Summary of findings 2. Macrolides compared to doxycycline for treating scrub typhus.

Macrolides compared to doxycycline for treating scrub typhus
Patient or population: adults and adolescents with scrub typhus Settings: hospitals in endemic areas Intervention: doxycycline 200 mg per day for 7 days (Kim 2004; Phimda 2007); doxycycline 200 mg per day for 5 days (Kim 2007) Comparison: azithromycin 500 mg single oral dose (Kim 2004); telithromycin 800 mg daily for 5 days (Kim 2007); azithromycin 1 g daily for 3 days, followed by 500 mg daily for 2 days (Phimda 2007)
Outcomes	Anticipated absolute effects* (95% CI)		Relative effect (95% CI)	Number of participants (trials)	Certainty of the evidence (GRADE)	Comments
	Risk with doxycycline	Risk with macrolides
Treatment failure	Assumed risk: 19 per 1000a	51 per 1000 (2 to 1000)	RR 2.71 (0.12 to 63.84)	242 (3 RCTs)	⊕⊝⊝⊝ VERY LOWb,c Due to risk of bias and imprecision	We are uncertain whether macrolides compared to doxycycline affect treatment failure, as the certainty of the evidence is very low.
Resolution of fever within 48 hours	671 per 1000	544 per 1000 (215 to 1000)	RR 0.81 (0.32 to 2.03)	150 (2 RCTs)	⊕⊝⊝⊝ VERY LOWb,d Due to risk of bias, imprecision, and inconsistency	We are uncertain whether macrolides compared to doxycycline affects the proportion of patients with resolution of fever within 48 hours.
Resolution of fever within 5 days	956 per 1000	1000 per 1000 (946 to 1000)	RR 1.05 (0.99 to 1.10)	185 (2 RCTs)	⊕⊕⊝⊝ LOWb,e Due to risk of bias and inconsistency	Macrolides compared to doxycycline may make little or no difference in the proportion of patients with resolution of fever within 5 days.
Time to defervescence	Each included study detected no significant difference between groups.			242 (3 RCTs)	⊕⊝⊝⊝ VERY LOWb,d Due to risk of bias and inconsistency	We are uncertain whether macrolides compared to doxycycline affect time to defervescence, as the certainty of the evidence is very low.
Serious adverse events	No included trial reported serious adverse events.			242 (3 RCTs)	⊕⊝⊝⊝ VERY LOWb,c Due to risk of bias and imprecision	We are uncertain whether macrolides compared to doxycycline affects serious adverse events, as the certainty of the evidence is very low.
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Abbreviations: CI: confidence interval; RCT: randomized controlled trial; RR: risk ratio.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect

^aDerived from risk across all included trials in patients treated with doxycycline (four events in 212 patients).
 ^bDowngraded by 1 due to serious risk of bias: all three included trials were open‐label; Kim 2007 was quasi‐randomized.
 ^cDowngraded by 2 due to very serious imprecision: sample size and number of events were small, and confidence intervals cross the line of no effect. Two trials reported no events in either treatment arm, so they do not contribute to the risk ratio.
 ^dDowngraded by 2 due to very serious inconsistency: data show quantitative and qualitative inconsistency between trials.
 ^eDowngraded by 1 due to serious inconsistency: Kim 2004 gave azithromycin as a single oral dose; Kim 2007 gave telithromycin for five days.