Table 1.
Overview of low-level drug resistance mechanisms for key first and second-line TB drugs and their corresponding PK/PD targets for TDM and increased dosing strategies
| Drug | Range* | Mode of susceptible MIC distribution* | CC* | LLR mutation(s)† | Typical LLR MIC-range* | Standard dose?‡ | High dose‡ | Maximum dose§ | TDM? | Target AUC/MIC¶ |
|---|---|---|---|---|---|---|---|---|---|---|
| RIF | 0.016–0.25 | 0.06 | 0.5 | Borderline resistance mutations# | 0.125–4 | No | 20–35 mg/kg | 2,100 mg | Yes | >271 |
| INH | 0.016–0.125 | 0.06 | 0.1 | inhA (c-15t) | 0.25–1 | No | 10 mg/kg | 900 mg | Yes | >567 |
| LVX | 0.125–1 | 0.5 | 1 | gyrA A90V, S91P and D94A | 2–4 | No | 15–20 mg/kg | 1,500 mg | Yes | >146 |
| MFX | 0.064–0.25 | 0.125 | 0.25 | gyrA A90V, S91P and D94A | 0.125–2 | No | 10–15 mg/kg | 800 mg | Yes | >53 |
* All figures in mg/L tested using non-standardised protocols as reported in the literature.109,110 These values apply to MGIT and cannot necessarily be used for other growth media because systematic differences may exist compared with MGIT.114
† A higher dose should only be considered, if no additional mutations are present that may raise the MIC even further, thereby conferring high-level resistance (e.g., katG S315T in addition to inhA c-15t or gyrA D94G in addition to gyrA A90V).109,110,176,177 Therefore, the detection of high-level resistance mutations or MICs of >1 mg/L for MFX (i.e., the WHO clinical breakpoint) and, >1 mg/L for INH (CLSI currently recommends >0.4 mg/L) are exclusion criteria for the use of these agents, irrespective of the dose used.109,110,176
‡ When one of these low-level resistance mutations is present, the standard dose is insufficient and should not be used. The level of evidence for whether, and to what extent, low-level resistance can be overcome with a high dose is very low and largely based on expert opinion.178–180 The use of high-dose MFX has been endorsed by the WHO to overcome low-level resistance as part of the long individualised regimen by extrapolating data to high-dose GFX, which is being extrapolated further to high-dose LVX in this publication.110 Given these uncertainties, increased dosing for low-level resistant isolates should be avoided but may be critical where only less effective or more toxic drugs are available. If higher doses are used in this context, the cautious approach would be to use TDM to verify the drug exposure and not to consider the agent in question as a core drug of the regimen.
§ Drug safety at higher dosages is important, active monitoring and use of TDM can help to increase safety.
¶ The PK/PD targets were previously reported and are dependent on the precise MIC methodology used in the respective studies.104 Because of the systematic differences between some MIC methods, these targets cannot be used directly with other MIC methods.114 The PK/PD targets should be used in a multi-professional team experienced in TDM.
# L430P, D435Y, H445L/N/S, L452P, and I491F.109
PK = pharmacokinetics; PD = pharmacodynamics; TDM = therapeutic drug monitoring; CC = critical concentration; LLR = low-level resistance; MIC = minimum inhibitory concentration; AUC = area-under the concentration time curve; RIF = rifampicin; INH = isoniazid; LVX = levofloxacin; MFX = moxifloxacin; MGIT = Mycobacteria Growth Indicator Tube; CLSI = Clinical and Laboratory Standards Institute.