This post is part of a series onAntibiotic Awareness Week 2022. For more information, check out the full post on the Nebraska Antimicrobial Stewardship Assessment and Promotion Program (ASAP) blog.
Knowing and implementing TJC and CMS requirements for ASPs is essential for a successful program. Furthermore, TJC recommendations are something to take note of for all facilities, as other accrediting bodies often follow TJC in their requirements. To increase awareness and understanding of these updates, they have been summarized below.
On July 6th, 2022, the Centers for Medicaid and Medicare Services (CMS) released updates to interpretive guidance for their current Conditions of Participation (CoP) for hospital regulatory requirements related to infection prevention and control and antibiotic stewardship programs (ASP), effective immediately. There was no change to the CoP themselves, but CMS clarified what exactly surveyors should be looking for when assessing sites. In addition, The Joint Commission (TJC) released prepublication standards for new and revised requirements addressing antibiotic stewardship for the hospital and critical access hospital programs. These standards were released in July of this year with an effective date of January 1st, 2023. These updates only pertain to hospitals and critical access hospitals, they do not pertain to nursing care centers.
This post is part of a series onAntibiotic Awareness Week 2022, authored by UNMC ID fellow Dr. Mackenzie Keintz. Read on to learn more about growing antimicrobial resistance in the United States and what can be done to stop it.
Antimicrobial resistance has been a growing problem within the United States. Antibiotic resistant bacteria are responsible for 2.8 million infections per year and 36,000 deaths per year1. In addition, antibiotic use can be associated with significant adverse events including infections with Clostridium difficile. There are an estimated 223,900 infections resulting in 12,800 deaths1. Outpatient antibiotic prescriptions account for more than half of all antibiotics prescribed. In 2021 this accounted for 211.1 antibiotic prescriptions in the United States, equivalent to 636 antibiotic prescriptions/ 1000 person. Nebraska has one of the highest outpatient antibiotic prescribing rates in the country with 760 prescriptions/ 1000 persons in 20212.
Drivers of inappropriate prescribing
The drivers of inappropriate antibiotic use have been well described. Qualitative studies have evaluated clinician perceptions on antibiotic resistance and inappropriate antibiotic prescribing. Ninety one percent of clinicians interview viewed inappropriate prescribing as a problem within the United States however only 37% thought that inappropriate prescribing was a problem within their own practice7. Without oversight of clinician prescribing, it is difficult for individuals to know how their prescribing rates compare with peer or national averages.
Clinicians often cite diagnostic uncertainty when prescribing antibiotics, including escalating to a more broad-spectrum agent when a narrow spectrum antibiotic would be sufficient, extending the duration, or giving an antibiotic in a clinical situation that it may not benefit8. This is of high concern in the outpatient setting when clinicians have little objective data when making antibiotic prescribing decisions and have an uncertainty regarding patient follow-up.
Many clinicians also cite patient expectation as a reason for inappropriate antibiotic use. They fear damaging the physician-patient relationship if antibiotics are not prescribed when patients expect them. Time constraints also increase inappropriate antibiotic use as clinicians may not feel as if they have time to explain why antibiotics are necessary8.
Qualitative data on patient antibiotic perception has demonstrated that while patients do frequently expect antibiotics, they are willing to defer to a clinician’s judgement on the subject. These studies also showed that although many patients understand that antibiotics do not treat viral infections, they have difficulty distinguishing between viral and bacterial infections. Furthermore, patients may not understand the significant risk of antibiotic use, both individually and for the population9.
Intervention
Interventions to improve antibiotic prescribing in the ambulatory setting should address the root cause of inappropriate antibiotic use which is often not a gap in knowledge. Some institutional implemented strategies that have been shown to be effective include peer to peer feedback, academic detailing, and communication training10-13.
Strategies for individual clinicians to improve their antibiotic use include identifying resources including to guide their antibiotic decision making such as national guidelines. The Agency for Healthcare Research and Quality (AHRQ) suggests a four-time point decision making process that includes:
1. Does my patient have a condition that requires an antibiotic?
2. Do I need to order any diagnostic tests?
3. If antibiotics are indicated what is the narrowest, safest, and shortest regimen I can prescribe? 4. Does my patient understand what to expect and the follow up plan?14
Prescribers can utilize a delayed prescription method to overcome clinical uncertainty. This strategy should not be used in situations in which antibiotics are never indicated, such as bronchitis or viral respiratory infections, but can be helpful in situations where an antibiotic is sometimes required i.e., sinusitis. This allows the physician to have a contingency plan in place for patients that may not wish to return to the office for evaluation if clear instructions are given to the patient15.
One strategy that has been shown to both decrease inappropriate antibiotic prescribing in acute respiratory infections and increase patient satisfaction includes both negative treatment recommendations (antibiotics will not help this viral infection), positive treatment recommendations (this viral infection can be managed symptomatically with xxx), and a contingency plan (if symptoms are not better in a week or have double worsening antibiotic plan can be revisited)16. In addition to education from individual clinicians, other efforts have been made on a national scale to educate patients about the risk of using antibiotics when not indicated, through campaigns like Be Antibiotic Aware by the CDC. During Antibiotic Awareness Week, think about how you can incorporate the 4 moments of antibiotic decision making into your clinical practice.
Fleming-Dutra, K. E. et al. “Prevalence of Inappropriate Antibiotic Prescriptions among Us Ambulatory Care Visits, 2010-2011.” JAMA, vol. 315, no. 17, 2016, pp. 1864-73, doi:10.1001/jama.2016.4151.
This post is part of a series onAntibiotic Awareness Week 2022. For more information, check out the full post on the Nebraska Antimicrobial Stewardship Assessment and Promotion Program (ASAP) blog.
Antimicrobial resistance rates continue to increase in hospitals across the United States. One of the five CDC core actions to combat the spread of antimicrobial resistance is improving the use of antimicrobials. Studies show that providing timely and reliable feedback of information to clinicians regarding their prescribing practices, such as through antimicrobial usage reports, can improve appropriateness of antimicrobial use.
The NHSN AUR Module provides a mechanism for facilities to report and to analyze antimicrobial use and/or resistance data to inform benchmarking, reduce antimicrobial resistant infections through antimicrobial stewardship, and interrupt transmission of resistant pathogens at individual facilities or facility networks.
Reporting antimicrobial use and resistance data will be included in the Public Health and Clinical Data Exchange Objective as a required measure for CMS beginning with the EHR reporting period in CY 2024. As of 2021, only 13 of 54 (24%) eligible facilities in Nebraska report antibiotic use data to NHSN.
This post is part of a series on Antibiotic Awareness Week 2022, authored by Scott Bergman, PharmD, FCCP, FIDSA, BCIDP. Read on to learn more about influential antibiotic stewardship research published this year.
This year for Antibiotic Awareness Week, I want to revisit a few studies that I selected for my presentation at the recent IDWeek conference on Most Influential Papers in Antimicrobial Stewardship from the Past Year. These are by no means ranked in order of quality or impact, but rather tell a story of where we are in terms of research and practice this year.
The first paper I want to highlight is titled “Rural-urban differences in antibiotic prescribing for uncomplicated urinary tract infection” in Infection Control and Hospital Epidemiology.1As we have become more aware of racial disparities in healthcare over the last few years, in Nebraska we have also thought about the difference in antimicrobial stewardship between our urban and rural areas of the state. This study included women 18-44 years old with uncomplicated UTIs from 2010-15 and classified them into groups based on their zip code as either rural or urban (metropolitan statistical areas > 50,000 population). Using insurance claims from the IBM Marketscan database, investigators evaluated whether prescriptions followed IDSA guidelines over this time period. Over 670,000 claims were reviewed to determine that almost half of prescriptions, 46.7%, were not for first-line antibiotics (table 1). To maintain that these were indeed uncomplicated, community-acquired UTIs, patients were excluded if they had been in the hospital within 90 days or received an antibiotic or had another infection with 30 days.
Table 1: Antibiotics prescribed for uncomplicated cystitis
This rate of guideline-discordant prescribing was not significantly different between rural & urban geographical designations. It was in length of therapy where the difference became more apparent – with rural women receiving inappropriate durations 83.9% of the time compared to 74.9% of urban prescriptions (table 2). Regardless of the amount of that difference, neither of these statistics are encouraging. I left feeling that we that we have a lot of education to do for prescribers to feel comfortable giving the antibiotics recommended by guidelines for uncomplicated cystitis over the durations of therapy that are based on evidence.
Table 2: Antibiotic durations of therapy matching guidelines for uncomplicated cystitis
As you can probably guess, the durations prescribed were considered inappropriate for being longer than recommended 99% of the time. While a few days extra of an antibiotic may not seem like a big deal, the adverse effects associated with these courses can really add up, especially when we are talking about almost half a million inappropriate prescriptions in this study.
That brings me to the other important paper from the last year I want to cover, “Estimating daily antibiotic harms: an umbrella review with individual study meta-analysis”, published in Clinical Microbiology and Infection.2This study conducted by Public Health Ontario was a meta-analysis of 71 randomized trials identified from 35 systematic reviews of shorter versus longer fixed durations of therapy ranging from 3 to 14 days. These studies were primarily for treatment of respiratory tract (n=36, 51%) and urinary tract infections (n=29, 41%). If you’ve ever read one of these many trials, you will know that the conclusion is almost always the same – shorter courses are equally effective to longer courses, but the adverse effects are greater in the long duration group. To quantify that, 23,174 patients were pooled in this analysis and 20,345 adverse effects were identified in 19.9% of patients these trials. Other documented harms associated with antibiotics included 5,776 superinfections in 4.8% of patients and 2330 cases of new resistance in 10.6% of patients. Overall, they concluded that each day of antibiotic therapy was associated with a 4% increased odds of having any adverse event. Furthermore, the risk of having a severe adverse event rose incrementally 9% for each subsequent day of therapy.
Combined, these two studies paint a fairly bleak picture for antimicrobial use in 2022, but there are bright spots as well. I don’t have time to elaborate, but I listed a few other studies below that I selected for my presentation on influential papers in antimicrobial stewardship which show benefit of education.
About the Author:
Scott Bergman, PharmD, FCCP, FIDSA, BCIDP
Pharmacy Coordinator, Antimicrobial Stewardship Program – Nebraska Medicine
Clinical Professor, University of Nebraska Medical Center – College of Pharmacy
This post is part of a series on Antibiotic Awareness Week 2022. For more information about how to manage a patient reported penicillin allergy, check out the full post on the Nebraska Antimicrobial Stewardship Assessment and Promotion Program (ASAP) blog.
Patient reported antibiotic allergies present clinicians with challenging decisions at the point of prescribing. Approximately half of all patients admitted to the hospital receive antibiotics, and 25% of inpatients who require antibiotics report at least one antimicrobial drug allergy. Specifically, penicillin (PCN) allergy is reported in up to 10% of the general population and up to 16% of inpatients.
Patients with reported PCN allergies often receive more costly and broad-spectrum antibiotics than patients without these reported allergies. Furthermore, many patients with reported PCN allergy are not receiving drugs, such as later-generation cephalosporins and carbapenems, that are safely tolerated despite a PCN allergy.
A 2022 update to the Practice Parameter Update in Drug Allergy is now available from the American Academy of Allergy, Asthma, and Immunology (AAAAI) and the American College of Allergy, Asthma, and Immunology (ACAAI).
Visit the Nebraska ASAP blog to learn more about how to manage a patient reported penicillin allergy.
Dr. Kelly Cawcutt, lead author on a new publication detailing the lessons learned from the COVID-19 pandemic.
From SARS to H1N1 to Ebola and now COVID-19, it is clear that pandemic infectious diseases are likely to be a constant challenge to the healthcare system and humanity for the foreseeable future. Luckily, past pandemics can help us learn to better combat these diseases in the future. This is the case made by a new article authored by Drs. Cawcutt, Kalil, and Hewlett. Their thesis: best summed up by the Winston Churchhill quote “Those who fail to learn from history are doomed to repeat it.”
Dr. Andre Kalil, co-author on this new pandemic preparedness publication.
The article begins with an overview of the impact of pandemics on medicine and society at large. They note that there is a silver lining to these damaging events- namely, they have been shown to accelerate improvements in patient care, especially among critically ill patient populations. We can emerge from pandemics better equipped to handle complex medical cases than we were before they started, but only if we are willing to study and learn from our mistakes.
Dr. Angela Hewlett, also a co-author on this new pandemic preparedness publication.
The next section of the paper explores the specific lessons to be learned from the COVID-19 pandemic. This includes anything from supply chain management to ethics and the use of media, each throughly described. They conclude this section exploring mistakes instead with an exploration of the triumphs of the medical community during the pandemic, as not all lessons learned were negative. We make significant advancements and accomplished incredible feats during the past few years, showing the community’s ability to rise to a challenge.
Next, the authors cover the intensive care unit specifically, outlining lessons learned in the four S’s of surge capacity: Space, Staffing, Stuff, and Systems. For each ‘S’, detailed and actionable considerations are enumerated for better pandemic preparedness in the future.
Lastly, the authors explore some final thoughts regarding the importance of research and addressing inequality in health care. They end with a call to action:
“If history has taught us anything, it is that future pandemics are inevitable. COVID-19 highlighted the critical infrastructure failures in preparedness for a large-scale lethal respiratory viral pandemic and those failures must be the lessons on which future pandemic preparedness strategies are built. This must be a multidisciplinary, broad reaching strategy, and perhaps there are no areas more critical to ensure preparedness than within ICUs.“
To read this article in its entirety, including for specific details regarding how we can better prepare for a future pandemic, see the full text here.
Please note that the following post was copied with permission from its original website. For more information about antimicrobial stewardship, check out the Nebraska Antimicrobial Stewardship Assessment and Promotion Program (ASAP) blog, Facebook, and Youtube page.
Are You Antibiotics Aware? U.S. Antibiotic Awareness Week is November 18-24, 2022
U.S. Antibiotic Awareness Week is an annual observance that raises awareness of the threat of antibiotic resistance and the importance of appropriate antibiotic use. The observance is a partnership between the CDC, state-based programs (such as the Nebraska Department of Health and Human Services, Healthcare-Associated Infections/Antibiotic Resistance Team), and non-profit/for-profit partners. The goal of this national observance is to improve antibiotic stewardship practices of both healthcare providers and consumers to achieve the best outcomes while minimizing untoward effects of antibiotic therapy.
CDC examined antibiotic prescribing and factors that influence prescribing practices such as provider type, geographic location, setting, and patient age to inform targets for antibiotic stewardship. A Mortality and Morbidity Weekly Report (MMWR) published in February 2022 evaluated publicly available data to better understand how antibiotics were prescribed for older adults (>65 years) in 2019. 1 The highest 10% of antibiotic prescribers prescribed 41% of total antibiotic prescriptions.
Outpatient Antibiotic Use in Nebraska
Outpatient antibiotic prescribing rates vary widely across the United States. This variation suggests that there are stewardship opportunities for healthcare providers, facility and healthcare system leadership, and other partners to improve how antibiotics are used. Monitoring of outpatient antibiotic prescribing data is regularly conducted by CDC to better understand trends in outpatient antibiotic prescribing, identify where interventions to improve prescribing are most needed, and measure progress.
Nebraska has an opportunity to improve antibiotic prescribing across all types of practice settings, but especially in outpatient facilities. In 2021, Nebraska’s prescribing rate was reported by the CDC as 760 prescriptions per 1,000 population. This ranks Nebraska 42nd in the nation. The lowest prescribing rate in the nation was 350 antibiotic prescriptions per 1,000 population – Nebraska was more than double that rate!
Hospital Antibiotic Stewardship in Nebraska
Hospital Antibiotic Stewardship Programs use the CDC’s Core Elements of Hospital Antibiotic Stewardship as a framework for implementation. These seven Core Elements include:
Hospital Leadership Commitment
Accountability
Pharmacy Expertise
Action
Tracking
Reporting
Education
As of 2021, 86% of hospitals in Nebraska reported meeting all seven of the Core Elements on the annual National Healthcare Safety Network Hospital Survey. This may seem like a large percentage of hospitals, but it ranks Nebraska 45th in the nation!
Nursing Home Antibiotic Use
Tracking and reporting antibiotic use in nursing homes is critical to monitor trends in antibiotic prescribing, inform opportunities to guide practice change, and evaluate the impact of stewardship interventions. CDC researchers evaluated the utility of electronic health record data to monitor antibiotic use and characterized antibiotic prescribing practices. Electronic health record data can be leveraged to support nursing homes in tracking and reporting antibiotic use.
Electronic health record antibiotic orders in 1,664 U.S. nursing homes were used to describe antibiotic use at the facility and national levels.5 In 2016, 54% of residents received an antibiotic. The antibiotic use rate was 88 days of therapy (DOT) per 1,000 resident days and the median antibiotic course duration was 7 days (interquartile range, 5–10). Antibiotic use rates varied considerably across nursing homes and were only partially explained by nursing home and resident characteristics, highlighting potential opportunities for targeted improvement of prescribing practices.
How can you help?
Be Antibiotics Aware, a CDC educational effort, complements U.S. Antibiotic Awareness Week by providing partners with up-to-date information to help improve human antibiotic prescribing and use in the United States.
The CDC invites healthcare stakeholders, providers as well as consumers to share the important Be Antibiotics Aware message during this week-long observance by
Printing and sharing Handouts and Posters with healthcare providers and consumers
Playing Videos on TV screens in medical offices, waiting rooms, and pharmacy
We look forward to your participation in U.S. Antibiotic Awareness Week from November 18 to 24!
Written by Jenna Preusker, Pharm.D., BCPS – Nebraska ASAP Pharmacy Coordinator
References
Gouin KA, Fleming-Dutra KE, Tsay S, Bizune D, Hicks LA, Kabbani S. Identifying Higher-Volume Antibiotic Outpatient Prescribers Using Publicly Available Medicare Part D Data – United States, 2019. MMWR Morb Mortal Wkly Rep. 2022 Feb 11;71(6):202-205. doi: 10.15585/mmwr.mm7106a3. PMID: 35143465; PMCID: PMC8830623
Antibiotic Use in the United States, 2022 Update: Progress and Opportunities https://www.cdc.gov/antibiotic-use/stewardship-report/current.html
UNMC ID has a long history of not only providing extraordinary medical care for people living with HIV (PLWH), but also contributing strongly to the research that informs the future of medicine. We have even featured many such articles on this blog. Today, we summarize a few recent publications focused at improving care for for this patient population through bettering medication adherence and important health screening measures.
Dr. Josh Havens
In the first article, led by Dr. Josh Havens along with others from the UNMC community, antiretroviral medication refill history is linked to risk of HIV viremia from suboptimal medication adherence. In fact, this article showed that lower adherence to medication regimens was extremely strongly predictive of eventual virologic failure and reemergence of detectible virus. This underscores the importance of finding ways to promote adherence to antiretroviral therapy, something our next article in this digest addresses as well. Read more here.
Dr. Susan Swindells
As hinted at in the article linked above, one of the most important aspects of medical care for PLWH is maintaining adherence to antiretroviral therapy, something that is often difficult as many regimens require multiple doses per day with little room for error. This very problem is addressed by this second article, authored by Dr. Susan Swindells. The authors report success of injectable antiretroviral medication at 96 weeks into the study. This regimen is dosed every four weeks instead of orally, decreasing the burden of daily medication and improving compliance. Astoundingly, 100% (27/27) of the study participants preferred this new injectable regimen to their previous medications, and it was found to be at least as effective. Read the rest of the article here.
The last article tackles a different but equally important aspect of HIV medical care; screening for other diseases. PLWH have an increased risk of many other medical conditions, including lung cancer- the screening guidelines for which have just been updated. However, little is known about how to adjust these guidelines for specific subgroups of the PLWH population with additional risk factors. The authors, among them Drs. Fadul and Bares (pictured with the first article), identified a low rate of lung cancer screening in the PLWH population which creates an opportunity for quality improvement programs in HIV clinics. Read the full details and analysis here.
A #PharmToExamTable question about antibiotic resistance in S. aureus, answered by Feiyang Ding, PharmD, a Graduate of UNMC College of Pharmacy.
(Reviewed by Andrew Watkins, PharmD)
Background
Staphylococcus aureus has been recognized as an important cause of human diseases ranging from minor skin and soft tissue infections to fatal endocarditis, chronic osteomyelitis, or sepsis. Vancomycin has been the treatment of choice for serious infections caused by methicillin-resistant S. aureus (MRSA), and for many years, vancomycin resistance did not seem to be a problem in S. aureus. However, in 1997, a case of vancomycin-intermediate Staphylococcus aureus (VISA, MIC = 4-8) was reported in Japan. In that case, the MIC of vancomycin was 8 mcg/mL, and the patient was successfully treated with amoxicillin-clavulanate plus gentamicin. Subsequently, cases of VISA infections have been reported worldwide. Generally, the incidence of VISA is hard to estimate due to the rarity of infection and challenges related to laboratory detection.1 Shariati et al.2 performed a comprehensive systematic review of literature from 1997 to 2019 and found the overall prevalence rate was 1.7% among 22,227 S. aureus isolates. Incidence of vancomycin-resistant S. aureus (VRSA, MIC ≥ 12) was much lower, with 23 out of 5855 (0.39%) S. aureus isolates being reported as VRSA.2
Mechanism
Various studies, from morphological to molecular level studies, have been performed to determine the mechanism of S. aureus resistance to vancomycin.3 In morphological studies, VISA strains appeared to have a thickened cell wall compared to non-VISA strains, and it is believed that this could prevent the diffusion of vancomycin to its active site. Moreover, a fluorescence imaging study demonstrated that the vancomycin binding site D-Ala-D-Ala was also increased in resistant strains; however, these residues are maintained in the mature peptidoglycan due to the low carboxypeptidase activity and, therefore, they constitute potential nonlethal binding sites for vancomycin. By binding to theses inactive sites, access of vancomycin to the active sites are reduced. Another early phenotypic change observed in resistant isolates is reduced autolytic activity. Impaired acetate metabolism has also been described in very resistant strains, which could lead to altered antibiotic resistance and cell death. On the molecular level, a variety of experiments have identified mutations at genes, such as walkR, vraSR and rpoB in various resistant isolates4. In most cases, these mutations are involved with changes in the cell wall, leading to reduced vancomycin activity.
Treatment Options
Currently, there are no clinical trials on VISA/VRSA treatment, and few successfully treated cases are reported in the literature. As a result, the optimal regimen for treating infections due to VISA/VRSA remains uncertain. According to the 2011 IDSA MRSA treatment guidelines,5 for infections due to S. aureus with reduced susceptibility to vancomycin and daptomycin, options may include the following: quinupristin-dalfopristin, sulfamethoxazole-trimethoprim (TMP-SMX), linezolid, and/or telavancin (C-III). These options may be given as a single agent or in combination with other antibiotics. Kullar et al.6 performed a systematic review of literature examining salvage therapy for resistant/persistent MRSA bacteremia. Their findings are summarized below:
High-dose Daptomycin
Daptomycin is approved by the FDA for the treatment of S. aureus bacteremia and right-sided IE at 6 mg/kg/day. At this dose, however, non-susceptibility may occur. As a result, the IDSA MRSAB treatment guidelines recommend daptomycin to be dosed at 10 mg/kg/day when used as monotherapy. But currently there is no randomized trial comparing high- and standard-dose daptomycin in MRSA bacteremia treatment.
Ceftaroline
Ceftaroline is distinguished from other β-lactams by its uniquely high binding affinity for PBP-2a, thus conferring its activity against MRSA. In a retrospective evaluation of 527 patients treated with ceftaroline, most patients (80%) were initiated on ceftaroline after receipt of another antimicrobial, with 48% citing disease progression as a reason for switching. A total of 271 (51%) patients were culture positive for S. aureus. The median duration of ceftaroline treatment was 6 days, with an interquartile range of 4 to 9 days.7More clinical data is needed to analyze the effect of in patients with persistent MRSA bacteremia.
Linezolid
There are several successful case reports indicating the effectiveness of treating persistent MRSA bacteremia with linezolid alone. However, linezolid is bacteriostatic and its toxicities such as thrombocytopenia may limit its use clinically.8
Telavancin
Telavancin is a lipoglycopeptide which can inhibit cell wall synthesis as well as depolarize the cell membrane. With this additional mechanism of action, it has activity against VISA/VRSA. In vitro PK/PD data has demonstrated its activity against vancomycin and daptomycin non-susceptible S. aureus.9 In vivo studies for bacteremia treatment are needed for further evaluation.
Quinupristin/dalfopristin
In an observational study by Sander et al.10, Quinupristin/dalfopristin has been used in 9 patients with MRSA infections who failed vancomycin treatment initially. Of these patients, 7 out 9 achieved bacterial clearance with quinupristin/dalfopristin therapy.10 However, the use of this medication is limited due to its substantial adverse reactions such as hepatotoxicity, risk of superinfection and need for a central catheter for administration.
Vancomycin + β-lactam
In vitro studies have shown synergistic activity between vancomycin and several β-lactams like ceftaroline and oxacillin against S. aureus, and this synergy can be extended to VISA isolates.11 As salvage therapy, vancomycin combined with a β-lactam at or near the initiation of therapy seems to yield improved results compared with vancomycin monotherapy. In a retrospective study, MRSA bacteremia microbiological eradication was achieved in 48/50 patients (96%) who received vancomycin with a β-lactam (ampicillin, nafcillin, amoxicillin/clavulanate, piperacillin-tazobactam, cephalexin and meropenem and etc.) compared with 24/30 patients (80%) (P = 0.021) who received vancomycin monotherapy.12 Another open-label, multicenter trial conducted in Australia showed a shorter duration of MRSA bacteremia in patients receiving vancomycin plus flucloxacillin (n = 31, 1.94 days) compared to vancomycin alone (n = 29, 3 days).13However, CAMERA2 trial indicated that the combination of antistaphylococcal β-lactam to vancomycin or daptomycin were associated an increased risk of acute kidney injury without an significant improvement on mortality, bacteremia, relapse or treatment failure. 14
Daptomycin + β-lactam
The combination of daptomycin and β-lactam also shows synergistic activity in in vitro studies. β-Lactams with PBP-1 binding (e.g. meropenem, ampicillin, nafcillin, cefepime and piperacillin/tazobactam) appear to enhance daptomycin anti-MRSA activity the most.15 Sakoulas et.al16 reported the results of salvage therapy with daptomycin and ceftaroline combination therapy for persistent MRSA bacteremia in 22 patients. Of these, 2 patients had vancomycin intermediate S. aureus infections and 4 patients had daptomycin non-susceptible S. aureus infections. With the initiation of daptomycin plus ceftaroline, bacteremia cleared in a median of 2 days (range 1-6 days).
TMP-SMX + daptomycin/ceftaroline
Although guidelines suggest using TMP-SMX either alone or in combination with other recommended medications, a recent randomized controlled trial showed a greater bacteremia persistence with TMP-SMX monotherapy.17 Claeys et.al18 investigated the combination of TMP-SMX with daptomycin. For patients with persistent MRSA bacteremia, adding TMP-SMX to daptomycin could allow clearance of bacteremia in 2.5 days. Microbiological eradication was demonstrated in 24 out of 28 patients, and in vitro synergy was demonstrated in 17 of the 17 recovered isolates. For the combination of TMP-SMX with ceftaroline, a retrospective analysis studied 29 patients using ceftaroline alone, in which 23 switched to combination therapy. The median duration of bacteremia was 9.5 days (range 7-15 days) before the switch and 3 days (range 2-5 days) after the switch.19
Conclusions
Although various regimens have been suggested, trials have enrolled small numbers of patients and have yielded inconsistent results. Possible monotherapies for VISA/VRSA infection include telavancin, ceftaroline and linezolid. Possible combination therapies that have been investigated include daptomycin or vancomycin combined with a β-lactam and daptomycin or ceftaroline combined with TMP-SMX.
2 Shariati, A. et al. Global prevalence and distribution of vancomycin resistant, vancomycin intermediate and heterogeneously vancomycin intermediate Staphylococcus aureus clinical isolates: a systematic review and meta-analysis. Sci Rep10, 12689, doi:10.1038/s41598-020-69058-z (2020).
3 Howden, B. P., Davies, J. K., Johnson, P. D., Stinear, T. P. & Grayson, M. L. Reduced vancomycin susceptibility in Staphylococcus aureus, including vancomycin-intermediate and heterogeneous vancomycin-intermediate strains: resistance mechanisms, laboratory detection, and clinical implications. Clin Microbiol Rev23, 99-139, doi:10.1128/CMR.00042-09 (2010).
4 Hafer, C., Lin, Y., Kornblum, J., Lowy, F. D. & Uhlemann, A. C. Contribution of selected gene mutations to resistance in clinical isolates of vancomycin-intermediate Staphylococcus aureus. Antimicrob Agents Chemother56, 5845-5851, doi:10.1128/AAC.01139-12 (2012).
5 Liu, C. et al. Clinical practice guidelines by the infectious diseases society of america for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis52, e18-55, doi:10.1093/cid/ciq146 (2011).
6 Kullar, R., Sakoulas, G., Deresinski, S. & van Hal, S. J. When sepsis persists: a review of MRSA bacteraemia salvage therapy. J Antimicrob Chemother71, 576-586, doi:10.1093/jac/dkv368 (2016).
7 Casapao, A. M. et al. Large retrospective evaluation of the effectiveness and safety of ceftaroline fosamil therapy. Antimicrob Agents Chemother58, 2541-2546, doi:10.1128/AAC.02371-13 (2014).
8 Jang, H. C. et al. Salvage treatment for persistent methicillin-resistant Staphylococcus aureus bacteremia: efficacy of linezolid with or without carbapenem. Clin Infect Dis49, 395-401, doi:10.1086/600295 (2009).
9 Steed, M. E., Vidaillac, C. & Rybak, M. J. Evaluation of telavancin activity versus daptomycin and vancomycin against daptomycin-nonsusceptible Staphylococcus aureus in an in vitro pharmacokinetic/pharmacodynamic model. Antimicrob Agents Chemother56, 955-959, doi:10.1128/AAC.05849-11 (2012).
10 Sander, A., Beiderlinden, M., Schmid, E. N. & Peters, J. Clinical experience with quinupristin-dalfopristin as rescue treatment of critically ill patients infected with methicillin-resistant staphylococci. Intensive Care Med28, 1157-1160, doi:10.1007/s00134-002-1358-7 (2002).
11 Werth, B. J. et al. Novel combinations of vancomycin plus ceftaroline or oxacillin against methicillin-resistant vancomycin-intermediate Staphylococcus aureus (VISA) and heterogeneous VISA. Antimicrob Agents Chemother57, 2376-2379, doi:10.1128/AAC.02354-12 (2013).
12 Dilworth, T. J. et al. beta-Lactams enhance vancomycin activity against methicillin-resistant Staphylococcus aureus bacteremia compared to vancomycin alone. Antimicrob Agents Chemother58, 102-109, doi:10.1128/AAC.01204-13 (2014).
13 Davis, J. S. et al. Combination of Vancomycin and beta-Lactam Therapy for Methicillin-Resistant Staphylococcus aureus Bacteremia: A Pilot Multicenter Randomized Controlled Trial. Clin Infect Dis62, 173-180, doi:10.1093/cid/civ808 (2016).
14 Tong, S. Y. C. et al. Effect of Vancomycin or Daptomycin With vs Without an Antistaphylococcal beta-Lactam on Mortality, Bacteremia, Relapse, or Treatment Failure in Patients With MRSA Bacteremia: A Randomized Clinical Trial. JAMA323, 527-537, doi:10.1001/jama.2020.0103 (2020).
15 Berti, A. D., Sakoulas, G., Nizet, V., Tewhey, R. & Rose, W. E. beta-Lactam antibiotics targeting PBP1 selectively enhance daptomycin activity against methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother57, 5005-5012, doi:10.1128/AAC.00594-13 (2013).
16 Sakoulas, G. et al. Antimicrobial salvage therapy for persistent staphylococcal bacteremia using daptomycin plus ceftaroline. Clin Ther36, 1317-1333, doi:10.1016/j.clinthera.2014.05.061 (2014).
17 Paul, M. et al. Trimethoprim-sulfamethoxazole versus vancomycin for severe infections caused by meticillin resistant Staphylococcus aureus: randomised controlled trial. BMJ350, h2219, doi:10.1136/bmj.h2219 (2015).
18 Claeys, K. C. et al. Impact of the combination of daptomycin and trimethoprim-sulfamethoxazole on clinical outcomes in methicillin-resistant Staphylococcus aureus infections. Antimicrob Agents Chemother59, 1969-1976, doi:10.1128/AAC.04141-14 (2015).
19 Fabre, V., Ferrada, M., Buckel, W. R., Avdic, E. & Cosgrove, S. E. Ceftaroline in Combination With Trimethoprim-Sulfamethoxazole for Salvage Therapy of Methicillin-Resistant Staphylococcus aureus Bacteremia and Endocarditis. Open Forum Infect Dis1, ofu046, doi:10.1093/ofid/ofu046 (2014).
The following content was provided by Dr. Jonathan Ryder who, along with Dr. Cortés-Penfield, recently authored a fantastic article on this content in the journal Clinical Infectious Diseases.
Infectious diseases clinicians have nightmares when thinking about necrotizing fasciitis and toxic shock syndrome from group A streptococcus (GAS), given the rapid progression and high mortality. Since the 1950s, evidence emerged that penicillin alone was inadequate for these infections.[1] Clindamycin, which has antitoxin effects against GAS, emerged as a potential adjunctive antibiotic in the 1980s with clinical evidence of benefit being published in the late 1990s.[2, 3] However, the rising rates of clindamycin resistance in GAS, as high as 29.2% in 2020 in the US (Figure 1), bring to question whether clindamycin remains effective for the treatment of these severe infections.[4]
Recently, Dr. Nicolás Cortés-Penfield and I published a viewpoint article in Clinical Infectious Diseases critically analyzing the existing literature to determine the pros and cons of using clindamycin versus linezolid for necrotizing soft tissue infections and toxic shock syndrome due to GAS.[5] I outline the salient points of this debate below:
Pros of Clindamycin:
Preponderance of clinical data demonstrating the benefit of adjunctive clindamycin in our meta-analysis, demonstrating an odds ratio of 0.45 favoring clindamycin compared to no clindamycin across 8 retrospective studies
Resistance to clindamycin, when used with penicillin as a primary treatment, is not definitively correlated with worse clinical outcomes, although this area warrants further study given low-quality evidence
Cons of Clindamycin:
Rising resistance rates are highly concerning for a decrease in the effectiveness of clindamycin, including one study showing an increased risk of amputation with clindamycin-resistant isolates
Associated with a high risk for Clostridioides difficile infection
Pros of Linezolid:
GAS remains universally susceptible to linezolid, so there are no concerns with resistance to this treatment
Linezolid can replace empiric use of vancomycin for methicillin-resistance Staphylococcus aureus. This may decrease risk of acute kidney injury associated with vancomycin
Linezolid has a low risk of C. difficile infection and may even be protective
Cons of Linezolid:
There is minimal comparative literature between clindamycin and linezolid. Two small studies have not demonstrated a difference in mortality between the two drugs
Linezolid is slightly more expensive than clindamycin, but the net benefits of linezolid may outweigh these cost differences
In summary, the rise of antimicrobial resistance necessitates re-evaluation of our current therapies. Local resistance rates of clindamycin for GAS should be evaluated and may warrant re-consideration of the optimal antibiotic regimen for these serious infections, as linezolid retains its effectiveness. Further studies comparing clindamycin and linezolid are highly desirable, as we adjust to threats from antimicrobial resistance.
Figure 1: Clindamycin Resistance in Group A Streptococcus (GAS) Isolates in the United States per the Centers for Disease Control’s Active Bacterial Core surveillance (ABCs)[4]
References
1. Eagle H. Experimental approach to the problem of treatment failure with penicillin. I. Group A streptococcal infection in mice. Am J Med 1952; 13(4): 389-99.
2. Stevens DL, Gibbons AE, Bergstrom R, Winn V. The Eagle Effect Revisited: Efficacy of Clindamycin, Erythromycin, and Penicillin in the Treatment of Streptococcal Myositis. Journal of Infectious Diseases 1988; 158(1): 23-8.
3. Zimbelman J, Palmer A, Todd J. Improved outcome of clindamycin compared with beta-lactam antibiotic treatment for invasive Streptococcus pyogenes infection. Pediatr Infect Dis J 1999; 18(12): 1096-100.
5. Cortés-Penfield N, Ryder JH. Should Linezolid Replace Clindamycin as the Adjunctive Antimicrobial of Choice in Group A Streptococcal Necrotizing Soft Tissue Infection and Toxic Shock Syndrome? A Focused Debate. Clin Infect Dis 2022.
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