Jason C. Gallagher, PharmD, FCCP, FIDP, FIDSA, BCPS, is a clinical professor at Temple University (TU) School of Pharmacy and a clinical pharmacy specialist in infectious diseases at Temple University Hospital in Philadelphia, Pennsylvania. He also is director of the PGY2 Residency in Infectious Diseases Pharmacy at TU.

Jason Gallagher, PharmD, FCCP, FIDP, FIDSA, BCPS*

It happened. Months after the Biden administration introduced its “test to treat” program, the US FDA authorized pharmacists to prescribe Paxlovid (nirmatrelvir/ritonavir) for patients with COVID-19 infection.

This move helps to realize the promise of the test-to-treat program, allowing patients to couple rapid testing with prompt treatment. It is particularly important in areas where access to other health care providers is limited. As with all new programs, this will be a work in progress that will take time to refine, but I think it is a potentially significant step forward. Some might argue that my perspective is obvious, but from that perspective I can say pharmacists are among our country’s most underused health care resources. US pharmacy education transformed in the early 2000s with the requirement that all schools of pharmacy offer the doctor of pharmacy (PharmD) degree as the sole entry-level degree. This accelerated changes in pharmacy curricula that were already in progress, moving programs based in basic sciences to those that emphasize clinical practice. This move has continued with augmented experiential education, increasingly transitioning students from the classroom to the clinic earlier to prepare pharmacists for less dispensing-focused roles. However, the move to the “all PharmD” degree has not been fully successful in advancing the profession. Clinical positions for pharmacists have indeed proliferated and become common, but these are most established within health systems, and many require additional residency training. Although outpatient clinical pharmacist positions have increased, many community pharmacies have not become the centers of advanced practice that were once envisioned. 

The COVID-19 pandemic has highlighted the important roles that pharmacists play in US health care. Pharmacists administered large proportions of vaccinations for COVID-19, and as vaccinations have shifted from primary series to boosters, an increasing proportion of COVID-19 vaccines are given by community pharmacists. Pharmacies have been testing sites throughout the pandemic, offering polymerase chain reaction–based tests before rapid antigen tests (RATs) became widely available, and they serve as points of sale, insurance billing partners, and interpreters of RATs now. Because almost 90% of the US population lives within 5 miles of a community pharmacy,

 expanding access to COVID-19 therapeutics by allowing pharmacists to prescribe can help improve health equity in areas without sufficient other health care practitioners. 

The move by the FDA comes with appropriate restrictions, however. Pharmacists must have access to laboratory values to assess patients for liver and renal function and a list of the medications that patients are taking, to screen for drug interactions.

 Of course, pharmacists must be state licensed, but because they cannot practice without a license, this is not a true restriction. More important, any patient whose medical history is too complex for pharmacist management should be referred to another health care provider, and patients with decreased oxygenation or labored breathing should be referred to acute care settings. Widespread implementation of pharmacist prescribing for Paxlovid is unlikely, and it should not replace prescribing from primary care providers as the primary route of care for COVID19. For one, pharmacist shortages are occurring throughout the country, and this new role is not coming with increased reimbursement or relief from traditional pharmacist roles, such as dispending and providing vaccination. Pharmacists are already busy. However, Paxlovid prescribing is 1 more tool that I am happy to see the FDA deploy to allow antiviral therapy for COVID-19 to reach more patients. Slowly but consistently, we continue to move forward.

https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-pharmacists-prescribe-paxlovid-certain-limitations

https://www.cdc.gov/heartdisease/pharmacist.htm

Articles

The Paxlovid approval reaffirms the importance of pharmacists in fighting COVID-19.

Paxlovid Prescribing by Pharmacists: A New Paradigm

Gram-negative bacterial resistance in the United States continues to increase. As it has spread to the community setting, common infections such as urinary tract infections (UTIs) have become increasingly difficult to manage using oral medications and may necessitate the use of intravenous antibiotics. For complicated UTIs, 1 in 5 patients will have an infection caused by an extended-spectrum β-lactamase (ESBL)-producing Enterobacterales, which limits options when they also are resistant to fluoroquinolones and trimethoprim-sulfamethoxazole.

Tebipenem and sulopenem are carbapenems with oral formulations that have been studied in phase 3 trials.

 Each typically has a broad spectrum of activity, including streptococci, methicillin-susceptible strains of staphylococci, Enterobacterales (including ESBL-producing strains), and many anaerobes. Notable exceptions to their useful activity include 

Enterococcus faecium, Clostridioides difficile

, and many nonfermenting gram-negative bacilli such as 

TEBIPENEM PIVOXIL HYDROBROMIDE (TEBIPENEM HBR)

Tebipenem pivoxil is a formulation of tebipenem marketed in Japan as Orapenem for the management of otitis media, sinusitis, and pneumonia in pediatric patients with difficult to treat infections. Tebipenem pivoxil is used to manage infections caused by penicillin-resistant 

 The drug has been reformulated as tebipenem HBr to improve stability and oral absorption. The oral bioavailability of tebipenem HBr is estimated to be 60%. It is rapidly converted to the active moiety, tebipenem, by carboxylesterases located in the intestinal epithelial cells.

 Tebipenem HBr is not metabolized by the liver or kidneys, but tebipenem undergoes renal elimination with 80% of the active metabolites excreted through the kidneys.

The clinical efficacy and safety of tebipenem HBr for complicated urinary tract infections (cUTIs) were evaluated in a published double-blind, phase III, randomized clinical trial (NCT03788967) conducted at 101 sites in 15 different countries within central and eastern Europe, South Africa, and the United States. Patients were randomly assigned to either receive tebipenem HBr 600 mg by mouth every 8 hours or ertapenem (Invanz) 1 g intravenously every 24 hours for 7 to 10 days. The primary end point was a composite of clinical cure and microbiologic response, typical of trials for cUTIs. The median patient age was 58.1 years, and 50.8% of patients had a cUTI, with the remainder having acute pyelonephritis. Bacteremia was found in 11.5% of patients, and 19.7% of patients met criteria for systemic inflammatory response syndrome. Of the infecting pathogens, 90% were Enterobacterales, primarily 

ESBL production was detected in 23.4% of infecting pathogens, 39% of pathogens were fluoroquinolone nonsusceptible, and 43% of pathogens were resistant to trimethoprim-sulfamethoxazole. Tebipenem HBr was shown to be noninferior to intravenous ertapenem with respect to the primary end point (58.8% and 61.6%; weighted difference, –3.3%; 95% CI, –9.7 to 3.2). Tebipenem HBr was effective against common gram-negative pathogens, but the clinical response for ESBL-producing pathogens trended lower, with 83.9% response compared with 93.3% for ertapenem (difference, –9.50; 95% CI, –21.62 to 2.10).

In January 2022, the FDA granted a priority review of a new drug application (NDA) for tebipenem HBr. The FDA then conducted an analysis of the microbiological intent-to-treat (micro-ITT) population separate from what was outlined in the original statistical analysis plan. From this analysis, the FDA concluded that the prespecified noninferiority margin of –12.5% was not met and halted the approval of the medication. Spero Therapeutics, the manufacturer of tebipenem HBr, released a statement shifting the company focus to other clinical therapeutics.

 These actions leave tebipenem HBr’s fate uncertain.

SULOPENEM AND SULOPENEM ETZADROXIL/PROBENECID

Sulopenem is another carbapenem being developed for cUTIs. It is available in both an intravenous formulation as sulopenem and oral formulation as sulopenem etzadroxil with probenecid.

 The pharmacokinetics and pharmacodynamics of sulopenem are similar to that of other intravenous carbapenems. Sulopenem etzadroxil is an esterified prodrug designed for oral administration. The oral bioavailability is estimated to be 20% to 34% under fasted conditions but can be increased when administered with food or probenecid. Food consumption increases the area under the curve (AUC) by 23.6%, and 500 mg of probenecid increases the AUC by 62%.

 The oral formulation is being paired with probenecid.

The clinical efficacy and safety of sulopenem etzadroxil/probenecid were first studied for the treatment of uncomplicated UTIs in adult women. Patients were randomly assigned to receive either sulopenem etzadroxil/probenecid (500 mg/500 mg) by mouth twice daily for 5 days with 3 days of placebo or ciprofloxacin 250 mg by mouth twice daily for 3 days with 5 days of placebo. The primary outcome was overall success, which was a composite outcome of clinical and microbiologic success. The data analysis in this trial included both a microbiologic modified ITT resistant (micro-MITT R) and microbiologic modified ITT susceptible (micro-MITT S) population. These populations included all randomly assigned patients who received at least 1 dose of study drug and had a baseline uropathogen that was either nonsusceptible or susceptible to ciprofloxacin, respectively. As expected, sulopenem etzadroxil/probenecid was superior to ciprofloxacin in the micro- MITT R population with an overall success rate of 62.2% with sulopenem etzadroxil/probenecid and 36.0% with ciprofloxacin (difference, 26.2%; 95% CI, 15.1-37.4). For the micro-MITT S population, sulopenem etzadroxil/probenecid was not noninferior to ciprofloxacin with overall success rates of 66.8% and 78.6%, respectively (difference, –11.8%; 95% CI, –18.0 to –5.6).

Following the oral-only study, a study focusing on an intravenous to oral strategy of sulopenem formulations was conducted to assess the clinical efficacy and safety of intravenous sulopenem followed by oral sulopenem etzadroxil/probenecid for complicated UTIs. Patients were randomly assigned to receive either sulopenem 1000 mg intravenously for 5 days followed by sulopenem etzadroxil/probenecid (500 mg/500 mg) by mouth twice daily for 7 to 10 days of total treatment or ertapenem 1 g intravenously for 5 days followed by ciprofloxacin 500 mg by mouth twice daily (or amoxicillin-clavulanate if patient was ciprofloxacin resistant) for 7 to 10 total days of treatment. The primary outcome was the same as the previous trial. The intravenous and oral combination of sulopenem was not found to be noninferior to the combination of ertapenem and ciprofloxacin (67.8% vs 73.0%; difference, –6.1%; 95% CI, –12.0 to –0.1). This trial did not investigate complicated UTIs caused by multidrug resistant pathogens.

 In the previous 2 trials, the failure was hypothesized to be due to lower rates of asymptomatic bacteriuria, resulting in microbiologic failure in the patients treated with ciprofloxacin. The combination of intravenous and oral sulopenem also was investigated in complicated intra-abdominal infections and did not meet noninferiority criteria compared to the combination of ertapenem with step down to ciprofloxacin and metronidazole.

 Three clinical trials were completed and unfortunately all 3 missed their end points. The manufacturing company, Iterum Therapeutics, applied for an NDA based on results from the trial (NCT03354598) completed in uncomplicated UTIs that showed sulopenem etzadroxil/probenecid could be used for infections caused by fluoroquinolone-resistant pathogens. The FDA denied this request and required more supporting evidence to approve the medication. The manufacturing company, Iterum Therapeutics, is working with external vendors to design a clinical trial to provide additional evidence for the FDA.

The approval of an effective oral carbapenem could change the way complicated UTIs caused by multidrug resistant organisms are managed. It could help reduce health care–related costs associated with the need for intravenous therapy by either preventing hospital admission or reducing hospital length of stay. However, the prospect of an oral carbapenem raises concern among health care professionals with regard to misuse further leading to antimicrobial resistance. Currently, tebipenem pivoxil, marketed in Japan as Orapenem for pediatric infections, is not recommended in first-line use but can be used after other antibiotics fail.

 The potential availability of oral carbapenems may worry infectious diseases clinicians, but they would increase options for oral therapy of infections currently treated parenterally. However, it seems these agents are not likely to be available as soon as once anticipated.

Talan DA, Takhar SS, Krishnadasan A, et al. Emergence of extended-spectrum β-lactamase urinary tract infections among hospitalized emergency department patients in the United States. 

. 2021;77(1):32-43. doi:10.1016/j.annemergmed.2020.08.022

Eckburg PB, Muir L, Critchley IA, et al. Oral tebipenem pivoxil hydrobromide in complicated urinary tract infection. 

. 2022;386(14):1327-1338. doi:10.1056/NEJMoa2105462

Dunne MW, Das AF, Zelasky M, et al. Efficacy and safety of oral sulopenem etzadroxil/probenecid versus oral ciprofloxacin in the treatment of uncomplicated urinary tract infections (uUTI) in adult women: results from the SURE-1 trial. 

2020:7(suppl 1):S844. doi:10.1093/ofid/ofaa515.1898

Dunne MW, Aronin SI. Efficacy and safety of intravenous sulopenem followed by oral sulopenem etzadroxil/probenecid versus intravenous ertapenem followed by oral ciprofloxacin or amoxicillin-clavulanate in the treatment of complicated urinary tract infections (cUTI): results from the SURE-2 trial. 

2020:7(suppl 1):S636. doi:10.1093/ofid/ofaa439.1417

Iterum Therapeutics. Iterum Therapeutics announces topline results from phase 3 clinical trial of oral and IV sulopenem for the treatment of complicated intra-abdominal infections. December 10, 2019. Accessed July 11, 2022. https://www.iterumtx.com/news/press-releases/detail/29/iterumtherapeutics-announces-topline-results-from-phase-3.

Sodhi V, Kronsberg KA, Clark M, Cho JC. Tebipenem pivoxil hydrobromide—no PICC, no problem! 

. 2021;41(9):748-761. doi:10.1002/phar.2614

Mahalingam A, Shenoy B. Tebipenem: A novel oral carbapenem. 

 2020;2(1):25-28. doi:10.5005/jp-journals-10081-1237

Zhanel GG, Pozdirca M, Golden AR, et al. Sulopenem: an intravenous and oral penem for the treatment of urinary tract infections due to multidrug-resistant bacteria. 

. 2022;82(5):533-557. doi:10.1007/s40265-022-01688-1

Kato K, Shirasaka Y, Kuraoka E, et al. Intestinal absorption mechanism of tebipenem pivoxil, a novel oral carbapenem: involvement of human OATP family in apical membrane transport. 

. 2010;7(5):1747-1756. doi:10.1021/mp100130b

Nakashima M, Morita J, Aizawa K. Pharmacokinetics and safety of oral carbapenem antibiotic tebipenem pivoxil tablets in healthy male volunteers. 

Spero Therapeutics. Spero Therapeutics announces new strategic direction focusing on advancing promising clinical-stage pipeline. May 3, 2022. Accessed May 26, 2022. https://investors.sperotherapeutics.com/news-releases/news-release-details/spero-therapeutics-announces-new-strategic-direction-focusing

Iterum Therapeutics. Our promise: responding to medical need. Accessed May 26, 2022. https://www.iterumtx.com/our-science/our-promise

Chandra R, Hazra A, Skogerboe T, Labadie R, Kirby D, Soma K. Pharmacokinetics (PK), safety and tolerability of single oral doses of PF-03709270, with and without co-administration of probenecid. Poster presented at: 48th Annual ICAAC/IDSA 46th Annual Meeting; October 25-28, 2008; Washington, DC.

Dunne M, Dunzo E, Puttagunta S. A phase 1 study to assess the pharmacokinetics of sulopenem etzadroxil (PF-03709270). Poster presented at: IDWeek 2017; October 4-8, 2017; San Diego, CA.

Iterum Therapeutics. Iterum Therapeutics provides update from FDA Type A Meeting regarding oral sulopenem. September 28, 2022. Accessed May 26, 2022. https://www.iterumtx.com/news/press-releases/detail/78/iterum-therapeutics-provides-update-from-fda-type-a-meeting

Hayashi T, Kitamura K, Hashimoto S, et al. Clinical practice guidelines for the diagnosis and management of acute otitis media in children-2018 update. 

. 2020;47(4):493-526. doi:10.1016/j.anl.2020.05.019

Lacasse E, Brouillette E, Larose A, Parr T, Rubio A, Malouin F. In vitro activity of tebipenem (SPR859) against penicillin-binding proteins of gram-negative and gram-positive bacteria. 

. 2019;63(4):e02181-e02218. doi:10.1128/AAC.02181-18

Nakashima M, Morita J, Aizawa K. Pharmacokinetics and safety of tebipenem pivoxil tablets in healthy volunteers and in patients with reduced renal function. 

Shihyakugari A, Miki A, Nakamoto N, Satoh H, Sawada Y. First case report of suspected onset of convulsive seizures due to coadministration of valproic acid and tebipenem. 

Here is a review of the literature for this class of antibiotics.

Oral Carbapenems: Promise, Peril, and Pushbacks

is a tricky business. Although all new drug products in the United States have to go through the rigorous process of obtaining FDA approval, only anti-infectives face targets that change as the approval process is being completed. Antibiotics are the only class of medications of which use in one person affects the utility in another and that have generally declining utility across their life span.

The 10 by ’20 Initiative spearheaded by the Infectious Diseases Society of America, which aimed to produce 10 new antibiotics during the 21st century’s second decade, was successful, much to my amazement.

In fact, 14 systemically active microbials were approved from 2010 to 2019: ceftaroline, dalbavancin, tedizolid, oritavancin, ceftolozane-tazobactam, ceftazidime-avibactam, delafloxacin, meropenem-vaborbactam, plazomicin, eravacycline, omadacycline, imipenem-cilastatin-relebactam, lefamulin, and cefiderocol. It was an impressive success, particularly against multidrug-resistant (MDR) gram-negative rod (GNR) infections previously treated with polymyxins or aminoglycosides.

However, look at that list and you will see a key omission: oral medications active against resistant GNRs. Although delafloxacin is active against many GNRs (including 

), its activity against these organisms is not appreciably better than other fluoroquinolones.

Omadacycline was evaluated in two Phase 2, adaptive-design studies in urinary tract infection (UTI), evaluating efficacy, safety, tolerability and pharmacokinetics in both uncomplicated UTI and pyelonephritis, a common subset of complicated UTI. In both studies, omadacycline showed generally comparable levels of clinical success to either nitrofurantoin or levofloxacin, as determined by the investigator’s assessment of clinical response at the post-treatment evaluation. However, the microbiological responses were generally lower than the comparator agents in those studies.

Thus, although the 2010s saw antibiotic development that we had not seen for many years, it left a major need unmet: the outpatient treatment of resistant GNR infections caused by high rates of resistance to fluoroquinolones, trimethoprim-sulfamethoxazole, and highly bioavailable β-lactams coupled with the limited utility of nitrofurantoin outside of uncomplicated cystitis. This leaves patients with UTIs with limited options, which oral carbapenems could address.

In the past 2 years, 2 oral agents completed phase 3 trials that could have addressed this need, specifically for UTIs. On page 8 of 

you will find a "News and Breakthroughs" piece I coauthored describing the bumpy road that these drugs, sulopenem and tebipenem, have faced.

 Unfortunately, the ending has not been a happy one because the US Food and Drug Administration (FDA) did not approve their new drug applications as submitted, sulopenem in 2021

I do not take issue with this, but I do find the FDA decisions disheartening for 2 reasons. First is the obvious concern for a continued lack of options to treat our patients with resistant infections without using intravenous agents (and the challenges they involve). The second is the chorus of concerned clinicians who vocalized umbrage over the prospect of oral carbapenem availability. Conceptually, it is easy to see why: Carbapenems have been the most broad-spectrum and reliable agents for resistant GNR in hospitals since the approval of imipenem-cilastatin in 1985.

 Widespread use of carbapenems in outpatient settings could have major effects on the utility of these drugs for serious infections. However, the need for better outpatient options is real.

This is a challenge that we will need to address. Either or both agents could still be further studied and approved one day, but if they are not, then other oral agents with activity against MDR GNRs will be needed to take their place. The effort to develop and promote antimicrobial stewardship in outpatient settings is still nascent.

 Hopefully those who expressed fear at the concept of an oral carbapenem can help to champion outpatient stewardship as a solution to both the known problems of today and the unknown resistance issues of tomorrow.



1. Boucher HW. Have we made progress in the 10 X' 20 initiative? 

https://www.contagionlive.com/view/have-we-made-progress-in-the-10-20-initiative

2. Jorgensen SCJ, Mercuro NJ, Davis SL, Rybak MJ. Delafloxacin: place in therapy and review of microbiologic, clinical and pharmacologic properties. 

. 2018;7(2):197-217. doi:10.1007/s40121-018-0198-x

3. Karlowsky JA, Steenbergen J, Zhanel GG. Microbiology and preclinical review of omadacycline. 

. 2019;69(suppl 1):S6-S15. doi:10.1093/cid/ciz395

4. Kennedy K, and Gallagher J. Oral Carbapenems: Promise, Peril, and Pushbacks. Contagion July 2022. 

5. Iterum Therapeutics receives complete response letter from u.s. food and drug administration for oral sulopenem. Iterum Therapeutics. July 26, 2021. Accessed June 13, 2022. https://www.iterumtx.com/news/press-releases/detail/73/iterum-therapeutics-receives-complete-response-letter-from

6. Spero Therapeutics announces new strategic direction focusing on advancing promising clinical-stage pipeline. Spero Therapeutics. May 3, 2022. Accessed June 13, 2022. https://investors.sperotherapeutics.com/news-releases/news-release-details/spero-therapeutics-announces-new-strategic-direction-focusing

7. Primaxin. Prescribing information. Merck & Co; 2016. Accessed June 13, 2022.

8. Core elements of outpatient antibiotic stewardship. CDC. Updated September 8, 2021. Accessed June 13, 2022. https://www.cdc.gov/antibiotic-use/core-elements/outpatient.html

Oral Carbapenems Are Failing to Break Through

COVID-19 has been quite an educator. One of its lessons has been a work in progress on how clinicians keep up-to-date on best practices while dealing with the sheer volume of studies about the disease. Fortunately, many groups have created guidelines to treat COVID-19, including individual hospitals, government organizations like the National Institutes of Health,

and professional organizations such as the Infectious Diseases Society of America (IDSA).

 No organization can claim a “best” guideline, but because I have had the experience of serving on the IDSA guideline panel for the past 2 years, I would like to explain how these guidelines have been developed “on the fly” and how the recommendations are formulated.

The IDSA guideline panel consists of a mix of clinicians and methodologists. The clinicians are a mix of physicians and pharmacists, with expertise in infectious diseases, microbiology, pediatrics, and critical care. The methodologists serve as experts in research design and analysis and construct the evidence summaries for clinical questions as they develop. Some of these questions are natural, such as when novel therapies are made available by emergency-use authorization or when arms or analyses of landmark trials are completed. Others are prompted by panel members themselves. Meetings occur on a generally biweekly basis using video conferencing software.

The literature evaluated is primarily randomized controlled trials (RCTs) when they are available, but other types of studies are considered when RCTs are not available or when the alternative design appropriately supplements RCTs, such as real-world safety studies. Peer-reviewed publications are, unsurprisingly, preferred, but the panel also evaluates data in preprints. When press releases are the only data available, preliminary assessments are made, sometimes with the benefit of additional data.

The methodologists create evidence summaries and synthesize clinical questions by PICO format (population, intervention, comparison, and outcomes) using GRADE (grading of recommendations assessment, development, and evaluation working group) methodology.

 If data from more than 1 trial are available with comparable outcomes, the data are analyzed together. This evidence is reviewed by panelists before meetings and discussed during them, often leading to a recommendation.

Only clinical panelists vote on recommendations, and the language is specific (

). The term “recommend” is a strong one, made only when the panel believes that both the evidence is of sufficient quality and that the recommendation could be reasonably adapted into policies. The term “suggest” is used when the evidence is not sufficiently strong to justify a recommend (such as due to fragility of the effect found) or when the intervention is one that patients may reasonably refuse. Thus far, the high threshold for a 

has limited this level to only one positive recommendation—the use of glucocorticoids for patients with critical COVID-19 disease.

Although the most-read statements from the panel are the recommendations themselves, effort is also directed into clarifying the recommendations with the remarks that accompany them, which may direct clinicians to specific subpopulations in whom benefits appear most substantial or may clarify other elements of the recommendation, such as dosing. The evidence summary is also posted for each recommendation, containing the data evaluated from the included studies. Also, a narrative is written for each recommendation to put it into context.

Admittedly, the guidelines are not the most user friendly. Because COVID-19 is a novel disease and each therapeutic has been studied compared with standard of care, each PICO is written as a comparison between the agent and not receiving the agent. This makes many of the recommendations read as binary, without the nuances that clinicians consider in their patient evaluations. Clinical questions are more along the lines of “How should I treat this patient with COVID-19 who requires supplemental oxygen?” than “Should remdesivir (Veklury) or not remdesivir be given to patients who require supplemental oxygen?” With few exceptions, COVID-19 therapies have not been studied comparatively, so choosing therapies to preferentially recommend is difficult and is done, instead, by strength of evidence and quality of data.

Another area in which miscommunications occur is in the use of therapies in combination. As the science of studying therapies during the pandemic has progressed, combination therapies have been studied more frequently as comparisons with standard-of-care regimens, strengthening the ability to recommend them. However, important deficits in the knowledge base about combination therapies remain, and the guidelines largely eschew recommendations about them where those deficits exist. Because the guidelines take an evidence-based approach, recommendations are dependent on the evidence generated.

The guidelines are quite long, keep growing, and will hopefully continue to grow with the evaluation of successful therapies. Most people look no further than the recommendations and possibly the remarks, but reading the narrative is important when these recommendations do not line up with preexisting expectations or are not sufficiently clear. The evidence summary shows the data the panel used to determine its recommendation and is included near the end of each section, showing not only the data from the studies themselves, but the determination of the strength of those data, the risk of bias from the study design(s), and the certainty that the effects seen are real.



Clinicians commonly note that “guidelines are not rules” but that people often treat them that way. The oft-mentioned phrase in guidelines that they do not substitute for clinical judgment is important though, in ways that I did not appreciate before serving on the guideline panel. First and most obviously, not every patient’s nuance will make it into a clinical trial. The recommendations made are for the broad base of patients with COVID-19—and plenty of exceptions exist. For example, patients with deficient antibody response may benefit from antiviral and antibody therapies in later stages of disease than the majority of patients enrolled in studies.

It is also important for guideline readers to realize that therapies that are not explicitly recommended in guidelines may have utility for some patients. For a therapy to reach the level of a guideline recommendation, it needs a sufficient evidence base for a judgment to be rendered. Now that effective therapeutics exist, if a promising but incompletely studied therapy is recommended before sufficient evidence justifies its use, then people may utilize it in lieu of one with greater evidence, potentially causing harm. However, that does not mean those therapies are not good choices for individual patients, and the lack of a recommendation for them does not mean they should be avoided.

Finally, the panel is careful to avoid making recommendations against therapies when clinical trials are continuing to explore their utility. Negative recommendations are made when the totality of evidence leads to a conclusion that a therapy is ineffective. However, new evidence can change a recommendation, particularly when populations studied are refined to those most likely to benefit.

Creating guidelines during a pandemic has been a continuous work in progress. Although the guidelines are a living document, parts can inevitably grow stale as the pace of SARS-CoV-2 and COVID-19 therapies change. A notable example of this is the recommendation for neutralizing antibody therapies, for which literature evaluated becomes out-of-date quickly as variants evolve and become less (or more) susceptible to various monoclonal antibodies. To date, the panel has taken the position of recommending that local variants are considered when these therapies are chosen instead of trying to keep up with the rapid changes being seen. Another major challenge is keeping up with the sheer volume of literature generated about COVID-19 therapy. Fortunately, the methodologists consistently review for updates, and most major studies and therapies receive the attention of multiple panel members as well.

The guidelines are a document that, although not without flaws, have hopefully helped guide treatment decisions that have aided numerous patients with COVID-19. The panelists are some of the most dedicated people with whom I have had the pleasure of working, and they are committed to the improvement of our collective work.

Coronavirus disease 2019 (COVID-19) treatment guidelines. National Institutes of Health. Updated April 8, 2022. Accessed April 18, 2022. 

https://www.covid19treatmentguidelines.nih.gov

IDSA guidelines on the treatment and management of patients with COVID-19. Infectious Diseases Society of America. April 11, 2020. Updated March 23, 2022. Accessed April 18, 2022.

https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/

With few exceptions, COVID-19 therapies have not been studied comparatively, so choosing therapies to preferentially recommend is difficult and is done, instead, by strength of evidence and quality of data.

Taking It As It Comes: Creating Evidence-Based Guidelines During a Rapidly Changing Pandemic

refreshing experience of my first in-person infectious diseases meeting since 2019. It was wonderful catching up with colleagues and friends that I haven’t seen in years, but it was also nice to talk infectious disease outside of COVID-19.

® is dedicated to just that. We are marking over 2 years since the disease began its domination of our lives, inboxes, and literature. Each 

In Acute Infections, Maureen McElligott, MD; Alice Gallo de Moraes, MD; and Kelly Cawcutt, MD, describe the complex issues that sepsis in patients with COVID-19 represents. Although much has been learned about this issue, complications with antibiotic use, infection control, and appropriate use and interpretation of laboratory results remain issues that clinicians in the intensive care uni t confront.

In Multidrug-Resistant Infections, Eli Goshorn, MD, describes the continued issue of multidrug-resistant organisms in patients with COVID-19 and the often-contrary literature around the topic.

For HIV, Jina Saltzman, PA-C; Caroline Teter, PA-C; Renslow Sherer, MD; and David Pitrak, MD, write an intriguing comparison of what HIV teaches us about COVID-19. I believe you will enjoy the perspective they bring, using a retrospective lens to remind us of history’s lessons and how they inform the future. I appreciate this—as the need to learn and take notes during the beginning of the pandemic was the first editor-in-chief column that I wrote about COVID-19.

In Antimicrobial Stewardship and Prevention, Anna Zhou, PharmD, BCIDP; Richelle L. Guerrero-Wooley, MD; and Karen Tan, PharmD, describe the multitude of impacts that COVID-19 has had on antimicrobial stewardship programs (ASP). They take us through both the obvious (burnout) and subtle (multidisciplinary collaboration) effects resulting from working on the pandemic together. If anyone has the bandwidth to conduct a before-and-after survey of what ASPs look like after the peak phases of the pandemic pass, it could be revealing.

In Emerging and Re-emerging Infections, Jessica Malaty Rivera, MS, and Katrine Wallace, PhD, discuss mandatory vaccine policies for students. This topic may heat up in the future as vaccines hopefully become available for young children soon and as emergency use authorizations for other age groups become full approvals.

Finally, for News and Breakthroughs, I wrote about the experience of developing treatment guidelines for COVID-19 “on the fly.” This piece covers not only how it was (and is) done, but also how to read and use the guidelines from the Infectious Diseases Society of America by hopefully providing a translation from “guideline-es e” to English.

As we recently surpassed the 2-year mark of the pandemic, the May issue reflects on lessons learned thus far.

An Issue About COVID-19

the world again finds itself wrapped in a heavy blanket of COVID-19, driven by the remarkably infectious Omicron variant. How many times can we go through the same pattern? Individuals are fatigued and confused as overpromises and misunderstandings about the degree of protection from vaccines do not live up to their understandably inaccurate expectations. Acceptance of a future with COVID-19 is settling in. Building strategies that improve quality of life as we live with this viral disease requires addressing the unknowns that still exist after 2 years of COVID-19. It is unclear what a future with endemic SARS-CoV-2 will look like. Will it be seasonal, like many other respiratory viruses? This seems likely, although so far changes in dominant variants have affected infection incidence at least as much as the weather has, so it is difficult to measure. Will SARS-CoV-2 be circulating at the same time as influenza and respiratory syncytial virus?

Future variants are inevitable, but their impact on society is difficult to predict. The combination of increased transmissibility and immune evasion led to the rapid dominance of Omicron. The plan to vaccinate the world and decrease the amount of mutable circulating virus needs to be scaled rapidly to protect us all.

“Long COVID-19” is an enormous unknown. Our diminished ability to control Omicron infection means most individuals will likely be exposed to it, with significant proportions of them becoming infected. Will the somewhat milder course of infection with Omicron, whether innate to the virus or due to partial immunity, attenuate cases of long COVID-19? What is the mechanism of long COVID-19, and can we come to a consensus on its definition? This problem may require resources for many years to come.

Antiviral benefits and pathways to access

A significant step forward in 2022 is the availability of oral antivirals. These therapies, highlighted in this issue of 

®, have prevented progression to hospitalization in clinical trials, with nirmatrelvir/ritonavir (Paxlovid) looking particularly promising. However, we know that starting antiviral therapy early in the course of infection is key to its success. How useful will these therapies be in real-world use? When availability improves, will test-to-treat 

protocols be established that shorten time from symptom development to clinician assessment to prescription to dispensing? Because at-home antigen tests are (intermittently) available, can patients utilize them in clinician-aided self-diagnosis to expedite this process?

Our vaccines had been a home run before Delta and Omicron each took some of the shine from their luster. They are still proving highly effective in preventing hospitalization, but can we improve their ability to prevent transmission? Will changing variants require constantly updated vaccines or can a pan–COVID-19 vaccine be created? And how long are they protective? We have learned much in these 2 years, but understanding COVID-19 is a work in progress. Filling the remaining knowledge deficits starts with identification.

The idea of a future with COVID-19 is settling in, and building strategies that improve quality of life as we live with this viral disease are paramount.

Jason Gallagher, PharmD, FCCP, FIDP, FIDSA, BCPS*

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