Systematic Review and Meta-analysis of the Efficacy of Short-Course Antibiotic Treatments for Community-Acquired Pneumonia in Adults
ABSTRACT
The duration of therapy for community-acquired pneumonia (CAP) remains undefined. We sought to investigate whether short-course antibiotic treatment for CAP is associated with favorable clinical outcomes in adult patients. We systematically searched PubMed, EMBASE, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for studies comparing the effectiveness and safety between treatment regimens administered for ≤6 days and ≥7 days. We defined treatment for ≤6 days as short-course treatment and treatment for ≥7 days as long-course treatment. Twenty-one clinical trials (4,861 clinically evaluable patients) were included, and 19 out of 21 trials were randomized. Clinical cure was similar between the compared groups (4,069 patients, risk ratio [RR] = 0.99 [95% confidence interval {CI}, 0.97 to 1.01]), irrespective of patient setting (RR = 0.98 [95% CI, 0.96 to 1.00] for the outpatient setting and RR = 1.00 [95% CI, 0.92 to 1.09] for the inpatient setting) or severity of pneumonia (RR = 1.05 [95% CI, 0.96 to 1.14]). Also, relapses were similar between the short- and long-course treatment groups (1,923 patients, RR = 0.67 [95% CI, 0.30 to 1.46]). Short-course treatment was associated with fewer serious adverse events (1,923 patients, RR = 0.73 [95% CI, 0.55 to 0.97]) and, importantly, resulted in lower mortality than long-course treatment (2,802 patients, RR = 0.52 [95% CI, 0.33 to 0.82]). In CAP, short-course antibiotic treatment (≤6 days) is as effective as and potentially superior to, in terms of mortality and serious adverse events, longer-course treatment.
INTRODUCTION
Pneumonia is a leading cause of mortality worldwide, is the 8th most common cause of death in the United States, and is associated with high health care costs (1–3). However, the duration of therapy for community-acquired pneumonia (CAP) remains undefined. Current guidelines regarding the duration of therapy indicate that short treatment is appropriate (4–6), but the definition of “short treatment” varies among them. Moreover, physicians tend to use much longer treatment for patients with CAP, even among patients with low comorbidities or a very low risk for death (7), with up to 40% patients receiving antibiotic treatment for >10 days for uncomplicated CAP (8).
The aim of the present study is to investigate whether short-course antibiotic treatment is associated with better clinical outcomes than long-course treatment in adult patients with CAP and to use the available data to define, in the optimal way possible, “short treatment” for this indication.
RESULTS
The literature search yielded a total of 3,235 articles: 2,027 from PubMed, 562 from the Cochrane Central Register of Controlled Trials, 503 from EMBASE, 137 from ClinicalTrials.gov, and 6 from a hand search. Of them, 21 studies were considered eligible and included in the review. The detailed study selection process is depicted in Fig. 1.
FIG 1
All included studies were clinical trials, among which 19 were randomized controlled trials (RCTs) (9–27), 10 were double blind (11–18, 26, 28), 11 were open label (9, 10, 19–25, 27, 29), and 18 were multicenter (9–21, 23–27). The characteristics of the included studies are presented in Table 1. In Table 2, the quality assessment of the included clinical trials is presented.
TABLE 1
| First author, yr (reference) | Study design, country | No. of CE pts, patient setting, severity of pneumonia | Causative pathogen (no. of pts) | Regimen | Time of clinical evaluation | No. of patients assessed/no. with clinical cure (%) | Time of mortality assessment | No. of patients assessed/no. who died (%) | |||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Short course | Long course | Short course | Long course | Short course | Long course | ||||||
| Masiá, 2017 (28) | Nonrandomized double-blind clinical trial with historical control, Spain | 253, outpatients, Fine I/IIb | Streptococcus pneumoniae (47), Mycoplasma pneumoniae (33), Haemophilus influenzae (6), Legionella pneumophila (5), Chlamydophila pneumoniae (4), Klebsiella pneumoniae (1) | Azithromycin, 500 mg/day p.o. for 5 days | Levofloxacin, 500 mg/day p.o. for 7 days | EOT | 207/216 (95.8) | 35/37 (94.6) | 30-day | 0/216 (0) | 0/37 (0) |
| Zhao, 2016 (27) | MC open-label RCT, China | 427, inpatients/outpatients, mild to moderate with CURB65c score of 0–2, 87% of which had a CURB65 score of 0 | S. pneumoniae | Levofloxacin, 750 mg/day i.v. for 5 days | Levofloxacin, 500 mg/day i.v./p.o. for at least 7 days (range, 7–14 days) | EOT | 195/208 (93.8) | 210/219 (95.9) | NA | NR | NR |
| Paris, 2008 (20) | MC open-label RCT, Italy | 267, outpatients, mild to moderate with Fine I/II | M. pneumoniae (47), C. pneumoniae (23), H aemophilus parainfluenzae (17), H. influenzae (16), Staphylococcus aureus (15), S. pneumoniae (4), Moraxella catarrhalis (3), Acinetobacter spp. (6) | Azithromycin, 1 g/day p.o. for 3 days | Amoxicillin-clavulanic acid, 875/125 mg b.i.d. p.o. for 7 days | EOT (days 8–12) | 126/136 (92.6) | 122/131 (93.1) | NA | NR | NR |
| File, 2007 (15) | MCd double-blind RCT | 483, outpatients, mild to moderate with Fine ≤III | S. pneumoniae (66), C. pneumoniae (49), M. pneumoniae (45), H. influenzae (40), S. aureus (38) | Gemifloxacin, 320 mg/day p.o. for 5 days | Gemifloxacin, 320 mg/day p.o. for 7 days | EOT (days 7–9) | 236/247 (95.5) | 226/236 (95.8) | NA | NR | NR |
| el Moussaoui, 2006 (14) | MC double-blind RCT, Netherlands | 114, inpatients, mild to moderate-severe | S. pneumoniae (37), H. influenzae (10), M. catarrhalis (4), influenza A or B virus (4), C. pneumoniae (2), H. parainfluenzae (1), other (4) | Amoxicillin, i.v. for 3 days | Amoxicillin i.v. for 3 days followed by amoxicillin p.o. for 5 days | Day 10 | 50/54 (92.6) | 56/60 (93.3) | NA | NR | NR |
| D'Ignazio, 2005 (11) | MCe double-blind RCT | 363, outpatients, mild to moderate with Fine I–III | S. aureus (43), H. parainfluenzae (35), S. pneumoniae (28), H. influenzae (26), M. catarrhalis (10) | Azithromycin, single 2.0-g dose of microspheres p.o. | Levofloxacin, 500 mg/day p.o. for 7 days | Days 14–21 | 156/174 (89.7) | 177/189 (93.7) | All cause | 1/174 (0.6) | 2/189 (1.1) |
| Drehobl, 2005 (12) | MCf double-blind RCT | 411, outpatients, mild to moderate with Fine I/II | C. pneumoniae (52), M. pneumoniae (47), S. pneumoniae (46), H. influenzae (41), M. catarrhalis (13) | Azithromycin, single 2.0-g dose of microspheres p.o. | Clarithromycin, 500 mg extended-release formulation b.i.d. p.o. for 7 days | Days 14–21 | 187/202 (92.6) | 198/209 (94.7) | NA | NR | NR |
| Rahav, 2004 (21) | MC open-label RCT, Israel | 108, outpatients | NR | Azithromycin, 500 mg/day p.o. for 3 days | Erythromycin, amoxicillin-clavulanic acid, roxithromycin, cefuroxime, amoxicillin, doxycycline, or cefaclor, p.o. for 10 days | Days 10–14 | 61/62 (98.4) | 40/46 (87) | NA | NR | NR |
| Sopena, 2004 (25) | MC open-label RCT, Spain | 63, inpatients/outpatients, mild to moderate | M. pneumoniae (6), S. pneumoniae (4), L. pneumophila (4), H. influenzae (2), Coxiella burnetii (2), C. pneumoniae (1) | Azithromycin, 500 mg/day p.o. for 3 days | Clarithromycin, 250 mg b.i.d. p.o. for at least 10 days (range, 10–14 days) | Days 10–13 | 18/31 (58.1) | 22/32 (68.8) | NA | NR | NR |
| Tellier, 2004 (26) | MCg double-blind RCT | 466, inpatients/outpatients, Fine I–V | S. pneumoniae (80), H. influenzae (67), M. catarrhalis (10) | Telithromycin, 800 mg/day p.o. for 5 days | Clarithromycin, 500 mg b.i.d. p.o. for 10 days | Days 17–21 | 142/159 (89.3) | 134/146 (91.8) | All cause | 1/159 (0.6) | 2/146 (1.4) |
| Dunbar, 2003 (13) | MC double-blind RCT, United States | 390, inpatients/outpatients, Fine I–V | M. pneumoniae (79), S. pneumoniae (42), C. pneumoniae (38), H. influenzae (27), H. parainfluenzae (22), L. pneumophila (14) | Levofloxacin, 750 mg/day i.v./p.o. for 5 days | Levofloxacin, 500 mg/day i.v./p.o. for 10 days | Days 7–14 | 183/198 (92.4) | 175/192 (91.1) | All cause (between days 31 and 38) | 5/256 (2) | 9/265 (3.4) |
| Sánchez, 2003 (29) | Open-label nonrandomized clinical trial, Spain | 603, inpatients, Fine III–V | C. pneumoniae (68), S. pneumoniae (62), viruses (37), L. pneumophila (31), C. burnetii (19), M. pneumoniae (16), Enterobacteriaceae (6), H. influenzae (3), S. aureus (1), S treptococcus pyogenes (1) | Ceftriaxone, 1 g for 3 days, followed by oral amoxicillin-clavulanic acid, 875/125 mg p.o. t.i.d.), + azithromycin, 500 mg/day p.o. for 3 days | Ceftriaxone, 1 g for 3 days, followed by oral amoxicillin-clavulanic acid, 875/125 mg p.o. t.i.d.), + clarithromycin, 500 mg b.i.d. i.v./p.o. for at least 10 days | NA | NR | NR | In hospital | 14/383 (3.7) | 16/220 (7.3) |
| Léophonte, 2002 (18) | MC double-blind RCT, France | 186, inpatients | From bronchial secretions, S. pneumoniae (18), H. influenzae (13), M. catarrhalis (4), K. pneumoniae (2), Pseudomonas aeruginosa (1) | Ceftriaxone, 1 g/day i.v. for 5 days | Ceftriaxone, 1 g/day i.v. for 5 days, followed by ceftriaxone, 1 g/day i.m. for 5 days | Day 10 | 77/94 (81.9) | 76/92 (82.6) | All cause | 4/94 (4.3) | 7/92 (7.6) |
| O'Doherty, 1998 (19) | MCh open-label RCT | 196, outpatients, mild to moderate | H. influenzae (34), S. pneumoniae (22), M. catarrhalis (9), S. aureus (2) | Azithromycin, 500 mg/day p.o. for 3 days | Clarithromycin, 250 mg b.i.d. p.o. for 10 days | EOT (12–16 days) | 57/88 (64.8) | 61/88 (69.3) | NA | NR | NR |
| Gris, 1996 (16) | MC double-blind RCT, Belgium | 6, outpatients | NR separately for pneumonia | Azithromycin, 500 mg/day p.o. for 3 days | Amoxicillin-clavulanic acid, 500 mg/125 mg t.i.d. p.o. for 10 days | EOT (12–16 days) | 2/2 (100) | 1/4 (25) | NA | NR | NR |
| Schönwald, 1994 (23) | MC open-label RCT, Croatia | 150, inpatients with atypical pneumonia | M. pneumoniae (104), Chlamydia psittaci (18), C. burnetii (4), unknown (16) | Azithromycin, 500 mg/day p.o. for 3 days | Roxithromycin, 150 mg b.i.d. p.o. for 10 days | Days 13–15 | 88/89 (98.9) | 50/53 (94.3) | NA | NR | NR |
| Bohte, 1995 (9) | MC open-label RCT, Netherlands | 104, inpatients | S. pneumoniae (26), viruses (9), M. pneumoniae (8), L. pneumophila (4), H. influenzae (3), Streptococcus spp. (3), Chlamydia spp. (2), M. catarrhalis (1) | Azithromycin, 500 mg b.i.d. on day 1, followed by 500 mg q.d. on days 2–5, or benzylpenicillin, i.v. 1 × 106 IU q.d. for 5 days | Erythromycin, 500 mg q.d. p.o. for 10 days | Days 12–15 | 52/83 (62.7) | 14/21 (66.7) | NA | NR | NR |
| Rizzato, 1995 (22) | Open-label RCT, Italy | 40, inpatients, low to moderately severe | M. pneumoniae (9), L. pneumophila (5), C. pneumoniae (3), C. pneumoniae/K. pneumoniae (1), H. parainfluenzae (2), H. influenzae (1), S. pneumoniae (1), unknown (18) | Azithromycin, 500 mg/day p.o. for 3 days | Clarithromycin, 250 mg b.i.d. p.o. for at least 8 days (10 ± 2) | NR | 20/20 (100) | 17/20 (85) | NA | NR | NR |
| Kinasewitz, 1991 (17) | MC double-blind RCT, United States | 71, NR | S. pneumoniae (30), H. influenzae (25), H. parainfluenzae (10), S. aureus (10), K. pneumoniae (5), M. catarrhalis (4), other Enterobacteriaceae (9), other (7) | Azithromycin, 500 mg p.o. on day 1 followed by 250 mg/day p.o. on days 2–5 | Cefaclor, 500 mg t.i.d. p.o. for 10 days | Days 10–13 | 15/32 (46.9) | 16/39 (41) | All cause | 1/32 (3.1) | 2/39 (5.1) |
| Brion, 1990 (10) | MC open-label RCT, France | 89, outpatients | S. pneumoniae (15), M. pneumoniae (4), H. influenzae (3), C. psittaci (2), L. pneumophila (2), S. aureus (1), other (4) | Azithromycin, 500 mg p.o. on day 1 followed by 250 mg/day p.o. on days 2–5 | Josamycin, 1 g b.i.d. p.o. for 10 days | Day 30 | 37/46 (80.4) | 38/43 (88.4) | All cause | 3/46 (6.5) | 3/43 (7) |
| Schönwald, 1990 (24) | MCi open-label RCT | 71, inpatients/outpatients with atypical pneumonia | M. pneumoniae (55), C. psittaci (16) | Azithromycin, 250 mg b.i.d. on day 1 followed by 250 mg/day on days 2–5 | Erythromycin, 500 mg q.d. for 10 days | NR | 39/39 (100) | 32/32 (100) | NA | NR | NR |
a
Abbreviations: CE, clinically evaluable; MC, multicenter; RCT, randomized controlled trial; pts, patients; EOT, end of treatment; NR, not reported; NA, not applicable; i.v., intravenously; p.o., per os; i.m., intramuscularly; q.d., once a day; b.i.d., twice a day; t.i.d., three times a day; IU, international units.
b
According to the pneumonia severity index (PSI)/PORT scoring system.
c
The scoring system for assessing the risk for mortality in pneumonia.
d
Sixty-eight centers in 9 countries: Bulgaria, Croatia, Czech Republic, Lithuania, Poland, Romania, Russia, Ukraine, and the United States.
e
Fifty-six centers in 8 countries: Canada, Chile, India, Lithuania, Mexico, Peru, Russia, and the United States.
f
Fifty-eight centers in 7 countries: the United States, Canada, Argentina, Russia, India, Estonia, and Lithuania.
g
Seventy-seven centers in 9 countries: Argentina, Brazil, Canada, Chile, Germany, Republic of South Africa, Spain, the United Kingdom, and the United States.
h
Twenty-eight centers in 4 countries.
i
The centers which participated in this study are not reported.
TABLE 2
| First author, yr (reference) | Randomization | Allocation concealment | Similarity of baseline characteristics | Eligibility criteria | Blinding | Completeness of follow-up | Intention-to-treat analysis | ||
|---|---|---|---|---|---|---|---|---|---|
| Outcome assessor | Care provider | Patient | |||||||
| Masiá, 2017 (28) | No | NA | Yes | Yes | Yes | Yes | Yes | Yes | No |
| Zhao, 2016 (27) | Yes | Yes | Nob | Yes | No | No | No | Yes | Yes |
| Paris, 2008 (20) | Yes | Yes | Yes | Yes | No | No | No | Yes | Yes |
| File, 2007 (15) | Yes | NR | Yes | Yes | Yes | Yes | Yes | Yes | Yes |
| el Moussaoui, 2006 (14) | Yes | Yes | Noc | Yes | Yes | Yes | Yes | Yes | Yes |
| D'Ignazio, 2005 (11) | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes |
| Drehobl, 2005 (12) | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes |
| Rahav, 2004 (21) | Yes | NR | Nod | Yes | No | No | No | No | No |
| Sopena, 2004 (25) | Yes | NR | Yes | Yes | No | No | No | Yes | Yes |
| Tellier, 2004 (26) | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes |
| Dunbar, 2003 (13) | Yes | NR | Yes | Yes | Yes | Yes | Yes | Yes | Yes |
| Sánchez, 2003 (29) | No | NA | Noe | Yes | No | No | No | Yes | No |
| Léophonte, 2002 (18) | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes |
| O'Doherty, 1998 (19) | Yes | NR | Yes | Yes | No | No | No | Yes | No |
| Gris, 1996 (16) | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | No |
| Schönwald, 1994 (23) | Yes | NR | Yes | Yes | No | No | No | Yes | No |
| Bohte, 1995 (9) | Yes | NR | Yes | Yes | No | No | No | Yes | No |
| Rizzato, 1995 (22) | Yes | NR | Yes | Yes | No | No | No | NR | No |
| Kinasewitz, 1991 (17) | Yes | Yes | NR | Yes | Yes | Yes | Yes | Yes | No |
| Brion, 1990 (10) | Yes | NR | Nof | Yes | No | No | No | Yes | No |
| Schönwald, 1990 (24) | Yes | NR | NR | Yes | No | No | No | Yes | No |
a
Abbreviations: NA, nonapplicable; NR, not reported.
b
Baseline characteristics except age were similar between the treatment groups. Patients in the short-course treatment group were significantly younger than those in the long-course treatment group.
c
The treatment groups had similar baseline characteristics, except for the number of smokers and symptoms at admission, which were significantly more severe in the short-course treatment group.
d
The treatment groups were comparable with respect to age and the severity of signs and symptoms, but significantly more females received the short-course treatment.
e
The severity of pneumonia was similar between the treatment groups compared, but patients in the short-course treatment group were significantly older than those in the long-course treatment group.
f
Significantly more males received the short-course treatment.
The included studies reported data on 4,861 clinically evaluable patients. The study populations included were outpatients in 9 reports (10–12, 15, 16, 19–21, 28), inpatients in 6 (9, 14, 18, 22, 23, 29), and both outpatients and inpatients in 5 (13, 24–27). Immunocompromised patients/patients with HIV infection were excluded from 13 studies (10, 11, 13–15, 18, 20–22, 25–28), while patients with renal or liver insufficiency were excluded from 9 studies (10, 11, 15, 17, 19, 20, 24, 27, 28). Also, patients with chronic obstructive pulmonary disease were excluded from 3 studies (17, 21, 28).
The pneumonia severity index (PSI)/PORT (31) and CURB65 (32) scoring systems were used to evaluate the severity of pneumonia in 8 studies (11–13, 15, 20, 26, 28, 29) and 1 study (27), respectively. Moreover, investigators classified the severity of pneumonia using a score based on a short questionnaire for patients admitted to the hospital (1 study) (14) or without any explanation for the classification (1 study) (19). Finally, 8 studies did not report any information on the severity of pneumonia (9, 10, 16–18, 21, 23, 24), and 2 studies excluded the more severe cases of pneumonia based on symptoms (22, 25).
The short-course regimens were azithromycin in 13 studies (for 3 days [16, 19–23, 25, 29] or 5 days [9, 10, 17, 24, 28]), single-dose azithromycin microspheres in 2 studies (11, 12), a fluoroquinolone antibiotic in 3 studies (levofloxacin for 5 days [13, 27] or gemifloxacin for 5 days [15]), amoxicillin for 3 days in 1 study (14), ceftriaxone for 5 days in 1 study (18), and telithromycin for 5 days in 1 study (26). Five studies included antibiotics that are not approved by the Food and Drug Administration (FDA) (single-dose azithromycin microspheres [11, 12], telithromycin [26], josamycin [10], and roxithromycin [23]).
Concerning the microbiological causes of pneumonia, Streptococcus pneumoniae was the most prevalent pathogen in 9 studies (9, 10, 14, 15, 17, 18, 26–28) and Mycoplasma pneumoniae was the most prevalent in 6 studies (13, 20, 22–25). Chlamydophila pneumoniae (12, 29), Haemophilus influenzae (19), and Staphylococcus aureus (11) were the most common pathogens in the remaining studies. Of note is that 2 studies included exclusively patients with atypical pneumonia (23, 24).
Clinical cure.
In total, 18 clinical trials provided comparative data on clinical cure between short-course and long-course treatment. Pooling of the outcomes of the 18 studies showed that there was no statistically significant difference in clinical cure between patients receiving short-course antibiotic treatment and those receiving long-course antibiotic treatment (89.4% versus 90%) (Fig. 2; 4,069 patients, risk ratio [RR] = 0.99 [95% confidence interval {CI}, 0.97 to 1.01]), and no heterogeneity was detected in this analysis (P = 0.56, heterogeneity [I2] = 0%). Publication bias was not detected by the funnel plot. In 5 of these studies, patients in both groups received the same antibiotic treatment (13–15, 18, 27), and pooling of these studies revealed no difference between the compared groups (92.5% versus 93%) (Fig. 2; 1,600 patients, RR = 1.00 [95% CI, 0.97 to 1.02], P = 0.91, I2 = 0%).
FIG 2
Moreover, no difference in clinical cure between short- and long-course treatment was found across subgroup analyses in either outpatients (91.1% versus 92.4%) (2,924 patients, RR = 0.98 [95% CI, 0.96 to 1.00], P = 0.4, I2 = 5%) or inpatients (79.3% versus 84.5%) (444 patients, RR = 1.00 [95% CI, 0.92 to 1.09], P = 0.48, I2 = 0%). Also, clinical cure was similar between short- and long-course treatment in the subgroup analysis of outpatients with mild to moderate pneumonia or pneumonia of the Fine I/II class (91.1% versus 91.4%) (2,156 patients, RR = 0.99 [95% CI, 0.96 to 1.01], P = 0.26, I2 = 21%) and in the subgroup analysis of patients with severe pneumonia (90.3% versus 86.1%) (278 patients, RR = 1.05 [95% CI, 0.96 to 1.14], P = 0.33, I2 = 11%).
Mortality.
Pooling of studies with treatments approved by the FDA (13, 17, 18, 28, 29) showed that mortality was lower in the short-course treatment group than in the long-course treatment group (2.4% versus 5.2%) (1,634 patients, RR = 0.54 [95% CI, 0.32 to 0.89]). Mortality was also lower among patients who received treatment for ≤6 days than among those who received treatment for ≥7 days when we pooled studies with both FDA-approved and non-FDA-approved treatments (9 clinical trials) (1.9% versus 3.6%) (Fig. 3; 2,802 patients, RR = 0.52 [95% CI, 0.33 to 0.82], P = 0.98, I2 = 0%). Publication bias was not detected by the funnel plot. Notably, in the analysis of mortality, the population included both outpatients and inpatients with variable severities of pneumonia. Only studies which defined “short-course treatment” as treatment for 5 or 6 days and provided data on mortality were included in that analysis. Importantly, when we pooled only the studies with treatments that were approved by the FDA and that reported on patients with severe pneumonia based on an acceptable scoring system (PSI/PORT or CURB65) (13, 28, 29), mortality was lower among patients receiving short-course treatment than among those receiving long-course treatment (2.2% versus 4.7%) (1,377 patients, RR = 0.52 [95% CI, 0.29 to 0.94], P = 0.84, I2 = 0%). In addition to this, when studies containing 5-day azithromycin treatment as the short-course treatment were excluded (10, 17, 28), mortality remained significantly lower in the short-course treatment group than in the long-course treatment group (1,310 patients, RR = 0.53 [95% CI, 0.31 to 0.90], P = 0.97, I2 = 0%). Studies with 3-day azithromycin treatment as the short-course treatment did not report data on mortality. No significant difference in mortality was found between patients treated for ≤6 days and those treated for ≥7 days in the subgroup analysis that included clinical trials reporting only on outpatients (2.6% versus 6.3%) (945 patients, RR = 0.56 [95% CI, 0.30 to 1.05], P = 0.47, I2 = 0%). Notably, when we pooled the 2 studies (13, 18) which contained the same antibiotic in the compared treatment arms, we noted a difference in mortality between the short- and long-course treatment groups (2.6% versus 4.5%), but the difference was not statistically significant (707 patients, RR = 0.57 [95% CI, 0.25 to 1.27], P = 0.97, I2 = 0%).
FIG 3
Adverse events.
Nine clinical trials reported data on the total adverse events that occurred during the study period (9, 14, 17, 18, 20, 23, 25–27), and 12 studies reported data on antibiotic-related adverse events (11–13, 15, 17–20, 23, 25–27). Among these studies, 7 provided data on serious adverse events (11–13, 15, 18, 20, 26). Interestingly, patients receiving treatment for ≤6 days suffered significantly lower numbers of serious adverse events (which mainly included death, a life-threatening event, and the prolongation of or need for hospitalization) than those treated for ≥7 days when studies with FDA-approved treatments were pooled (8.2% versus 11.2%) (1,543 patients, RR = 0.73 [95% CI, 0.54 to 0.98], P = 0.88, I2 = 0%) (13, 15, 18, 20). In all but 1 study (20), short-course treatment was 5 days, and when only those studies were pooled, serious adverse events were also lower with short-course treatment than with long-course treatment (8.3% versus 11.4%) (1,655 patients, RR = 0.73 [95% CI, 0.54 to 0.97], P = 0.90, I2 = 0%). When studies with both FDA- and non-FDA-approved treatments were pooled, serious adverse events were again significantly lower in patients receiving treatment for ≤6 days than those receiving treatment for ≥7 days (7.5% versus 10.1%) (Fig. 4; 1,923 patients, RR = 0.73 [95% CI, 0.55 to 0.97], P = 0.95, I2 = 0%). In addition, when one study containing 3 days of azithromycin treatment as the short-course treatment was excluded (20), serious adverse events remained significantly lower in the short-course treatment group than in the long-course treatment group (1,275 patients, RR = 0.72 [95% CI, 0.53 to 0.97], P = 0.76, I2 = 0%). Last, when we pooled the only 2 studies (13, 18) which contained the same antibiotic in the compared treatment arms, the difference in serious adverse events was not significantly different between the short- and long-course treatment groups (13.6% versus 18%) (765 patients, RR = 0.75 [95% CI, 0.54 to 1.04], P = 0.68, I2 = 0%).
FIG 4
On the other hand, no difference in the occurrence of total adverse events was detected between the short- and long-course treatment groups (32.1% versus 30.7%) (1,903 patients, RR = 1.08 [95% CI, 0.88 to 1.32], with moderate heterogeneity detected [P = 0.06, I2 = 47%]). With regard to antibiotic-related events, their occurrence was similar between patients receiving short-course treatment and those receiving long-course treatment (18.9% versus 16.4%) (Fig. 5; 2,901 patients, RR = 1.11 [95% CI, 0.94 to 1.31], P = 0.42, I2 = 2%). It should be noted that those antibiotic-related adverse events mainly included gastrointestinal symptoms, rash, headache, and elevation in transaminases. However, when we pooled all studies providing relevant data and included those having single-dose azithromycin microspheres in the short-course treatment (11, 12), the occurrence of antibiotic-related events was higher in the short-course treatment group than in the long-course treatment group (18.9% versus 16.4%) (3,814 patients, RR = 1.16 [95% CI, 1.01 to 1.33], P = 0.31, I2 = 14%). The antibiotic-related events observed with the single-dose azithromycin microspheres were mainly diarrhea. Pooling of the two studies (13, 18) comparing the same antibiotic with short- versus long-course treatment showed that, again, there was no difference in antibiotic-related events between the compared groups (10% versus 10.7%) (765 patients, RR = 0.92 [95% CI, 0.55 to 1.53], P = 0.22, I2 = 33%).
FIG 5
Relapse.
Nine clinical trials provided comparative data on clinical relapse (11–14, 17, 19, 20, 27). No difference was found between patients who received antibiotic treatment for ≤6 days and those who received treatment for ≥7 days (1% versus 1.5%) (Fig. 6; 1,923 patients, RR = 0.67 [95% CI, 0.30 to 1.46], P = 0.53, I2 = 0%). One study provided data on clinical relapse within 3 years after diagnosis, and for this reason it was excluded from this analysis (28).
FIG 6
Three days versus 5 days as short-course treatment.
When studies with 3-day and 5-day treatments were pooled separately (3 versus ≥7 days and 5 versus ≥7 days) in an effort to investigate whether there is an optimal short-course treatment duration, no difference was found in clinical cure (87.6% versus 85% and 89.5% versus 90.4%, respectively) (916 patients, RR = 1.01 [95% CI, 0.97 to 1.07], P = 0.18, and I2 = 31% for 3 versus ≥7 days and 2,379 patients, RR = 0.99 [95% CI, 0.97 to 1.02], P = 0.97, and I2 = 0% for 5 versus ≥7 days). With respect to relapse among patients who received FDA-approved treatments, short-course treatment was defined as 3 days in 3 studies (14, 19, 20) and as 5 days in the other 3 studies (13, 17, 27) which provided relevant data. When those groups of studies were pooled separately, no difference in relapse rates between short- and long-course treatment was detected (3 versus ≥7 days and 5 versus ≥7 days) (1% versus 1.9% and 1.5% versus 1.2%, respectively) (416 patients, RR = 0.52 [95% CI, 0.10 to 2.81], P = 0.62, and I2 = 0% for 3 versus ≥7 days and 808 patients, RR = 1.31 [95% CI, 0.42 to 4.14], P = 0.19, and I2 = 40% for 5 versus ≥7 days).
DISCUSSION
The duration of antibiotic treatment in CAP is not well established. In this study, we compared the clinical outcomes in adult patients treated with short- versus long-course antibiotic treatment. Interestingly, we found that treatment for ≤6 days in patients with CAP not only may be similar to treatment for ≥7 days in terms of effectiveness and relapses but also may be associated with significantly lower mortality and fewer serious adverse events. The randomized nature of most of the included studies and the lack of statistical heterogeneity in almost all analyses strengthen these findings. Importantly, there was no difference in the demographic characteristics, underlying diseases, and severity of pneumonia between the compared groups in 16 out of 21 included studies that provided relevant information (9–15, 18–21, 23, 25–27, 29), and the results of the analyses remained unchanged for all outcomes when we pooled only studies with FDA-approved antibiotics or when we excluded studies reporting on azithromycin, an antibiotic with a prolonged half-life. Given the fact that clinical cure and relapses were similar between short- and long-course treatment but mortality was significantly lower with 5 to 6 days of treatment, it appears that this duration of antibiotic treatment not only may be adequate but may even be a preferable approach for the management of CAP.
Current guidelines suggest a standard duration of treatment but qualify this recommendation on the basis of less well and variably defined parameters, such as severity (5), response to treatment (4, 6), or the potential causative pathogen (5). More specifically, counting from the time of initiation of treatment, the Infectious Diseases Society of America suggests that patients should be treated “for a minimum of 5 days,” should be afebrile for 48 to 72 h, and should have no more than 1 CAP-associated sign of clinical instability before discontinuation of treatment (4). The duration proposed by the British Thoracic Society, also counting from the time of initiation of treatment, is “7 days” for outpatients and most patients admitted to hospital with low- or moderate-severity and uncomplicated pneumonia, “7 to 10 days” for high-severity or microbiologically undefined pneumonia, and even longer treatment when Staphylococcus aureus or Gram-negative bacteria are suspected (5). The collaboration of the European Respiratory Society with the European Society of Clinical Microbiology and Infectious Diseases suggests that in a responding patient, antibiotic treatment “should not exceed 8 days” from the time of initiation (6). However, the clinical studies give a set duration of treatment for both short- and long-course treatment groups. Future clinical trials should evaluate the additional parameters included in guidelines, while revisions of guidelines can help by reevaluating the need for clinical parameters in defining the duration for CAP and clearly defining these clinical considerations.
Overall, short-course treatment appears to be an effective approach for CAP, and clinicians should evaluate each case individually before the discontinuation of antibiotics. However, a new finding from our meta-analysis is that shorter treatment is associated with decreased mortality. So far, clear conclusions regarding the impact of the duration of antibiotic treatment on mortality cannot be drawn, and two previous meta-analyses which showed that short-course treatment was as effective as long-course treatment reported that there was no difference in mortality between short- and long-course treatment (33, 34). One reason for the lack of a difference in mortality could be that the definitions for “short-course” and “long-course” treatment used previously are slightly different from the definitions used in our study and/or the smaller sample size of the analyses on mortality (1,297 [33] and 1,571 patients [34] versus 2,802 patients). Also, one of them included only studies in which the antibiotic was the same between the compared treatment arms (33).
The lower mortality observed in the short-course treatment group could be justified, at least partially, by the smaller number of serious adverse events observed in this group of patients. Such serious events included severe allergic reaction (20); cardiovascular events, such as arrhythmia (15) or cardiac arrest (26); and acute renal failure (15). Also, the decreased exposure to antibiotics achieved through shorter regimens can decrease the selection pressure of resistant strains, leading to lower rates of infection or colonization with drug-resistant organisms. For example, in one of the included studies, a patient who received long-course treatment (ceftriaxone for 10 days) developed Clostridium difficile diarrhea, which resulted in hemodynamic shock and, finally, death (18). Finally, compliance with treatment is another important parameter to be considered, since a higher rate of compliance leads to a higher rate of clinical cure (35, 36).
In an effort to investigate whether a specific short-course regimen is superior, we pooled separately studies with different durations of the short-course treatment. Short-course treatment was administered for either 3 days or 5 or 6 days, and the results for clinical cure, serious adverse events, and the relapse rate were similar between the short- and long-course treatment groups. Further evaluation could not be performed, as studies with 3-day short-course treatment did not provide data on mortality. Lastly, data on the pharmacokinetic/pharmacodynamic (PK/PD) properties of the antibiotic used are also necessary to specify the optimal treatment for CAP (27).
Certain limitations should be considered during the interpretation of the findings of this meta-analysis. Two of the included trials were nonrandomized, but according to the quality assessment, the baseline characteristics were similar among the compared treatment groups and also an adequate follow-up of the participants was performed in both trials. In addition, different severity scoring systems were used for the evaluation of pneumonia. However, analysis of data from studies including patients with severe pneumonia (assessed by PSI/PORT or CURB65) confirmed the lower rate of mortality observed with short-course treatment, and clinical efficacy was similar between the short- and long-course treatments in the subgroup analysis of 6 randomized studies where the administered antibiotic was the same between the compared arms. Moreover, the inconsistency in the definition of “clinical cure” and the different times of clinical evaluation in the included studies, as well as the fact that the classification of adverse events as “antibiotic related” was based on clinical judgment, further suggest that the findings of the respective analyses should be interpreted with caution.
In order to decrease antimicrobial resistance, toxicity, and health care costs, it is crucial to delineate the duration of antibiotic treatment for CAP. Evidence, mainly derived from RCTs, suggests that in adult patients, antibiotic treatment for 6 days or less is as effective as longer courses of treatment in patients with CAP. Moreover, antibiotic treatment for 5 to 6 days may reduce the rate of mortality. Future well-designed trials should include evaluation of clinical improvement in the evaluation of treatment duration, use consistent definitions for short- and long-course treatment, consider and study the PK/PD properties of the antibiotic used, and focus on the comparison of the outcomes between different durations of treatment with the same antibiotic.
MATERIALS AND METHODS
Literature search.
We systematically reviewed the available literature in the PubMed, EMBASE, and Cochrane Central Register of Controlled Trials databases through October 2017. The following search terms were applied: pneumonia AND antibiotic AND treatment AND (short-term OR long-term OR prolonged OR short-course OR long-course OR -day OR duration) AND (cure OR failure OR mortality). We also searched the ClinicalTrials.gov database and performed a manual search of the reference lists of all relevant articles. We set no year limit, and all articles published in English, German, and French were evaluated.
Study selection.
We defined “short-course treatment” as treatment for ≤6 days. This comparison was selected arbitrarily but was based on the definition of “short-course treatment” in the majority of the trials and the current guidelines (see above). As a result, eligible studies were considered those comparing outcomes between patients treated for ≤6 days (short-course treatment) and those treated for ≥7 days (long-course treatment). Studies reporting the mean or median and not the standard or minimum duration of therapy, case reports, and abstracts presented at scientific conferences as well as those including individuals younger than 18 years of age were not eligible.
Data extraction and quality assessment.
The data extracted from each study comprised the main characteristics of the study (first author name, year, study design, and country), the number of clinically evaluable patients, the patient setting (outpatient/inpatient), the severity of pneumonia, the causative pathogen of pneumonia, the detailed antibiotic treatment regimen in each patient group, the time of clinical evaluation, and the assessment of mortality. We also recorded the number of patients that were cured and those that died (all-cause mortality), as well as the adverse events in each patient group.
The quality of each trial was evaluated by the use of the Delphi criteria list: randomization and allocation concealment, the similarity of the baseline characteristics between the compared groups, eligibility criteria, blinding, completeness of follow-up, and intention-to-treat analysis (37).
Definitions and outcomes.
The primary outcomes of this meta-analysis were clinical cure, as defined by the investigators of the particular studies, and all-cause mortality. Adverse events and relapse of the infection were secondary outcomes. Antibiotic-related adverse events were included according to the discretion of the investigators of the included studies. Serious adverse events were defined according to the definition by the Food and Drug Administration (FDA) (30). Also, when a study used the term “severe” for serious events, we counted those events as “serious” in the meta-analysis. In all included studies, relapse of the infection was evaluated at the follow-up visit after the end of treatment. Because some of the studies included antibiotics that are not approved by the FDA, we performed separate analyses for all outcomes both with and without those studies, and any notable data are presented using both data pools.
Statistical analysis.
Patients were allocated into short-course and long-course treatment groups for all analyses. The meta-analysis was performed using Review Manager for Windows, v.5.3 (38). The pooled RR and 95% CI regarding the outcomes of interest were calculated. Statistical heterogeneity among studies was assessed by using a χ2 test (a P value of <0.10 was defined to indicate significant heterogeneity) and I2. The Mantel-Haenszel fixed-effect model was used when there was no significant statistical heterogeneity between the studies (39). Otherwise, the random effects model with the DerSimonian and Laird approach was used as appropriate (40). Publication bias was assessed by use of the funnel plot (40).
ACKNOWLEDGMENTS
Eleftherios Mylonakis has received grant support from T2 Biosystems, Astellas Pharma, Boehringer Ingelheim, and Sanofi Pasteur for work outside this work. Giannoula S. Tansarli has no financial disclosure.
REFERENCES
1.
Broulette J, Yu H, Pyenson B, Iwasaki K, Sato R. 2013. The incidence rate and economic burden of community-acquired pneumonia in a working-age population. Am Health Drug Benefits 6:494–503.
2.
Marston BJ, Plouffe JF, File TM, Jr, Hackman BA, Salstrom SJ, Lipman HB, Kolczak MS, Breiman RF. 1997. Incidence of community-acquired pneumonia requiring hospitalization. Results of a population-based active surveillance study in Ohio. The Community-Based Pneumonia Incidence Study Group. Arch Intern Med 157:1709–1718.
3.
National Center for Health Statistics, U.S. Centers for Disease Control and Prevention. 2016. Leading causes of death. National Center for Health Statistics, U.S. Centers for Disease Control and Prevention, Atlanta, GA.
4.
Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC, Dowell SF, File TM, Jr, Musher DM, Niederman MS, Torres A, Whitney CG. 2007. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 44(Suppl 2):S27–S72.
5.
Lim WS, Baudouin SV, George RC, Hill AT, Jamieson C, Le Jeune I, Macfarlane JT, Read RC, Roberts HJ, Levy ML, Wani M, Woodhead MA. 2009. BTS guidelines for the management of community acquired pneumonia in adults: update 2009. Thorax 64(Suppl 3):iii1–iii55.
6.
Woodhead M, Blasi F, Ewig S, Garau J, Huchon G, Ieven M, Ortqvist A, Schaberg T, Torres A, van der Heijden G, Read R, Verheij TJ. 2011. Guidelines for the management of adult lower respiratory tract infections—summary. Clin Microbiol Infect 17(Suppl 6):S1–S24.
7.
Avdic E, Cushinotto LA, Hughes AH, Hansen AR, Efird LE, Bartlett JG, Cosgrove SE. 2012. Impact of an antimicrobial stewardship intervention on shortening the duration of therapy for community-acquired pneumonia. Clin Infect Dis 54:1581–1587.
8.
Walsh TL, DiSilvio BE, Hammer C, Beg M, Vishwanathan S, Speredelozzi D, Moffa MA, Hu K, Abdulmassih R, Makadia JT, Sandhu R, Naddour M, Chan-Tompkins NH, Trienski TL, Watson C, Obringer TJ, Kuzyck J, Bremmer DN. 2018. Impact of procalcitonin guidance with an educational program on management of adults hospitalized with pneumonia. Am J Med 131:201.e1–201.e8.
9.
Bohte R, van't Wout JW, Lobatto S, Blussé van Oud Alblas A, Boekhout M, Nauta EH, Hermans J, van den Broek PJ. 1995. Efficacy and safety of azithromycin versus benzylpenicillin or erythromycin in community-acquired pneumonia. Eur J Clin Microbiol Infect Dis 14:182–187.
10.
Brion JP, Sedallian A, Le Noc P, Briffod J, Micoud M. 1990. Azithromycin versus josamycin: treatment of 89 cases of acute pneumonia. Pathol Biol (Paris) 38(Pt 2):521–525. (In French).
11.
D'Ignazio J, Camere MA, Lewis DE, Jorgensen D, Breen JD. 2005. Novel, single-dose microsphere formulation of azithromycin versus 7-day levofloxacin therapy for treatment of mild to moderate community-acquired pneumonia in adults. Antimicrob Agents Chemother 49:4035–4041.
12.
Drehobl MA, De Salvo MC, Lewis DE, Breen JD. 2005. Single-dose azithromycin microspheres vs clarithromycin extended release for the treatment of mild-to-moderate community-acquired pneumonia in adults. Chest 128:2230–2237.
13.
Dunbar LM, Wunderink RG, Habib MP, Smith LG, Tennenberg AM, Khashab MM, Wiesinger BA, Xiang JX, Zadeikis N, Kahn JB. 2003. High-dose, short-course levofloxacin for community-acquired pneumonia: a new treatment paradigm. Clin Infect Dis 37:752–760.
14.
el Moussaoui R, de Borgie CA, van den Broek P, Hustinx WN, Bresser P, van den Berk GE, Poley JW, van den Berg B, Krouwels FH, Bonten MJ, Weenink C, Bossuyt PM, Speelman P, Opmeer BC, Prins JM. 2006. Effectiveness of discontinuing antibiotic treatment after three days versus eight days in mild to moderate-severe community acquired pneumonia: randomised, double blind study. BMJ 332:1355.
15.
File TM, Jr, Mandell LA, Tillotson G, Kostov K, Georgiev O. 2007. Gemifloxacin once daily for 5 days versus 7 days for the treatment of community-acquired pneumonia: a randomized, multicentre, double-blind study. J Antimicrob Chemother 60:112–120.
16.
Gris P. 1996. Once-daily, 3-day azithromycin versus a three-times-daily, 10-day course of co-amoxiclav in the treatment of adults with lower respiratory tract infections: results of a randomized, double-blind comparative study. J Antimicrob Chemother 37(Suppl C):93–101.
17.
Kinasewitz G, Wood RG. 1991. Azithromycin versus cefaclor in the treatment of acute bacterial pneumonia. Eur J Clin Microbiol Infect Dis 10:872–877.
18.
Léophonte P, Choutet P, Gaillat J, Petitpretz P, Portier H, Montestruc F, Pecking M, De Bels F. 2002. Efficacité comparée de la ceftriaxone dans un traitement de dix jours versus un traitement raccourci de cinq jours des pneumonies aigues communautaires de l'adulte hospitalisé avec facteur de risque. Med Mal Infect 32:369–381.
19.
O'Doherty B, Muller O. 1998. Randomized, multicentre study of the efficacy and tolerance of azithromycin versus clarithromycin in the treatment of adults with mild to moderate community-acquired pneumonia. Azithromycin Study Group. Eur J Clin Microbiol Infect Dis 17:828–833.
20.
Paris R, Confalonieri M, Dal Negro R, Ligia GP, Mos L, Todisco T, Rastelli V, Perna G, Cepparulo M. 2008. Efficacy and safety of azithromycin 1 g once daily for 3 days in the treatment of community-acquired pneumonia: an open-label randomised comparison with amoxicillin-clavulanate 875/125 mg twice daily for 7 days. J Chemother 20:77–86.
21.
Rahav G, Fidel J, Gibor Y, Shapiro M. 2004. Azithromycin versus comparative therapy for the treatment of community acquired pneumonia. Int J Antimicrob Agents 24:181–184.
22.
Rizzato G, Montemurro L, Fraioli P, Montanari G, Fanti D, Pozzoli R, Magliano E. 1995. Efficacy of a three day course of azithromycin in moderately severe community-acquired pneumonia. Eur Respir J 8:398–402.
23.
Schönwald S, Barsic B, Klinar I, Gunjaca M. 1994. Three-day azithromycin compared with ten-day roxithromycin treatment of atypical pneumonia. Scand J Infect Dis 26:706–710.
24.
Schönwald S, Gunjaca M, Kolacny-Babic L, Car V, Gosev M. 1990. Comparison of azithromycin and erythromycin in the treatment of atypical pneumonias. J Antimicrob Chemother 25(Suppl A):123–126.
25.
Sopena N, Martinez-Vazquez C, Rodriguez-Suarez JR, Segura F, Valencia A, Sabrià M. 2004. Comparative study of the efficacy and tolerance of azithromycin versus clarithromycin in the treatment of community-acquired pneumonia in adults. J Chemother 16:102–103.
26.
Tellier G, Niederman MS, Nusrat R, Patel M, Lavin B. 2004. Clinical and bacteriological efficacy and safety of 5 and 7 day regimens of telithromycin once daily compared with a 10 day regimen of clarithromycin twice daily in patients with mild to moderate community-acquired pneumonia. J Antimicrob Chemother 54:515–523.
27.
Zhao T, Chen LA, Wang P, Tian G, Ye F, Zhu H, He B, Zhang B, Shao C, Jie Z, Gao X, Wang D, Song W, Pan Z, Chen J, Zhang X, Gao Z, Chen P, Liu Y. 2016. A randomized, open, multicenter clinical study on the short course of intravenous infusion of 750 mg of levofloxacin and the sequential standard course of intravenous infusion/oral administration of 500 mg of levofloxacin for treatment of community-acquired pneumonia. J Thorac Dis 8:2473–2484.
28.
Masiá M, Padilla S, Ortiz de la Tabla V, Gonzalez M, Bas C, Gutiérrez F. 2017. Procalcitonin for selecting the antibiotic regimen in outpatients with low-risk community-acquired pneumonia using a rapid point-of-care testing: a single-arm clinical trial. PLoS One 12:e0175634.
29.
Sánchez F, Mensa J, Martinez JA, García E, Marco F, González J, Marcos MA, Soriano A, Torres A. 2003. Is azithromycin the first-choice macrolide for treatment of community-acquired pneumonia? Clin Infect Dis 36:1239–1245.
30.
Food and Drug Administration. 2016. What is a serious adverse event? Food and Drug Administration, Silver Spring, MD.
31.
Fine MJ, Auble TE, Yealy DM, Hanusa BH, Weissfeld LA, Singer DE, Coley CM, Marrie TJ, Kapoor WN. 1997. A prediction rule to identify low-risk patients with community-acquired pneumonia. N Engl J Med 336:243–250.
32.
Lim WS, van der Eerden MM, Laing R, Boersma WG, Karalus N, Town GI, Lewis SA, Macfarlane JT. 2003. Defining community acquired pneumonia severity on presentation to hospital: an international derivation and validation study. Thorax 58:377–382.
33.
Dimopoulos G, Matthaiou DK, Karageorgopoulos DE, Grammatikos AP, Athanassa Z, Falagas ME. 2008. Short- versus long-course antibacterial therapy for community-acquired pneumonia: a meta-analysis. Drugs 68:1841–1854.
34.
Li JZ, Winston LG, Moore DH, Bent S. 2007. Efficacy of short-course antibiotic regimens for community-acquired pneumonia: a meta-analysis. Am J Med 120:783–790.
35.
File TM, Jr. 2004. Clinical efficacy of newer agents in short-duration therapy for community-acquired pneumonia. Clin Infect Dis 39(Suppl 3):S159–S164.
36.
Kardas P. 2002. Patient compliance with antibiotic treatment for respiratory tract infections. J Antimicrob Chemother 49:897–903.
37.
Verhagen AP, de Vet HC, de Bie RA, Kessels AG, Boers M, Bouter LM, Knipschild PG. 1998. The Delphi list: a criteria list for quality assessment of randomized clinical trials for conducting systematic reviews developed by Delphi consensus. J Clin Epidemiol 51:1235–1241.
38.
Cochrane Community. 2014. Review Manager (RevMan) v 5.3. The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark. https://community.cochrane.org/help/tools-and-software/revman-5.
39.
Mantel N, Haenszel W. 1959. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 22:719–748.
40.
DerSimonian R, Laird N. 1986. Meta-analysis in clinical trials. Control Clin Trials 7:177–188.
Information & Contributors
Information
Published In
Antimicrobial Agents and Chemotherapy
Volume 62 • Number 9 • September 2018
eLocator: 10.1128/aac.00635-18
Copyright
© 2018 American Society for Microbiology. All Rights Reserved.
History
Received: 30 March 2018
Returned for modification: 25 May 2018
Accepted: 29 June 2018
Published online: 27 August 2018
Keywords
Contributors
Metrics & Citations
Metrics
Note:
- For recently published articles, the TOTAL download count will appear as zero until a new month starts.
- There is a 3- to 4-day delay in article usage, so article usage will not appear immediately after publication.
- Citation counts come from the Crossref Cited by service.
Citations
Citation
2018.
Systematic Review and Meta-analysis of the Efficacy of Short-Course Antibiotic Treatments for Community-Acquired Pneumonia in Adults. Antimicrob Agents Chemother
62:10.1128/aac.00635-18.
If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. For an editable text file, please select Medlars format which will download as a .txt file. Simply select your manager software from the list below and click Download.