Advanced Compounding; How to Investigate Microbiological Excursions at a Sterile Compounding Facility.

Per United States Pharmacopeia Chapter <797>, effective November 1, 2023, uncovering non-conforming cleanroom microbiological conditions must be investigated thoroughly and in a timely manner. This article's objective is to outline the basic elements in investigating microbiological excursions at a sterile compounding facility, which models the use of an Ishakawa diagram to conduct a root cause investigation and discusses important concepts such as: product impact analysis, corrective and preventive action effectiveness checks, trend analysis, and investigational pitfalls to avoid. While this article focuses on investigating microbiological excursions, the concepts can be applied to investigating an out-of-range temperature, relative humidity, pressure differential, total particle count, or compounded sterile preparation failure.

Considerations in Qualifying Critical Suppliers.

The impending updates to United States Pharmacopeia Chapter <797> and Chapter <795> specify that compounders must obtain active pharmaceutical ingredients and should obtain excipients from FDA-registered facilities. Additionally, the U.S. Food and Drug Administration cautions compounders to know their bulk active pharmaceutical ingredients and excipients suppliers. While the U.S. Food and Drug Administration expects 503B outsourcing facilities to qualify their critical suppliers, pharmacy boards and accrediting bodies are beginning to ask 503A compounders for their list of approved suppliers and how they qualify them. As such, pharmacies should become comfortable in qualifying suppliers as part of their quality assurance program. This article discusses how pharmacies can apply the elements of supplier qualification to their practice to ensure that critical supplies and services meet company specifications for quality and compliance.

Sterile Basics: How to Know if Your Cleanroom Can Consistently Operate Within a State of Control.

Whether sterile compounds are prepared in a brand new state-of-the-art cleanroom suite or in an aging space, compounders rely heavily on their primary and secondary engineering controls when sterilizing or maintaining sterility of the final preparation. With the release of the latest revision to United States Pharmacopeia Chapter <797>, organizations that prepare sterile compounds must now sample and test each classified area for the presence of microbiological contaminants at a higher frequency. Facilities that are not purpose-built, as well as those that do not operate within a state of control, are predicted to repeatedly exceed action levels as set by the United States Pharmacopeia Convention, Inc. Before the United States Pharmacopeia revision becomes active and enforceable, it is advised that sterile compounding practice sites undergo an environmental-baseline study to gather statistically significant data to demonstrate how the cleanroom(s) perform and to assess whether or not dynamic operations increase the levels of bioburden.

Sterile Basics of Compounding: How to Implement a Robust Visual-inspection Program.

Dispensing compounded sterile injectable drug preparations that contain particulates can have serious patient-safety implications. While there is a lack of controlled human studies to demonstrate the clinical concerns that particles can be carriers for microbiological contamination, they have been shown to potentially block blood vessels. Anecdotal studies found that foreign body emboli and granulomas are the most common result of particulate matter present in intravenous solutions. The compounding of absolutely particle-free injectable preparations is nearly impossible under real-life conditions. Hence, inspection of each filled and sealed compounded injectable drug before it is labeled and dispensed is mandatory. To avoid a noncompliance observation, this article aims to outline the regulatory expectations, visual inspector training and qualification program, and adequate visual-inspection procedures and equipment.

Sterile Basics of Compounding: Contamination Control Strategies, Part 1.

Compounded sterile preparations are required to be at the very least sterile. If not, the parenteral administration of such a preparation can cause serious patient harm, even death. Therefore, cleanroom contamination control strategies must be employed to protect the final preparation and the patient. This article is part one of a two-part series describing a holistic and multi-faceted approach to implementing basic cleanroom contamination control strategies at sterile compounding facilities so that safer pharmaceutical compounds are produced. This segment uncovers where cleanroom contamination comes from, the costs and implications associated with cleanroom contamination, and focuses on the various facility controls required to prevent the ingress of contaminants and cross-contamination. The second part concentrates on personnel and processes that support the same initiative.

Sterile Basics of Compounding: Contamination Control Strategies, Part 2.

Compounded sterile preparations are required to be at the very least sterile. If not, the parenteral administration of such a preparation can cause serious patient harm, even death. Therefore, cleanroom contamination-control strategies must be employed to protect the final preparation and the patient. This article is part two of a two-part series describing a holistic and multi-faceted approach to implementing basic cleanroom contamination-control strategies at sterile compounding facilities so that safer pharmaceutical compounds are produced. The first segment uncovered the origin of cleanroom contamination, the various facility controls required to prevent the ingress of contaminants and cross-contamination, and the costs and implications associated with cleanroom contamination. This second part concentrates on personnel and processes that support the same initiative.

Quality Control: How to Produce a Well-closed Sealed Vial in a Regulated CGMP Environment: Part 1.

Container closure integrity provides assurance that compounded sterile preparation quality attributes are met throughout its shelf life. Since compounded sterile preparations lacking container-closure integrity are considered adulterated as per the Federal Food, Drug and Cosmetic Act and are therefore unsafe for patient use, compounders must be able to produce a well-closed sealed vial. Furthermore, 503B outsourcing facilities must qualify the capping process as described by the proposed "Current Good Manufacturing Practice - Guidance for Human Drug Compounding Outsourcing Facilities Under Section 503B of the Federal Food, Drug and Cosmetic Act Guidance for Industry." This article is the first in a series describing vial crimping and capping equipment selection and the qualification necessary to create a well-closed sealed vial in a Current Good Manufacturing Practice environment to ensure patient safety and maintain compliance.

Quality Control: How to Produce a Well-closed Sealed Vial in a Regulated CGMP Environment: Part 2.

Container-closure integrity provides assurance that compounded sterile preparation quality attributes are met throughout its shelf life. Since compounded sterile preparations lacking container-closure integrity are considered adulterated as per the Federal Food, Drug and Cosmetic Act and are therefore unsafe for patient use, compounders must be able to produce a well closed sealed vial. Furthermore, 503B outsourcing facilities must qualify the capping process as described by the proposed "Current Good Manufacturing Practice - Guidance for Human Drug Compounding Outsourcing Facilities Under Section 503B of the Federal Food, Drug and Cosmetic Act Guidance for Industry." This article is the second in a series describing vial crimping and capping equipment selection and the qualification necessary to create a well-closed sealed vial in a Current Good Manufacturing Practice environment to ensure patient safety and maintain compliance.

Interdisciplinary Education Apartment Simulation (IDEAS) Project: An Interdisciplinary Simulation for Transitional Home Care.

Introduction: Home-based care (HBC) is a valuable tool to provide care to rural, medically underserved populations. By mitigating geographic and transportation barriers for vulnerable populations, HBC is a promising modality of health care delivery. Interprofessional education has become an integral part in undergraduate and professional curricula; however, applications of team-based training in HBC are often missing from curricula. When included, instruction in HBC often utilizes didactic instruction or laboratory experiences, which are discipline-specific and lack a focus on integration of team-based care. Methods: We implemented a standardized patient (SP) simulation of a posthospital discharge home visit using a team of learners from nursing, physical therapy (PT), occupational therapy (OT), dentistry, pharmacy, and medicine in a simulated home environment. Pre- and postsimulation competencies of interprofessional care were measured using the 20-item Interprofessional Collaborative Competency Attainment Survey (ICCAS). Results: Throughout the academic years of August 2018 - August 2020, 68 students from nursing, PT, OT, pharmacy, medicine, and dentistry completed a simulated home visit with an SP discharged from a hospital. For all 20 perceived abilities on the ICCAS, learners showed a statistically significant increase in postsurvey measurement. A modest to large (.31 ≤ r ≤ .94) effect size was observed in the majority of responses. Discussion: This SP simulation described a novel, interdisciplinary approach to incorporating HBC into interprofessional curricula.

In vitro activity of the aminoglycoside antibiotic arbekacin against Acinetobacter baumannii-calcoaceticus isolated from war-wounded patients at Walter Reed Army Medical Center.

We determined the in vitro MIC of arbekacin against 200 Acinetobacter isolates recovered from wounded soldiers. The median MIC was 2 microg/ml (range, 0.5 to > 64 microg/ml). A total of 97.5% of the isolates had arbekacin MICs of < 8 microg/ml and 86.5% had MICs of < or = 4 microg/ml. There was no association between the arbekacin MIC and susceptibility to 16 other antibiotics or the specimen source (P = 0.7239). Synergy testing suggested an enhanced effect of arbekacin-carbapenem combinations.

Ertapenem susceptibility of extended spectrum beta-lactamase-producing organisms.

BACKGROUND: Infections caused by multiply drug resistant organisms such as extended spectrum beta-lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae are increasing. Carbapenems (imipenem and meropenem) are the antibiotics commonly used to treat these agents. There is limited clinical data regarding the efficacy of the newest carbapenem, ertapenem, against these organisms. Ertapenem susceptibility of ESBL-producing E. coli and K. pneumoniae clinical isolates were evaluated and compared to imipenem to determine if imipenem susceptibility could be used as a surrogate for ertapenem susceptibility. METHODS: 100 ESBL isolates (n = 34 E. coli and n = 66 K. pneumoniae) collected from 2005-2006 clinical specimens at WRAMC were identified and tested for susceptibility by Vitek Legacy [bioMerieux, Durham, NC]. Ertapenem susceptibility was performed via epsilometer test (E-test) [AB Biodisk, Solna, Sweden]. RESULTS: 100% of ESBL isolates tested were susceptible to ertapenem. 100% of the same isolates were also susceptible to imipenem. CONCLUSION: These results, based on 100% susceptibility, suggest that ertapenem may be an alternative to other carbapenems for the treatment of infections caused by ESBL-producing E. coli and K. pneumoniae. Clinical outcomes studies are needed to determine if ertapenem is effective for the treatment of infection caused by these organisms. However, due to lack of resistant isolates, we are unable to conclude whether imipenem susceptibility accurately predicts ertapenem susceptibility.

Draft Genome Sequences of Klebsiella pneumoniae Clinical Type Strain ATCC 13883 and Three Multidrug-Resistant Clinical Isolates.

Klebsiella pneumoniae is a Gram-negative human pathogen capable of causing hospital-acquired infections with an increasing risk to human health. The total DNA from four clinically relevant strains was sequenced to >100× coverage, providing high-quality genome assemblies for K. pneumoniae strains ATCC 13883, KP4640, 101488, and 101712.

AB5075, a Highly Virulent Isolate of Acinetobacter baumannii, as a Model Strain for the Evaluation of Pathogenesis and Antimicrobial Treatments.

UNLABELLED: Acinetobacter baumannii is recognized as an emerging bacterial pathogen because of traits such as prolonged survival in a desiccated state, effective nosocomial transmission, and an inherent ability to acquire antibiotic resistance genes. A pressing need in the field of A. baumannii research is a suitable model strain that is representative of current clinical isolates, is highly virulent in established animal models, and can be genetically manipulated. To identify a suitable strain, a genetically diverse set of recent U.S. military clinical isolates was assessed. Pulsed-field gel electrophoresis and multiplex PCR determined the genetic diversity of 33 A. baumannii isolates. Subsequently, five representative isolates were tested in murine pulmonary and Galleria mellonella models of infection. Infections with one strain, AB5075, were considerably more severe in both animal models than those with other isolates, as there was a significant decrease in survival rates. AB5075 also caused osteomyelitis in a rat open fracture model, while another isolate did not. Additionally, a Tn5 transposon library was successfully generated in AB5075, and the insertion of exogenous genes into the AB5075 chromosome via Tn7 was completed, suggesting that this isolate may be genetically amenable for research purposes. Finally, proof-of-concept experiments with the antibiotic rifampin showed that this strain can be used in animal models to assess therapies under numerous parameters, including survival rates and lung bacterial burden. We propose that AB5075 can serve as a model strain for A. baumannii pathogenesis due to its relatively recent isolation, multidrug resistance, reproducible virulence in animal models, and genetic tractability. IMPORTANCE: The incidence of A. baumannii infections has increased over the last decade, and unfortunately, so has antibiotic resistance in this bacterial species. A. baumannii is now responsible for more than 10% of all hospital-acquired infections in the United States and has a >50% mortality rate in patients with sepsis and pneumonia. Most research on the pathogenicity of A. baumannii focused on isolates that are not truly representative of current multidrug-resistant strains isolated from patients. After screening of a panel of isolates in different in vitro and in vivo assays, the strain AB5075 was selected as more suitable for research because of its antibiotic resistance profile and increased virulence in animal models. Moreover, AB5075 is susceptible to tetracycline and hygromycin, which makes it amenable to genetic manipulation. Taken together, these traits make AB5075 a good candidate for use in studying virulence and pathogenicity of this species and testing novel antimicrobials.

Detection of qacA/B in clinical isolates of methicillin-resistant Staphylococcus aureus from a regional healthcare network in the eastern United States.

We describe the clinical, microbiologic, and molecular features of the first series of qacA/B-containing strains of methicillin-resistant Staphylococcus aureus from infected US patients. All qac-carrying strains were clonally diverse, and qacA strains exhibited increased tolerance to chlorhexidine as measured by minimum inhibitory concentrations, minimum bactericidal concentrations, and postexposure colony counts.

Capsular serotype of Staphylococcus aureus in the era of community-acquired MRSA.

Capsular polysaccharide (CP) plays an important role in the pathogenicity and immunogenicity of Staphylococcus aureus, yet the common serotypes of S. aureus isolated from US pediatric patients have not been reported. We investigated capsular serotype as well as methicillin susceptibility, presence of Panton-Valentine leukocidin (PVL), and clonal relatedness of pediatric S. aureus isolates. Clinical isolates were tested for methicillin susceptibility, presence of mecA, lukS-PV and lukF-PV, cap5 and cap8 genes by PCR, and for capsular or surface polysaccharide expression (CP5, CP8, or 336 polysaccharide) by agglutination. Genetic relatedness was determined by pulsed-field gel electrophoresis. All S. aureus isolates encoded cap5 or cap8. Sixty-nine percent of 2004-2005 isolates were methicillin-susceptible (MSSA) and most expressed a detectable capsule. The majority of MRSA isolates (82%) were unencapsulated, exposing an expressed cell wall techoic acid antigen 336. Pulsed-field type USA300 were MRSA, PVL-positive, unencapsulated strains that were associated with deep skin infections and recurrent disease. Over half (58%) of all isolates from invasive pediatric dermatologic infections were USA300. All pediatric isolates contained either capsule type 5 or capsule type 8 genes, and roughly half of the S. aureus clinical disease isolates from our population were diverse MSSA-encapsulated strains. The majority of the remaining pediatric clinical disease isolates were unencapsulated serotype 336 strains of the PVL(+) USA300 community-associated-MRSA clone.

High incidence of multidrug-resistant gram-negative bacteria recovered from Afghan patients at a deployed US military hospital.

OBJECTIVE: To investigate potential sources and risks associated with multidrug-resistant (MDR) bacteria in a deployed US military hospital. DESIGN: Retrospective analysis of factors associated with recovery of MDR bacteria, supplemented by environmental sampling. SETTING: The largest US military hospital in Afghanistan. PATIENTS: US and Afghan patients with positive bacterial culture results, from September 2007 through August 2008. METHODS: Microbiologic, demographic, and clinical data were analyzed. Potential risk factors included admission diagnosis or mechanism of injury, length of stay, gender, age, and nationality (US or Afghan). Environmental sampling of selected hospital high-touch surfaces and equipment was performed to help elucidate whether environmental MDR bacteria were contributing to nosocomial spread. RESULTS: A total of 266 patients had 411 bacterial isolates that were identified during the study period, including 211 MDR bacteria (51%). Gram-negative bacteria were common among Afghan patients (241 [76%] of 319), and 70% of these were classified as MDR. This included 58% of bacteria recovered from Afghan patients within 48 hours of hospital admission. The most common gram-negative bacteria were Escherichia coli (53% were MDR), Acinetobacter (90% were MDR), and Klebsiella (63% were MDR). Almost one-half of potential extended-spectrum ß-lactamase (ESBL) producers were community acquired. Of 100 environmental swab samples, 18 yielded MDR bacteria, including 10 that were Acinetobacter, but no potential ESBL-producing bacteria. CONCLUSIONS: Gram-negative bacteria from Afghan patients had high rates of antimicrobial resistance. Patients experiencing complex trauma and prolonged hospital stays likely contribute to the presence of MDR bacteria in this facility. However, many of these patients had community-acquired cases, which implies high rates of colonization prior to hospital admission.

Natural history of colonization with gram-negative multidrug-resistant organisms among hospitalized patients.

OBJECTIVE: To determine the anatomic sites and natural history of colonization with gram-negative multidrug-resistant organisms (MDROs). DESIGN: Prospective, longitudinal cohort study. SETTING: Walter Reed Army Medical Center, a 236-bed tertiary care center in Washington, DC. PATIENTS: Deployed subjects (ie, inpatients medically evacuated from Iraq or Afghanistan) or nondeployed subjects admitted to the same hospital. METHODS: Consenting patients had 6 anatomic sites cultured every 3 days for 2 weeks and then weekly. Gram-negative organisms resistant to 3 or more classes of antibiotics were considered MDROs. Isolates were genotyped using pulsed-field gel electrophoresis. Clinical data, data on antibiotic use, and clinical culture results were collected. RESULTS: Of 60 deployed subjects, 14 (23%) were colonized with an MDRO at admission, and 13 (22%) had incident colonization during hospitalization. The groin was the most sensitive anatomic site for detecting MDRO colonization, and all but one subject remained colonized for the duration of their hospitalization. Sixty percent of subjects with incident Acinetobacter colonization and 25% of subjects with incident Klebsiella colonization had strains that were related to those isolated from other subjects. Of 60 nondeployed subjects, 5 (8%) were colonized with an MDRO at admission; all had recent healthcare contact, and 1 nondeployed subject had an isolate related to a strain recovered from a deployed subject. CONCLUSIONS: Colonization with gram-negative MDROs is common among patients with war-related trauma admitted to a military hospital and also occurs among nondeployed patients with recent healthcare contact. The groin is the most sensitive anatomic site for active surveillance, and spontaneous decolonization is rare.