycin microspheres is at least as effective and well tolerated as a 7-day treatment with either clarithromycin XL or levoftoxacin.

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[27] Drehobl MA, De Salvo MC, Lewis DE, Breen JD. Single-dose azithromycin microspheres vs clarithromycin extended release for the treatment of mild-to-moderate community-acquired pneumonia in adults. Chest 2005;128:2230 7. [28] D' Ignazio J, Camere MA, Lewis DE, Jorgensen D, Breen JD. Novel, single-dose microsphere formulation of azithromycin versus 7-day levoftoxacin therapy for treatment of mild to moderate communityacquired pneumonia in adults. Antimicrob Agents Chemother 2005; 49:403541. [29] Schentag JJ, Ballow CH. Tissue-directed pharmacokinetics. A m J Med 1991;91(Suppl 3A):5S-11S. [30] Rothermel CD. Single-dose azithromycin for acute otitis media: a pharmacokinetic/pharmacodynamic rationale. Curr Ther Res 2003; 64(Suppl 1):4 15. [31] Girard D, Finegan SM, Cimochowski CR, Dunne MW, Giovanis A. Accelerated dosing of azithromycin in preclinical infection models. Poster presented at the 102nd American Society for Microbiology General Meeting, Salt Lake City, UT, May 1923, 2002. Abstract A-57. [32] Kamicker BJ, Bertsche CD, Medina IA. In rodent models, single dose of azithromycin was more effective than dosing split over 3 or 5 days. In: Abstracts of the 44th Annual Meeting of ICAAC; 2004. Abstract B-1181. [33] Handsfield HH, Dalu ZA, Martin DH, et al. Multicenter trial of singledose azithromycin vs. ceftriaxone in the treatment of uncomplicated gonorrhea. Azithromycin Gonorrhea Study Group. Sex Transm Dis 1994;21:107 11. [34] Craig WA. Postantibiotic effects and the dosing of macrolides, azalides, and streptogramins. In: Zinner SH, Young LS, Acar JF, Neu HC, editors, Expanding Indications for the New Macrolides, Azalides and Streptogramins. New York: Marcel Dekker; 1997. p. 27 38. [35] File TM. Clinical efficacy of newer agents in short-duration therapy for community-acquired pneumonia. Clin Infect Dis 2004;39:S159 64. [36] Pichichero ME. Short course antibiotic therapy for respiratory infections: a review of the evidence. Pediatr Infect Dis J 2000; 19:929 37.