Antibiotics for eradicating meningococcal carriages: Network meta-analysis and investigation of evidence inconsistency

Table 1 Main characteristics of studies included in network meta-analysis

Ref.	Antibiotics	Country and population	Carrier status	Serogroups and susceptibility	Study design	Sequence generation	Allocation concealment
Blakebrough et al[14]	Rifampin: 4 × 75 mg for 0-2 yr, 4 × 150 mg for 2-4 yr, 4 × 300 mg for 5-14 yr, 4 × 600 mg for > 15 yr (bid, 2 d) Sulphadimidine: 4 × 250 mg for 0-4 yr, 4 × 500 mg for 5-14 yr, 4 × 1 g for > 15 yr (bid, 2 d)	Nigeria Household contacts	Any carriers	Group A Susceptibility tested	Cluster quasi-RCT	Inadequate	Inadequate
Borgoño et al[15]	Rifampin: 2 × 10 mg/kg Placebo	Chile Children	Any carriers	Group unknown Susceptibility not tested	RCT	Unclear	Unclear
Cuevas et al[16]	Rifampin: 4 × 600 mg for > 18 yr, 4 × 20 mg/kg for 2-18 yr (bid, 2 d) Ciprofloxacin: 1 × 750 mg for > 18 yr, 1 × 15 mg/kg for 2-18 yr	Malawi Household contacts	Any carriers	Group A: 51% (unknown 49%) Susceptibility tested	Cluster RCT	Unclear	Unclear
Deal et al[17]	Rifampin: 4 × 600 mg (4 d) Placebo	United States Healthy students	Heavy/ Persistent (3 positive cultures)	Group B Susceptibility tested	RCT	Adequate	Adequate
Deal et al[18]	Cephalexin: 12 × 500 mg (tid, 4 d) Placebo	United States Students	Persistent (3 positive cultures)	Group B Susceptibility tested	RCT	Adequate	Adequate
Deviatkina et al[19]	Rifampin: 4 × 300 mg (4 d) Placebo	Russia Unclear	Unknown	Group unknown Susceptibility tested	RCT	Unclear	Unclear
Devine et al[20]	Rifampin: 4 × 600 mg (4 d) Placebo	United States Army recruits	Any carriers	Group Y: 79% Susceptibility tested	RCT	Adequate	Unclear
Devine et al[21]	Coumermycin A1: 14 × 50 mg (bid, 7 d) Placebo	United States Army recruits	Any carriers	Group unknown Susceptibility tested	RCT	Adequate	Unclear
Devine et al[22]	Minocycline: 1 × 200 mg + 9 × 100 mg (bid, 5 d) Placebo	United States Army recruits	Any carriers	Group Y: 63% Susceptibility tested	RCT	Adequate	Unclear
Devine et al[22]	Minocycline: 4 × 200 mg (bid, 2 d) No antibiotic	United States Army recruits	Any carriers	Group Y: Most Susceptibility tested	RCT	Adequate	Unclear
Dowd et al[23]	Ampicillin: 30 × 500 mg (tid, 10 d) Penicillin: 30 × 462 mg (tid, 10 d) Placebo	United States Amy recruits	Any carriers	Group B and sulfadiazine-resistant	RCT	Unclear	Unclear
Dworzack et al[24]	Ciprofloxacin: 1 × 750 mg Placebo	United States Young adults	Persistent (3 positive cultures)	Group B: 41%, Z: 33% Susceptibility tested	RCT	Unclear	Unclear
Girgis et al[25]	Rifampin: 4 × 600 mg (bid, 2 d) Azithromycin: 1 × 500 mg	Egypt Nursing students	Any carriers	Group A: 37%; B: 33% Susceptibility tested	RCT	Adequate	Unclear
Guttler et al[26]	Rifampin: 5 × 600 mg (5 d) Minocycline 10 × 100 mg (bid, 5 d) Ampicillin 10 × 500 mg (bid, 5 d) Placebo	United States Army recruits	Any carriers	Group B or C: 31% (non- groupable 67%) Susceptibility tested	Cluster RCT	Adequate	Unclear
Judson et al[27]	Ceftriaxone: im 1 × 125 mg Spectinomycin: im 1 × 2 g	United States Patients with gonorrhoea	Any carriers	Group unknown Susceptibility tested	RCT	Unclear	Unclear
Kaiser et al[28]	Rifampin: 4 × 600 mg for weight ≥ 66 lb, or 4 × 300 mg for weight < 66 lb (4 d) Placebo	United States Household contacts	Any carriers	Group C: 35% Susceptibility tested	RCT	Adequate	Unclear
Kaya et al[29]	Rifampin: 4 × 600 mg (bid, 2 d) Ciprofloxacin: 1 × 750 mg	Turkey Healthy adults	Any carriers	Group unknown Susceptibility not tested	Quasi RCT	Inadequate	Inadequate
Munford et al[30]	Rifampin: 4 × 600 mg (bid, 2 d) Minocycline: 1 × 200 mg + 5 × 100 mg (bid, 3 d) Rifampin + Minocycline: as above Sulphadiazine: 4 × 1 g (bid, 2 d)	Brazil Household contacts	Any carriers	Group C: Most Susceptibility tested	Cluster quasi-RCT	Inadequate	Inadequate
Pugsley et al[32]	Sch29482: 16 × 250 mg (every 6 h for 4 d) Placebo	United States	Persistent carriers (2 positive cultures)	Group Z: 36%; B: 24%	RCT	Adequate	Unclear
Pugsley et al[31]	Ciprofloxacin: 10 × 500 mg (bid, 5 d) Placebo	Young men United States	Persistent (2 positive cultures)	Susceptibility tested Group B: 79%	RCT	Adequate	Unclear
Renkonen et al[33]	Ciprofloxacin: 4 × 250 mg (bid, 2 d) Placebo	Young adults Finland	Heavy (> 100 colonies per plate)	Susceptibility tested Group B: 45%	RCT	Adequate	Adequate
Schwartz et al[34]	Rifampin: 4 × 600 mg or 4 × 10 mg/kg (bid, 2 d)	Army recruits Saudi Arabia	Any carriers	Susceptibility tested Group A	Cluster RCT	Unclear	Unclear
Simmons et al[35]	Ceftriaxone: im 1 × 250 mg (or 125 mg for < 15 yr) Rifampin: 4 × 600 mg for adults, 4 × 5 mg/kg for children < 1 mo, and 4 × 10 mg for children > 1 mo (bid, 2 d) Ceftriaxone: im 1 × 250 mg, or 1 × 125 mg for < 12 yr	Household contacts New Zealand Household contacts	Any carriers	Susceptibility tested Group B: 53% Susceptibility tested	RCT	Unclear	Unclear

im: Intramuscular; bid: Twice a day; tid: Three times a day; RCT: Randomized controlled trials.

Table 2 Antibiotics compared and data from the included trials for network meta-analysis

Trial	Regimen	n	Failure to eradicate
Guttler et al[26]	Placebo	18 (146)	8 (65)
	Rifampin	18 (147)	2 (13)
	Minocycline	18 (147)	1 (12)
	Ampicillin	18 (147)	3 (22)
Munford et al[30]	Rifampin	65 (67)	6 (6)
	Sulphadiazine	79 (82)	37 (38)
	Minocycline	56 (58)	6 (6)
	Rifampin + Minocycline	59 (61)	0 (0)
Schwartz et al[34]	Rifampin	34 (36)	9 (9)
	Ceftriaxone	65 (68)	2 (2)
Dowd et al[23]	Placebo	47	26
	Penicillin	20	9
	Ampicillin	26	8
Borgoño et al[15]	Placebo	110	71
	Rifampin	118	10
Deal et al[17]	Placebo	15	13
	Rifampin	15	2
Deviatkina et al[19]	Placebo	43	10
	Rifampin	46	3
Devine et al[20]	Placebo	28	25
	Rifampin	38	7
Kaiser et al[28]	Placebo	6	6
	Rifampin	13	1
Dworzack et al[24]	Placebo	22	20
	Ciprofloxacin	24	1
Pugsley et al[31]	Placebo	21	14
	Ciprofloxacin	21	0
Renkonen et al[33]	Placebo	53	46
	Ciprofloxacin	56	2
Deal et al[18]	Placebo	15	14
	Cephalexin	15	11
Devine et al[22]	Placebo	48	42
	Minocycline	41	14
Devine et al[22]	Placebo	29	27
	Minocycline	53	16
Devine et al[21]	Placebo	39	28
	Coumermycin A1	33	31
Pugsley et al[32]	Placebo	29	26
	Sch29482	29	23
Cuevas et al[16]	Rifampin	84 (88)	3 (3)
	Ciprofloxacin	75 (79)	9 (9)
Kaya et al[29]	Rifampin	25	1
	Ciprofloxacin	26	2
Girgis et al[25]	Rifampin	59	3
	Azythromycin	60	4
Simmons et al[35]	Rifampin	82	4
	Ceftriaxone	100	3
Blakebrough et al[14]	Rifampin	46 (48)	11 (11)
	Sulphadimidine	33 (34)	33 (34)
Judson et al[27]	Ceftriaxone	29	0
	Spectinomycin	9	8

For cluster trials, ICC = 0.05 was assumed for estimating effective sample sizes, and original sample size and events in cluster trials are shown in brackets

Table 3 Results of network meta-analysis of antibiotics for preventing meningococcal infections (odds ratio of failure to eradicate)

	2 Rifampin	3 Ciprofloxacin	4 Cephalexin	5 Minocycline	6 Ampicillin	7 Penicillin	8 Ceftriaxone	9 Rifampin + minocycline	10 Azythromycin	11 Spectinomycin	12 Coumermycin A1	13 Sch29482	14 Sulphadiazine	15 Sulphadimidine
1 Placebo	0.038a	0.020a	0.274	0.058a	0.267	0.611	0.009a	0.004a	0.071a	5.971	5.524	0.498	0.487	23.17
2 Rifampin		0.53	7.201	1.536	7.028a	16.20a	0.247	0.098	1.89	156.2a	146.2a	13.15a	12.88a	601a
3 Ciprofloxacin			13.7	2.911	13.29a	30.67a	0.467	0.184	3.54	301.0a	278.0a	24.87a	24.4a	1174a
4 Cephalexin				0.214	0.980	2.26	0.035a	0.013a	0.262	22.42	20.6	1.826	1.825	91.1a
5 Minocycline					4.577	10.52	0.161	0.064	1.212	102.3a	95.57a	8.53	8.42a	396a
6 Ampicillin						2.291	0.035a	0.014a	0.266	22.54	20.85a	1.864	1.84	88.6a
7 Penicillin							0.015a	0.006a	0.116	9.808	9.128	0.81	0.8	39.09
8 Ceftriaxone								0.385	7.566	620a	597a	53.17a	52.94a	2493a
9 Rifampin + minocycline									20.15	1776a	1584a	140.2a	134.3a	7088a
10 Azythromycin										83.64a	78.9a	7.03	7	334a
11 Spectinomycin											0.924	0.082	0.084	4.032
12 Coumermycin A1												0.089	0.088	4.372
13 Sch29482													0.992	48.75
14 Sulphadiazine														47.14

^a95%CIs did not contain zero.

Table 4 Results of covariate effects in network meta-analysis: Regression coefficient and between study variation

Covariate	Regression coefficient, β (95%CI)	Between-study variation (τ)
Persistent carrier (1) vs any carriers (0)	-2.904 (-4.695 to -1.186)	0.434
Household (1) vs other (0)	-6.178 (-16.79 to -0.069)	0.975
Cluster/quasi RCT (1) vs RCT (0)	0.405 (-2.235 to 2.881)	1.082
Sequence generation inadequate (1) vs adequate (0)	0.461 (-1.301 to 2.014)	1.025
Open design (1) vs blinded (0)	0.055 (-1.877 to 1.662)	1.087

β > 0 indicating that treatment effect is smaller when the covariate exists. RCT: Randomized controlled trial.

Table 5 Results of different methods for four comparisons that provided sufficient trials for both direct and indirect comparisons

	MTC estimate		Direct estimate		Indirect estimate
Comparison	No. of trials	OR (95%CrI)	No. of trials	OR (95%CrI)	No. of trials	OR (95%CrI)
Rifampin vs ciprofloxacin	23	0.52 (0.13, 1.89)	2	2.51 (0.36, 15.64)	21	0.09 (0.017, 0.40)
Rifampin vs minocycline	23	1.55 (0.40, 6.07)	2	0.85 (0.11, 5.59)	21	2.27 (0.28, 19.89)
Rifampin vs ampicillin	23	6.94 (1.21, 37.53)	1	1.62 (0.09, 29.82)	20	12.23 (1.04, 146.9)
Minocycline vs ampicillin	23	4.52 (0.67, 28.30)	1	3.46 (0.16, 91.10)	20	6.50 (0.41, 93.6)

MTC: Mixed treatment comparison based on all data in the network of trials.