The contribution of contaminated medications to serious, and at times fatal, healthcare-associated infections (HAIs) has become prominent in the United States healthcare delivery landscape. Microbial contamination of medications intended to be sterile most commonly results from infection control breaches at the point-of-care, for example when common syringes or single-use vials are shared among multiple patients. Unsafe injection practices such as these at the hospital bedside or in outpatient clinics have resulted in transmission of bacterial infections and bloodborne pathogens such as hepatitis C virus [1–3]. Upstream contamination of medications at the point-of-manufacture is rarer, but has also been reported [4,5].

Pharmacies play a crucial, intermediate role in the pathway of medications from point-of-manufacture to point-of-care, including compounding, repackaging, and labeling sterile medications, such as injectable and ophthalmic products. The Food and Drug Administration (FDA) regards compounding as the practice in which a licensed pharmacist, a licensed physician, or, in the case of an outsourcing facility, a person under the supervision of a licensed pharmacist, combines, mixes, or alters ingredients of a drug to create a medication tailored to the needs of an individual patient [6]. Over the last two decades, pharmacies have taken on a more prominent role in compounding and re-packaging sterile products for hospitals, outpatient clinics, home health, and other healthcare settings, and sterile compounding practices have evolved to become more wide-ranging and complex [7,8]. These practices can sometimes include preparation of large quantities of sterile products in advance of prescriptions or in non-patient-specific fashion, often for distribution to multiple facilities and at times across state lines [8,9]. With this evolution in pharmacy compounding practices, new threats to patient safety have emerged.

Regulatory and professional standards for ensuring safe preparation of sterile medications have long-been established and have facilitated advancements in the quality and safety assurance of sterile compounding by pharmacies [7,8,10–12]. However, failures to adhere to these standards have been documented and these standards were not originally intended to address compounding activities at the large scale currently undertaken by some compounding pharmacies [7–9,13]. Consequently, compounding pharmacies have been increasingly identified as sources of contaminated products contributory to large and serious healthcare outbreaks [14,15]. The most prominent example of such an outbreak occurred in 2012 and involved nationwide distribution of contaminated injectable methylprednisolone acetate (MPA) [16]. This incident, one of the largest U.S. healthcare-related outbreaks on record, was characterized by nearly14,000 exposed individuals and at least 751 cases of fungal meningitis, other infections, and stroke, including at least 64 deaths across 20 states [16].

The nationwide fungal meningitis outbreak was not an isolated incident. Since 2001, the Centers for Disease Control and Prevention (CDC), along with its federal and state public health partners, have responded to and investigated numerous outbreaks of infectious illnesses linked to pharmacy-compounded sterile preparations (P-CSPs). Here, we provide an updated and expanded overview of the burden and characteristics of outbreaks linked to P-CSPs, briefly summarize common forces driving the use of products involved in these outbreaks, and identify public health and patient safety lessons learned that could inform prevention of similar outbreaks in the future.

We identified outbreaks occurring in the U.S. in which infections were linked to P-CSPs based on a search of internal data for relevant incidents reported to and investigated by CDC between January 1, 2001 and December 31, 2013. We also searched Medline, CINAHAL, and Embase databases for reports during the same time period using combinations of the terms: disease outbreaks, drug compounding, compounding pharmacy, and infectious diseases. For the purposes of this overview, sterile products that were re-packaged by compounding pharmacies (e.g., contents of an already sterile single-dose vial re-packaged into multiple syringes without undergoing any additional manipulation of the drug, such as sterilization, at the pharmacy) were also considered P-CSPs. Food and Drug Administration notices of compounding pharmacy regulatory actions and publicly-available pharmacy inspection reports were also reviewed and used to obtain details regarding lapses in sterile compounding procedures that may have contributed to P-CSP contamination [17]. Information about clinical drivers for P-CSP demand was based on descriptions of indications for which compounded products were being used as provided in outbreak and related reports, as well as published literature.

We excluded outbreaks linked to products prepared in hospital pharmacies that were not identified as institutional compounding pharmacies [18,19] and products prepared in specialty (e.g., nuclear) pharmacies [20], outbreaks where the source of contamination was extrinsic (e.g., product contamination due to mishandling at the bedside) [1]. Also excluded were CSP contamination incidents that did not result in infectious illnesses (e.g., those that led solely to pharmacy inspections, warning letters, or product recalls, but no reported infections) and incidents related to compounding pharmacy dispensing errors (e.g., errors in dosage calculation or mistaken active ingredients) [21–23], intentional adulteration [24], or veterinary medicines [25].

We identified 19 U.S. outbreaks since 2001 that were linked to contaminated medications prepared by compounding pharmacies [16,26–50]. These incidents were associated with a range of 2 to 751 cases (Table 1); almost one-half (8/19) of these incidents involved deaths possibly related to exposure to contaminated P-CSPs [16,26,28,32,36,41,45,50]. The exact numbers of CSPs dispensed or distributed each year by compounding pharmacies is not known, but the current figure is likely in the tens of millions [51], with at least two-thirds of U.S. hospitals reporting reliance on outside pharmacies for CSPs [52,53]. Although the number of recognized outbreaks linked to contaminated P-CSPs can be considered relatively small given these figures, these incidents are being reported with an increased frequency [14,15]. Additionally, these outbreaks have often resulted in devastating consequences to patients, including serious adverse events such as blindness and life-threatening sepsis, a need to institute additional medical and procedural interventions, and fatalities [16,26,28–32,36,39,41–43,45,50].

The number of recognized outbreaks linked to contaminated P-CSPs should also be viewed as an underestimate for a number of reasons (Table 2). First, identification of healthcare outbreaks linked to contaminated medications, including P-CSPs, is challenging as identification relies on clinician recognition of a possible link between clusters of infections and a potentially contaminated product, followed by prompt reporting to public health authorities [4,54]. Outbreaks linked to P-CSPs, especially, present numerous challenges, as they have often involved products that are ubiquitous in healthcare settings (e.g., electrolyte solutions) (Table 1), thus clinicians may not readily recognize the medication as a potential source of infections. Further challenging clinician recognition of a link between a contaminated compounded product and an infection is the fact the most pathogens that have contributed to P-CSP contamination incidents to date, such as Pseudomonas spp. and Serratia spp., are common causes of infections that patients acquire during exposure to healthcare for a multitude of reasons other than exposure to contaminated medications [55]. Delayed presentation of infectious symptoms after exposure to contaminated P-CSPs has also been reported with certain types of contaminants (e.g., fungal pathogens) [43,56] and routes of administration (e.g., via indwelling catheter) [33], which can also potentially delay identification of an outbreak.

Second, compounding pharmacies have been increasingly engaging in multi-facility and multi-state distribution of large quantities of sterile products [8,9], such that patients exposed to contaminated P-CSPs could present in widespread and disparate fashion. This poses additional challenges in finding a common link if there are only small clusters of infections across a number of healthcare settings [16,43]. For example, in one recent investigation of endophthalmitis infections linked to compounded Brilliant Blue Green intraocular dye, a cluster of infections reported from one facility prompted enhanced nationwide case finding that identified a second, previously unrecognized outbreak of endophthalmitis linked to compounded ophthalmic triamcinolone prepared by the same pharmacy [43].

Third, except for facilities that voluntarily register with FDA as outsourcing facilities, a new category of compounders created by the Compounding Quality Act enacted in November 2013 [57], compounding pharmacies generally do not report adverse events from CSPs to the FDA. Since the onset of the 2012 fungal meningitis outbreak associated with contaminated MPA [16,44], numerous compounding pharmacies have voluntarily conducted nationwide recalls of other CSPs [17]. Although some of these recalls involve P-CSPs linked to already recognized outbreaks, the possibility that other contaminated P-CSPs have contributed to infections that have gone undetected cannot be excluded. For these reasons, the true burden of HAIs from contaminated P-CSPs is likely higher than is suggested by the numbers of outbreak cases or fatalities identified to date.

Underlying the recognized outbreaks linked to P-CSPs are common driving forces for sterile pharmaceutical compounding that have served to catalyze and potentiate the impact of these incidents. Broadly, these drivers can be categorized as operational, clinical, and economic.

This overview of recognized compounding pharmacy-related outbreaks points to salient targets that can be addressed by public health authorities, regulators, compounders, and clinicians in efforts to prevent similar outbreaks from occurring in the future. First, almost all outbreaks linked to contaminated P-CSPs have been associated with non-patient-specific production practices that have gone beyond the original intent of pharmacy compounding—compounding by a pharmacist, in response to a prescription, for an individual patient [6]. The recent passage of the Compounding Quality Act after the 2012 nationwide meningitis outbreak is expected to facilitate more rigorous federal oversight of facilities engaged in this type of compounding [57]. Compounding facilities that voluntarily elect to register as “outsourcing facilities” will be subject to requirements and oversight more closely resembling those applicable to drug manufacturers, such as compliance with standards more aligned with those for pharmaceutical manufacturing [87], mandatory reporting of adverse drugs events to the FDA, and inspections of their facilities by the FDA according to a risk-based schedule [57]. The FDA has recently recommended that healthcare facilities that outsource preparation of sterile products obtain CSPs only from registered outsourcing facilities [88].

Second, with the passage of the Compounding Quality Act, there will remain a category of pharmacies engaged in more traditional compounding practices that are not subject to the same standards as those for outsourcing facilities. For these pharmacies, there remains the need to address poor adherence to sterile compounding standards that have been consistently identified across recognized outbreaks linked to P-CSPs. Compliance with sterile compounding standards, including those of USP Chapter <797>, is known to be highly variable [13,89]. Currently, not all state public health departments or boards of pharmacy uniformly incorporate USP Chapter <797> guidelines into state laws that govern pharmacy practice [90]. State public health departments and boards of pharmacy can play a critical role in facilitating more uniform application of and adherence to professional and regulatory compounding standards. Clarifying federal versus state oversight roles, improving state resources and staffing to allow for adequate oversight, and enhancing communication between state and federal oversight bodies have been identified as important opportunities to strengthen public health protection from contaminated P-CSPs at the state level [91]. Improving professional and technical competencies of pharmacists and other providers in sterile compounding practices within didactic curriculums and experiential settings has also been recommended to help enhance knowledge of and adherence to sterile compounding standards [92,93].

Third, only a few commonly used sterile injectable products (preservative-free steroids and bevacizumab) formulated or re-packaged for off-label uses were responsible for the overwhelming majority of compounding pharmacy-related outbreaks, suggesting that better scrutiny of the drivers for demand of these products is warranted. For example, the use of epidural steroid injections for the treatment of chronic back pain is considered to be highly controversial owing to a paucity of evidence to support long-term benefits and recognized risks associated with administration of steroids by the epidural route [79,94–97]. Nevertheless, epidural steroid administration remains one of the most commonly utilized approaches to chronic low back pain treatment and the most commonly performed interventional pain procedure in the U.S., with millions of these procedures performed each year [58,96,98].

Likewise, the off-label use of bevacizumab for the treatment of wet AMD in lieu of its commercially manufactured counterpart has been increasingly explored as a means of achieving savings for Medicare and patients in the billions of dollars [83,85]. However, the safeguards necessary to ensure that bevacizumab is re-packaged safely for the purposes of intraocular administration have not been uniformly applied by compounding pharmacies [38,39,42,47,48,62,65]. National shortages of commercially manufactured products were an additional driver underlying the demand for P-CSPs in recognized outbreaks [26–28,41,50]. Manufacturer shortages of sterile medications that are critically relied upon across healthcare settings is currently receiving national attention from regulators and healthcare policy-makers, and attempts at mitigating the negative impact of these shortages on patient care are actively being explored [77,78].

As compounding pharmacies continue to play a prominent role in preparation and distribution of sterile pharmaceuticals across U.S. healthcare settings, the number, impact, and severity of infectious risks and outbreaks secondary to potentially contaminated CSPs may increase. Recognized outbreaks linked to compounding pharmacies have been most commonly associated with non-patient-specific re-packaging of sterile products and non-sterile to sterile compounding. These practices were consistently characterized by lack of adherence to regulatory and professional standards for sterile compounding, suggesting that outbreak incidents are likely highly preventable with improved oversight of and adherence to such standards. Given the recent passage and ongoing implementation of the Compounding Quality Act, it is unclear what impact the new regulatory oversight framework will have in preventing these outbreaks. Regardless, improving compounding personnel competency, strengthening environmental quality controls, and implementing rigorous quality assurance processes, especially during non-patient-specific compounding, will be critical for ensuring the safety of patients receiving compounded sterile medications. Drivers for P-CSP demand, such as off-label uses and lower costs, warrant closer scrutiny. Strong federal and state public health partnerships, as well as early recognition and notification of possible outbreaks on the part of clinicians, will continue to be critical in facilitating rapid identification and control of these types of outbreaks.