ID drug shortages threaten patient safety

Source: Griffith MM, et al. The impact of anti-infective drug shortages on hospitals in the United States: Trends and causes. CID 2012: 54: 684-691

Recent efforts to treat a patient in hospital with acute pneumocystis pneumonia (PCP) were hampered by a lack of available injectable trimethoprim-sulfamethoxazole. The hospital pharmacy staff begged a few doses from the county and from the veteran's hospital in Palo Alto, but eventually I was forced to switch this patient to oral atovaquone, a second-line agent. At least the patient got through the more critical period of treatment, and gradually improved. Unfortunately, this scenario is becoming all too familiar to infectious disease specialists. Hardly a month goes by where I am not faced with a difficult therapeutic decision precipitated by a drug shortage of some kind. Coupled with the rise in antibacterial resistance, drug shortages can have a significant impact on medical care.

This salient article examines the clinical dilemmas created by the increasing frequency of critical drug shortages, and summarizes the current anti-infective drug shortages in the United States. Were you aware there is an entity called the Center for Drug Evaluation and Research (CDER) Drug Shortage Program of the FDA, which tracks the availability (or non-availability) of pharmaceuticals and anti-infectives in use? The CDER defines a drug shortage as "a situation in which the total supply of all clinically interchangeable versions of an FDA-regulated drug is inadequate to meet the current or projected demand..."

Such shortages often lead to clinical dilemmas, result in delays in initiation of treatment (while staff attempt to clarify availability of drug and hunt for a supply); often require an alternate and possibly less effective therapy, with the potential for worse outcome.

As of February 2011, a total of 193 agents were officially listed on the CDER's drug shortage list, 13% of which were anti-infectives. Some of these agents have been on the CDER list for months or years. In 2008, 5 anti-infective agents were listed on the CDER drug shortage list, one of which had not been resolved as of February 2011. Shortages of 6 of 11 agents listed in 2009 and 12 of 17 listed in 2011 had not been resolved and remain in short supply or are unavailable.

The government's role is mostly passive in this process, and can provide only oversight and monitoring, although they are charged with monitoring good manufacturing practice (GMP), and can help to precipitate a drug shortage by halting production of a drug or vaccine if a company fails to meet GMP standards. Drug shortages occur for a variety of reasons, including the lack of raw materials; a company can shut down manufacturing because of problems in a facility, or the FDA can interrupt production (as has been the case with Influenza vaccine and PCN G). For example, manufacturing issues hampered the production of injectable acyclovir, the only agent recommended for the treatment of HSV and VZV encephalitis. The shortage of PCN G in 2007, which is manufactured by a single company, created a serious problem for physicians attempting to treat neurosyphilis (inferior agents such as tetracycline and ceftriaxone had to be used). Manufacturing issues hampered production of injectable TMP-SMZ in May 2010, a problem that has still not been fully resolved; creating difficult decisions when attempting to treat PCP and infections due to Stenotrophomas maltophilia.

Occasionally, the demand for certain anti-infectives may outstrip production (as has occurred with Polymixin B, isoniazid, and mupirocin nasal ointment). Changes in clinical guidelines may also create an increased demand for certain agents, which existing production can not meet. Shortages of vaccines have also posed problems, including vaccines for Influenza, varicella, herpes zoster, yellow fever, and Hepatitis B.

In addition, a company can choose to halt or stop production of any agent for any reason, and they are not legally required to provide an explanation, nor are they required to provide status updates regarding any particular drug. Some drugs just disappear from the market, presumably as a marketing decision. Companies are required to provide 6 months notice to the FDA before ending production of a "medically necessary" drug. If they are the only manufacturer, the definition of medically necessary may be open for debate. For example, when Wyeth began marketing tigecycline in 2005, their other product, parenteral minocycline, was dropped from the market. It turns out that IV minocycline may prove to be one of the most useful agents against some strains of multidrug resistant Acinetobacter baumannii.

A panel of experts from several national associations has proposed changes to the FDAs current role, and a current U.S. Senate bill seeks to amend the law regarding manufacturer notification before halting production of any agent that could potentially lead to a shortage, as well as other recommendations made by a U.S House of Representatives Bill (Preserving Access to Life-Saving Medications Act). Those with opinions regarding this subject should contact their U.S. congressman or senator.