Efficacy and Safety of Moxifloxacin and Gatifloxacin as Initial TB Treatment

12 Dec, 17

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Introduction

The fourth-generation fluoroquinolones (FQs) gatifloxacin (GAT) and moxifloxacin (MOX) have shown promising mycobactericidal activity. In vitro studies suggested that FQs might reduce the duration of treatment in new TB cases.

Aim

To evaluate efficacy and safety of the MOX- or GAT-containing regimens as initial therapy for drug-sensitive tuberculosis (TB).

Patient Profile

N= 6980 participants with a range of 170 to 1931 participants per trial.
Male patients comprised 62%–74% of population
The mean age was approximately 30 years old
Seven out of nine trials included both HIV-positive and HIV-negative patients with the total HIV prevalence ranging from 3% to 58.5%

Methods

A meta-analysis and systematic review
RCTs that evaluated the MOX- or GAT-containing regimen for drug-sensitive pulmonary tuberculosis were selected
9 studies were included in this meta-analysis

Table 1: Baseline characteristics of studies included in analysis

Study	Enrolled patients	Number of each arm ^a	Male	Mean age (interquartile range)	HIV prevalence	Treatment regimens ^b		Duration of follow-up
						Experimental group	Control group
Burman et al.	336	169 vs 167	67%	31 (24–40)	21.7%	2HRZM/4HR	2HRZE/4HR	2m
Rustomjee et al.	217	163 vs 54	66.8%	31.5 (25–37)	58.5%	2HRZM/4HR	2HRZE/4HR	2m
						2HRZG/4HR
						2HRZO/4HR
Dorman et al.	433	185 vs 196	72%	30 (25–38)	11%	2RZEM/4HR	2HRZE/4HR	2m
Conde et al.	170	74 vs 72	62%	32 (na)	3%	2HRZM/4HR	2HRZE/4HR	18 m
Jawahar et al.	429	251 vs 165	74%	Na	0	2HRZM/2HRM	2HRZE/4HR	30 m
						2HRZG/2HRG
Velayutham et al.	801	616 vs 164	75%	Na	0		2HRZE/4HR	2m
						2HRZEM/2HRM(daily);	(thrice wk)
						2HRZEM/2HRM(thrice wk)
Jindani et al.	827	552 vs 275	64%	Na	27%	2R(high-dose)ZEM/2MP	2HRZE/4HR	18 m
						2R(high-dose)ZEM/4MP
Gillespie et al.	1931	1291vs 640	70%	Na	7%		2HRZE/4HR
Merle et al.	1836	848 vs 844	72.7%	30.7(na)	18.1%	2HRZG/2HRG	2HRZE/4HR	30 m

H, isoniazid; R, rifampicin; E, ethambutol; Z, pyrazinamide; M, moxifloxacin; G, gatifloxacin; O, ofloxacin; P, rifapentine; na, not available.

a Number of patients in an experimental group vs a control group in intention-to-treat analysis.

b In each regimen, the number indicates the number of months of treatment: e.g., ‘2HRZM/4HR’ represents two months of treatment with HRZM followed by four months of treatment with HR.

All of the controlled regimens included
- standard doses of isoniazid, rifampicin, pyrazinamide and ethambutol.
The mean duration of follow-up ranged from two months of treatment to 24 months after the end of treatment.

Primary and Secondary Outcomes

The rate of unfavorable outcomes was set as the primary outcome.
The unfavorable outcomes were
- treatment failure
- relapse
- death or withdrawal from the trial at the end of follow-up
The rate of sputum culture conversion at the end of the intensive phase (2-month) was set as the secondary efficacy outcome.
Safety outcomes were the rates of death from any cause, TB-related death and serious adverse events

Results

More frequent unfavorable treatment outcomes were associated with fluoroquinolone substitution for isoniazid or ethambutol in short-course regimens compared with the standard regimen, particularly an increased incidence of relapse.

Table 2: Rates of unfavorable outcomes, including treatment failure and relapse, between MOX-/GAT-containing regimens and the standard regimen in an intention-to-treat analysis or a modified intention-to-treat analysis

Study	Treatment regimens a		Unfavorable outcome rates		Treatment failure rates b		Relapse rates b
	Experimental	Control	Experimental	Control	Experimental	Control	Experimental	Control
Jawahar et al.30	2HRZM/2HRM	2HRZE/4HR	13.9%	8.1%	2/108 (1.9%)	2/137 (1.5%)	11/104 (10.6%)	8/132 (6.1%)
	2HRZG/2HRG		16.9%		6/118 (5.1%)		17/115 (14.8%)
Merle et al.22	2HRZG/2HRG	2HRZE/4HR	21%	17.2%	12/694 (1.4%)	16/662 (2.4%)	101/694 (14.6%)	47/662 (7.1%)
Gillespie et al.20	4HRZM	2HRZE/4HR	23%	16%	5/568 (0.9%) 7/555 (1.3%)		46/568 (8.1%) 13/555 (2.3%)
	4ERZM 24%				5/551 (0.9%)		64/551 (11.6%)
Jindani et al.	2R(high-dose)ZEM/2MP	2HRZE/4HR	26.9%	14.4%	2/193 (1.0%) 2	/188 (1.1%)	27/193 (15.8%)	6/188 (3.1%)
	2R(high-dose)ZEM/4MP		13.7%		0/212 (0.0%)		5/212 (2.7%)

H, isoniazid; R, rifampicin; E, ethambutol; Z, pyrazinamide; M, moxifloxacin; G, gatifloxacin; P, rifapentine; na, not available.

a In each regimen, the number indicates the number ofmonths of treatment: e.g., ‘2HRZM/4HR’ represents two months of treatment with HRZM followed by four months of treatment with HR.

Rates of sputum culture conversion at two months were slightly higher with MOX-containing regimens than the standard regimen (RR 1.08, P<0.001).
Rate of sputum conversion between the GAT-containing regimens and the standard regimen (RR 1.13, P = 0.13) were not significantly different.
The incidence of death from any cause, including TB, nor were there serious adverse events between the MOX- or GAT-containing regimens and the standard regimen were not significantly different.

Table 3: Safety outcomes of the GAT-containing regimens and the standard regimen in the included studies

Study	Experimental regimen ^a	Control regimen ^a	Follow-up (month)	Death from any cause ^b		TB-related death ^b			Serious side effects ^b
				Experimental	Control	Experimental	Control	Experimental	Control
Rustomje et al.	2HRZG/4HR	2HRZE/4HR	2	0/55 (0%)	2/54 (3.7%)	0/55 (0%)	0/50 (0%)	3/55 (5.5%)	7/54 (13.0%)
Jawahar et al.	2HRZG/2HRG	2HRZE/4HR	24	na	na	na	na	4/136 (2.9%)	1/165 (0.6%)
Merle et al.	2HRZG/2HRG	2HRZE/4HR	30	10/848 (1.2%) 12/844 (1.4%)		2/848 (0.2%)	3/844 (0.4%) 20/848 (2.4%) 23/844 (2.7%)

a In each regimen, the number indicates the number ofmonths of treatment: e.g., ‘‘2HRZG/4HR’’ represents twomonths of treatment with HRZG followed by four months of treatment with HR.

b The number of events or the number of patients included in each arm (rate).

Conclusion

In this study, MOX or GAT demonstrated slightly better efficacy or non-inferiority in early phase of treatment compared with the standard regimen.
Shortening treatment duration in the initial therapy can be achieved with MOX or GAT
MOX and GAT demonstrated good safety profile in initial TB treatment.

Emerging Microbes and Infections (2016) 5, e12; doi:10.1038/emi.2016.12

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