Antimicrobial Shortages Research Articles

Antimicrobial Shortages: A Global Issue Impacting Infectious Diseases.

Shortages of antimicrobial agents rank second among all pharmaceutical classes and are persistent and increasing. Underlying reasons for shortages include manufacturing and quality issues, market economics, and changes in demand. Antimicrobial shortages result in compromised outcomes, higher treatment costs, contribute to antibiotic resistance, and may lead to increased adverse effects.

Preserving Resources: The Vital Role of Antimicrobial Stewardship Programs in Mitigating Antimicrobial Shortages

Preserving Resources: The Vital Role of Antimicrobial Stewardship Programs in Mitigating Antimicrobial Shortages

The impact of meropenem shortage and post-prescription review and feedback on broad-spectrum antimicrobial use: An interrupted time-series analysis

Meropenem (MEPM) holds significance in treating severe infections and drug-resistant bacteria. There are concerns that antimicrobial shortages may lead to the use of alternative antimicrobials that are less effective and safer. We have responded to the MEPM shortage with post-prescription monitoring and feedback (PPRF) with no restrictions on MEPM initiation. We aimed to assess the impact of the MEPM shortage and the PPRF on broad-spectrum antimicrobial use and mortality. This retrospective study was conducted in a single hospital in Japan. The period from October 2021 to August 2022 was defined as the period before the MEPM shortage, and the period from September 2022 to March 2023 was defined as the period during the MEPM shortage. To support the appropriate use of antimicrobials during MEPM shortages, the antimicrobial stewardship team (AST) developed a list of alternatives to MEPM. An interrupted time series analysis was used to assess changes in use and mortality among patients receiving broad-spectrum antimicrobials over the study period. The shortage of MEPM and PPRF temporarily increased the use of alternative cefepime; however, the subsequent change in days of therapy and days of coverage of broad-spectrum antimicrobials suggests a decrease in the use of these antimicrobials. Despite these shifts, the mortality rates remained stable, suggesting that the response to the shortage did not adversely affect treatment outcomes. In the context of antimicrobial shortages, AST support plays an important role in enabling physicians to make optimal use of antimicrobials.

Culturable Streptomyces spp. from high-altitude, oligotrophic North Western Himalaya: a comprehensive study on the diversity, bioactivity and insights into the proteome of potential species.

The increasing global concern of antimicrobial resistance and shortage of new antimicrobials necessitates exploring untapped terrestrial environments for new bioactive microbiome diversity. The low-temperature and oligotrophic North Western Himalaya (NWH) region has a vast diversity of Streptomyces with potential antimicrobial properties that remain largely unexplored. This study evaluates the diversity of culturable Streptomyces from high-altitude NWH and their potential as a source of new antimicrobials through genus-specific isolation and identification. The results demonstrate a distinct phylogenetic clustering of Streptomyces from different sampling regions of NWH, site-specific variation in culturable β-diversity and species commonness with varying intersite bioactivity among different sites. Further, the study optimized the media selection for large-scale culture cultivation in antibiotic production processes and demonstrated the antimicrobial efficacy of Streptomyces against a range of pathogens through in vitro bioassays using minimum inhibitory concentration determination and antibiofilm activity. Untargeted label-free proteomic profiling also revealed variable expression of stress-response proteins and antibiotic regulators as a competitive survival strategy for selective antagonistic Streptomyces. The findings highlight the potential of NWH in augmenting antimicrobial discovery and combating antimicrobial resistance through the isolation and study of novel bioactive Streptomyces.

Design, Synthesis, and Evaluation of New 1H-Benzo[d]imidazole Based PqsR Inhibitors as Adjuvant Therapy for Pseudomonas aeruginosa Infections.

Pseudomonas aeruginosa is one of the top priority pathogens that requires immediate attention according to the World Health Organisation (WHO). Due to the alarming shortage of novel antimicrobials, targeting quorum sensing (QS), a bacterial cell to cell signaling system controlling virulence, has emerged as a promising approach as an antibiotic adjuvant therapy. Interference with the pqs system, one of three QS systems in P. aeruginosa, results in reduction of bacterial virulence gene expression and biofilm maturation. Herein, we report a hit to lead process to fine-tune the potency of our previously reported inhibitor 1 (IC50 3.2 μM in P. aeruginosa PAO1-L), which led to the discovery of 2-(4-(3-((6-chloro-1-isopropyl-1H-benzo[d]imidazol-2-yl)amino)-2-hydroxypropoxy)phenyl)acetonitrile (6f) as a potent PqsR antagonist. Compound 6f inhibited the PqsR-controlled PpqsA-lux transcriptional reporter fusion in P. aeruginosa at low submicromolar concentrations. Moreover, 6f showed improved efficacy against P. aeruginosa CF isolates with significant inhibition of pyocyanin, 2-alkyl-4(1H)-quinolones production.

An Insurance Value Modeling Approach That Captures the Wider Value of a Novel Antimicrobial to Health Systems, Patients, and the Population.

Background: Traditional health economic evaluations of antimicrobials currently underestimate their value to wider society. They can be supplemented by additional value elements including insurance value, which captures the value of an antimicrobial in preventing or mitigating impacts of adverse risk events. Despite being commonplace in other sectors, constituents of the impacts and approaches for estimating insurance value have not been investigated. Objectives: This study assessed the insurance value of a novel gram-negative antimicrobial from operational healthcare, wider population health, productivity, and informal care perspectives. Methods: A novel mixed-methods approach was used to model insurance value in the United Kingdom: (1) literature review and multidisciplinary expert workshops to identify risk events for 4 relevant scenarios: ward closures, unavoidable shortage of conventional antimicrobials, viral respiratory pandemics, and catastrophic antimicrobial resistance (AMR); (2) parameterizing mitigable costs and frequencies of risk events across perspectives and scenarios; (3) estimating insurance value through a Monte Carlo simulation model for extreme events and a dynamic disease transmission model. Results: The mean insurance value across all scenarios and perspectives over 10 years in the UK was £718 million, should AMR remain unchanged, where only £134 million related to operational healthcare costs. It would be 50%-70% higher if AMR steadily increased or if a more risk-averse view (1-in-10 year downside) of future events is taken. Discussion: The overall insurance value if AMR remains at current levels (a conservative projection), is over 5 times greater than insurance value from just the operational healthcare costs perspective, traditionally the sole perspective used in health budgeting. Insurance value was generally larger for nationwide or universal (catastrophic AMR, pandemic, and conventional antimicrobial shortages) rather than localized (ward closure) scenarios, across perspectives. Components of this insurance value match previously published estimates of operational costs and mortality impacts. Conclusions: Insurance value of novel antimicrobials can be systematically modeled and substantially augments their traditional health economic value in normal circumstances. These approaches are generalizable to similar health interventions and form a framework for health systems and governments to capture broader value in health technology assessments, improve healthcare access, and increase resilience by planning for adverse scenarios.

An Insurance Value Modeling Approach That Captures the Wider Value of a Novel Antimicrobial to Health Systems, Patients, and the Population

Background: Traditional health economic evaluations of antimicrobials currently underestimate their value to wider society. They can be supplemented by additional value elements including insurance value, which captures the value of an antimicrobial in preventing or mitigating impacts of adverse risk events. Despite being commonplace in other sectors, constituents of the impacts and approaches for estimating insurance value have not been investigated. Objectives: This study assessed the insurance value of a novel gram-negative antimicrobial from operational healthcare, wider population health, productivity, and informal care perspectives. Methods: A novel mixed-methods approach was used to model insurance value in the United Kingdom: (1) literature review and multidisciplinary expert workshops to identify risk events for 4 relevant scenarios: ward closures, unavoidable shortage of conventional antimicrobials, viral respiratory pandemics, and catastrophic antimicrobial resistance (AMR); (2) parameterizing mitigable costs and frequencies of risk events across perspectives and scenarios; (3) estimating insurance value through a Monte Carlo simulation model for extreme events and a dynamic disease transmission model. Results: The mean insurance value across all scenarios and perspectives over 10 years in the UK was £718 million, should AMR remain unchanged, where only £134 million related to operational healthcare costs. It would be 50%-70% higher if AMR steadily increased or if a more risk-averse view (1-in-10 year downside) of future events is taken. Discussion: The overall insurance value if AMR remains at current levels (a conservative projection), is over 5 times greater than insurance value from just the operational healthcare costs perspective, traditionally the sole perspective used in health budgeting. Insurance value was generally larger for nationwide or universal (catastrophic AMR, pandemic, and conventional antimicrobial shortages) rather than localized (ward closure) scenarios, across perspectives. Components of this insurance value match previously published estimates of operational costs and mortality impacts. Conclusions: Insurance value of novel antimicrobials can be systematically modeled and substantially augments their traditional health economic value in normal circumstances. These approaches are generalizable to similar health interventions and form a framework for health systems and governments to capture broader value in health technology assessments, improve healthcare access, and increase resilience by planning for adverse scenarios.

In vitro and in vivo susceptibility to cefalexin and amoxicillin/clavulanate in canine low-level methicillin-resistant Staphylococcus pseudintermedius.

Methicillin-resistant Staphylococcus pseudintermedius (MRSP) lineages harbouring staphylococcal cassette chromosome (SCC) mec types IV, V and ΨSCCmec57395 usually display low oxacillin MICs (0.5-2 mg/L). To evaluate how oxacillin MICs correlate with PBP mutations and susceptibility to β-lactams approved for veterinary use. Associations between MICs and PBP mutations were investigated by broth microdilution, time-kill and genome sequence analyses in 117 canine MRSP strains harbouring these SCCmec types. Clinical outcome was retrospectively evaluated in 11 MRSP-infected dogs treated with β-lactams. Low-level MRSP was defined by an oxacillin MIC <4 mg/L. Regardless of strain genotype, all low-level MRSP isolates (n = 89) were cefalexin susceptible, whereas no strains were amoxicillin/clavulanate susceptible according to clinical breakpoints. Exposure to 2× MIC of cefalexin resulted in complete killing within 8 h. High (≥4 mg/L) oxacillin MICs were associated with substitutions in native PBP2, PBP3, PBP4 and acquired PBP2a, one of which (V390M in PBP3) was statistically significant by multivariable modelling. Eight of 11 dogs responded to systemic therapy with first-generation cephalosporins (n = 4) or amoxicillin/clavulanate (n = 4) alone or with concurrent topical treatment, including 6 of 7 dogs infected with low-level MRSP. Oxacillin MIC variability in MRSP is influenced by mutations in multiple PBPs and correlates with cefalexin susceptibility. The expert rule recommending that strains with oxacillin MIC ≥0.5 mg/L are reported as resistant to all β-lactams should be reassessed based on these results, which are highly clinically relevant in light of the shortage of effective antimicrobials for systemic treatment of MRSP infections in veterinary medicine.

Supply-chain factors and antimicrobial stewardship.

Efficient and secure supply chains are vital for effective health services worldwide. In low- and middle-income countries, the accessibility, affordability and availability of essential medicines, including antimicrobials, remain challenging. Ineffective supply chains often cause antimicrobial shortages, leading to inappropriate use of alternative agents and increasing the risk of antimicrobial resistance. Shortages, coupled with insecure supply chains, also encourage the infiltration of substandard and falsified medicines, leading to suboptimal treatment and further promoting antimicrobial resistance. Addressing antimicrobial supply-chain issues should be considered a key component of antimicrobial stewardship programmes. We have explored the link between medicine supply chains and antimicrobial use in seven focus countries: Kenya, Malawi, Nigeria, Sierra Leone, Uganda, United Republic of Tanzania and Zambia. We explored country medicine supply-system structures, national medicine supply-chain policy documents and global study reports. Our aim was to develop evidence-based strategies to enhance the effectiveness and efficiency of the medicine supply chains in supporting antimicrobial stewardship efforts. Better management of medical supply chains involves rational selection, quantification, forecasting, procurement, storage, distribution, use and stock management of antimicrobials. Important supply-chain considerations include pooled procurement networks to ensure consistent pricing of quality-assured antimicrobials, and improved resource utilization and information exchange among relevant stakeholders. We propose adaptable recommendations for integrating medicine supply chains as an essential part of antimicrobial stewardship programmes, with a call for action at the local, regional and national levels in low- and middle-income countries.

1005. Financial and clinical impact of ceftolozane/tazobactam global recall on the treatment of multi-drug resistant Pseudomonas in a large health system

Abstract Background In December 2020, ceftolozane/tazobactam (CT) was voluntarily recalled due to failed sterility tests. With this recall, clinicians were forced to utilize alternatives for multi-drug resistant (MDR) Pseudomonas (PSA) infections until CT returned in late December, 2021. While many studies have examined the impact of medication shortages, few have evaluated the impact of antimicrobial shortages. We evaluated the impact of the CT recall by assessing cost, clinical outcomes, and utilization of novel alternative agents. Methods This multi-site retrospective cohort study compared patients treated for MDR PSA prior to the CT recall (Jan-Jul 2020) to patients treated during the CT recall (Jan-Jul 2021) across seven AdventHealth Central Florida (AHCF) adult hospitals. The primary outcome was percentage of patients treated with novel therapies (CT, ceftazidime/avibactam, or cefiderocol). Secondary outcomes included length of therapy (LOT), inpatient mortality, 30-day readmissions, length of say (LOS), pharmacy expenditures, and average cost per case. Results A total of 203 patients with MDR PSA were evaluated: 100 in the pre-recall cohort and 103 in the post-recall cohort. The majority (58%) of patients were male with an average age of 64 years. The most common source of infection in both cohorts was pneumonia, followed by complicated urinary tract infection. Significantly more patients were treated with novel agents as definitive therapy in the post-recall cohort (65% vs. 29%, p&amp;lt; 0.0001). Average LOT for all anti-PSA therapy was 12 days in the pre-recall cohort compared to 14 days in the post-recall cohort (p=0.1753). Inpatient mortality and 30-day readmissions were not statistically different between groups. Hospital LOS was significantly different between the two groups (18 days vs. 25 days, p=0.006). Significantly higher pharmacy expenditures were found in the post recall cohort (Figure 1) and the average cost per case was significantly higher in the post-recall cohort ($125,254 vs. $62,249). Figure 1:Pharmacy Expenditures for Novel Agents Novel agents: cefiderocol, ceftazidime/avibactam, ceftolozane/tazobactam Conclusion The CT recall had a significant impact on both economic and clinical outcomes, particularly increased length of stay, length of therapy, and cost to both the patient and health system. Higher utilization of novel agents is concerning given rising rates of PSA resistance. Disclosures Amy L. Carr, PharmD, BCIDP, Shionogi: Advisory Board.

Bacterial susceptibility changes post national shortage of first cephalosporin in Japan: a longitudinal retrospective database study using interrupted time series analysis

ObjectivesThe clinical evidence for the effect of narrow-spectrum antimicrobial shortages on bacterial susceptibility is limited. Our purposes were to determine the affects of the disruption of most of the cefazolin (CEZ) supply in Japan on the susceptibility of pathogens and to analyze how long these changes persisted after the shortage of CEZ. MethodsWe performed an interrupted time series analysis using the Japanese Infectious Disease Nationwide database. We analyzed each pathogen before and after CEZ shortage in 52 university hospitals from 2018 to 2020. May to November 2019 was designated as the implementation term for CEZ shortage. The primary outcome was the susceptibility to CEZ and other antimicrobial agents. Amongst all pathogens isolated from facilities, we identified pathogens that were tested for susceptibility to CEZ. ResultsOf the 26 pathogens identified, analysis was performed on a total of 36,346 isolates of five pathogens (Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Proteus mirabilis, and Staphylococcus aureus). Amongst four Gram-negative pathogens with low susceptibility, there were no significant immediate changes after the CEZ shortage; however, the slope change significantly increased by 1.29 to 2.69% per month and continued to improve one year after the shortage. Regarding S. aureus, which was highly susceptible at the baseline, neither immediate change nor slope was significant. ConclusionThis quasi-experimental analysis using a nationwide-large database revealed that restriction of use because of narrow-spectrum antimicrobial shortages may lead to improved susceptibility over the subsequent year. The results suggest that temporary switching of antimicrobial agents on a national scale could be effective.

Antimicrobial Susceptibility Profile of Fosfomycin and Nitrofurantoin despite Dissemination of Fluoroquinolones and Trimethoprim/ Sulfamethoxazole Resistant Urinary Tract Isolates

The widespread growth of multidrug-resistant (MDR), extended drug resistant (XDR) uropathogens and the shortage of new antimicrobials are the most significant obstacles challenging the treatment of urinary tract infections. The study is aimed to identify the antimicrobial susceptibility profile against MDR and XDR uropathogens. A total of 2485 urine samples were processed from 2267 patients, 361 uropathogens were grown. The antimicrobial susceptibility was determined by the Kirby-Bauer disk diffusion method, following the Clinical and Laboratory Standards Institute’s guidelines. Eighty-nine percent of the samples had Multidrug-resistant microorganisms, while 32% had XDR uropathogens. In comparison to fluoroquinolones and trimethoprim/sulfamethoxazole, fosfomycin and nitrofurantoin demonstrated a significantly higher sensitivity rate against uropathogens, including MDR and XDR uropathogens, in both gender groups with community-acquired and nosocomial UTIs (P&lt;0.001). Fosfomycin revealed the highest sensitivity rate, about 94.8%. Klebsiella pneumonia and E. coli showed the highest resistance rate against fosfomycin in 3.7% and 3.4% of the cases. Nitrofurantoin showed a similar sensitivity rate both in community and hospitalized patients in 86.1%. Fluoroquinolones (61%) and trimethoprim/sulfamethoxazole (86.6%) revealed the highest resistance rate against uropathogens. The prevalence of extended-spectrum beta-lactamases producing pathogens was 10.2%. Fosfomycin and nitrofurantoin revealed a higher sensitivity rate against gram-negative MDR uropathogens in community and nosocomial UTIs compared to fluoroquinolones and trimethoprim/sulfamethoxazole.

Shortage of essential antimicrobials: a major challenge to global health security

The lack of access to safe and effective antimicrobials for human populations is a threat to global health security and a contributor to the emergence and spread of antimicrobial resistance...

Effects of the cefazolin shortage on the sales, cost, and appropriate use of other antimicrobials

BackgroundShortages of antimicrobials lead to treatment failures, increase medical costs, and accelerate the development of antimicrobial resistance. We evaluated the effects of the serious cefazolin shortage in 2019 in Japan on the sales, costs, and appropriate use of other antimicrobials.MethodsWe evaluated monthly defined daily doses/1000 inhabitants/day (DID) values of antimicrobial sales from January 2016 to December 2019 using wholesaler’s sales databases. Using 2016–2018 sales data, we generated a prediction model of DID in 2019 under the assumption that the cefazolin shortage did not occur. We then compared the predicted DID and actual DID. Cefazolin, government-recommended alternatives, and government-not-recommended broad-spectrum alternatives were assessed. Antimicrobial groups according to the AWaRe classification were also assessed to evaluate the effect on appropriate antimicrobial use. In addition, we evaluated changes in costs between 9 months before and after the cefazolin shortage.ResultsDID values of total antimicrobials increased sharply 1 month before the decrease in cefazolin. Actual DIDs were higher than predicted DIDs for ceftriaxone, flomoxef, clindamycin, cefotiam, piperacillin/tazobactam, and meropenem. Actual DID values were higher than the predicted DID values in the Watch group. The costs of antimicrobials between pre- and post- cefazolin shortage were unchanged.ConclusionThe cefazolin shortage brought confusion to the antimicrobial market and led to a setback in the appropriate use of antimicrobials. Early recognition and structures for prompt reactions to antimicrobial shortages are needed. Moreover, development of a system to secure the supply of essential antimicrobials is required.

Pharmaceutical Approaches on Antimicrobial Resistance: Prospects and Challenges.

The rapid increase in pathogenic microorganisms with antimicrobial resistant profiles has become a significant public health problem globally. The management of this issue using conventional antimicrobial preparations frequently results in an increase in pathogen resistance and a shortage of effective antimicrobials for future use against the same pathogens. In this review, we discuss the emergence of AMR and argue for the importance of addressing this issue by discovering novel synthetic or naturally occurring antibacterial compounds and providing insights into the application of various drug delivery approaches, delivered through numerous routes, in comparison with conventional delivery systems. In addition, we discuss the effectiveness of these delivery systems in different types of infectious diseases associated with antimicrobial resistance. Finally, future considerations in the development of highly effective antimicrobial delivery systems to combat antimicrobial resistance are presented.

Critical National Shortage of Cefazolin in Japan: Management Strategies.

The shortage of antimicrobials poses a global health threat. In Japan, for instance, the current, critical shortage of cefazolin, a first-line agent for the treatment of common infectious diseases and surgical antimicrobial prophylaxis, has had a substantial impact on inpatient care. A shortage of essential antimicrobial agents like cefazolin leads to increased consumption of alternative antimicrobial agents with broad-spectrum activity, with the unintended consequence of militating against antimicrobial stewardship efforts in inpatient settings and potentially promoting antimicrobial resistance. Although there is global awareness of the shortage of crucial antimicrobials, action to resolve this problem, especially with a view to preventing antimicrobial resistance and promoting antimicrobial stewardship, has been slow, possibly due to the failure to appreciate the urgency of the dilemma. A comprehensive plan for stabilizing antimicrobial access and international collaboration to secure a continuous supply of essential antimicrobials are urgently needed.

Availability and Use of Therapeutic Interchange Policies in Managing Antimicrobial Shortages among South African Public Sector Hospitals; Findings and Implications.

Background: Therapeutic interchange policies in hospitals are useful in dealing with antimicrobial shortages and minimising resistance rates. The extent of antimicrobial shortages and availability of therapeutic interchange policies is unknown among public sector hospitals in South Africa. This study aimed to ascertain the extent of and rationale for dealing with antimicrobial shortages, describe policies or guidelines available, and the role of pharmacists in the process. Methods: A quantitative and descriptive study was conducted with a target population of 403 public sector hospitals. Data were collected from hospital pharmacists using an electronic questionnaire via SurveyMonkeyTM. Results: The response rate was 33.5% and most (83.3%) hospitals had experienced shortages in the previous six months. Antimicrobials commonly reported as out of stock included cloxacillin (54.3%), benzathine benzylpenicillin (54.2%), and erythromycin (39.6%). Reasons for shortages included pharmaceutical companies with supply constraints (85.3%) and an inefficient supply system. Only 42.4% had therapeutic interchange policies, and 88.9% contacted the prescriber, when present, for substitution. Conclusions: Antimicrobial shortages are prevalent in South African public sector hospitals with the most affected being penicillins and cephalosporins. Therapeutic interchange policies are not available at most hospitals. Effective strategies are required to improve communication between pharmacists and prescribers to ensure that safe, appropriate, and therapeutically equivalent alternatives are available.

Antibiotic Shortages in Pediatrics.

* Abbreviation: FDA — : US Food and Drug Administration Medication shortages are increasingly common and severe in the United States and are a serious health threat. Medication shortages occur when reduced supply of a drug influences how it is prepared, dispensed, or prescribed by pharmacies or providers.1 According to the US Food and Drug Administration (FDA), most shortages are caused by quality and manufacturing problems.2 Consequences of shortages include rationing limited supplies, delays in therapy, medication errors, use of less-efficacious alternatives, and death.3 Recently, critical drugs like sodium chloride and amino acids have been on shortage, exacerbated by damage to manufacturing plants by natural disasters like Hurricane Maria. Although shortages have affected virtually all classes of medications, antimicrobial shortages are common and account for 15% of all drug shortages.1,4 Medication shortages can force clinicians to treat patients with suboptimal therapy, which, in turn, can lead to poor outcomes. Examples relating to antimicrobial agents are when a penicillin shortage led to use of second-line therapies for neurosyphilis, an intravenous trimethoprim-sulfamethoxazole shortage led to alternative therapies for Pneumocystis jiroveci infections, an acyclovir shortage led to use of alternative antiviral … Address correspondence to Ritu Banerjee, MD, PhD, Vanderbilt University Medical Center, 1161 21st Ave, Nashville, TN 37232. E-mail: ritu.banerjee{at}vumc.org

Antimicrobial Stewardship Program's Approach to Managing Critical Antimicrobial Shortages

Antimicrobial Stewardship Program's Approach to Managing Critical Antimicrobial Shortages

Antimicrobial Agent Shortages and Concerns for Adverse Patient Outcomes Are Now Part of Everyday Practice

Antimicrobial Agent Shortages and Concerns for Adverse Patient Outcomes Are Now Part of Everyday Practice