The standard regimen::Tuberculosis management


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The standard regimen

Rationale and evidence for the standard regimen

For treatment of lung tuberculosis, see main article pathophysiology

Tuberculosis has been treated with combination therapy for over fifty years. Drugs are not used singly (except in latent TB or chemoprophylaxis), and regimens that use only single drugs result in the rapid development of resistance and treatment failure.<ref name="MRC1948">{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref><ref name="Wang2006">{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref> The rationale for using multiple drugs to treat TB are based on simple probability. The frequency of spontaneous mutations that confer resistance to an individual drug are well known: 1 in 107 for EMB, 1 in 108 for STM and INH, and 1 in 1010 for RMP.<ref name="David1970">{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref>

Patients with extensive pulmonary TB have approximately 1012 bacteria in their body, and therefore will probably be harboring approximately 105 EMB-resistant bacteria, 104 STM-resistant bacteria, 104 INH-resistant bacteria and 10² RMP-resistant bacteria. Resistance mutations appear spontaneously and independently, so the chances of them harbouring a bacterium that is spontaneously resistant to both INH and RMP is 1 in 108 x 1 in 1010 = 1 in 1018, and the chances of them harbouring a bacterium that is spontaneously resistant to all four drugs is 1 in 1033. This is, of course, an oversimplification, but it is a useful way of explaining combination therapy.

There are other theoretical reasons for supporting combination therapy. The different drugs in the regimen have different modes of action. INH are bacteriocidal against replicating bacteria. EMB is bacteriostatic at low doses, but is used in TB treatment at higher, bactericidal doses. RMP is bacteriocidal and has a sterilizing effect. PZA is only weakly bactericidal, but is very effective against bacteria located in acidic environments, inside macrophages, or in areas of acute inflammation.

All TB regimens in use were 18 months or longer until the appearance of rifampicin. In 1953, the standard UK regimen was 3SPH/15PH or 3SPH/15SH2. Between 1965 and 1970, EMB replaced PAS. RMP began to be used to treat TB in 1968 and the BTS study in the 1970s showed that 2HRE/7HR was efficacious. In 1984, a BTS study showed that 2HRZ/4HR was efficacious,<ref name="BTS1984">{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref> with a relapse rate of less than 3% after two years.<ref name="Ormerod1987">{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref> In 1995, with the recognition that INH resistance was increasing, the British Thoracic Society recommended adding EMB or STM to the regimen: 2HREZ/4HR or 2SHRZ/4HR,<ref>{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref> which are the regimens currently recommended. The WHO also recommend a six-month continuation phase of HR if the patient is still culture positive after 2 months of treatment (approximately 15% of patients with fully sensitive TB) and for those patients who have extensive bilateral cavitation at the start of treatment.

Monitoring, DOTS, and DOTS-Plus

DOTS stands for "Directly Observed Treatment, Short-course" and is a major plank in the WHO Global Plan to Stop TB. The DOTS strategy focuses on five main points of action. These include government commitment to control TB, diagnosis based on sputum-smear microscopy tests done on patients who actively report TB symptoms, direct observation short-course chemotherapy treatments, a definite supply of drugs, and standardized reporting and recording of cases and treatment outcomes.<ref name="Elzinga2004">{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref> The WHO advises that all TB patients should have at least the first two months of their therapy observed (and preferably the whole of it observed): this means an independent observer watching patients swallow their anti-TB therapy. The independent observer is often not a healthcare worker and may be a shopkeeper or a tribal elder or similar senior person within that society. DOTS is used with intermittent dosing (thrice weekly or 2HREZ/4HR3). Twice weekly dosing is effective<ref>{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref> but not recommended by the WHO, because there is no margin for error (accidentally omitting one dose per week results in once weekly dosing, which is ineffective).

Treatment with properly implemented DOTS has a success rate exceeding 95% and prevents the emergence of further multi-drug resistant strains of tuberculosis. Administering DOTS, decreases the possibilities of tuberculosis from recurring, resulting in a reduction in unsuccessful treatments. This is in part due to the fact that areas without the DOTS strategy generally provide lower standards of care.<ref name="Elzinga2004"/> Areas with DOTS administration help lower the number of patients seeking help from other facilities where they are treated with unknown treatments resulting in unknown outcomes.<ref name="Dye2003">{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref> However if the DOTS program is not implemented or done so incorrectly positive results will be unlikely. In order for the program to work efficiently and accurately health providers must be fully engaged,<ref name="Elzinga2004"/> links must be built between public and private practitioners, health services must be available to all,<ref name="Dye2003" /> and global support is provided to countries trying to reach their TB prevention, and treatment aims.<ref>{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref> Some researchers suggest that, because the DOTS framework has been so successful in the treatment of tuberculosis in sub-Saharan Africa, DOTS should be expanded to non-communicable diseases such as diabetes mellitus, hypertension, and epilepsy.<ref name="pmid18547138">{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref>

The WHO extended the DOTS programme in 1998 to include the treatment of MDR-TB (called "DOTS-Plus").<ref>{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref> Implementation of DOTS-Plus requires the capacity to perform drug-susceptibility testing (not routinely available even in developed countries) and the availability of second-line agents, in addition to all the requirements for DOTS. DOTS-Plus is therefore much more resource-expensive than DOTS, and requires much greater commitment from countries wishing to implement it. Resource limitations mean that the implementation of DOTS-Plus may lead inadvertently to the diversion of resources from existing DOTS programmes and a consequent decrease in the overall standard of care.<ref>{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref>

Monthly surveillance until cultures convert to negative is recommended for DOTS-Plus, but not for DOTS. If cultures are positive or symptoms do not resolve after three months of treatment, it is necessary to re-evaluate the patient for drug-resistant disease or nonadherence to drug regimen. If cultures do not convert to negative despite three months of therapy, some physicians may consider admitting the patient to hospital so as to closely monitor therapy.

Extra-pulmonary tuberculosis

Tuberculosis not affecting the lungs is called extra-pulmonary tuberculosis. Disease of the central nervous system is specifically excluded from this classification.

The UK and WHO recommendation is 2HREZ/4HR; the US recommendation is 2HREZ/7HR. There is good evidence from randomised-controlled trials to say that in tuberculous lymphadenitis<ref>{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref> and in TB of the spine,<ref>{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref><ref>{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref><ref>{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref> the six-month regimen is equivalent to the nine-month regimen; the US recommendation is therefore not supported by the evidence.

Up to 25% of patients with TB of the lymph nodes (TB lymphadenitis) will get worse on treatment before they get better and this usually happens in the first few months of treatment.{{ safesubst:#invoke:Unsubst||date=__DATE__ |$B= {{#invoke:Category handler|main}}{{#invoke:Category handler|main}}[citation needed] }} A few weeks after starting treatment, lymph nodes often start to enlarge, and previously solid lymph nodes may soften and develop into tuberculous cervical lymphadenitis. This should not be interpreted as failure of therapy and is a common reason for patients (and their physicians) to panic unnecessarily. With patience, two to three months into treatment the lymph nodes start to shrink again and re-aspiration or re-biopsy of the lymph nodes is unnecessary: if repeat microbiological studies are ordered, they will show the continued presence of viable bacteria with the same sensitivity pattern, which further adds to the confusion: physicians inexperienced in the treatment of TB will then often add second-line drugs in the belief that the treatment is not working. In these situations, all that is required is re-assurance. Steroids may be useful in resolving the swelling, especially if it is painful, but they are unnecessary. Additional antibiotics are unnecessary and the treatment regimen does not need to be lengthened.{{ safesubst:#invoke:Unsubst||date=__DATE__ |$B= {{#invoke:Category handler|main}}{{#invoke:Category handler|main}}[citation needed] }}

Tuberculosis of the central nervous system

Tuberculosis may affect the central nervous system (meninges, brain or spinal cord) in which case it is called TB meningitis, TB cerebritis, and TB myelitis respectively; the standard treatment is 12 months of drugs (2HREZ/10HR) and steroid are mandatory.

Diagnosis is difficult as CSF culture is positive in less than half of cases, and therefore a large proportion of cases are treated on the basis of clinical suspicion alone. PCR of CSF does not significantly improve the microbiology yield; culture remains the most sensitive method and a minimum of 5 ml (preferably 20 ml) of CSF should be sent for analysis. TB cerebritis (or TB of the brain) may require brain biopsy in order to make the diagnosis, because the CSF is commonly normal: this is not always available and even when it is, some clinicians would debate whether it is justified putting a patient through such an invasive and potentially dangerous procedure when a trial of anti-TB therapy may yield the same answer; probably the only justification for brain biopsy is when drug-resistant TB is suspected.

It is possible that shorter durations of therapy (e.g., six months) may be sufficient to treat TB meningitis, but no clinical trial has addressed this issue. The CSF of patients with treated TB meningitis is commonly abnormal even at 12 months;<ref name="Kent1993">{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref> the rate of resolution of the abnormality bears no correlation with clinical progress or outcome,<ref name="Teoh1986">{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref> and is not an indication for extending or repeating treatment; repeated sampling of CSF by lumbar puncture to monitor treatment progress should therefore not be done.

Although TB meningitis and TB cerebritis are classified together, the experience of many clinicians is that their progression and response to treatment is not the same. TB meningitis usually responds well to treatment, but TB cerebritis may require prolonged treatment (up to two years) and the steroid course needed is often also prolonged (up to six months). Unlike TB meningitis, TB cerebritis often required repeated CT or MRI imaging of the brain to monitor progress.

CNS TB may be secondary to blood-borne spread: therefore some experts advocate the routine sampling of CSF in patients with miliary TB.<ref name="Chang1998">{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref>

The anti-TB drugs that are most useful for the treatment of CNS TB are:

  • INH (CSF penetration 100%)
  • RMP (10–20%)
  • EMB (25–50% inflamed meninges only)
  • PZA (100%)
  • STM (20% inflamed meninges only)
  • LZD (20%)
  • Cycloserine (80–100%)
  • Ethionamide (100%)
  • PAS (10–50%) (inflamed meninges only)

The use of steroids is routine in TB meningitis (see section below). There is evidence from one poorly designed trial that aspirin may be beneficial,<ref>{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref> but further work is required before this can be recommended routinely.<ref>{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref>


The usefulness of corticosteroids (e.g., prednisolone or dexamethasone) in the treatment of TB is proven for TB meningitis and TB pericarditis. The dose for TB meningitis is dexamethasone 8 to 12 mg daily tapered off over six weeks (for those who prefer more precise dosing should refer to Thwaites et al., 2004<ref name="Thwaites2004">{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref>). The dose for pericarditis is prednisolone 60 mg daily tapered off over four to eight weeks.

Steroids may be of temporary benefit in pleurisy, extremely advanced TB, and TB in children:

  • Pleurisy: prednisolone 20 to 40 mg daily tapered off over 4 to 8 weeks
  • Extremely advanced TB: 40 to 60 mg daily tapered off over 4 to 8 weeks
  • TB in children: 2 to 5 mg/kg/day for one week, 1 mg/kg/day the next week, then tapered off over 5 weeks

Steroids may be of benefit in peritonitis, miliary disease, tubercular osteomyelitis, TB osteomyelitis, laryngeal TB, lymphadenitis and genitourinary disease, but the evidence is scant and the routine use of steroids cannot be recommended. Steroid treatment in these patients should be considered on a case by case basis by the attending physician.<ref name="Ordonez2014">{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref>

Thalidomide may be of benefit in TB meningitis and has been used in cases where patients have failed to respond to steroid treatment.<ref name="Roberts2003">{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref>

Tuberculosis management sections
Intro  Drugs  The standard regimen  Non-compliance  Adverse effects  Deviations from the standard regimen  Tuberculosis and other conditions  Drug-resistant tuberculosis  Treatment failure  Treatment relapse  Society and culture  Trial of therapy  Surgical treatment  Nutrition  Latent tuberculosis  Current research  See also  National and international guidelines   Bibliography   

The standard regimen
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