Sterility of Antiseptic Skin Prep Products: FDA Hearing Stirs Debate

In light of a number of high-profile recalls of contaminated alcohol prep products in the last several years, the Food and Drug Administration (FDA) held a hearing recently to receive expert testimony and public comment on how to address microbial contamination of these patient preoperative skin preparation drug products. It is a step in the ongoing investigational process that the agency is undertaking to determine issues related to sterility impacted by manufacturing processes.

By Kelly M. Pyrek

Editor's note: This is a two-part series examining the issue of antiseptic sterility, a topic of ongoing investigation by the Food and Drug Administration (FDA). Part 1 lays the groundwork for this series and establishes what antiseptic prep products are, reviews the types of contamination that may occur, establishes what current good manufacturing practices (CGMPs) are, and provides the perspectives of clinicians and several associations. Part 2, which will appear in the July issue of ICT, dives deeper into the discussions held at a recent FDA hearing, presents the perspectives of the manufacturers and other experts and addresses if sterility of antiseptic prep products can be achieved.  

In light of a number of high-profile recalls of contaminated alcohol prep products in the last several years, the Food and Drug Administration (FDA) held a hearing recently to receive expert testimony and public comment on how to address microbial contamination of these patient preoperative skin preparation drug products. It is a step in the ongoing investigational process that the agency is undertaking to determine issues related to sterility impacted by manufacturing processes.

Currently, patient preoperative skin preparations are not required to be sterile, since bacteria can contaminate these products at the time of manufacture or during product use. But because contaminated patient preoperative skin preparations have been associated with clinical infections and adverse outcomes, the FDA is exploring certain scientific and product-use issues related to patient preoperative skin preparations.
Patient preoperative skin preparations are over-the-counter (OTC) topical antiseptic drug products used to reduce the number of bacteria on the skin prior to medical procedures or injections. Although they are marketed predominantly to healthcare facilities, the use of these products extends beyond the healthcare facility setting. For example, consumers with medical conditions requiring regular injections may use these products at home. Patient preoperative skin preparations are marketed through one of three regulatory pathways: an OTC drug monograph, an approved new drug application (NDA), or an approved abbreviated new drug application (ANDA). Many patient preoperative skin preparations contain antiseptic active ingredients subject to an OTC drug monograph, such as povidone-iodine or alcohol. Products that are marketed under approved NDAs or ANDAs include those that contain chlorhexidine gluconate (either alone or in combination with an alcohol). Patient preoperative skin preparations are marketed as solutions, swabs, pads saturated with a solution, and applicators containing a solution. Some patient preoperative skin preparation products are intended for one-time use only (single-use); others are intended for repeated use from the same container (multiple-use). Multiple-use containers of patient preoperative skin preparations may also be labeled for other indications, such as surgical hand scrub, healthcare personnel handwash, or skin wound and general skin cleanser.

Despite their inherent antimicrobial activity, patient preoperative skin preparations may become contaminated with bacteria. A number of product recalls have been prompted by the identification of bacterial contamination. One notable recall was announced on  Jan. 5, 2011, when Triad Group initiated a voluntary product recall involving all lots of alcohol prep pads, alcohol swabs and alcohol swabsticks manufactured by Triad Group but which are private labeled for many accounts to the consumer level. This recall involves those products marked as sterile as well as non-sterile products. This recall was initiated due to concerns from a customer about potential contamination of the products with Bacillus cereus. The alcohol prep pads, alcohol swabs and alcohol swabsticks affected by the recall were used to disinfect prior to an injection. They were distributed nationwide to retail pharmacies.

On Feb. 1, 2011 the FDA reminded healthcare professionals about the safe use of non-sterile alcohol prep pads to clean and disinfect the surface of the skin. In a statement, Karen Weiss, MD, director of the Safe Use Initiative in the FDAs Center for Drug Evaluation and Research, noted, "Healthcare professionals should always check the labeling on a prep pad to determine if it is sterile or non-sterile. Non-sterile pads are not intended to prep patients prior to procedures requiring strict sterility measures and should not be used on patients with a depressed immune system, to prep patients for catheter insertion, or to prep patients prior to surgery."

Weiss added that many patients in hospitals are particularly susceptible to infections, and the FDA recommends sterile antiseptics (including chlorhexidine gluconate, alcohol or iodine applicators, pads, and swabs) in that setting. Manufacturers often package a prep pad with an injectable drug, selling them as a kit. But not all marketed pads are sterile. Some are marketed as non-sterile alcohol pads. If a pad does not state sterile on the label, healthcare professionals should be aware that they are using a non-sterile pad. Healthcare professionals and consumers should check the label to confirm that the product is sterile, and may also want to consider washing the area with soap and water prior to using the antiseptic for skin surface preparation.

Contamination of patient preoperative skin preparations occurs by two known mechanisms. Intrinsic contamination occurs when microorganisms gain entry to the product during the manufacturing process and remain viable. Bacterial contaminants have been isolated from pharmaceutical water supplies and non-sterile antiseptic manufacturing environments. By contrast, extrinsic contamination occurs when microorganisms are introduced into a finished product by the end user. Extrinsic contamination can arise from a variety of causes, including dilution of the product with contaminated water, failure to use appropriate aseptic techniques during handling, and repeated use of non-sterile containers for product storage.

The FDA's current good manufacturing practice (CGMP) regulations require manufacturers to have appropriate procedures in place to prevent the presence of objectionable organisms in drug products that are not sterile (21 CFR 211.113). However, the microbial limits test (United States Pharmacopeia Chapter 1111) currently in use by many manufacturers may not detect very low levels of microbial contamination and does not screen for the types of intrinsically antiseptic-resistant organisms frequently identified as contaminants in patient preoperative skin preparations, such as Burkholderia cepacia and Bacillus cereus. Therefore, a product that passes the premarket microbial limits test may still support the growth of contaminating microorganisms and become the source of clinical infection.

The subject of contaminated patient preoperative skin preparations was discussed at an Advisory Committee meeting held on August 5, 2009. The FDA asked the committee whether it should require patient preoperative skin preparations to be manufactured as sterile products. The committee did not vote on the FDA's question, but rather emphasized adherence to CGMP.

There are a number of CGMP regulations that have meaning for manufacturers of topical antiseptic drug products. Section 501(a) (2) (B) of the Federal Food, Drug, and Cosmetic Act requires all drugs to be manufactured in conformance with CGMP. The CGMP regulations provide the minimum legal requirements for conducting reliable operations. 
Regarding manufacturing design and control, manufacturing facilities (21 CFR 211.42) must demonstrate processes to prevent microbial contamination. For non-sterile drug products, manufacturers must establish control procedures to monitor output and validate processes to include bioburden testing (21 CFR 211.110 (a) (6)), 211.111) and establish and follow written procedures designed to prevent the introduction of objectionable microorganisms (211.113(a)). For sterile drug products, manufacturers must establish and follow written procedures designed to prevent microbial contamination (211.113(b)).

They must conduct process validation studies to ensure acceptable output (e.g., with topical antiseptics, particularly product microbiological quality); they also must implement and validate needed changes when deficient manufacturing steps, equipment, or raw materials may be adversely affecting process control. They must ensure that operating procedures will consistently produce a quality product (211.100); they must review and evaluate any deviations or discrepancies documented during manufacturing and testing to determine if a product lacks assurance of sterility (for sterile antiseptics) or may be contaminated with objectionable microorganisms (for non-sterile antiseptics); and they must document and implement any corrective actions deriving from the evaluation. They must ensure that all equipment, including water systems, is clean, sanitary, operates consistently, and is suitable for its intended use; and they must establish and follow in-process bioburden testing procedures to help monitor in-process control, including understanding the bioburden challenge to a final sterilization process. 

In-process and finished product testing is also mandatory. Manufacturers must test each lot of a drug product component and container/closure, including those that may be vulnerable to microbiological contamination, including applicator material and water used as an ingredient in the product. They also must conduct appropriate microbiological tests before a batch disposition decision is made; additionally, they must test each batch of a sterile product for sterility, and test each batch of a non-sterile product to ensure absence of objectionable microorganisms.

Since there are potentially many different root causes of product contamination by microorganisms, the FDA says it is imperative that manufacturers perform a manufacturing risk assessment to understand manufacturing failure modes and implement prevention measures. In addition, any risk assessment approach should be informed by an understanding of the microbial contamination vulnerabilities of the product.  For example, some product considerations for manufacturers include:
- Determine the types of microbes that might survive or thrive in products; provide additional controls and testing based on the output of the risk assessment to ensure product quality.
- Ensure that microbial recovery methods are capable of detecting the types of microbes that may affect product quality.
- Evaluate risk of contamination from components, including during component production, storage, or due to the intrinsic risk from source materials. Consider all possible sources of microbial contamination, including the following: Components or products stored in open bins can be at risk for contamination by spore-forming microbes, such as Bacillus cereus as well as by Serratia species and other airborne microbes.  Manufacturing areas exposed to windy or poor HVAC conditions may increase the potential for this environmental contamination risk. Some materials, especially from natural sources, may have high or objectionable intrinsic bioburden. Water quality can pose a significant risk, as most antiseptics include water as a key ingredient.  Contaminated purified water has been the root cause of multiple recalls of antiseptics, including instances of antiseptics contaminated with Burkholderia cepacia.

One Clinician's Experience
Susan Dolan, RN, MS, CIC, hospital epidemiologist at Children's Hospital Colorado (CHCO) in Aurora, Colo., knows first-hand the impact that lack of sterility can have on patient outcomes. In 2010, Dolan and her team investigated two cases of serious Bacillus cereus infections that required intensive and extensive medical treatment. The epidemiologic investigation initially focused on three single-use, disposable items used in the treatment of both patients: sterile syringes prefilled with sterile saline solution; sterile applicators packaged with a 2 percent chlorhexidine gluconate/70 percent alcohol solution for skin preparation; and pledgets packaged with 70 percent isopropyl alcohol (alcohol prep pads [APPs]). The APPs were not labeled as either sterile or non-sterile on the outside of the individual APP packages or the box in which the APPs were contained. Bacterial cultures of samples from three saline syringes and the liquid and pads from nine packages of chlorhexidine gluconate/alcohol skin preparation applicators were negative. The internal alcohol pads from 60 APPs, obtained from various locations around CHCO, also were cultured. Hospital investigators found that 40 of 60 pads, representing eight of 10 different manufacturing lots, yielded B. cereus or Bacillus spp. All of the pads were supplied by a single manufacturer. CHCO contacted the Colorado Department of Public Health and Environment (CDPHE), which notified the CDC and the Food and Drug Administration who performed independent APP testing confirming the CHCO laboratory findings.

B. cereus isolates from eight CHCO patients with positive cultures during May through November 2010 and numerous APP isolates were characterized and compared by Repetitive sequence-based PCR (Rep-PCR) and pulsed-field gel electrophoresis (PFGE). Wide diversity was observed among the isolates, and no patient isolates matched APP isolates. Given this diversity and the time lapse between positive patient clinical specimens and subsequent APP sampling, the lack of a match between the two groups was not considered to rule out APPs as the source of the B. cereus isolated from patients.

As reported in the MMWR, Dolan, et al. (2011)  note, "APPs are supplied both as sterile and non-sterile products. Sterile products are clearly labeled as such and should not be mistaken and/or interchanged for non-sterile products. B. cereus group and Bacillus species are resistant to killing by alcohol and have caused healthcare-associated outbreaks of invasive disease. Pseudoinfections caused by B. cereus-contaminated products also have been reported. Healthcare facilities, healthcare providers, and users of APPs should know whether the APPs in clinical use are sterile or non-sterile and be aware of the risk for iatrogenic infection if non-sterile APPs are used. Manufacturers should know the importance of clearly labeling their products as sterile or non-sterile to avoid misuse by healthcare facilities and healthcare providers."

Based on the findings in this investigation, Dolan, et al. (2011) TCH immediately halted any use of non-sterile APPs and began using sterile APPs exclusively from another manufacturer. In January 2011, the manufacturer voluntarily recalled all of its alcohol wipe products because of potential contamination.

Dolan's experience at her hospital parallels that of the high-profile Houston, Texas case in which 2-year-old Harrison Kothari developed lethal bacterial meningitis after surgery and died in 2010. His parents sued the manufacturers of the alcohol prep pads used on their son, claiming that they transmitted the Bacillus cereus bacterium that triggered his infection. The Kotharis settled their claim and two of the manufacturers filed for bankruptcy. It's a cautionary tale for clinicians trying to ensure the best outcomes possible for their patients, and Dolan says these cases may have opened healthcare workers eyes to previously held assumptions of sterility that were incorrect.

"While speaking throughout the country on this recall issue, I ask the question, 'How many people in this room (before the APP recall) knew that alcohol prep pads were not sterile?' and I rarely encounter one hand raised in very large room," Dolan says. "So I think maybe there was not a clear understanding of what APP products really were because of unclear product labeling. I think IPs were quite aware of contamination of similar antiseptic-type products occurring in either manufacturing or subsequently in the handling/manipulation of these product. There have been reports in the literature about contaminated skin prep and hand hygiene products, so IPs know that  if we are dealing with an outbreak we should at least consider that such a  product could be contaminated -- however I didn't fully appreciate that specifically that the alcohol prep pads might not be  sterile.   The issue was unclear because manufacturers produce them both ways -- sterile and non-sterile, but the non-sterile pads don't say that on the label."

Dolan continues, "This recall caused me to add an additional step when reviewing product labels. We should always look to see if the word 'sterile' is there and make note if it has any other descriptive words attached to it. If the word 'sterile' (alone) is not listed on a package, there's something in that package that's not sterile. As an example, one skin prep product package states that the applicator is sterile if the package is intact. So, I am trying to teach people that it's a clue when the term sterile has other words connected to it.  What we learned is that while the applicator is sterile, the fluid inside that applicator is not  -- you can take the applicator and put this on the sterile field, however, once you crack it and disperse the fluid, the fluid inside is not considered sterile. I think in the alcohol prep pad issue, we shouldn't have to wonder about sterility.  When these APPs were first manufactured, things were much different and it was acceptable by the FDA for them to be either sterile or non-sterile.  Healthcare has changed dramatically, the patient population is very different,  and the frequency and ways in which we use APPs has changed requiring the need for only sterile APPs to be manufactured.   Just think of the number of times we scrub the hub to avoid introducing organism into an intravascular catheter.  As for other antiseptics, I do think manufacturers should develop mechanisms to make their products sterile, but we are hearing from some of them that it's not possible because it will denature the active ingredient in the product.  There are manufacturers that have managed to make some of these products sterile.   We must ask at a minimum that the product label should clearly state whether a product is sterile or non-sterile. If we are not going to get to sterility, at least we need to get better labeling on the package so that users know what they are purchasing and using on their patients."

The FDA's Call for Information
At the public hearing held on Dec. 12, 2012, the FDA heard testimony from a variety of stakeholders, including product manufacturers, those representing healthcare facilities, healthcare professionals, and consumers who use these products. The FDA's panel of experts sought information and public comment on issues relating to intrinsic and extrinsic contamination to determine challenges to sterility and good manufacturing practices. At the hearing, manufacturers, policy analysts and clinicians indicated that it would be challenging to connect mandatory product sterility to a decrease in infections or adverse events associated with the use of skin prep products. What's more, they said that a requirement for sterility would create an expensive and burdensome proposition for manufacturers. These issues will be explored more fully in part 2 of this series.

In separate communications to the FDA, the Association for Professionals in Infection Control and Epidemiology (APIC) and the Society for Healthcare Epidemiologists of America (SHEA) expressed that the antiseptic prep product recalls may have surprised clinicians who assumed that all prep products were sterile. In a letter to the FDA, APIC president Patricia S. Grant, RN, BSN, MS, CIC, noted that the organization "believes that healthcare providers and consumers alike are not aware that patient pre-operative skin preparations are generally not sterile. We recommend that products be clearly labeled so it is obvious to the consumer if the product is sterile or not sterile. Consumers and healthcare personnel assume that APPs are sterile because non-sterile APPs are not labeled as such. A recent recall attributed to contamination with Bacillus cereus and Bacillus species was associated with the use of APPs that did not indicate that the product was not sterile and the users assumed they were sterile."

In its own letter to the FDA, Stephen W. Weber, MD, chair of SHEA's  Public Policy and Government Affairs Committee, said that "SHEA does not perceive consistent awareness by providers or consumers that pre-operative skin preparations are or are not marketed as sterile. Most applications of preoperative skin preparations involve procedures where there will be entry into the skin, vascular system, or to disinfect devices used to collect microbiologic specimens. We therefore feel these preparations need to be labeled clearly and we advocate for use of sterile products consistent with use of aseptic technique during the procedure. Measures to improve awareness involve labeling requirements for such products and perhaps additional language that directs users that, if not sterile, to avoid use for aseptic procedures. This will require input from manufacturers of such products and collaboration between them and the FDA."

APIC says it believes that "all skin preparation products should be manufactured to be sterile. While we are aware that research and work needs to be done to enable the production of sterile prep agents, APIC believes the time has come to begin those processes to provide sterile prep products. These agents are being used to eliminate, to the best of the healthcare sector's ability, the microbiological contamination of the skin prior to an invasive procedure (intravascular lines to surgical incision sites). These agents should provide protection rather than possible contamination."

SHEA agrees that products used for aseptic procedures need to be sterile, however, it acknowledges that sterilization of topical antiseptics is problematic: "We urge FDA to engage manufacturers however on the possible technical limitations of sterlizatiion of select topical antimicrobials such as chlorhexidine gluconate (CHG). According to a chapter on chlorhexidine by Denton GW in Block SS (ed) Disinfection, Sterilization, and Preservation (Lippincott Williams & Wilson, 2001), "autoclaving of solutions greater than 1.0 percent chlorhexidine can result in the formation of insoluable residues and is therefore unsuitable. " CHG in concentrations > 2 percent are currently available and are very effective antiseptics. We would not want a requirement of sterility of the CHG solution to lead to disruption in availability of this important antiseptic... There is a need to engage manufacturers however on this topic as we do not have expertise to discern whether all or some antiseptics would remain effective after sterilization. For example there may be some sterilization processes that could inactivate or compromise the antimicrobial activity of a particular antiseptic. Additional research is likely warranted on this as well as examination of the elements, e.g., time, concentration or microbial challenge, etc., involved in contamination of antiseptics. There is fairly limited evidence to date but manufacturers may have internal laboratory testing that could assist the FDA and the public with better understanding."

If terminal sterilization of certain antiseptic prep products is not viable, the dialogue shifts again to current good manufacturing practices.  As Grant notes in APIC's letter to the FDA, "The dependability of sound environmental and aseptic conditions during the manufacturing process is not controlled to the level required, and therefore heightens the concern for product contamination. The need for more stringent processing and product sterility, along with evidence of lack of product contamination at the completion of the manufacturing process is necessary."

APIC says the FDA must establish "clear science-based expectations and guidance for manufacture and sterility of skin preparation products. It is incumbent upon the FDA to provide oversight, enforcement, and adherence to those processes that enhance patient safety. This could include increasing the requirements for product testing to include organisms that are currently not part of the testing protocol. The continued contamination of surgical skin products and other products used in healthcare with Burkholderia cepacia as well as Bacillus species indicates that existing methods are insufficient to detect low levels of microbial growth. There needs to be a critical look at these testing criteria for manufacturers followed by development of enhanced requirements to cover the recurring contaminating organism culprits as well as the resistant organisms of great concern in healthcare today."

Scott Furness, director of the Division of Non-Prescription Regulation Development in the Office of Drug Evaluation IV within the FDA, explained at the Dec. 12, 2012 hearing that the agency's current good manufacturing practice regulations require manufacturers to have appropriate procedures in place to prevent the presence of objectionable organisms in drug products that are not manufactured as sterile. However, Furness adds, "It should be pointed out that the microbial limits test that's currently in use by most manufacturers, which is actually a USP test, may not detect very low levels of microbial contamination. And even more significantly, it does not screen for the types of intrinsically antiseptic-resistant organisms that we've already seen in these products, such as Burkholderia cepacia, as well as Bacillus cereus. What this means is that a product that passes the most commonly observed pre-market microbial limits test may still support the growth of contaminating microorganisms and may become the source of clinical infection."

Dolan says product testing is another important key to the issue, something she says she learned through personal experience when her facility saw an outbreak of Burkholderia cepacia complex linked to a contaminated nasal spray. Dolan and her colleagues conducted an epidemiologic investigation to identify possible causes for an apparent outbreak of B. cepacia complex in pediatric patients who had new positive cultures with this organism from December 2003 to February 2004. Chart review, microbiology reports, surgical records, site visits, literature review, staff interviews, and cultures of common products and equipment were performed to determine a source of contamination. Random amplified polymorphic DNA and pulsed-field gel electrophoresis typing, performed by two independent laboratories, were used for molecular typing of patient and source isolates. Five pediatric patients had new positive B. cepacia complex cultures from either the sinus or the respiratory tract, and all five patients had prior exposure to 0.05 percent oxymetazoline hydrochloride (Major Twice-A-Day 12-hour) nasal spray. Four of the five patients had isolates that were identical to the B. cepacia complex isolates recovered from the unopened nasal spray. Intrinsic contamination of this nasal spray with B. cepacia complex resulted in a voluntary product recall by the manufacturer.

"When we first cultured  the nasal spray, it didn't grow but we subsequently added an additional step to our methodology which involved using a neutralizing agent, Dey/Engley Neutralizing Broth, which neutralizes any preservative or active ingredient so that the organism will grow," Dolan says.  "That step is not routinely part of manufacturer testing processes for these types of products so I think there could be some improvement in the testing methods used prior to prodcut distribution. Even with supposedly sterile products, there should be some assurance through microbial testing in case something didn't go right with the sterilization process. It is an opportunity to potentially improve the science, learn how we can break that sterilization barrier for antiseptics, and figure out how we can do so in a cost-effective way so it is not too burdensome for the manufacturer as well as for those who have to purchase the product because costs are ultimately passed along to the end users."

Dolan adds, "The last thing we want to do is put an antiseptic on a patient's skin that could result in an infection. In reading some of the testimony that came out of the FDA hearing, there was comment around the fact thatsome experts didn't feel like the product needed to be sterile because the skin itself is not sterile.  We perform the skin prep procedure in an aseptic fashion and no, you can't sterilize the skin, but that does not seem like a logical reason to not require the skin prep product be sterile. I struggled with that logic because we need to avoid placing contaminated antiseptic skin solution on a patients skin prior to a procedure when the purpose of skin prep is to decrease the microbial load.   We know we can't sterilize the skin but let's not put additional organisms on the skin. The frequency with which products can become contaminated with certain organisms, and the fact that contaminated products are distributed by manufacturers because their testing is not able to identify those organisms, is alarming. Manufacturers are not doing it in bad faith, they are hopefully doing what the current FDA requirements dictate.  The comprehensiveness and rigor with which the microbial testing is conducted is not really well standardized and I think it needs to be improved."

Central to this issue is the debate about the role that skin and its natural flora play in the development of infection, since a patient's normal skin flora is part of the host's defense mechanism and can serve as a protective barrier when intact. But when the skin has been compromised, such as around a catheter port, or when the skin has been punctured during an injection, delivering even a small number of microorganisms to the site can be disastrous. While skin cannot be sterilized, experts are debating the need for skin prep products to be sterile. At the FDA hearing, Bhaveen Kapadia from the Rubin Institute of Advanced Orthopedics at Sinai Hospital, addressed whether or not antiseptic preoperative preparations require sterilization: "Basically we want to see what are the potential sources that we could have contamination of these preoperative solutions," he says. "Of course, you could have contaminated water sources, contaminated sources such as the cloth and material, as well as contaminated packaging from the manufacturing company itself. Now, is this enough to warrant sterilization? We don't believe that sterilization is necessary for preoperative antiseptic preparations. Manufacturing facilities are typically low risk for harboring multidrug-resistant organisms as compared to hospital institutions.... The literature has not really demonstrated that there is any iatrogenic infection following the use of preoperative scrubs."

Kapadia explained that he and his colleagues recently conducted a prospective randomized trial (180 subjects) in which patients using non-sterile chlorhexidine scrubs were compared to patients who did not use them. They found six infections in the group of patients not using chlorhexidine compared to zero in the group that did use chlorhexidine gluconate the night before and the morning of surgery. Observed Kapadia, "We believe that sterilization may add an unnecessary process to the manufacturing company and could potentially increase the cost to the patient as well as to the institution, which could prevent its widespread distribution and potential benefits of helping to reduce the instances of surgical site infections."

Kapadia added, "The literature has demonstrated some evidence of contaminated liquids, antiseptic agents; however, it's uncertain whether this has occurred intrinsically or extrinsically. We believe that it's more likely the extrinsic contamination that could occur from dilution in the hospital environment and pharmacy environment that is more likely to do that, more specifically because the manufacturing agencies themselves are at low risk for harboring multidrug-resistant organisms. The clinical evidence from our hospital has demonstrated that no patients have had infections using chlorhexidine gluconate cloths, and these are, of course, non-sterile cloths that we have our patients use the night before surgery."

Christina Chang, medical officer in the Division of Non-Prescription Clinical Evaluation, one of the FDA panelists at the Dec. 12, 2012 hearing, asked Kapadia if, in the case of a post-operative infection, he had looked to antiseptic prep products as the potential source of the infection. Kapadia noted that it would be challenging to identify the actual contaminating solution, noting, "Obviously, most surgical site infections are from the endogenous skin flora. So it's difficult to, at that point, determine whether or not it was the preoperative preparation we used."

It is important to note that the original recalls focused on contaminated alcohol prep products, not chlorhexidine skin prep products, and this will be examined in more detail in part 2 of this series.

As we have seen, intrinsic contamination is key to the dialogue; however,  no discussion is complete without further examining extrinsic contamination, wherein products manufactured sterile can be contaminated as soon as they are opened for the first time. While manufacturers bear responsibility for intrinsic contamination, clinicians are urged to use utmost care at the point of use in order to prevent extrinsic contamination.  To reduce this risk of extrinsic contamination of patient preoperative skin preparations, APIC recommends that manufacturers "produce single-use size containers, which are cost effective to use, as well as provide appropriate labeling for sterility factors, proper storage, and use and disposal guidance. It would be a proactive patient safety design for manufacturers to develop product that would not allow a previously opened product to be reclosed, or to place a container down on a surface in order to avoid contamination caused by contact with that surface. Healthcare providers need to adhere to proper storage, use and disposal guidance. Internal inspections of healthcare facilities should include attention to adherence to expiration dates proper disposal after opening, and proper aseptic product use. Additionally, surveillance by healthcare providers for infections and complications related to improper use or contaminated products needs to occur."

It is also important to remember that the conversation about antiseptic prep products must address the realities of dilution, mixing and repackaging that may occur, either in healthcare settings or in the home healthcare environment. As APIC notes, "Healthcare providers should follow manufacturers directions for dilution, mixing and repackaging. The expectation would be that such manipulation would be performed aseptically. APIC does not support the adulteration of any product outside of the manufacturers directions or recommendations."

The once-only usage of single-use products should be evident to clinicians; however, more education is warranted especially if multiple-use patient preoperative skin preparations are used. As APIC notes in its letter to the FDA, "APIC believes that healthcare facilities in general do train and educate to proper aseptic techniques in handling any patient product, single-use or multiple-use. However, ongoing reinforcement of proper procedures is needed, especially in non-acute healthcare settings that may not be overseen by internal and regulatory agencies to help enforce these aseptic approaches. Some healthcare facilities, despite cost escalation and in the absence of single-use products, have begun to use multi-use designated products as single-use only in an attempt to eliminate possible contamination risks. This adds to the cost of healthcare for patients." And SHEA notes, " Some additional efforts are needed however among the range of health professionals as lapses in aseptic technique have been identified too often across the continuum that resulted in iatrogenic exposure of patients to pathogens that could have been avoided."

Correlation of an intervention to a direct decrease in infection rates is the Holy Grail in infection prevention, but establishing causation can be elusive. At the FDA hearing, some experts questioned if an FDA mandate for sterility of antiseptic skin prep products could actually produce verifiable reductions in infections or the prevention of adverse events.  "I think it's a fair statement to say this correlation is difficult to prove at this time because there's an absence of evidence on SSI risk in well-controlled studies," Dolan says. "It's not that it doesn't exist, it's just that we don't have well-controlled studies, yet we have numerous published outbreaks that have been associated with contaminated products. Most of these studies have been related to Mycobacteria or Gram-negative organisms such as Burkholderia cepacia.  Surgical instruments have to be sterile and yet skin prep products don't have that same standard. These organisms found in contaminated skin prep products are very serious. People have died from Burkholderia cepacia, and with Bacillus cereus, we say, 'Be serious about B. cereus.' If manufacturers currently can't make their products sterile, let's package them single-patient use, and let's be aware of contamination at the point of use. IPs can help spread this message but the bottom line for me is, if there's a sterile alternative then we need to strongly advocate for using that product. What we can glean from the numerous recalls and this FDA hearing is generally more awareness about sterility issues, better, clearer labeling, and better testing of these products at the manufacturers' level, with more robust testing for quality assurance. We don't have authority over the manufacturers, but as IPs we can try to influence the FDA and others to understand the urgency and importance of sterility in healthcare today."

Dolan says IPs can use the numerous recalls to raise awareness about aseptic practices and the vigilance needed to prevent product contamination. "IPs have a strong voice in their institutions and in their communities," she says. "They also have the perfect skill sets with which to identify these concerns, educate our constituents and provide information to the higher levels. I was elated to see there was an FDA hearing on the subject but when I read the transcript of the proceedings I was cautious and yet pleased this issue is in the spotlight  -- any attention to the topic is warranted and it's terrific that at that level people came to the table to discuss a very important issue.  I hope that this momentum is sustained and the issue remains in the forefront for the sake of patient safety."


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