How does AMR affect TB, HIV and gonorrhoea?
Matthew is Professor of Public Health and Adjunct Professor of Medicine at Drexel University, in Philadelphia. He is also Associate Editor of ProMED-mail, the Internet-based reporting system dedicated to rapid global dissemination of information on outbreaks of infectious diseases. He can be contacted on matt [at] promedmail [dot] org.
TB is a very common infection. About one-third of the world’s population, or 2.5 billion people, have latent TB infection (asymptomatic and not contagious). Without treatment, about 5% to 10% of those, who also have normal immune systems, will develop symptomatic and often contagious TB at some time during their lives. In contrast, 30% of those co-infected with HIV will develop active TB.
The pathogen that causes TB is Mycobacterium tuberculosis and was identified in 1882, but 60 years went by with no specific medical therapy for it.
The hope of a cure for TB first came in 1943 with the discovery of the antibiotic streptomycin. After small observational studies, a controlled clinical trial in 1946 showed that streptomycin plus bed rest achieved greater clinical improvement in comparison to bed rest alone. However, improvement thanks to streptomycin was greatest in the first 3 months of therapy, after which many patients began to deteriorate in part due to the emergence of resistance (1).
Similarly, several years later resistance developed to other antibiotics when these drugs were used alone for the treatment of TB.
Transmission of resistance
Drug resistance that is caused by person-to-person transmission of drug-resistant organisms is referred to as primary drug-resistant TB.
Drug-resistance that develops during TB treatment, either because the patient was not treated appropriately or because the patient did not follow the treatment regimen, is referred to as secondary drug-resistant TB.
Unfortunately, diagnosing drug resistance and administering treatment are often delayed, which allows the infected patient to remain contagious and spread drug resistant disease to others.
Levels of resistance
There is currently a worldwide problem of multidrug-resistant TB (MDR TB). MDR-TB is defined as resistance to at least the two most potent anti-TB drugs (isoniazid and rifampin).
Extensively drug resistant TB (XDR-TB) is resistance to these two drugs plus resistance to other antibiotics called fluoroquinolones and at least one of three injectable second-line drugs. Because XDR-TB involves resistance to the most potent TB drugs, patients are left with treatment options that are much less effective, more toxic, and much costlier.
Current treatments that involve a combination of drugs, with at least 2 drugs to which the strain is susceptible, forms the basis of the standard of care for TB. The addition of a single drug to a failing anti-TB drug regimen can only lead to additional drug resistance.
Diagnosing TB worldwide
In 2014, of the estimated 9.6 million newly diagnosed cases of TB, approximately:
- 480,000 (5%) were MDR-TB
- About 40,000 (0.4%) were XDR-TB
A greater availability of rapid molecular testing can diagnose MDR-TB in several hours, rather than weeks as was the case with old tests. Rapid diagnosis of MDR-TB will get these patients on appropriate drug therapy earlier and end their ability to transmit MDR-TB to others earlier.
Gonorrhoea is a sexually transmitted disease and the second most commonly reported bacterial infection in the US and the UK.
In women, gonorrhoea can spread into the uterus and fallopian tubes, causing pelvic inflammations, scarring of the tubes, greater risk of pregnancy complications and infertility. Babies born to mothers infected at the time of birth can develop blindness. In men, untreated gonorrhoea can spread and sometimes lead to infertility. In both men and women, infection may also spread through the bloodstream to infect joints, skin and heart valves. Untreated gonorrhoea may also increase the risk of getting or giving HIV.
Gonorrhoea is caused by Neisseria gonorrhoeae.
The bacteria that causes gonorrhoea, Neisseria gonorrhoeae, has developed resistance to several antibiotics (sulfonamides, penicillin, tetracyclines, fluoroquinolones, and the extended-spectrum oral cephalosporin cefixime).
The most effective drug for treatment of gonorrhoea is an injectable antibiotic (ceftriaxone, an extended-spectrum cephalosporin). IT is now used in combination with azithromycin, another antibiotic, to improve treatment efficacy and potentially delay emergence and spread of resistance.
Unfortunately, susceptibility to ceftriaxone is steadily decreasing and resistance to azithromycin has increased in settings where it has been used frequently. With the emergence of resistance to these two antibiotics, gonococcal disease could become untreatable. This would be an exceedingly serious public health problem at a time of worldwide explosion in sexually transmitted diseases, especially among young people ages 15-24 and men who have sex with men.
Worldwide, 35 million people are living with HIV infection. The epidemic that started in the early 1980s has killed almost 40 million people.
HIV is an RNA virus, meaning RNA makes up its genetic material. However, HIV is unable to replicate its RNA to give rise to an identical copy. Therefore, some of the resulting genetic variants are drug-resistant. On exposure to an anti-HIV drug, the drug susceptible portion of the HIV population is suppressed and the drug-resistant variants emerge.
Emergence of drug resistance was first documented in HIV-infected individuals receiving AZT therapy alone. Resistance has also been reported for other anti-HIV drugs when used alone. However, combining three or more drugs from two or more classes has proved to be extremely effective in suppressing the concentration of HIV in blood below the limit of detection.
Unfortunately, despite combination drug therapy, suppression of viral replication is often incomplete: the virus continues to mutate and eventually variants accumulate enough key mutations to develop resistance to the antiretroviral drug regimen being used. This risks disease progression.
Drug-resistance testing has enabled tailoring drug regimens for patients with varying resistance profiles. In this respect, therapy can now be individualized, based on results of drug-resistance testing.
1. Marshall, G. Streptomycin in the treatment of pulmonary tuberculosis. A Medical Research Council investigation. BMJ 1949;1: 382–386.