Treatment of MDR-TB

The treatment and prognosis of MDR-TB are much more akin to that for cancer than to that for infection. It has a mortality rate of up to 80%, which depends on a number of factors, including

1. How many drugs the organism is resistant to (the fewer the better),
2. How many drugs the patient is given (Patients treated with five or more drugs do better),
3. Whether an injectable drug is given or not (it should be given for the first three months at least),
4. The expertise and experience of the physician responsible,
5. How co-operative the patient is with treatment (treatment is arduous and long, and requires persistence and determination on the part of the patient),
6. Whether the patient is HIV positive or not (HIV co-infection is associated with an increased mortality).

Treatment courses are generally measured in months to years; it may require surgery, though death rates remain high despite optimal treatment. That said, good outcomes are still possible.

The treatment of MDR-TB must be undertaken by a physician experienced in the treatment of MDR-TB. Mortality and morbidity in patients treated in non-specialist centres is significantly inferior to those patients treated in specialist centres.

In addition to the obvious risks (i.e., known exposure to a patient with MDR-TB), risk factors for MDR-TB include male sex, HIV infection, previous incarceration, failed TB treatment, failure to respond to standard TB treatment, and relapse following standard TB treatment.

Treatment of MDR-TB must be done on the basis of sensitivity testing: it is impossible to treat such patients without this information. If treating a patient with suspected MDR-TB, the patient should be started on SHREZ+MXF+cycloserine pending the result of laboratory sensitivity testing.

A gene probe for rpoB is available in some countries and this serves as a useful marker for MDR-TB, because isolated RMP resistance is rare (except when patients have a history of being treated with rifampicin alone). If the results of a gene probe (rpoB) are known to be positive, then it is reasonable to omit RMP and to use SHEZ+MXF+cycloserine. The reason for maintaining the patient on INH is that INH is so potent in treating TB that it is foolish to omit it until there is microbiological proof that it is ineffective (even though isoniazid resistance so commonly occurs with rifampicin resistance).

When sensitivities are known and the isolate is confirmed as resistant to both INH and RMP, five drugs should be chosen in the following order (based on known sensitivities):

• An aminoglycoside (e.g., amikacin, kanamicin) or polypeptide antibiotic (e.g., capreomycin)
• PZA
• EMB
• a fluoroquinolones: moxifloxacin is preferred to ciprofloxacin or ofloxacin;
• rifabutin
• cycloserine
• a thioamide: prothionamide or ethionamide
• PAS
• a macrolide: e.g., clarithromycin
• linezolid
• high-dose INH (if low-level resistance)
• interferon-γ
• thioridazine

Drugs are placed nearer the top of the list because they are more effective and less toxic; drugs are placed nearer the bottom of the list because they are less effective or more toxic, or more difficult to obtain.

Resistance to one drug within a class generally means resistance to all drugs within that class, but a notable exception is rifabutin: rifampicin-resistance does not always mean rifabutin-resistance and the laboratory should be asked to test for it. It is only possible to use one drug within each drug class. If it is difficult finding five drugs to treat then the clinician can request that high level INH-resistance be looked for. If the strain has only low level INH-resistance (resistance at 1.0mg/l INH, but sensitive at 0.2mg/l INH), then high dose INH can be used as part of the regimen. When counting drugs, PZA and interferon count as zero; that is to say, when adding PZA to a four drug regimen, you must still choose another drug to make five. It is not possible to use more than one injectable (STM, capreomycin or amikacin), because the toxic effect of these drugs is additive: if possible, the aminoglycoside should be given daily for a minimum of three months (and perhaps thrice weekly thereafter). Ciprofloxacin should not be used in the treatment of tuberculosis if other fluoroquinolones are available.

There is no intermittent regimen validated for use in MDR-TB, but clinical experience is that giving injectable drugs for five days a week (because there is no-one available to give the drug at weekends) does not seem to result in inferior results. Directly observed therapy certainly helps to improve outcomes in MDR-TB and should be considered an integral part of the treatment of MDR-TB.

Response to treatment must be obtained by repeated sputum cultures (monthly if possible). Treatment for MDR-TB must be given for a minimum of 18 months and cannot be stopped until the patient has been culture-negative for a minimum of nine months. It is not unusual for patients with MDR-TB to be on treatment for two years or more.

Patients with MDR-TB should be isolated in negative-pressure rooms, if possible. Patients with MDR-TB should not be accommodated on the same ward as immunosuppressed patients (HIV infected patients, or patients on immunosuppressive drugs). Careful monitoring of compliance with treatment is crucial to the management of MDR-TB (and some physicians insist on hospitalisation if only for this reason). Some physicians will insist that these patients are isolated until their sputum is smear negative, or even culture negative (which may take many months, or even years). Keeping these patients in hospital for weeks (or months) on end may be a practical or physical impossibility and the final decision depends on the clinical judgement of the physician treating that patient. The attending physician should make full use of therapeutic drug monitoring (particularly of the aminoglycosides) both to monitor compliance and to avoid toxic effects.

XDR-TB

Extensively drug-resistant tuberculosis

Extensively drug-resistant tuberculosis (XDR-TB) is defined as tuberculosis that has evolved resistance to rifampicin and isoniazid (resistance to these first line anti-TB drugs defines Multi-drug-resistant tuberculosis, or MDR-TB), as well as to any member of the quinolone family and at least one of the following second-line TB treatments: kanamycin, capreomycin, or amikacin. The old case definition of XDR-TB is MDR-TB that is also resistant to three or more of the six classes of second-line drugs. This definition should no longer be used, but is included here because many older publications refer to it.

The principles of treatment for MDR-TB and for XDR-TB are the same. The main difference is that XDR-TB is associated with a much higher mortality rate than MDR-TB, because of a reduced number of effective treatment options. The epidemiology of XDR-TB is currently not well studied, but it is believed that XDR-TB does not transmit easily in healthy populations, yet is capable of causing epidemics in populations which are already stricken by HIV and therefore more susceptible to TB infection.

Epidemiology of drug-resistant TB

A 1997 survey of 35 countries found mortality rate above 2% in about a third of the countries surveyed. The highest rates were in the former USSR, Argentina, India and China, and was associated with poor or failing national tuberculosis control programs. Likewise, the appearance of high rates of MDR-TB in New York city in the early 1990s was associated with the dismantling of public health programmes.

MDR-TB strains appear to be less fit and less transmissible. It has been known for many years that INH-resistant TB is less virulent in guinea pigs, and the epidemiological evidence is that MDR strains of TB do not dominate naturally. A study in Los Angeles found that only 6% of cases of MDR-TB were clustered. MDR-TB has a mortality rate comparable to lung cancer. People who have weakened immune systems (because of diseases such as HIV or because of drugs) are more susceptible to catching TB.

South African epidemic

Since late 2006, there has been an epidemic of XDR-TB in South Africa. The outbreak was first reported as a cluster of 53 patients in a rural hospital in Kwa Zulu-Natal of whom 52 died. What was particularly worrisome was that the median survival from sputum specimen collection to death was only 16 days and that the majority of patients had never previously received treatment for tuberculosis. This is the epidemic for which the acronym XDR-TB was first used, and although TB strains that fulfill the current definition have been identified retrospectively, this was the largest group of linked cases ever found. Since the initial report in September 2006, cases have now been reported in most provinces in South Africa. As of 16 March 2007, there were 314 cases reported, with 215 deaths. It is clear that the spread of this strain of TB is closely associated with a high prevalence of Aids and poor infection control; in other countries where XDR-TB strains have arisen, drug resistance has arisen from mismanagement of cases or poor patient compliance with drug treatment instead of being transmitted from person to person. This strain of TB does not respond to any of the drugs currently available in South Africa for first- or second-line treatment. It is now clear that the problem has been around for much longer than health department officials have suggested, and is far more extensive. By 23 November 2006, 303 cases of XDR-TB had been reported, of which 263 were in KwaZulu-Natal. Serious thought has been put to isolation procedures that may deny some patients their mobility. This has been seen as unconstitutional by the government and patients come and go as they see fit. The few that do get quarantined start riots and stone security guards. Quarantining patients is necessary to prevent further spread of this strain of TB.

Latent Tuberculosis

The treatment of latent tuberculosis infection (LTBI) is essential to controlling and eliminating TB by reducing the risk that TB infection will progress to disease.

The terms "preventive therapy" and "chemoprophylaxis" have been used for decades and are preferred in the UK because it involves giving medication to people who have no active disease and are currently well, the reason for treatment is primarily to prevent people from becoming unwell. The term "latent tuberculosis treatment" is preferred in the US because the medication does not actually prevent infection: it prevents an existing silent infection from becoming active. The feeling in the US is that the term "treatment of LTBI" promotes wider implementation by convincing people that they are receiving treatment for disease. There are no convincing reasons to prefer one term over the other.

It is essential that assessment to rule out active TB is carried out before treatment for LTBI is started. To give LTBI treatment to someone with active TB is a serious error: the TB will not be adequately treated and there is a risk of developing drug-resistant strains of TB.

There are several treatment regimens available:

• 9H—Isoniazid for 9 months is the gold standard and is 93% effective.
• 6H—Isoniazid for 6 months might be adopted by a local TB program based on cost-effectiveness and patient compliance. This is the regimen currently recommended in the UK for routine use. The US guidance exclude this regimen from use in children or persons with radiographic evidence of prior tuberculosis (old fibrotic lesions). (69% effective)
• 6 to 9H₂—A twice-weekly regimen for the above 2 treatment regimens is an alternative if administered under Directly observed therapy (DOT).
• 4R—Rifampicin for 4-months is an alternative for those who are unable to take isoniazid or who have had known exposure to isoniazid-resistant TB.
• 3HR—Isoniazid and rifampicin may be given for three months.

2RZ—The two month regimen of rifampicin and pyrazinamide is no longer recommended for treatment of LTBI because of the greatly increased risk of drug-induced hepatitis and death.

Faktor Kuman Tb

[sumber: Aditama TY, Soepandi PZ. Tuberkulosis: Diagnosis, Terapi dan Masalahnya. Edisi 3. Lab Mikobakteriologi RSUP Persahabatan/WHO Collaborating Center for Tuberculosis. Jakarta. 2000; p.14]

Mycobacterium tuberculosis
panjang : 1-4 mikron
lebar : 0,3-0,3 mikron
suhu optimal : 37C
pH optimal : 6,4 - 7,0
generation time: 14-20 jam (waktu membelah diri menjadi 2)
komposisi sel: terdiri dari lemak dan protein. 30% berat dinding kuman merupakan lemak, terdiri dari asam stearat, asam mikolik, mycosides, sulfolipid, dan cord factor. Komponen protein utama adalah tuberkuloprotein (tuberkulin)

Secera eksperimental, populasi M.tbc di dalam lesi dapat dikelompokkan menjadi 4 golongan yaitu:

• Populasi A : aktif berkembang biak dengan cepat, banyak terdapat pada dinding kavitas atau dalam lesi yang pH-nya netral.
  
• Populasi B : tumbuh sangat lambat, berada dalam lingkungan pH yang rendah. Lingkungan asam melindungi kuman dari obat anti-tuberkulosis tertentu.
  
• Populasi C : berada dalam keadaan dormant hampir sepanjang waktu, hanya kadang-kadang saja kuman ini mengadakan metabolisme secara aktif dalam waktu yan singkat, banyak terdapat dalam dinding kavitas.
• Populasi D : bersifat dormant sepenuhnya sehingga sama sekali tidak bisa dipengaruhi oleh obat-obat anti-tuberkulosis. Jumlah populasi ini tidak jelas dan hanya dapat dimusnahkan oleh mekanisme pertahanan tubuh manusia itu sendiri.
  

Lag phase:
Bila kuman tbc kontak dengan obat anti tbc, maka pertumbuhannya akan amat melemah dalam 2-3 hari dan kemudian aktif kembali. Masa 2-3 hari nini disebut lag phase.
Hal ini menjadi dasar pemberian obat secara intermittent dua atau tiga kali perminggu.

Mengapa harus multi-drug?
Dalam populasi kuman, sejak awal telah ada sebagian yang resisten terhadap satu jenis obat. Bila pada populasi itu hanya diberi satu jenis obat saja maka kuman yang sensitif akan turun jumlahnya dan yang resisten akan naik. Dalam beberapa waktu populasi kuman akan beruba menjadi kuman yang resisten seluruhnya.
Hal ini yang disebut dengan fall and rise phenomena, dan menjadi salah satu dasar mengapa kita harus memberikan beberapa obat sekaligus pada penderita tuberkulosis.

Dimulainya era baru..

Setelah melalui program magister, sekarang mulai kembali ke departemen, pelajaran sudah mulai menjurus, dan berbagi ilmu merupakan suatu keharusan. Semoga blog ini bisa memfasilitasi pembagian ilmu diantara kita.

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