Table 1.
Independent predictors of oral antibiotic failure in fast breathing WHO non-severe childhood pneumoniaa
| Study overview | Awasthi S et al. | CATCH UP | MASCOT | Agarwal G et al. | Noorani QA et al. | Hazir T et al. | |
|---|---|---|---|---|---|---|---|
| Region (country) | Asia (India) | Asia (Pakistan) | Asia (Pakistan) | Asia (India) | Asia (Pakistan) | Asia (Pakistan) | |
| Data collection dates | 2004–2006 | 1998–1999 | 1999–2001 | 2000–2002 | 2000–2001 | 2005–2008 | |
| Enrollment criteria | 2–59 months old | 2–59 months old | 2–59 months of age | 2–59 months of age | 2–59 months of age | 2–59 months of age | |
| Study design | Cluster randomized study | Randomized multicenter equivalency study | Randomized multicenter equivalency study | Randomized multicenter equivalency study | Multicenter observational study | Randomized multicenter equivalency study | |
| Intervention arm | Oral amoxicillin 31–51 mg/kg/day for 3 days | Oral amoxicillin 50 mg/kg/day for 5 days | Oral amoxicillin 45 mg/kg/day for 3 days | Oral amoxicillin 31–54 mg/kg/day for 3 days | - | Placebo for 3 days | |
| Control arm (or standard of care) | Oral trimethoprim (7–11 mg/kg/day)-sulfamethoxazole for 5 days | Oral trimethoprim (8 mg/kg/day)-sulfamethoxazole for 5 days | Oral amoxicillin 45 mg/kg/day for 5 days | Oral amoxicillin 31–54 mg/kg/day for 5 days | Oral trimethoprim (8 mg/kg/day)-sulfamethoxazole for 5 days | Oral amoxicillin 45 mg/kg/day for 3 days | |
| Blinding | No | Yes | Yes | Yes | - | Yes | |
| Study site types | Health centers | Tertiary care and secondary-level hospitals, and health center | Tertiary care and secondary-level hospitals | Tertiary care hospitals | Health centers | Tertiary care hospitals | |
| Number of sites | 14 | 8 | 7 | 7 | 14 | 4 | |
| Primary outcome | Treatment failure | Equivalency | Equivalency | Equivalency | Treatment failure | Equivalency | |
| Treatment failure definition | |||||||
| Day of assignment | Day 3 (intervention); Day 5 (control) | Days 3 to 5 | Day 5 | Days 3 to 5 | Day 5 | Day 3 | |
| Respiratory ratea | Yes, elevated for age (days 3–5) | Yes, +/−5 breaths/min or higher versus enrollment (days 3–5) | Yes, elevated for age (days 3–5) | Yes, elevated for age (days 3–5) | Yes, +/−5 breaths/min or higher versus enrollment (days 3–5) | No | |
| Fever >38 °C and LCI | No | No | No | No | No | No | |
| Fever >38 °C | Yes (days 3–5) | No | No | No | No | No | |
| LCI | Yes (days 1–5) | Yes (days 3–5) | Yes (days 1–5) | Yes (days 1–5) | Yes (days 1–5) | Yes (days 1–3) | |
| Convulsions | Yes (days 1–5) | Yes (days 3–5) | Not specified | Yes (days 1–5) | Not specified | Yes (days 1–3) | |
| Abnormally sleepy | Yes (days 1–5) | Yes (days 3–5) | Not specified | Yes (days 1–5) | Not specified | Yes (days 1–3) | |
| Inability to drink | Yes (days 1–5) | Yes (days 3–5) | Not specified | Yes (days 1–5) | Not specified | Yes (days 1–3) | |
| Stridor in calm child | Yes (days 1–5) | Yes (days 3–5) | No | No | No | Yes (days 1–3) | |
| Malnutrition | No | Yes (days 3–5) | No | No | No | Yes (days 1–3) | |
| Cyanosis | Yes (days 1–5) | No | Yes | No | Yes | No | |
| SpO2 | No | No | No | Yes, <90 % (on day 3 only) | No | No | |
| Antibiotic change | No | Yes (days 3–5) | Yes (days 1–5) | No | Yes (days 1–5) | No | |
| Hospitalization | No | Yes (days 1–5) | No | No | No | No | |
| Lost to follow-up | Yes (days 3–5) | Yes (days 3–5) | No | Yes (days 1–5) | Yes (days 5–11) | No | |
| Study withdrawal | Yes (days 1–5) | No | No | Yes (days 1–5) | No | No | |
| Death | Yes (days 1–14) | Yes (days 1–5) | Yes (days 1–5) | Yes (days 1–5) | Yes (days 1–5) | Yes (days 1–5) | |
| Study participants and description | |||||||
| Sample sizeb | 2009 | 1459 | 1953 | 2188 | 944 | 873 | |
| Age 2–11 months | 594/2009 (29.6 %) | 732/1459 (50.2 %) | 1051/1953 (53.8 %) | 954/2188 (43.6 %) | 334/944 (35.4 %) | 573/873 (65.6 %) | |
| Age 12–59 months | 1415/2009 (70.4 %) | 727/1459 (49.8 %) | 902/1953 (46.2 %) | 1234/2188 (56.4 %) | 610/944 (64.6 %) | 300/873 (34.4 %) | |
| Treatment failure rateb | 234/2009 (11.6 %) | 256/1459 (17.5 %) | 364/1953 (22.9 %) | 225/2188 (10.3 %) | 110/944 (11.6 %) | 68/873 (7.8 %) | |
| Independent predictors of treatment failure OR (95 % CI)c,d | Diarrhea, 1.65 (1.24–2.19) | History of difficulty breathing, 1.61 (1.13–2.15) | Excess respiratory rate >10 breaths/min for agea, 1.4 (1.1–1.9) | Excess respiratory rate >10 breaths/min for agea, 2.89 (1.83–4.55) | Excess respiratory rate ≥15 breaths/min for agea, 2.0 (1.2–3.4) | History of difficulty breathing, 2.86 (1.29–7.23) | |
| Age 12–59 months, 1.5 (1.12–1.91) | Antibiotic non-adherence, 4.5 (95 % CI 2.9–7.0) | Antibiotic non-adherence, 11.57 (7.4–18.0 | Wheeze on examination, 1.7 (1.1–2.6) | Temperature >37.5 °C at enrollment, 1.99 (1.37–2.90) | |||
| Illness >3 days, 1.4 (1.03–1.8) | Illness ≥3 days, 1.7 (1.3–2.1) | RSV, 1.95 (1.0–3.8) | |||||
| Age 2–11 months, 1.7 (1.1–2.1) | |||||||
| Persistent vomiting, 1.4 (1.0–2.0) | |||||||
Serious adverse event or drug reaction, and new comorbid condition were not considered in the treatment failure definitions for any of the studies. WHO: World Health Organization; LCI: lower chest wall indrawing; SpO2: peripheral oxygen saturation; OR: odds ratio; CI: confidence interval; RSV: human respiratory syncytial virus
aRespiratory rate norms: <50 breaths/min for ages 2–11 months; <40 breaths/min for ages 12–59 months
bIf primary outcome of trial was equivalency or no difference was found then intervention and control arm data was combined
cMultivariate logistic regression modeling was performed to determine independent predictors of treatment failure in all included studies. CATCHUP trial modeled age, history of difficulty breathing, duration of illness, and respiratory rate. The models were not reported for the MASCOT trial, Agarwal G et al., Noorani QA et al., Awasthi S et al., and Hazir T et al
dFor Hazir T et al. multivariate logistic regression modeling was performed on cumulative treatment failure data from day 5 although primary outcome data was analyzed from day 3 treatment failure data