Multi-drug-resistant tuberculosis overview

# Overview
Multi-drug resistant tuberculosis (MDR-TB) is defined as TB that is resistant at least to isoniazid (INH) and rifampicin (RMP).  Isolates that are resistant to any other combination of anti-TB drugs but not to INH and RMP are not classed as MDR-TB.

# Historical Perspective
Mycobacterium tuberculosis was first described by Robert Koch in 1882 and in 1970 drug-resistant tuberculosis was first reported. Since then, several drugs and strategies have been implemented to control the disease. Cases in the US have decreased, however worldwide MDR-TB diagnosis is increasing, specially in developing countries.

# Classification
Classification of drug resistant tuberculosis is based on drug susceptibility , pathophysiology, clinical classification and molecular classification. According to drug susceptibility it is classified as monoresistance, poly resistance, multidrug resistance, extensive drug resistance and rifampicin resistance. Clinically it is classified as acquired and primary resistance. The restriction fragment length polymorphism helps for molecular classification into unique and cluster type.

# Pathophysiology
Tuberculosis is a granulomatous infection tansmitted mainly through droplets and can have pulmonary and extra pulmonary manifestations. Multi drug resistant strains of tuberculosis have been emerging at an alarming rate and they might be developed due to primary resistance or acquired resistance. These type of resistance are mainly through genetic mutations in genes like inhA, katG and rpob genes. These molecular pathophysiology can be detected through pyrosequencing, DNA sequencing and electrophoresis.

# Causes
Mycobacterium tuberculosis is the bacterium responsible for tuberculosis. It is an aerobic, non-encapsulated, non-motile, acid-fast bacillus.  M. tuberculosis belongs to the Mycobacterium tuberculosis complex, that also includes bacteria, such as M. bovis and M. africanum.  The bacterium has a very slow rate of replication, and its genetic variations account for the geographical distribution of different strains, and are involved in drug resistance.  M. tuberculosis has tropism for different kinds of human cells, with preference for cells of the lung.  It may infect different species, yet human beings are its frequent natural reservoir.

# Differential Diagnosis
Pulmonary tuberculosis must be differentiated from other diseases that cause cough, fever, night sweats, hemoptysis and weight loss, such as: brucellosis, bronchogenic carcinoma, Hodgkin lymphoma, bacterial pneumonia, sarcoidosis, mycoplasmal pneumonia.

# Epidemiology and Demographics

# Risk Factors
Risk factors for multi-drug resistant tuberculosis include exposure to an individual with MDR-TB, previous TB treatment, HIV infection, and a low socioeconomic status.

# Screening
Screening for tuberculosis is generally done with using a mantoux tuberculin skin test, also known as a tuberculin skin test or a PPD. The test involves injecting a small amount of a purified protein derivative of the tuberculosis bacterium intradermally, and watching for a reaction in the following days.

# Natural history, complications and prognosis
Tuberculosis has been classified as primary and post primary infection. It can have pulmonary and extra pulmonary manifestations as well as severe parenchymal, vascular, pleural and chest wall complications. The post primary infection can be due to a recent infection or reactivation of an old infection.  Further multi drug resistant strains can develop through acquired resistance through inadequate treatment / treatment failure as well as slow gradual genetic mutation resulting in primary resistance. These are transmitted to healthy people resulting in emerging multi drug resistant strains. They can be rifampicin resistant, multi drug resistant, extensively drug resistant and totally drug resistant. The more the number of drugs the strain is resistant to , the poorer is the prognosis.

# Diagnosis

## History and Symptoms
The general symptoms of MDR-TB will be the same as drug suceptible tuberculosis, these include weakness, weight loss, fever, and night sweats.  Symptoms of pulmonary tuberculosis include cough, chest pain, and hemoptysis.  Tuberculosis is particularly difficult to diagnose in children, as these may not present with common findings.

## Physical Examination
A physical examination can provide valuable information about the patients overall condition and other factors that may affect how tuberculosis is treated, such as HIV infection or other illnesses. The most common physical findings include fever, decreased breath sounds, tachypnea and tachycardia.  Physical findings will depend on the location of the tuberculosis infection.

## Laboratory findings
Routine laboratory exams are usually in the normal ranges. The presence of acid-fast-bacilli (AFB) on a sputum smear or other specimen often indicates TB disease and a positive culture for M. tuberculosis confirms the diagnosis.  Other laboratory test include peritoneal fluid or CSF analysis, urinalysis, and Interferon-Gamma release assays.  The Xpert MTB/RIF test is a molecular test that detects the DNA of the M. tuberculosis and resistance to rifampin. The use of this test has increased in the past years.

## Chest X-Ray
An X-ray is a very important diagnostic tool in pulmonary tuberculosis. Chest X-ray findings include parenchymal infiltrates, hiliar adenopathy, cavitation, nodules and pleural effusion.  The most common location of a pulmonary tuberculosis lesion is the upper lobes.

## CT
The majority of patients with pulmonary tuberculosis will have abnormal findings in a chest CT, which include micronodules, interlobular septal thickening, cavitation and consolidation.  CT scan is more sensitive than an X-ray to detect lymphadenopathies.

## MRI
MRI is used for the assessment of extrapulmonary tuberculosis, such as CNS tuberculosis, osteoarticular tuberculosis, Pott's disease, and parotid gland tuberculosis.

## Other Imaging findings
The abreugraphy is a smaller variant of the chest X-ray that allows the identification of lung abnormalities that may suggest the diagnosis of TB.  With the decrease of incidence of TB, the abreugraphy is no longer recommended in most countries for low risk populations.  However, depending on the screening resources of each country, it may be used for the screening of high-risk groups, such as HIV-positive patients and alcoholics.

## Other Diagnostic Studies
Other diagnostic studies that could be performed in a patient with tuberculosis are the adenosine deaminase test and Nucleic Acid Amplification Test(NAAT).

# Treatment

## Medical Therapy
Medical therapy for MDR-TB is based on the combination at least 4 drugs, one drug from each of the drug groups for TB.  The duration of the treatment should be at least 18 months, depending on the culture results and clinical improvement.

## Surgery

## Primary Prevention
Primary prevention of tuberculosis is targeted to avoid the disease transmission and infection of healthy individuals. The BCG vaccines is used in children susceptible to TB infection. Infection control measures for multi drug resistant tuberculosis include prompt diagnosis and treatment, isolation of patients already infected with Mycobacterium tuberculosis , early diagnosis and treatment of HIV infected tuberculosis. Primary prevention also includes enviornmental control measures like improving ventilation and use of personal respiratory protection like respiratory masks.

## Secondary Prevention
Secondary prevention for tuberculosis includes methods for screening and early diagnosis, such as tuberculin skin test (TST) and IGRAs; and to guarantee the correct treatment regimen at the right time to prevent disease progression.

## Cost effectiveness of therapy
Treatment of tuberculosis must be analysed for relative cost effectiveness of inpatient and outpatient models of care as it will benefit regions where tuberculosis is highly prevalent. Unless there is severe complications it is highly recommended to treat the TB patient in ambulatory care rather than inpatient services.

## Future or investigational therapy
Since new drug resistant tuberculosis have been emerging, the role of future therapies is vital in curbing outbreaks. The new drugs should be more effective than the current regimen and a few drugs in clinical trials have been showing good results.