2Monitoring the response to MDR-TB treatment

Recommendation

The use of sputum smear microscopy and culture rather than sputum smear microscopy alone is recommended for the monitoring of patients with MDR-TB during treatment (conditional recommendation, ⊕○○○/very low quality evidence).

Evidence

The evidence used to assess how best to monitor treatment in MDR-TB patients using sputum smear microscopy and culture in settings with reliable direct microscopy was based on data pooled from 10 published observational studies (12–19). Monthly monitoring by culture was used as the reference in all the analyses. Random-effects Cox proportional hazards models were used to estimate the hazard ratio of failure, comparing monthly culture to alternative monitoring strategies.

Summary of findings

Performing monthly sputum smear microscopy and culture was the best strategy in identifying failures earlier. Sputum smear microscopy alone resulted in delayed detection of failure: when done at monthly rather than two monthly intervals it increased the detection of failure slightly (not significantly). In patients who were smear-negative at the start of treatment, monthly smear monitoring (compared with culture) resulted in a statistically significantly greater risk of delayed detection of failure compared with smear-positive patients. Stratified estimates by HIV serostatus, body mass index, and extent of disease on chest radiograph, were not significantly different (P>0.05).

The related end-points of drug resistance, initiation of appropriate treatment and the acquisition of resistance were not measured. There was no information about reversion or reinfection and no data were available to assess the quality of culture and smear testing. Other methods of evaluating response to treatment such as clinical indicators or chest radiography were not evaluated.

Benefits

Concomitant use of sputum smear microscopy and culture test results helps identify patients whose bacteriology remains positive or reverts to positive following initial conversion to negative. This is of use to clinicians in identifying patients likely to fail their treatment and instituting infection control measures in a timely manner. There was overall certainty about the risk of missing or delaying the detection of failure if smear alone was used instead of culture. Additional benefits would be expected from reduced transmission and development of resistance as well as appropriate changes to treatment regimens, but these were not explicitly addressed by the analysis.

Risks

Delayed detection of failure is expected to increase transmission and increase the probability of acquisition of resistance. Up to now, a minimum of monthly sputum smear microscopy and culture examination prior to culture conversion to negative² and quarterly culture with monthly smear examination after conversion has been recommended for the monitoring of patients on treatment for MDR-TB (3).

Even if monthly culture performed throughout treatment showed the highest benefit to detect failures, resource implications are important. Cost for sputum smear testing alone ranged between one-fourth to a half of the combined cost of culture and smear testing (based on information from nine studies reviewed for these guidelines) (20–26). It is likely that this difference may be higher where culture diagnosis is not readily available. More laboratory resources (staff, equipment, utilities) are required to perform culture, and fewer culture laboratories exist in the low-resource conditions of most high-burden countries. In settings where the risk of failure is low, selected patients can be prioritized for monthly culture.

The quality of culture performance differs importantly. False-positive cultures could lead to changes in regimen that may entail more potentially toxic medication. A false-negative culture result may influence a treatment decision based on clinical and direct microscopy findings.

Values and preferences

A high value was placed on outcomes such as preventing death, decreasing the transmission of MDR-TB that could result from its delayed diagnosis, and avoiding increased use of resources. The recommendation is conditional in part because of the resources required for implementing it.

As direct microscopy of sputum smear can identify the most infectious cases within a very short time, it has added value alongside culture for infection control purposes.

Footnotes

2

Defined as two consecutive sets of negative results of sputum smear microscopy and culture from samples collected at least 30 days apart.