Alternative eradication regimens for Helicobacter pylori infection in Indonesian regions with high metronidazole and levofloxacin resistance

Figures & data

Figure 1 The chart showing the enrollment of patients in the current study.

Note: *One strain (Malang1) could not grow well, and hence, we excluded it from the study.

Table 1 Rates of resistance to alternative antibiotics in Helicobacter pylori strains isolated in Indonesia

Characteristics	N	Resistance (%)
		Furazolidone	Sitafloxacin	Garenoxacin	Rifaximin	Rifabutin
Total	105	0 (0.0)	0 (0.0)	7 (6.7)	40 (38.9)	0 (0.0)
Sex
Male	67	0 (0.0)	0 (0.0)	5 (7.6)	28 (42.4)	0 (0.0)
Female	38	0 (0.0)	0 (0.0)	2 (5.2)	12 (31.5)	0 (0.0)
Age (years)
17–30	12	0 (0.0)	0 (0.0)	0 (0.0)	3 (25.0)	0 (0.0)
31–40	13	0 (0.0)	0 (0.0)	1 (7.6)	5 (38.4)	0 (0.0)
41–50	28	0 (0.0)	0 (0.0)	2 (7.1)	12 (42.8)	0 (0.0)
51–60	34	0 (0.0)	0 (0.0)	3 (8.8)	13 (38.2)	0 (0.0)
>60	18	0 (0.0)	0 (0.0)	1 (5.5)	6 (33.3)	0 (0.0)
Clinical outcome
Gastritis	95	0 (0.0)	0 (0.0)	6 (6.3)	34 (35.7)	0 (0.0)
PUD	9	0 (0.0)	0 (0.0)	0 (0.0)	3 (33.3)	0 (0.0)
Cancer	1	0 (0.0)	0 (0.0)	1 (100)	1 (100)	0 (0.0)

Abbreviation: PUD, peptic ulcer disease.

Table 2 Rates of resistance to alternative antibiotics in Helicobacter pylori strains isolated in specific regions of Indonesia

Region	N	Resistance (%)
		Furazolidone	Sitafloxacin	Garenoxacin	Rifaximin	Rifabutin
Bali	6	0 (0.0)	0 (0.0)	0 (0.0)	3 (50.0)	0 (0.0)
Java	13	0 (0.0)	0 (0.0)	2 (15.4)	4 (30.7)	0 (0.0)
Kalimantan	5	0 (0.0)	0 (0.0)	0 (0.0)	3 (60.0)	0 (0.0)
Papua	16	0 (0.0)	0 (0.0)	1 (6.2)	6 (37.5)	0 (0.0)
Sulawesi	21	0 (0.0)	0 (0.0)	1 (4.7)	11 (52.4)	0 (0.0)
Sumateraa	30	0 (0.0)	0 (0.0)	3 (10.0)	7 (23.3)	0 (0.0)
Timor	14	0 (0.0)	0 (0.0)	0 (0.0)	6 (42.8)	0 (0.0)

Note:

a Strains obtained from patients from Nias Island were combined with those of Sumatera Island due to the low sample number.

Table 3 Prevalence of antibiotic resistance in Helicobacter pylori isolates based on ethnicity

Ethnicity	Island	N	Resistance (%)
			FUR	SIT	GAR	RFX	RIF
Ambonese	Java	4	0 (0.0)	0 (0.0)	0 (0.0)	2 (50.0)	0 (0.0)
Bataknese	Sumatera and Java	31	0 (0.0)	0 (0.0)	3 (9.6)	8 (25.8)	0 (0.0)
Balinese	Bali	6	0 (0.0)	0 (0.0)	0 (0.0)	3 (50.0)	0 (0.0)
Buginese	Sulawesi	13	0 (0.0)	0 (0.0)	1 (7.7)	9 (69.2)	0 (0.0)
Chinese	Java and Kalimantan	10	0 (0.0)	0 (0.0)	2 (20.0)	3 (30.0)	0 (0.0)
Dayak	Kalimantan	2	0 (0.0)	0 (0.0)	0 (0.0)	1 (50.0)	0 (0.0)
Javanese	Java	1	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
Minahasanese	Sulawesi	8	0 (0.0)	0 (0.0)	0 (0.0)	2 (25.0)	0 (0.0)
Papuan	Papua	16	0 (0.0)	0 (0.0)	1 (6.2)	6 (37.5)	0 (0.0)
Timor	Timor	14	0 (0.0)	0 (0.0)	0 (0.0)	6 (42.8)	0 (0.0)

Abbreviations: FUR, furazolidone; GAR, garenoxacin; RFX, rifaximin; RIF, rifabutin; SIT, sitafloxacin.

Table 4 Comparison of the five alternative antibiotics with the standard regimens as reported by Miftahussurur et al¹⁸

Island	n	Resistant regimens (%)
		CAM	AMX	MNZ	TCN	LVX	FUR	SIT	GAR	RFX	RIF
Total	76	7 (9.1)	4 (5.2)	36 (46.7)	2 (2.6)	24 (31.2)	0 (0.0)	0 (0.0)	5 (6.5)	27 (35.5)	0 (0.0)
Bali	6	1 (16.7)	0 (0.0)	2 (33.3)	0 (0.0)	1 (16.6)	0 (0.0)	0 (0.0)	0 (0.0)	3 (50.0)	0 (0.0)
Java	13	3 (23.0)	0 (0.0)	7 (46.1)	2 (15.4)	7 (53.8)	0 (0.0)	0 (0.0)	2 (15.4)	4 (30.7)	0 (0.0)
Kalimantan	5	0 (0.0)	0 (0.0)	1 (20.0)	0 (0.0)	1 (20.0)	0 (0.0)	0 (0.0)	0 (0.0)	3 (60.0)	0 (0.0)
Papua	7	1 (14.3)	1 (14.3)	3 (42.9)	0 (0.0)	2 (28.6)	0 (0.0)	0 (0.0)	0 (0.0)	2 (28.5)	0 (0.0)
Sulawesi	13	1 (7.7)	1 (7.7)	4 (30.8)	0 (0.0)	2 (15.4)	0 (0.0)	0 (0.0)	0 (0.0)	6 (46.1)	0 (0.0)
Sumatera	18	1 (5.6)	1 (5.6)	16 (88.9)	0 (0.0)	8 (44.4)	0 (0.0)	0 (0.0)	3 (16.7)	3 (16.7)	0 (0.0)
Timor	14	0 (0.0)	1 (7.1)	3 (21.4)	0 (0.0)	3 (21.4)	0 (0.0)	0 (0.0)	0 (0.0)	6 (42.8)	0 (0.0)

Abbreviations: AMX, amoxicillin; CAM, clarithromycin; FUR, furazolidone; GAR, garenoxacin; LVX, levofloxacin; MNZ, metronidazole; RFX, rifaximin; RIF, rifabutin; SIT, sitafloxacin; TCN, tetracycline.

Figure 2 The associations among rates of resistance to metronidazole, levofloxacin, garenoxacin, and rifaximin.

Table 5 Mutations associated with quinolones

No.	Strains	gyrA mutation	gyrB mutation	MIC of LVX (mg/L)	MIC of GAR (mg/L)	MIC of SIT (mg/L)
1	Jayapura1	N87K	None	>32	0.25	0.063
2	Jayapura21	N87K	None	>32	0.125	0.063
3	Kupang2	D91N, A129T	S479G	4	0.125	<0.063
4	Kupang11	D91Y	None	>32	0.25	<0.063
5	Kupang23	A129T	S479G	>32	0.125	<0.063
6	Kupang41	D91N	R484K	8	0.5	<0.063
7	Malang1a	D91N	None	16	n.a.	n.a.
8	Manado18	None	None	8	0.5	<0.063
9	Manado20	D91Y	None	8	0.25	<0.063
10	Medan3	N87I	None	>32	2	0.25
11	Medan10	None	None	25	<0.063	<0.063
12	Medan15	R140K, D192N	None	>32	2	0.5
13	Medan17	D34N	None	16	0.5	<0.063
14	Medan18	D91G, D161N	None	4	<0.063	0.063
15	Medan22	D91N	None	>32	0.5	0.125
16	Medan23	D34Y, R140K	None	4	0.063	<0.063
17	Medan30	D91N	None	>32	1	0.125
18	Pontianak50	D91G	None	>32	0.063	<0.063
19	Surabaya71	D91N	None	>32	2	0.25
20	Surabaya79	N87Y	R484K	>32	0.5	<0.063
21	Surabaya137	N87K	None	>32	0.5	<0.063
22	Surabaya151	N87K	None	>32	0.5	0.125
23	Surabaya283	D91Y	None	>32	2	<0.063
24	Surabaya304	D91G	None	>32	0.5	0.063
25	Merauke20b	E103G	None	na	1	<0.063
26	Kolaka72b	D91G	None	na	1	<0.063

Notes: An MIC >1 mg/L was used as a resistance breakpoint for levofloxacin, garenoxacin, and sitafloxacin.

a One of the previously isolated strains could not sustain growth.

b The new strains with high MIC of garenoxacin that were not reported in our previous study.

Abbreviation: GAR, garenoxacin; LVX, levofloxacin; MIC, minimum inhibitory concentration; na, not available; SIT, sitafloxacin.

Table 6 Mutations associated with rifaximin resistance

No.	Strain name	MIC (mg/L)	rpoB mutation
1	Surabaya47	4	S355Y, I741V, T2002M, Q2079K
2	Jayapura21	4	V1125I, A2454V
3	Jayapura06	8	L547F, K786R, I837V, A964T, V1275I, A1533S, P1623S, D1697N, G1908E, A2099T, S2640Y
4	Jakarta9	4	I64V, L295I, S355Y, V657I, T1023I, S1197A, Q2042R, K2068R
5	Kupang10	4	G523C, I832V, E877K, K1006E, E1528D, Q1666H, N1944S, A2255V, G2512S, S2619I, V2774M
6	Kupang23	4	L169S, S355H, A693T, I837V, K854R, L977I, I1351T, N1999H, K2068R, Q2079K, S2415N, I2481V, V2528L, P2679S, M2696T
7	Kupang26	4	L169A, S355H, I837V, L977I, N1999H, Q2079K, S2415N, A2472V, I2481V, V2528L, P2679S, M2696T
8	Kupang29	4	K42R, I748V, T773I, A958T, E969D, S986G, A1025V, V1052I, V1122I, A2414V, S2619I
9	Kupang30	4	S355H, S627N, I837V, A1025V, D1162N, K1165R, L1401I, R1711H, Q2079K, A2234T, D2380E
10	Kupang34	4	S355H, A732V, I837V, V955I, L977I, V1028A, N1999H, K2068R, Q2079K, S2415N, I2481V, V2528L, P2679S, M2696T
11	Bangli42	4	I141V, E163D, N642D, R954W, E996G, M1264I, E1407K, Y2275C, K2462E, V2469I, G2480R, T2539A
12	Bangli47	4	L314F, E1151K, I1190T, R1711H, K2068R, Y2326C, K2418Q, V2528L, T2536A, F2537L, K2538S, K2557R, V2561M, A2570T, S2734G
13	Bangli64	4	R63H, E162K, L295I, I336T, M667I, A735T, P816S, I837V, V867A, R973H, T975I, Q1010R, E1572Q, A1691V, A2346T, S2390G, G2491D, A2541V
14	Manado29	4	D255N, P259S, A1168V, A1181V, A1533T, L1765F, V1939I, A1950T, L2328I, R2694H, I2824V
15	Manado31	8	K307E, R984H, V1028A, A1533T, A2255V, Y2326C, A2494T
16	Merauke20	4	K786R, A964T, R2313H, G2512S
17	Merauke21	4	A1181V, G2180S, A2472T, P2545S, V2664M
18	Merauke27	4	I140V, A1533T, S1701N, A2505T, V2664M
19	Merauke37	4	S78P, P95H, M313L, K786R, A964T, L977F, E1014K, M1242I, D1379N, A1533S, G2180S, A2414T, R2477H, A2494T, I2730V
20	Kolaka72	4	R274I, S355Y, V538I, T635A, R1248H, G2403S, A2541, N2602D, R2641K, D2788G
21	Kolaka79	4	–
22	Kolaka96	4	R708K, L982S, E1161K, N1709D, E2382K, V2469I, R2477Y, V2528L, T2536A, F2537L, K2538S, K2557R, V2561M, R2882K
23	Kolaka98	4	P259S, A735T, S743A, I837V, T975S, A1025S, K1165R, D1379Y, K2068R, Q2079K, K2421R
24	Kolaka99	4	L295I, S355Y, A473V, M1175I, R1711H, Q2079K, A2454V, P2612S, S2675G
25	Makasar31	8	L295I, I336T, G615D, A735V, I837V, Q1010R, D1379Y, V1491I, H1985Y, V2237M, A2317V, D2380E, R2506C
26	Makasar45	4	E1161K, A2414V
27	Makasar52	4	E1161K, A2414V
28	Makasar55	4	P931S, A1643M, A1950T, K2068R, D2380E
29	Medan56	4	V303I, K1540N, A2414V, A2454V
30	Medan67	4	A497T, A958T, N1598H, T2002M, R2313C, A2414V
31	Medan75	4	I512V, M667I, A964V, T1402M, A2414V, E2599A, V2638I, S2791G
32	Padang42	4	H153Y, P931S, H1985Y, E2183K, A2414V, E2604G
33	Pontianak44	4	A487T, E969D, V1291I, A2255V, V2447I
34	Pontianak50	4	S355Y, S627N, E969K, R1563K, M1627I, A1676V, S1794N, N1999H, V2037I, D2449N, A2459T, T2533M, M2696T, E2859G
35	Pontianak5	4	V2802L
36	Surabaya283	4	P259S, T440A, A497T, E1232D, N1944S, V2037I, I2428V, I2564V, Y2740H, K2889R
37	Surabaya304	8	S78A, S355Y, K398R, V657I, E1486D, D2226S, L2328I, A2357V
38	Medan15	4	A473V, Q991R, E1059G, S1197A, K2068R
39	Medan22	32	I66V, L295I, S355Y, I586L, E655K, V657I, G1620S, A2541T, L2881I
40	Medan25	8	V52I, I66V, E106G, V657I, A756V, D2380E, K2482R

Note: S355Y means tyrosine replaced serine amino acid in the position 355.

Abbreviation: MIC, minimal inhibitory concentration.

Table S1 Mutations associated with rifaximin resistance

No.	Strain ID	Average coverage	Q30 percentage	Rifaximin
1	Manado1	326.27	91.21	S
2	Surabaya71	346.57	90.99	S
3	Surabaya47	264.51	88.23	R
4	Surabaya68	408.21	91.31	S
5	Surabaya69	504.26	88.53	S
6	Surabaya71	560.21	88.06	S
7	Surabaya79	554.35	94.39	S
8	Jayapura1	570.45	95.95	S
9	Jayapura3	560.85	96.31	S
10	Jayapura6	589.56	95.97	R
11	Jayapura8	231.21	84.54	S
12	Jayapura15	489.67	96.36	S
13	Jayapura16	509.21	95.14	S
14	Jayapura21	502.21	96.49	R
15	Jakarta9	115.74	91.23	R
16	Medan17	142.34	80.59	S
17	Medan23	166.24	90.67	S
18	Medan27	91.58	80.76	S
19	Medan3	93.57	80.88	S
20	Medan10	85.96	80.44	S
21	Medan11	278.2	87.68	S
22	Medan15	260.45	80.59	R
23	Medan19	176.28	83.32	S
24	Medan20	164.28	82.27	S
25	Medan22	115.51	82.74	R
26	Medan23	264.07	81.06	S
27	Medan25	219.52	80.97	R
28	Medan28	169.54	80.8	S
29	Medan30	237.04	80.42	S
30	Makasar31	87.65	81.19	R
31	Makasar45	156.35	89.51	R
32	Makasar47	85.35	80.68	S
33	Makasar52	87.07	83.13	R
34	Makasar55	89.29	83.49	R
35	Makasar56	82.43	82.46	S
36	Pontianak63	82.77	88.97	S
37	Pontianak75	85.13	86.89	R
38	Pontianak20	191.58	89.57	S
39	Pontianak44	128.24	89.45	R
40	Pontianak50	99.51	91.01	R
41	Manado5	171.08	89.76	S
42	Manado18	136.04	90.18	S
43	Manado20	110.47	87.37	S
44	Manado26	151.85	86.67	S
45	Manado28	175.98	93.44	S
46	Manado29	90.53	93.63	R
47	Manado31	102.87	93.18	R
48	Kupang2	156.23	82.79	S
49	Kupang5	132.2	85.25	S
50	Kupang6	120.2	83.27	S
51	Kupang10	105.54	82.16	R
52	Kupang11	196.38	80.2	S
53	Kupang15	192.96	82.36	S
54	Kupang23	125.05	84.94	R
55	Kupang26	98.87	89.29	R
56	Kupang28	146.88	86.58	S
57	Kupang29	144.7	81.55	R
58	Kupang30	85.85	85.47	R
59	Kupang33	158.02	83.55	S
60	Kupang34	238.16	87.82	R
61	Kupang35	240.73	85.3	S
62	Kupang41	112.69	85.57	S
63	Kupang42	86.98	81.43	R
64	Kupang47	142.12	85.5	R
65	Kupang64	171.52	82.59	R
66	Kupang73	134.33	88.07	S
67	Kupang83	152.03	85.08	S
68	Medan18	201.24	89.67	S
69	Medan31	162.6	90.39	S
70	Medan32	264.33	88.11	S
71	Medan33	368.99	86.63	S
72	Nias9	123.05	84.92	S
73	Medan36	97.32	84.74	S
74	Medan37	95.96	85.43	S
75	Medan40	125.98	85.11	S
76	Medan49	163.37	83.54	S
77	Medan50	146.38	83.51	S
78	Medan56	192.02	83.51	R
79	Medan67	223.14	85.69	R
80	Medan68	137.93	84.11	S
81	Medan73	224.19	83.87	S
82	Medan75	194.47	83.86	R
83	Padang42	157.75	88.29	R
84	Surabaya106	84.06	80.06	S
85	Surabaya137	104.09	86.49	S
86	Surabaya151	96.79	82.68	S
87	Surabaya192	106.55	85.02	S
88	Surabaya283	107.28	87.04	R
89	Surabaya304	112.26	86.21	R
90	Merauke3	243.44	85.05	S
91	Merauke5	219.32	84.41	S
92	Merauke7	225.09	83.16	S
93	Merauke8	269.32	86.05	S
94	Merauke12	191.03	85.7	S
95	Merauke20	145.23	88.24	R
96	Merauke21	338.84	87.53	R
97	Merauke27	185.99	80.84	R
98	Merauke37	304.88	86.56	R
99	Kolaka56	219.48	85.48	S
100	Kolaka72	196.53	86.86	R
101	Kolaka79	343.49	86.15	R
102	Kolaka94	256.4	83.82	S
103	Kolaka96	190.85	82.58	R
104	Kolaka98	206.04	83.99	R
105	Kolaka99	279.25	81.86	R

Abbreviations: R, resistant; S, sensitive.

MiftahussururMSyamAFNusiIASurveillance of Helicobacter pylori antibiotic susceptibility in indonesia: different resistance types among regions and with novel genetic mutationsPlos One20161112e016619927906990

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