Explorative Analysis of Treatment Outcomes of Levofloxacin- and Moxifloxacin-Based Regimens and Outcome Predictors in Ethiopian MDR-TB Patients: A Prospective Observational Cohort Study

Figures & data

Table 1 Baseline Socio-Demographic, Laboratory and Clinical Characteristics of the Study Participants in Both Moxifloxacin and Levofloxacin Groups

Patient Characteristics	Moxifloxacin Group (n=43)	Levofloxacin Group (n=37)	P-value
Age (years)	25 (19–37)	26 (20–30)	0.34*
Sex Male	22 (51.2)	22 (59.5)	0.46^†
Female	21 (48.8)	15 (40.5)	0.46^†
Body mass index (kg/m^2)	17.3 (16.0–19.2)	16.7 (15.6–18.4)	0.40*
Past history of TB treatment	35 (81.4)	25 (67.6)	0.15^†
Nutritional status			0.21^†
Normal	15 (34.9)	18 (48.6)
Moderately malnourished	28 (65.1)	19 (51.4)
Smoking			0.75^†
No	37 (86.1)	33 (89.2)
Yes	6 (13.9)	4 (10.8)
Khat Chewer			0.29^†
No	40 (93.0)	31 (83.8)
Yes	3 (7.0)	6 (16.2)
Alcohol consumption			0.39^†
No	33 (76.7)	32 (86.5)
Yes	10 (23.3)	5 (13.5)
Comorbidities
Peritonitis	1 (2.3)	1 (2.7)	0.91^†
HIV	5 (13.5)	6 (16.2)	0.55^†
Typhoid	0 (0.0)	1 (2.7)	0.46^†
Hypocalcemic tetany	0 (0.0)	1 (2.7)	0.46^†
Dyspepsia	1 (2.3)	0 (0.0)	0.54^†
DVT	0 (0.0)	3 (8.1)	0.10^†
CHF	1 (2.3)	4 (10.8)	0.18^†
PUD and abdominal infection	2 (4.7)	1 (2.7)	0.56^†
Pneumonia	2 (4.7)	2 (5.4)	0.63^†
Hypertension	0 (0.0)	1 (2.7)	0.46^†
Radiographic findings (chest X-ray)			0.11^†
No cavitary lesion	28 (65.1)	30 (81.1)
Cavitary lesion	15 (34.9)	7 (18.9)
Degree of acid fast bacilli (AFB)			0.07^†
Scanty	2 (4.7)	7 (18.9)
1+	14 (4.7)	5 (13.5)
2+	20 (46.5)	20 (54.1)
3+	7 (16.3)	5 (13.5)
Culture test			0.13^†
Positive for MTBC (1+)	27 (62.8)	29 (78.4)
Positive for MTBC (2+)	16 (37.2)	8 (21.6)
Biochemistry & Hematological characteristics⁑
Alanine aminotransferase (AST)			0.17*
Mean ± SD	33.4±13.6	32.0±17.9
Median (IQR)	33.0 (22–42)	29.0 (20–36.5)
Alanine transaminase (ALT)			0.27*
Mean ± SD	36.5±25.2	27.8±15.8
Median (IQR)	29.0 (18–48)	22.0 (14–45)
Hemoglobin (HG)			0.60*
Mean ± SD	14.7±5.8
Median (IQR)	13.8 (12.4–14.7)
Serum albumin (ALB)			0.32*
Mean ± SD	3.3±0.4
Median (IQR)	3.3 (3.1–3.5)

Notes: Data presented as n (%) or median (IQR); *P value from Wilcoxon rank-sum test. ^†P value from chi-square test or Fisher exact test, ⁑these are the average measurement at three different occasions.

Abbreviations: DVT, deep vein thrombosis; CHF, congestive heart failure; HIV, human immunodeficiency virus; IQR, interquartile range; MTBC, Mycobacterium tuberculosis complex; PUD, peptic ulcer disease; SD, standard deviation.

Table 2 Duration of Treatment and Number of Companion Drugs Included in Moxifloxacin-and Levofloxacin-Based Regimens

	Moxifloxacin Group (n=43)	Levofloxacin Group (n=37)	P-value
Duration of treatment, days	297 (169–355)	522 (321–570)	0.007
Duration of fluoroquinolones use, days	297 (169–355)	522 (321–570)	0.007
Drugs used	7 (5–7)	5 (4–6)	0.001
Isoniazid	38 (88.4)	0 (0.0)	0.001
Ethambutol	36 (83.7)	1 (2.7)	0.001
Pyrazinamide	39 (90.7)	23 (62.2)	0.002
Cycloserine	2 (4.7)	36 (97.3)	0.001
Delamanid	1 (2.3)	3 (8.1)	0.331
Clofazimine	41 (95.4)	34 (91.9)	0.524
Bedaquiline	2 (4.7)	17 (45.9)	0.001
Linezolid	2 (4.7)	23 (56.8)	0.001
Prothionamide	35 (81.4)	21 (56.7)	0.055
Injectable agents
Capreomycin	1 (2.35)	9 (24.3)	0.005
Amikacin	7 (16.3)	0 (0.0)	0.013
Kanamycin	26 (60.5)	2 (5.4)	0.001

Notes: Data presented as n (%) or median (interquartile range). P-values are using chi-square test or Fisher exact test.

Table 3 Treatment Outcome, Sputum Culture Conversion and Line Probe Assay Results by Treatment Regimen of the Study Subjects with MDR-TB

	Moxifloxacin Group (n=43)	Levofloxacin Group (n=37)	P-value
Treatment outcome
Cure	19 (44.2)	24 (64.9)	0.06^†
Completion	3 (7.0)	6 (16.2)	0.29^†
Death	5 (11.6)	3 (8.1)	0.72^†
Failed or moved to Pre-XDR-TB	7 (16.3)	2 (5.4)	0.17^†
Lost to follow-up	9 (20.9)	2 (5.4)	0.06^†
Overall treatment success	22 (51.2)	30 (81.1)	0.01^†
First sputum culture conversion
Within 90 days of treatment started	32 (74.4)	31 (83.8)	0.46^†
After 90 days of treatment	11 (25.6)	6 (16.2)	0.41^†
Line probe assay result
Resistance to FQs	7 (16.3)	2 (5.4)	0.17^†
Resistance to both FQs and IAs	2 (4.6)	1 (2.7)	0.56^†
Duration of follow-up	290 (162–348)	515 (314–563)	0.01*

Notes: n=80; Data presented as n (%) or median (interquartile range); *P value from Wilcoxon rank-sum test. ^†P value from chi-square test or Fisher exact test.

Abbreviations: FQs, fluoroquinolones; IAs, injectable agents; MDR-TB, multidrug resistant TB; XDR-TB, extremely drug resistant TB.

Figure 1 Summary of the Molecular line probe assay for the two core groups of second- line drugs.

Abbreviations: XDR, extremely drug resistant, occurs when there is resistance to both fluoroquinolones and injectable drugs; FQs, fluoroquinolones.

Table 4 Univariate and Backward Multivariate Cox Proportional Hazard Regression to Determine Outcome Predicting Factors in MDR-TB Patients

Univariate Cox Regression
Patient Variable	n (%)	Outcome		P-value	HR [95% CI]
		Success	Failure
Sex, male	44 (55)	28 (53.8)	16 (57.1)	0.38	1.39 [0 0.66–2.97]
Comorbidity	29 (36.3)	18 (34.6)	11 (39.3)	0.88	0.94 [0.62–3.50]
Age (years), >35	15 (18.8)	8 (15.4)	7 (25.0)	0.37	0.94 [0.27–3.22]
Prior TB treatment	60 (75.0)	39 (75.0)	21 (75.0)	0.14*	1.97 [0.80, 4.87]
Body mass index, <18.5	58 (72.5)	38 (73.1)	20 (71.4)	0.55	0.96 [0.83–1.10]
Treatment group, MXF	43 (53.4)	22 (42.3)	21 (75.0)	0.00*	0.22 [0.09–0.53]
Khat consumption	9 (11.3)	3 (5.8)	6 (21.4)	0.29	1.63 [0.46–1.10]
Smoking	10 (12.5)	4 (7.7)	6 (21.4)	0.58	1.30 [0.50–3.38]
Alcohol consumption	16 (20.0)	4 (7.7)	12 (42.9)	0.00*	3.96 [1.83–8.56]
Resistance to FQs	9 (11.3)	3 (5.8)	6 (21.4)	0.09*	3.31 [1.32–6.65]
Resistance to FQs & IAs	3 (3.8)	1 (1.9)	2 (7.1)	0.58	1.42 [0.42–4.83]
FSCC after 90 days	26 (32.5)	5 (9.6)	11 (39.3)	0.01*	2.66 [1.24–5.73]
Malnourished	47 (58.8)	28 (53.8)	19 (67.8)	0.09*	2.07 [0.89–4.81]
Cavitary lung lesion	30 (37.5)	10 (19.2)	20 (71.4)	0.00*	5.11 [2.24–11.65]
Mean AST, ≥32.7^†	35 (43.8)	23 (44.2)	12 (42.9)	0.50	2.14 [0.99–1.03]
Mean ALT, ≥32.5^†	36 (45.0)	21 (40.4)	15 (53.8)	0.04*	1.58 [0.72–3.49]
Mean ALB, <3.3^†	38 (47.5)	24 (46.2)	14 (50.0)	0.57	0.58 [0.58–2.62]
Mean HG, <15.12^†	57 (71.3)	37 (71.2)	20 (71.4)	0.69	1.20 [0.96–1.08]
Adverse drug event	60 (75.0)	39 (75.0)	21 (75.0)	0.66	0.82 [0.33–1.99]
Mean Scr. (mg/dL), ≥ 0.87^†	31 (38.8)	14 (26.9)	17 (60.7)	0.09*	0.17 [0.030–1.02]

Notes: n=80; *Variables with P-value<0.2.

Abbreviations: CHR, crude hazard ratio; CI, confidence interval; FQs, fluoroquinolones; FSCC, first sputum culture conversion; IAs, injectable agents.

Figure 2 Kaplan–Meier curve showing the probability of survival of MDR-TB patients for moxifloxacin-and levofloxacin-based regimens since commencement to end of treatment follow-up.

Figure 3 Kaplan–Meier analysis comparing time-to-culture positivity between moxifloxacin- and levofloxacin-based regimens treated MDR-TB patients (n=80).

Table 5 Multivariate Cox Proportional Hazard Regression Analysis of Treatment Outcome Predicting Covariates in MDR-TB Patients

Patient Variable	n (%)	Outcome n (%)		P-value	AHR [95% CI]
		Successful	Unfavorable Outcome
Treatment group		52 (65.0)	28 (35.0)	0.011*	0.27 [0.10–0.74]
Moxifloxacin	43 (53.8)	22 (42.3)	21 (75.0)
Levofloxacin	37 (46.2)	30 (57.7)	7 (25.0)
Prior TB treatment		52 (65.0)	28 (35.0)	0.882	1.08 [0.38–3.08]
None	20 (25)	13 (25.0)	7 (25.0)
Treated	60 (975)	39 (75.0)	21 (75.0)
Nutritional Status		52 (65.0)	28 (35.0)	0.652	1.23 [0.50–3.04]
Normal	33 (41.3)	23 (69.7)	10 (30.3)
Malnourished	47 (58.7)	29 (61.7)	18 (38.3)
Resistance FQs				0.336	1.75 [0.56–5.46]
FSCC				0.020*	2.80 [1.18–6.66]
Within 90 days	54 (67.5)	42 (77.8)	12 (22.2)
After 90 days	26 (32.5)	10 (38.5)	16 (61.5)
Alcohol use				0.003*	4.09 [1.62–10.34]
No	65 (81.2)	51 (78.5)	14 (21.5)
Yes	15 (18.8)	1 (6.7)	14 (93.3)
Chest X-ray				0.032*	3.09 [1.10–8.70]
No lesion	58 (72.5)	43 (74.1)	15 (25.9)
Cavitary lesion	22 (27.5)	9 (40.9)	13 (59.1)
Mean Scr. (mg/dL)		52 (65.0)	28 (35.0)	0.029*	0.27 [08–0.88]
< 0.87^†	49 (61.3)	32 (61.5)	17 (60.7)
≥ 0.87^†	31 (38.7)	20 (38.5)	11 (39.3)
Mean ALT (IU/L)				0.047 *	3.11 [1.01–9.54]
≤ 32.5^†	44 (55)	36 (69.2)	21 (75.0)
> 32.5^†	36 (45)	16 (30.8)	7 (25.0)

Notes: n=80; *P-value <0.05; ^†These were the average values considered as a cut-off point below or above which the outcomes were assessed.

Abbreviations: ALT, alanine aminotransferase; IU/L, international units per liter; Scr., serum creatinine; FSCC, first sputum culture conversion (in days); FQs, fluoroquinolones.

Table 6 Adverse Drug Reactions Occurred Among the MDR-TB Patients

	Moxifloxacin Group (n=43)	Levofloxacin Group (n=37)	P-value
Adverse events	37 (86.1)	23 (62.2)	0.014*
Myalgia	11 (25.6)	11 (29.7)	0.679
Hematological abnormalities	7 (16.3)	6 (16.2)	0.994
GI upset	5 (11.6)	2 (5.4)	0.442
Ototoxicity	9 (16.2)	1 (2.7)	0.017*
Hepatotoxicity	9 (20.9)	5 (13.5)	0.556
Psychotic problems	3 (8.1)	1 (2.7)	0.620
Peripheral neuropathy	3 (8.1)	1 (2.7)	0.620
Elevated serum creatinine (nephrotoxicity).	3 (7.0)	2 (5.4)	0.990
Others^†	9 (11.6)	7 (10.8)	0.823

Notes: n=80, Data presented as n (%). P values are using chi-square test or Fisher exact test. *The P-value is statistically significant (P<0.05); ^†Others refers ADRs like weakness, fatigue, sweating, and chills.