It’s Time for a world without DRUG RESISTANT TB: Dr Srikant Sharma

On the eve of World TB Day on 24 March 2019, it is desired that we should take a resolve to the continuation of the joint efforts to keep elimination of TB high on the global and national agenda.

It’s Time...

• ...to keep the promises made at the UN High-Level Meeting on TB


• ...for a world without TB


• ...to treat 40 million people affected by TB by 2022


• ...to know your TB status

...and many more!

Certain facts worth remembering about tuberculosis are -

• Tuberculosis (TB) is a leading cause of morbidity and mortality worldwide.


• Globally in 2016, the World Health Organisation (WHO) estimated that 4.1% of new cases and 19% of previously treated cases of TB were of MDR/RR-TB.


• There were an estimated 600,000 incident cases of MDR/RR-TB.
  Cases of MDR-TB (490,000) accounted for 82% of the total.


• The countries with the largest number of MDR/RR-TB cases (47% of the total) are China, India and the Russian Federation.


• There were an estimated 240,000 deaths from MDR/RR-TB in 2016.


• There are two ways that people get drug-resistant TB.


• Firstly, people get acquired drug-resistant TB when their TB treatment is inadequate. This can be for a number of reasons, including the fact that patients fail to keep to proper TB treatment regimes.


• It can also be that the wrong TB drugs are prescribed, or substandard TB drugs are used for treatment.


• Secondly, transmitted or primary drug-resistant TB results from the direct transmission of drug-resistant TB from one person to another.

Predictors of drug-resistant TB

• A previous episode of TB treatment.


• Persistent or progressive clinical and/or radiographic findings while on TB therapy.


• Residence in or travel to a region with high prevalence of drug-resistant TB.•


• Exposure to an individual with known or suspected infectious drug-resistant TB.

Types of drug-resistant TB

• The term "drug-resistant TB" refers to TB caused by an isolate of Mycobacterium tuberculosis that is resistant to one or more antituberculous drugs.


• The term "monoresistant TB" refers to TB caused by an isolate of M. tuberculosis that is resistant to a single antituberculous agent.


• The term "poly-resistant TB" refers to TB caused by an isolate of M. tuberculosis that is resistant to more than one antituberculous agent; the isolate may be resistant to either isoniazid or rifampin but not both.


• The term "multidrug-resistant TB" (MDR-TB) refers to TB caused by an isolate of M. tuberculosis that is resistant to both isoniazid and rifampin and possibly additional agents.


• The term "pre-extensively drug-resistant TB" (pre-XDR-TB) refers to an isolate of M. tuberculosis that is resistant to isoniazid and rifampin and either quinolones or all injectable agents (streptomycin, amikacin, kanamycin, or capreomycin).


• The term "extensively drug-resistant TB" (XDR-TB) refers to TB caused by an isolate of M. tuberculosis that is resistant to at least isoniazid, rifampin, and fluoroquinolones as well as either aminoglycosides (amikacin, kanamycin) or capreomycin or both.


• The term "totally drug-resistant TB" (TDR-TB) refers to an isolate of M. tuberculosis resistant to all locally tested medications. However, the published studies initially describing TDR-TB did not include susceptibility testing for less frequently used agents with activity against TB (including cycloserine, terizidone, clofazimine, linezolid, or carbapenems) or more recently introduced agents (including bedaquiline and delamanid).


• Primary drug resistance refers to infection caused by a drug-resistant strain of M. tuberculosis contracted in the absence of previous antituberculous therapy.


• Secondary drug resistance refers to the development of drug resistance during or following antituberculous therapy in patients who previously had drug-susceptible TB and have not been re-infected by a different drug-resistant organism.

Categories of drugs

• First-line drugs –


• First-line drugs include:


• isoniazid,


• rifampin,


• pyrazinamide, and


• ethambutol


• These drugs that constitute the initial empiric treatment regimen for presumed drug-susceptible TB where background drug resistance is <4 percent.


• Second-line drugs – Second-line drugs are drugs added to or substituted for first-line drugs when drug resistance is encountered (or suspected), or in cases of drug intolerance or toxicity.


• Injectable agents are no longer among the priority medicines to be used when designing longer MDR-TB regimens and WHO recommends that oral regimens should become the preferred option for most patients.

Fluoroquinolones (levofloxacin or moxifloxacin), bedaquiline and linezolid are strongly recommended for use in longer regimens, which are completed with other drugs ranked by their relative balance of effectiveness to potential toxicity.

As per 2016 guidelines
Group A:(FQ) Levofloxacin (Lfx), Gatifloxacin (Gfx) Moxifloxacin (Mfx ).

Group B: (injectables): Kanamycin, Amikacin (Am), Capreomycin (Cm), Streptomycin.

Group C: Ethionamide/Prothionamide (Eto/Pto), Cycloserine / Terizidone (Cs Trd), Clofazimine (Cfz), Linezolid (Lzd).

Group D1: Pyrazinamide, Ethambutol (E), High-dose isoniazid (Hh ).
D2: Bedaquiline (Bdq), Delamanid (Dlm)
D3: p-aminosalicylic acid (PAS), imipenem-cilastatin (lpm), Meropenem (Mpm), Amoxicillin-clavulanate (Amx-Clv), Thioacetazone (T).

As per 2018 guidelines

• Group A includes: Levofloxacin (Lfx) or Moxifloxacin (Mfx), Bedaquiline (Bdq), and Linezolid (Lzd). All three medicines in Group A should be included.
• Group B includes: Clofazimine (Cfz), Cycloserine (Cs) or Terizidone (Trd). In group B one or both medicines should be included.
• Group C includes: Ethambutol (E), Delamanid (Dlm), Pyrazinamide (Z), Imipenem-cilastatin (Ipm-Cln) or Meropenem (Mpm), Amikacin (Am) or (Streptomycin), Ethionamide (Eto) or Prothionamide (Pto), p-aminosalicylic acid (PAS). Group C medicines should be included to complete the regimen when medicines from Groups A and B cannot be used.

TREATMENT OF MONORESISTANT TB

• The clinical approach to treatment of mono resistant TB varies depending on the agent to which the isolate is resistant.

• Isoniazid mono resistance:

• Option 1: Daily rifampin, ethambutol, and pyrazinamide (with or without a fluoroquinolone) for six to nine months (or four months after culture conversion).


• Option 2: If the patient does not tolerate pyrazinamide, a regimen consisting of rifampin, ethambutol, and a fluoroquinolone for 9 to 12 months may be used; fluoroquinolone susceptibility should be confirmed.

• For treatment of patients for whom drug susceptibility testing is not available but who are known to reside in a region with a background level of INH resistance >7 percent, an acceptable approach consists of a standard intensive phase (eg, INH, rifampin, pyrazinamide, and ethambutol), followed by continuation phase consisting of INH and rifampin with addition of ethambutol (rather than INH and rifampin alone).


• Effective therapy for INH-monoresistant TB is associated with very high bacteriologic and clinical response rates (>95 percent) and low relapse rates (<5 percent).


• Rifampin – Same as MDR-TB.


• Pyrazinamide – Patients with pyrazinamide monoresistance should be treated with INH and rifampin for nine months. This combination has a success rate >96 percent in large trials.


• Other agents – Monoresistance to ethambutol, streptomycin, or second-line agents is of little clinical significance; patients with disease caused by these isolates may be treated as for drug-susceptible TB (intensive phase: INH, rifampin, pyrazinamide, and ethambutol [if not resistant] for two months; followed by continuation phase: INH and rifampin for four months).

EMPIRIC TREATMENT

• Patients with treatment failure (AFB sputum culture positive after four months of therapy).


• Patients with relapse (recurrent TB after prior completion of treatment with apparent cure).


• Patients with exposure to an individual with drug-resistant TB.


• Patients with residence in or travel to a region with high prevalence of drug-resistant TB.

It may be reasonable to defer treatment until drug susceptibility results are available for patients who are not severely ill and can be isolated.

Treatment of MDR-TB

• The approach to treatment of MDR-TB depends on results of drug susceptibility testing (DST) and availability of anti tuberculous agents.


• If MDR-TB is documented, drugs to which the isolate is resistant should be discontinued, and new drugs should be added such that at least four drugs active against the isolate are included in the regimen.


• Selecting a regimen:


• Options for treatment of MDR-TB include a longer regimen (total duration of therapy generally 18 to 20 months) or, for selected patients, a shorter regimen (total duration of therapy 9 to 12 months).


• In general, use of the longer regimen is favored.


• Longer regimen is definitely given in:


• Disseminated, meningeal, or central nervous system disease


• In patients with HIV infection


• Presence of any extra pulmonary disease.


• Pregnancy.


• The longer, individualized regimen (total duration 18 to 20 months) for treatment of MDR-TB consists of an intensive phase (administration of at least four effective drugs) for at least 6 months after sputum culture conversion, followed by a continuation phase (administration of at least three effective drugs) for 15 to 17 months beyond sputum culture conversion.


• Repeat sputum should be obtained for acid-fast bacillin (AFB) microscopy and culture two months after initiation of therapy.


• If culture positive, the sputum evaluation should be repeated monthly until negative, and the duration of the intensive phase should continue until at least six months after sputum culture conversion.


• A positive sputum culture ≥3 months after initiation of treatment should prompt a search for an explanation (eg, non-adherance to treatment, inappropriate/incorrect medications, mal-absorption or suboptimal pharmacokinetics, or emergence of resistance).


• During treatment, sputum should be obtained for AFB smear and culture and drug susceptibility testing at monthly intervals until two consecutive cultures are negative.


• Following two successive months of negative sputum cultures, repeat culture and drug susceptibility testing are usually reserved only for persistent or worsening symptoms despite adequate adherence to therapy.


• An empiric longer regimen consists of the following:


• An intensive phase: Administration of at least four drugs, given for six months following sputum culture conversion:


• It includes use of a fluoroquinolone (levofloxacin or moxifloxacin), bedaquiline, and linezolid.


• If bedaquiline is not available, an injectable agent (amikacin or streptomycin) should be used.


• A continuation phase: Administration of the drugs used during the intensive phase (excluding bedaquiline or injectable agent), given for 15 to 17 months beyond sputum culture conversion. Patients with extensive disease or cavitary disease may warrant a longer duration and/or use of an additional oral second-line drug.


• Prior WHO guidelines (2016) favored use of five drugs in the intensive phase; this practice was modified in the WHO 2018 guidelines given increased availability of newer agents (bedaquiline and delamanid) and reduced cost of moxifloxacin and linezolid.


• The shortened regimen consists of the following components:


• Intensive phase – Four months (daily) of seven drugs: high- dose isoniazid (15 to 20 mg/kg/day), ethambutol, pyrazinamide, moxifloxacin, kanamycin, prothionamide, and clofazimine. The duration of the intensive phase is extended to six months for patients with positive sputum AFB microscopy and culture performed two months after initiation of therapy.


• Continuation phase – Five months (daily) of four drugs: ethambutol, pyrazinamide, moxifloxacin, and clofazimine.

Outcomes

• Treatment success rates for MDR-TB range from 30 to 80 percent; factors associated with treatment success in previous studies include:


• Duration of therapy at least 18 months


• Directly observed therapy throughout treatment


• Surgical resection


• Fluoroquinolone use


• No previous treatment.


• Factors associated with unfavorable outcomes include:


• Male gender


• Alcohol abuse


• Lack of weight gain


• Smear positivity at diagnosis


• Fluoroquinolone resistance


• Late appearance for care


• HIV co-infection

TREATMENT OF EXTENSIVELY DRUG-RESISTANT TB

• An intensive phase – Administration of at least five drugs, comprised of susceptible first-line drugs if any (pyrazinamide and/or ethambutol), a luoroquinolone (preferably higher-dose moxifloxacin or levofloxacin, bedaquiline, linezolid, and additional oral agents (clofazimine, cycloserine, or terizidone) as needed.


• If needed, other agents (ethionamide, para-aminosalicylic cacid, high-dose isoniazid, delamanid, a carbapenem [meropenem or imipenem] plus clavulanate) may be added. An injectable agent (such as capreomycin, which can retain susceptibility against some amikacin and kanamycin resistant strains) may be considered if susceptibility is confirmed and not enough oral drugs are available or susceptible to create the regimen.


• The intensive phase regimen should be given for at least six months beyond sputum culture conversion (performed after two months of treatment).


• A continuation phase – Administration of the drugs used uring the intensive phase (with the exception of bedaquiline or the injectable agent), to complete a total of 18 to 24 months (depending on the time of culture conversion). Patients with extensive disease or cavitary disease may warrant a longer duration of therapy.


• Outcomes — The overall prognosis for adults with XDR-TB is poor with high mortality; delays in diagnosis, malnutrition, and level of immunosuppression contribute to an increased risk of death.

ROLE OF SURGERY FOR PULMONARY MDR- OR XDR-TB

• In general, surgery for treatment of TB is most effective for patients with poor clinical response or intolerance to supervised medical therapy who have a pulmonary disease that is amenable to complete resection (lobectomy, wedge resection, or pneumonectomy) and adequate pulmonary reserve.


• It is considered for:


• Persistently positive sputum cultures beyond four to six months of antituberculous therapy.


• Presence of extensive drug resistance that is unlikely to be cured with antituberculous therapy alone.


• Presence of complications such as massive hemoptysis or persistent bronchopleural fistula.


• In general, surgery should be performed only after several months of antituberculous therapy have been administered, after smear conversion (if possible), and ideally after culture conversion.


• A full course of antituberculous therapy should be administered following surgical resection.

The author is Dr Srikant Sharma is a Senior Consultant Physician at Moolchand Hospital, New Delhi.Dr.Karishma Walia of Moolchand Hospital, New Delhi has co-authored the article.