Antimicrobial shortages: Another hurdle for clinicians

In an era of bacterial resistance, recently highlighted by the WHO global report on surveillance (1), choosing the best antimicrobial agent is more complex than ever. Prescribing the appropriate antimicrobial agent no longer involves simply selecting an empirical or definitive agent that will appropriately target the causative pathogens for a given patient; it also involves choosing the best agent for a given patient by taking into consideration the potential impact on bacterial resistance, lower risk for Clostridium difficile infection, lower toxicity, a schedule that improves compliance or discharge, etc (2). The past several years have witnessed frequent shortages of antimicrobials and, more rarely, discontinuation of agents (3). These shortages pose substantial challenges, such as delays in initiation of the most optimal treatment, and increases in the use of agents with unnecessarily broad spectrums, as well as secondor third-line agents for which few clinical data are available; this can ultimately lead to suboptimal treatment and poorer outcomes (3). In addition, shortages may have a considerable impact on appropriate use in a manner that may be contrary to stewardship objectives. Shortages occur either because of a decreased supply or an increased demand. The reasons for supply interruptions are typically not well known because manufacturers have no legal obligation of transparency. Manufacturing issues include raw material shortages, quality issues, capacity issues, manufacturing delays, etc. Increased demand can be associated with a new therapeutic usage, increase in incidence, stockpiling in preparation for announced outbreaks, etc (4,5). Antimicrobial shortages are not a new problem, but have clearly been increasing over the past two decades. According to the United States Food and Drug Administration (6), antimicrobial agents accounted for 13% of all drugs in shortage in 2011, second only to antineoplastic agents. From 2006 to 2010, the number of antimicrobial shortages increased significantly (3). In Canada, they are believed to be more prevalent in the generic drug market than in the brand name market. Shortages vary among countries, suppliers and over time. In Canada, since 2012, the Canadian Drug Shortage Database, an industry-run website, provides information on current and resolved drug shortages. Although this tool facilitates access to important information, it is not perfect because shortage reporting by manufacturers in Canada was, until recently, performed on a voluntary basis. Also, compared with other resources, such as the American Society of Health-System Pharmacists Drug Shortages Resource Center (www. ashp.org/menu/DrugShortages.aspx), data are limited and no analyses of the potential impact on clinical care are provided. However, in February 2015, Canadian Health Minister Rona Ambrose announced new mandatory reporting regulations. Although this initiative alone will not end shortages, it could at least make updated and exhaustive information more readily available. According to the Infectious Diseases Society of America, five important anti-infective injectables have a high probability of experiencing shortages in the near future: amikacin, clindamycin, trimethoprim/sulfamethoxazole (TMP/SMX), acyclovir and doxycycline (7). These shortages would have a significant impact on patient care and public health. However, none of the antimicrobial shortages that have recently impacted our clinical practice are even listed; these include cefepime, cefixime, ticarcilline-clavulanate and gentamicin. We will discuss their potential impacts and alternatives. In September 2014, the sole Canadian manufacturer of adult preparations of gentamicin announced a shortage that would last several months. At the Centre Hospitalier Universitaire de Sherbrooke (CHUS, Sherbrooke, Quebec), to restrict the use of our limited stocks of gentamicin, we released local guidelines to automatically replace all gentamicin prescriptions with tobramycin unless patients fulfilled one of the criteria listed in Box 1. A switch to amikacin was recommended for treatment of a severe infection in which Serratia species are involved. As of March 2015, we are now facing a complete shortage of gentamicin; thus, we must seek alternatives to gentamicin for these patients. In the specific situations listed in Box 1, other aminoglycosides cannot be used interchangeably. For enterococcal endocarditis, Enterococcus species are intrinsically resistant to tobramycin and amikacin. A priori, streptomycin may appear to be a potential alternative for enterococcal endocarditis because most laboratories can test strains for high-level resistance to streptomycin and its use is recommended in the American Heart Association endocarditis guidelines (8). However, increased use of streptomycin could rapidly end in a ‘rebound’ shortage because the demand and supply for this drug is usually limited, eg, for multidrug-resistant tuberculosis. Also, assessment of streptomycin serum concentrations requires special laboratory Adult infectious diseAses notes