Second-Line Anti-Tuberculosis and Other Drug Shortages Cause Deadly Adverse Outcomes, Promote Resistance, and Increase Drug-Resistant Disease

A nationwide survey of TB programs found that the majority of programs reporting multidrug resistant (MDR) TB also have difficulty in obtaining the drugs needed to treat it. In comparison to drug-susceptible TB, treatment of drug-resistant TB requires a lengthy regimen with additional drugs that are less effective, more toxic, and more expensive. These shortages must be addressed, as consequences of such drug shortages can be severe and have a serious impact on both patient health and public health.


Second-line anti-tuberculosis drug (SLD) shortages can contribute to adverse outcomes such as delays and interruptions in treatment, the need to use potentially less effective treatment regimens, prolonged infectiousness and increased transmission of drug-resistant TB in the community, the further development of drug resistance, and worse outcomes for patients. Additionally, drug shortages lead to rationing, increased drug costs, and inefficient use of staff time, and increase the risk for medication errors because regimens must be adjusted, leading to confusion over drug administration schedules, adverse reactions, and interactions.


In November 2010, a nationwide survey of TB control programs conducted by the National Tuberculosis Controllers Association (NTCA) indicated that shortages and other problems that hinder access to SLDs interfere with patient care and could promote the development of drug resistance as well as the transmission of drug-resistant Mycobacterium tuberculosis. Twenty-six (79%) of the 33 responding health departments, representing approximately 75% of the U.S. TB burden, reported MDR TB during 2005–2010. The survey found that 81 percent of TB programs that responded to the survey and reported MDR TB also reported difficulties in obtaining the drugs needed to treat drug-resistant cases of TB. Among programs reporting these difficulties, the following reasons were cited: nationwide shortages (cited by 100 percent of those programs), shipping delays (71 percent), lack of resources (presumably meaning that neither the program, the patient, nor a health insurer could afford the drugs) (62 percent), and the complicated process related to protocols needed to obtain certain drugs (48 percent). As a result, adverse outcomes or other problems related to difficulties with SLD procurement were reported by 19 (90%) of 21 jurisdictions, with treatment delay (58%), a treatment lapse or interruption (32%), or the use of an inadequate –and potentially less effective–regimen (32%) most commonly reported.


TB is caused by the bacterium Mycobacterium tuberculosis, which is most typically transmitted through the air from one person to another. For most TB cases, cure is achieved with a standard combination of drugs. For the treatment of confirmed or suspected TB disease, isoniazid, rifampin, pyrazinamide, and ethambutol are the four first-line drugs used worldwide as a 6-month standard regimen.


In contrast, MDR TB is caused by tuberculosis that is resistant to at least isoniazid and rifampin, the two most potent of the four first-line anti-TB drugs. MDR TB generally requires 18–24 months of treatment with five or six drugs that are less effective, more toxic, and more costly than first-line drugs. Extensively drug-resistant tuberculosis (XDR TB) is MDR TB with additional resistance to any fluoroquinolone and at least one of the injectable TB drugs (kanamycin, capreomycin, and amikacin). As a result, MDR TB and XDR TB cause greater morbidity, and, overall, patient outcomes are worse.


Drug shortages, in which supplies of all clinically interchangeable versions of a given FDA–regulated drug become inadequate to meet actual or projected user demand, have been well-documented in many areas of medicine. For several years, drug shortages in the United States have affected the availability of SLDs for treatment of TB.


Potential solutions for alleviating SLD shortages include stockpiling drugs centrally, sharing SLDs among jurisdictions, obtaining drugs from foreign manufacturers, and taking advantage of new legal requirements for drug suppliers to report shortages and impending shortages to FDA within a specified timeframe. Reliable, consistent access to SLDs will require the collaboration of the CDC, FDA, state and local health departments, national health professional societies, and the pharmaceutical industry. Currently, the CDC and FDA are collaborating to identify solutions to ameliorate a national shortage of isoniazid.


SLD shortages also can disrupt treatment of drug-susceptible TB in patients who cannot tolerate first-line drugs and can complicate the treatment of MDR TB and XDR TB, putting patients and communities at greater risk for morbidity and mortality. For example, in April 2011, shortages of capreomycin and amikacin, two SLDs used to treat MDR TB and XDR TB, posed a serious threat for a father and his infant who had MDR TB. Despite intensive efforts by public health personnel to obtain the two drugs, the initiation of treatment was delayed by eight days for both patients, prolonging the father's infectious period and thereby increasing the risk for transmission to the community. The infant, who had basilar meningitis and severe communicating hydrocephalus, was placed in a particularly dangerous situation. TB meningitis in young children is a medical emergency, and delays in treatment lead to worse outcomes, such as severe cognitive impairment, epilepsy, and death.


The CDC does not formally monitor SLD supplies, but TB control officials in local and state health departments request assistance from the CDC when they encounter difficulties with drug procurement. Since 2005, CDC has received reports of difficulty obtaining each of the following SLDs: streptomycin, cycloserine, ethionamide, rifabutin, amikacin, capreomycin, and kanamycin. Shortages of rifampin also have been reported, and, in the past two months, a national shortage of isoniazid has developed.


Shortages of MDR TB medications have been experienced by most U.S. TB programs that have diagnosed and reported MDR TB cases. In 2010, most (130 [73%] of 178) of these reports of SLD shortages involved sterile injectable antibiotics essential for the treatment of MDR TB. Since September 2011, the availability of injectable SLDs for MDR TB treatment has been precarious. Kanamycin is no longer produced in the United States, streptomycin has been intermittently unavailable because of increased international demand, and capreomycin and amikacin have been available on an intermittent basis in only small amounts because of manufacturing problems and lack of raw materials.


Drug shortages in the Unites States have become increasingly common. In 2005, a total of 61 impending drug shortages were reported to the FDA. In 2010, there were 178. The FDA maintains a website to alert the public of drug shortages and their causes. A recent FDA review of medical product shortages underscored the complexity of the problem, identifying poor drug quality leading to product recalls as the most common cause for a shortage. Difficulties procuring raw materials and components also were problems.


Early notification to the FDA can help prevent some impending shortages. For example, in 2010, of 178 drugs with impending drug shortages, the FDA was able to prevent shortages of 38 (21%). In 2011, 195 shortages were prevented. In October 2011, Executive Order 13588 directed the FDA and the U.S. Department of Justice to take action to combat drug shortages, protect consumers, and prevent deliberate price inflation. As of November 1, 2012, shortages of at least 150 drugs had been prevented in 2012. On July 9, 2012, the FDA Safety and Innovation Act of 2012 was signed into law. In the law, Congress provided the FDA with authorities to combat shortages of drug products in the United States and imposed requirements on manufacturers regarding early notification to FDA of issues that could lead to a potential shortage or disruption in supply of a product.


In March 2011, the Federal Advisory Council for the Elimination of Tuberculosis, which provides recommendations for TB elimination to the U.S. Department of Health and Human Services, formed a workgroup to design strategies for improving SLD access. In November 2011, a recurrent bimonthly national forum of 60 TB experts assessed the findings of the NTCA survey and data from the FDA and the CDC in the context of case presentations. Potential solutions for improving continuity of SLD supplies were suggested by the TB experts present, although no report resulted from the meeting. These proposed solutions included the sharing of drugs in short supply among state and local TB programs, centralized drug stockpiling, obtaining drugs from foreign manufacturers when not available in the United States, and having the CDC be responsible for a nationally centralized application protocol for certain drugs to expedite access to these drugs for all U.S. patients. Currently, the CDC is responsible for nine similar protocols and is developing such a proposal for clofazimine, an SLD.


See the CDC Report