Frequency histograms of the MICs of each of the tested drugs are shown in Figure 1. MIC90 and MIC50 values of each drug are shown in Table 2, alongside the MIC90 values for the H37Rv controls. The range of MICs of each of the drugs varied widely, but had the least variability for trimethoprim/sulfamethoxazole, mefloquine, thioridazine and linezolid. The drugs with documented serum peak levels above the MIC90 were trimethoprim/sulfamethoxazole, nitazoxanide, meropenem/clavulanate and linezolid (Tables 2 and 3). 
Figure 1.
MICs, in mg/L, of various antibiotics for initial MDR M. tuberculosis isolates; n = 153. One hundred and fifty initial isolates had valid results for trimethoprim/sulfamethoxazole and 152 had valid results for oxyphenbutazone.
Table 2.
MICs, in mg/L, for initial isolates and control H37Rv
| Drug | Initial isolates, n = 153 | Control H37Rv, n = 25 | ||
|---|---|---|---|---|
| MIC50 | MIC90 | MIC range | MIC90 (MIC range) | |
| Trimethoprim/sulfamethoxazolea | 0.2/4 | 0.4/8 | 0.05/1–1.7/32 | 0.2/4 (0.1/2–0.4/8) |
| Mefloquine | 8 | 8 | 1–16 | 8 (4–8) |
| Thioridazine | 4 | 8 | <1–8 | 8 (4–8) |
| Clofazimine | 0.25 | 0.5 | <0.03–2 | 0.25 (0.125–0.5) |
| Amoxicillin/clavulanate | 16/8 | 32/16 | <0.5/0.25 to >64/32 | 32/16 (16/8–32/16) |
| Meropenem/clavulanate | 1/2.5 | 8/2.5 | <0.12/2.5 to >16/2.5 | 2/2.5 (2/2.5–4/2.5) |
| Nitazoxanide | 16 | 16 | <1–64 | 16 (8–32) |
| Linezolid | 0.25 | 0.25 | <0.06–0.5 | 0.5 (0.25–0.5) |
| Oxyphenbutazoneb | 40 | 60 | 20 to >80 | 60 (40–90) |
| Isoniazidb | 4 | >4 | <0.03 to >4 | <0.03 (<0.03–0.06) |
| Drug | Initial isolates, n = 153 | Control H37Rv, n = 25 | ||
|---|---|---|---|---|
| MIC50 | MIC90 | MIC range | MIC90 (MIC range) | |
| Trimethoprim/sulfamethoxazolea | 0.2/4 | 0.4/8 | 0.05/1–1.7/32 | 0.2/4 (0.1/2–0.4/8) |
| Mefloquine | 8 | 8 | 1–16 | 8 (4–8) |
| Thioridazine | 4 | 8 | <1–8 | 8 (4–8) |
| Clofazimine | 0.25 | 0.5 | <0.03–2 | 0.25 (0.125–0.5) |
| Amoxicillin/clavulanate | 16/8 | 32/16 | <0.5/0.25 to >64/32 | 32/16 (16/8–32/16) |
| Meropenem/clavulanate | 1/2.5 | 8/2.5 | <0.12/2.5 to >16/2.5 | 2/2.5 (2/2.5–4/2.5) |
| Nitazoxanide | 16 | 16 | <1–64 | 16 (8–32) |
| Linezolid | 0.25 | 0.25 | <0.06–0.5 | 0.5 (0.25–0.5) |
| Oxyphenbutazoneb | 40 | 60 | 20 to >80 | 60 (40–90) |
| Isoniazidb | 4 | >4 | <0.03 to >4 | <0.03 (<0.03–0.06) |
Table 2.
MICs, in mg/L, for initial isolates and control H37Rv
| Drug | Initial isolates, n = 153 | Control H37Rv, n = 25 | ||
|---|---|---|---|---|
| MIC50 | MIC90 | MIC range | MIC90 (MIC range) | |
| Trimethoprim/sulfamethoxazolea | 0.2/4 | 0.4/8 | 0.05/1–1.7/32 | 0.2/4 (0.1/2–0.4/8) |
| Mefloquine | 8 | 8 | 1–16 | 8 (4–8) |
| Thioridazine | 4 | 8 | <1–8 | 8 (4–8) |
| Clofazimine | 0.25 | 0.5 | <0.03–2 | 0.25 (0.125–0.5) |
| Amoxicillin/clavulanate | 16/8 | 32/16 | <0.5/0.25 to >64/32 | 32/16 (16/8–32/16) |
| Meropenem/clavulanate | 1/2.5 | 8/2.5 | <0.12/2.5 to >16/2.5 | 2/2.5 (2/2.5–4/2.5) |
| Nitazoxanide | 16 | 16 | <1–64 | 16 (8–32) |
| Linezolid | 0.25 | 0.25 | <0.06–0.5 | 0.5 (0.25–0.5) |
| Oxyphenbutazoneb | 40 | 60 | 20 to >80 | 60 (40–90) |
| Isoniazidb | 4 | >4 | <0.03 to >4 | <0.03 (<0.03–0.06) |
| Drug | Initial isolates, n = 153 | Control H37Rv, n = 25 | ||
|---|---|---|---|---|
| MIC50 | MIC90 | MIC range | MIC90 (MIC range) | |
| Trimethoprim/sulfamethoxazolea | 0.2/4 | 0.4/8 | 0.05/1–1.7/32 | 0.2/4 (0.1/2–0.4/8) |
| Mefloquine | 8 | 8 | 1–16 | 8 (4–8) |
| Thioridazine | 4 | 8 | <1–8 | 8 (4–8) |
| Clofazimine | 0.25 | 0.5 | <0.03–2 | 0.25 (0.125–0.5) |
| Amoxicillin/clavulanate | 16/8 | 32/16 | <0.5/0.25 to >64/32 | 32/16 (16/8–32/16) |
| Meropenem/clavulanate | 1/2.5 | 8/2.5 | <0.12/2.5 to >16/2.5 | 2/2.5 (2/2.5–4/2.5) |
| Nitazoxanide | 16 | 16 | <1–64 | 16 (8–32) |
| Linezolid | 0.25 | 0.25 | <0.06–0.5 | 0.5 (0.25–0.5) |
| Oxyphenbutazoneb | 40 | 60 | 20 to >80 | 60 (40–90) |
| Isoniazidb | 4 | >4 | <0.03 to >4 | <0.03 (<0.03–0.06) |
Table 3.
PK properties of tested drugs
| Drug | Time versus concentration dependent | Serum peak | AUC | References |
|---|---|---|---|---|
| Trimethoprim/ sulfamethoxazole | both | 52 (free) and 68 (total) mg/L at steady-state for 160/800 mg twice-daily dosing | 471 mg·h/L steady-state to 800 mg daily dose | http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/17377slr057_Bactrim_lbl.pdf; Winter et al.69 |
| Mefloquine | concentration | 1.20–1.60 mg/L at steady-state for 250 mg weekly dosing | 645 mg·h/L (post-prandial) after single 750 mg dose | http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/019591s023lbl.pdf; Wernsdorfer et al.;20 Karbwang et al.;70 Crevoisier et al.71 |
| Amoxicillin/ clavulanate | time | 17.0 mg/L after single post-prandial dose of 2000 mg of AUGMENTIN XR | 71.6 mg·h/L after single post-prandial dose of 2000 mg of AUGMENTIN XR | http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/050785s007lbl.pdf |
| Clofazimine | concentration | 0.369 mg/L after single 200 mg dose administered with anti-TB medicines and a high-fat meal; 1.0 mg/L average serum concentration for 300 mg daily dosing | 3.690 mg·h/L after single 200 mg dose administered with anti-TB medicines and a high-fat meal | http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/19500slr010_lamprene_lbl.pdf; Nix et al.;28 Xu et al.;72 Steel et al.73 |
| Thioridazine | undetermined | 0.3718 mg/L after single 100 mg dose | 2.603 mg·h/L after single 100 mg dose | Chakraborty et al.74 |
| Nitazoxanide | both | tizoxanide: 10.6 mg/L; tizoxanide-gluconurate: 10.5 mg/L after single 500 mg dose and tizoxanide: 9.05 mg/L; tizoxanide-gluconurate: 12.2 mg/L after repeated doses of 500 mg twice daily | tizoxanide: 41.9 mg·h/L; tizoxanide-gluconurate: 63.0 mg·h/L after single 500 mg dose | http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021818lbl.pdf; Stockis et al.;54 Lam et al;55 Stockis et al.75 |
| Meropenem/ clavulanate | time | 112 mg/L after 1 g intravenous bolus administered over 5 min | 28.6 mg·h/L for 8 h | http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/050706s022lbl.pdf; Li et al.;76 Nicolau77 |
| Oxyphenbutazone | undetermined | |||
| Linezolid | time (concentration enhanced) | 21.2 mg/L with every 12 h dosing 600 mg | 138 mg·h/L with every 12 h dosing 600 mg | http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021130s032,021131s026,021132s031lbl.pdf |
| Drug | Time versus concentration dependent | Serum peak | AUC | References |
|---|---|---|---|---|
| Trimethoprim/ sulfamethoxazole | both | 52 (free) and 68 (total) mg/L at steady-state for 160/800 mg twice-daily dosing | 471 mg·h/L steady-state to 800 mg daily dose | http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/17377slr057_Bactrim_lbl.pdf; Winter et al.69 |
| Mefloquine | concentration | 1.20–1.60 mg/L at steady-state for 250 mg weekly dosing | 645 mg·h/L (post-prandial) after single 750 mg dose | http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/019591s023lbl.pdf; Wernsdorfer et al.;20 Karbwang et al.;70 Crevoisier et al.71 |
| Amoxicillin/ clavulanate | time | 17.0 mg/L after single post-prandial dose of 2000 mg of AUGMENTIN XR | 71.6 mg·h/L after single post-prandial dose of 2000 mg of AUGMENTIN XR | http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/050785s007lbl.pdf |
| Clofazimine | concentration | 0.369 mg/L after single 200 mg dose administered with anti-TB medicines and a high-fat meal; 1.0 mg/L average serum concentration for 300 mg daily dosing | 3.690 mg·h/L after single 200 mg dose administered with anti-TB medicines and a high-fat meal | http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/19500slr010_lamprene_lbl.pdf; Nix et al.;28 Xu et al.;72 Steel et al.73 |
| Thioridazine | undetermined | 0.3718 mg/L after single 100 mg dose | 2.603 mg·h/L after single 100 mg dose | Chakraborty et al.74 |
| Nitazoxanide | both | tizoxanide: 10.6 mg/L; tizoxanide-gluconurate: 10.5 mg/L after single 500 mg dose and tizoxanide: 9.05 mg/L; tizoxanide-gluconurate: 12.2 mg/L after repeated doses of 500 mg twice daily | tizoxanide: 41.9 mg·h/L; tizoxanide-gluconurate: 63.0 mg·h/L after single 500 mg dose | http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021818lbl.pdf; Stockis et al.;54 Lam et al;55 Stockis et al.75 |
| Meropenem/ clavulanate | time | 112 mg/L after 1 g intravenous bolus administered over 5 min | 28.6 mg·h/L for 8 h | http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/050706s022lbl.pdf; Li et al.;76 Nicolau77 |
| Oxyphenbutazone | undetermined | |||
| Linezolid | time (concentration enhanced) | 21.2 mg/L with every 12 h dosing 600 mg | 138 mg·h/L with every 12 h dosing 600 mg | http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021130s032,021131s026,021132s031lbl.pdf |
Table 3.
PK properties of tested drugs
| Drug | Time versus concentration dependent | Serum peak | AUC | References |
|---|---|---|---|---|
| Trimethoprim/ sulfamethoxazole | both | 52 (free) and 68 (total) mg/L at steady-state for 160/800 mg twice-daily dosing | 471 mg·h/L steady-state to 800 mg daily dose | http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/17377slr057_Bactrim_lbl.pdf; Winter et al.69 |
| Mefloquine | concentration | 1.20–1.60 mg/L at steady-state for 250 mg weekly dosing | 645 mg·h/L (post-prandial) after single 750 mg dose | http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/019591s023lbl.pdf; Wernsdorfer et al.;20 Karbwang et al.;70 Crevoisier et al.71 |
| Amoxicillin/ clavulanate | time | 17.0 mg/L after single post-prandial dose of 2000 mg of AUGMENTIN XR | 71.6 mg·h/L after single post-prandial dose of 2000 mg of AUGMENTIN XR | http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/050785s007lbl.pdf |
| Clofazimine | concentration | 0.369 mg/L after single 200 mg dose administered with anti-TB medicines and a high-fat meal; 1.0 mg/L average serum concentration for 300 mg daily dosing | 3.690 mg·h/L after single 200 mg dose administered with anti-TB medicines and a high-fat meal | http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/19500slr010_lamprene_lbl.pdf; Nix et al.;28 Xu et al.;72 Steel et al.73 |
| Thioridazine | undetermined | 0.3718 mg/L after single 100 mg dose | 2.603 mg·h/L after single 100 mg dose | Chakraborty et al.74 |
| Nitazoxanide | both | tizoxanide: 10.6 mg/L; tizoxanide-gluconurate: 10.5 mg/L after single 500 mg dose and tizoxanide: 9.05 mg/L; tizoxanide-gluconurate: 12.2 mg/L after repeated doses of 500 mg twice daily | tizoxanide: 41.9 mg·h/L; tizoxanide-gluconurate: 63.0 mg·h/L after single 500 mg dose | http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021818lbl.pdf; Stockis et al.;54 Lam et al;55 Stockis et al.75 |
| Meropenem/ clavulanate | time | 112 mg/L after 1 g intravenous bolus administered over 5 min | 28.6 mg·h/L for 8 h | http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/050706s022lbl.pdf; Li et al.;76 Nicolau77 |
| Oxyphenbutazone | undetermined | |||
| Linezolid | time (concentration enhanced) | 21.2 mg/L with every 12 h dosing 600 mg | 138 mg·h/L with every 12 h dosing 600 mg | http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021130s032,021131s026,021132s031lbl.pdf |
| Drug | Time versus concentration dependent | Serum peak | AUC | References |
|---|---|---|---|---|
| Trimethoprim/ sulfamethoxazole | both | 52 (free) and 68 (total) mg/L at steady-state for 160/800 mg twice-daily dosing | 471 mg·h/L steady-state to 800 mg daily dose | http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/17377slr057_Bactrim_lbl.pdf; Winter et al.69 |
| Mefloquine | concentration | 1.20–1.60 mg/L at steady-state for 250 mg weekly dosing | 645 mg·h/L (post-prandial) after single 750 mg dose | http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/019591s023lbl.pdf; Wernsdorfer et al.;20 Karbwang et al.;70 Crevoisier et al.71 |
| Amoxicillin/ clavulanate | time | 17.0 mg/L after single post-prandial dose of 2000 mg of AUGMENTIN XR | 71.6 mg·h/L after single post-prandial dose of 2000 mg of AUGMENTIN XR | http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/050785s007lbl.pdf |
| Clofazimine | concentration | 0.369 mg/L after single 200 mg dose administered with anti-TB medicines and a high-fat meal; 1.0 mg/L average serum concentration for 300 mg daily dosing | 3.690 mg·h/L after single 200 mg dose administered with anti-TB medicines and a high-fat meal | http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/19500slr010_lamprene_lbl.pdf; Nix et al.;28 Xu et al.;72 Steel et al.73 |
| Thioridazine | undetermined | 0.3718 mg/L after single 100 mg dose | 2.603 mg·h/L after single 100 mg dose | Chakraborty et al.74 |
| Nitazoxanide | both | tizoxanide: 10.6 mg/L; tizoxanide-gluconurate: 10.5 mg/L after single 500 mg dose and tizoxanide: 9.05 mg/L; tizoxanide-gluconurate: 12.2 mg/L after repeated doses of 500 mg twice daily | tizoxanide: 41.9 mg·h/L; tizoxanide-gluconurate: 63.0 mg·h/L after single 500 mg dose | http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021818lbl.pdf; Stockis et al.;54 Lam et al;55 Stockis et al.75 |
| Meropenem/ clavulanate | time | 112 mg/L after 1 g intravenous bolus administered over 5 min | 28.6 mg·h/L for 8 h | http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/050706s022lbl.pdf; Li et al.;76 Nicolau77 |
| Oxyphenbutazone | undetermined | |||
| Linezolid | time (concentration enhanced) | 21.2 mg/L with every 12 h dosing 600 mg | 138 mg·h/L with every 12 h dosing 600 mg | http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021130s032,021131s026,021132s031lbl.pdf |
