INTRODUCTION

As with all parts of life for most everyone in the world, the infectious diseases landscape has been dominated by the coronavirus disease 2019 (COVID-19) pandemic since January 2020. From initial isolation in Wuhan, China, to ultimate spread around the world, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused tens of millions of cases and millions of deaths. Through significant efforts by scientists, clinical researchers, and health care providers, COVID-19 vaccinations had begun to interrupt transmissions and infections at the time this program was prepared, with promising declines in numbers of new cases, hospital admissions, and deaths.

Several infectious disease topics not named COVID-19 are the subject of this 2021 update in infectious diseases. Updated recommendations for patients living with human immunodeficiency virus (HIV) have been published. Oral antimicrobial therapy for more complicated infections as well as shortened durations of therapy are 2 significant hot topics within infectious diseases. Rapid diagnostic technologies and newer antimicrobials are discussed. Pharmacists are also becoming more involved with penicillin allergy reconciliation and intervention with the ultimate goal of delabeling patients’ medical record to improve their overall quality and cost of care.

HIV PROPHYLAXIS AND TREATMENT

Updated Antiretroviral Therapy Recommendations in Treatment-Naive People Living With HIV

The U.S. Department of Health and Human Services (HHS)¹ and the International Antiviral Society (IAS)-USA Panel² recently updated recommendations for antiretroviral therapy (ART) in treatment-naive persons living with HIV (PLWH) (Table 1). Initial ART must be individualized based on the patients’ comorbidities, coinfections, pregnancy status (confirmed pregnancy or potential to become pregnant), HIV-1 RNA viral load, CD4 cell count, results of pretreatment genotype drug-resistance testing, HLA-B*5701 status, tablet burden, dosing frequency, anticipated adherence, potential adverse effects, and drug interactions, as well as cost and availability. All first-line options include an integrase strand transfer inhibitor (INSTI) combined with at least 1 nucleoside reverse transcriptase inhibitor (NRTI) due to high rates of virologic suppression and tolerability coupled with low tablet burden. While there are no studies comparing INSTIs, bictegravir and dolutegravir are preferred given their high barrier to resistance, lower tablet burden compared with raltegravir, and lower risk of drug interactions compared with elvitegravir-containing regimens.

While most ART regimens include 3 individual antiretroviral agents, data from the GEMINI 1 and 2 studies demonstrated noninferior efficacy with dolutegravir/lamivudine compared with dolutegravir plus tenofovir disoproxil fumarate/emtricitabine in treatment-naive PLWH with HIV-1 RNA ˂500,000 copies/mL through 96 weeks of follow-up.^3,4 No treatment-emergent resistance mutations were observed in patients who met protocol-defined confirmed virologic withdrawal. However, of the 8% of patients who had CD4 counts ˂ 200 cells/μL, virologic suppression was lower with dolutegravir/lamivudine as compared with dolutegravir plus tenofovir disoproxil fumarate/emtricitabine but was not associated with virologic failure. Although dolutegravir/lamivudine is now recommended alongside traditional 3-drug ART regimens, it should not be used in PLWH with HIV-1 RNA ≥500,000 copies/mL.

Dolutegravir in Pregnant Women and Women Who Are Trying To Conceive

Selecting appropriate ART regimens in pregnant women or those of childbearing age is crucial to prevent perinatal viral transmission while avoiding potential birth defects.^1,5 In 2018, preliminary data from Botswana showed a higher rate of neural tube defects occurring in infants born to pregnant females receiving dolutegravir compared with other ART regimens at the time of conception (0.67% vs. 0.1%, respectively).⁶ These findings prompted recommendations in the HHS guidelines against using dolutegravir-containing ART during the first trimester and in PLWH of childbearing potential not using effective contraception.^1,5

However, the risk of neural tube defects with dolutegravir was determined to be lower than originally thought based on more recent data from Botswana (0.3% vs. 0.1%).⁷ Given the efficacy data of dolutegravir, HHS and IAS-USA guidelines now recommend dolutegravir as a component of preferred ART regimens in pregnant women and alternative ART regimens in women trying to conceive, but clinicians should discuss the potential risks of neural tube defects and other adverse pregnancy outcomes with patients prior to initiation of this agent.^1,2,5

Fostemsavir

Heavily treated PLWH have few treatment options available. A new option, fostemsavir (Rukobia) is a first-in-class attachment inhibitor that prevents interaction between HIV-1 and host immune cells. A prodrug that is hydrolyzed to temsavir, fostemsavir was recently approved by the U.S. Food and Drug Administration (FDA) for PLWH with limited treatment options.⁸ The BRIGHTE study, an ongoing international, randomized, double-blind, phase 3 trial, compared fostemsavir to placebo added to their current regimen in 371 treatment-experienced adults with multidrug-resistant HIV-1 and detectable HIV-1 RNA viral load ≥400 copies/mL.⁹ From day 1 to day 8, the mean HIV-1 RNA viral load (primary end point) was significantly decreased in the fostemsavir group (0.79 log₁₀ copies/mL versus 0.17 log₁₀ copies/mL in the placebo group). After 48 weeks, 54% of participants in the randomized cohort achieved virologic suppression with fostemsavir plus an optimized background therapy regimen. Nausea (4%), diarrhea (2%), and headache (2%) were the most commonly reported adverse events. Based on these data, fostemsavir represents a potential treatment option for heavily treatment experienced PLWH.

HIV Prevention

HIV can be transmitted via perinatal transmission, sexual intercourse, or exposure to infected blood. ART is one of several interventions for preventing viral transmission, with a decreased risk of transmission corresponding to virologic suppression.¹ The shorthand expression “Undetectable = Untransmittable” (or “U=U”) was developed to signify that virologically suppressed PLWH adherent to ART are unable to transmit HIV via sexual intercourse, including condomless sex.^10-12 This slogan is based on data from several studies spanning 2007 to 2016 that included more than 100,000 condomless sex acts in heterosexual and male–male serodiscordant couples,^10-13 and highlights the benefit of frequent HIV testing and rapid initiation of ART in PLWH.

Pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate/emtricitabine (Truvada) or tenofovir alafenamide/emtricitabine (Descovy) is a safe and efficacious option for HIV prevention in patients at risk of acquiring HIV, including men who have sex with men (MSM), persons at risk via heterosexual contact, and persons who inject drugs.^14-16 The latest United States Preventive Services Task Force (USPSTF) recommendations continue to promote daily tenofovir disoproxil fumarate/emtricitabine for PrEP,¹⁵ but were published prior to the FDA approval of tenofovir alafenamide/emtricitabine for PrEP.

Data from the phase 3, randomized, double-blind DISCOVER trial demonstrated comparable safety and efficacy of tenofovir alafenamide/emtricitabine versus tenofovir disoproxil fumarate/emtricitabine for PrEP in adult MSM and adult transgender women who have sex with men.¹⁶ Patients randomized to the tenofovir alafenamide/emtricitabine group had lower incidence of documented new HIV infections (0.16 per 100 person–years vs. 0.34 per 100 person–years), but improved bone and renal safety as compared with those in the tenofovir disoproxil fumarate/emtricitabine group. While tenofovir disoproxil fumarate/emtricitabine is approved by FDA for adults and adolescents weighing more than 35 kg, tenofovir alafenamide/emtricitabine is approved for adults and adolescents weighing more than 35 kg excluding cisgender women at risk of HIV acquisition via vaginal sex (due to limitations of the DISCOVER trial).^14-16 Clinicians should limit prescriptions to a 90-day supply to ensure adherence and facilitate HIV testing every 3 months. In addition, patients should have their renal function monitored and undergo screening for sexually transmitted diseases every 3 to 6 months.^14,15

TRANSITIONS IN CARE: IV-TO-PO SWITCHES

A core antimicrobial stewardship activity, endorsed by the U.S. Centers for Disease Control and Prevention (CDC) Core Elements for Hospital Antibiotic Stewardship Programs, is timely transition from intravenous (IV) to oral/enteral, or by mouth (PO), antimicrobial therapy.¹⁷ There are numerous benefits for both the patient and institution when administering oral as compared to IV antimicrobial therapy. These include improved patient satisfaction, quality of life, comfort, decreased cost and risk of catheter-related infections, and decreased length of hospitalization.¹⁸

Before transitioning from IV to PO therapy, patients should be able to tolerate oral medication(s) with a functioning gastrointestinal (GI) tract to absorb oral therapy and be hemodynamically stable with a normal white blood cell (WBC) count and temperature. In addition, an oral antimicrobial agent should be selected that achieves comparable serum concentrations as the IV formulation, and examples include trimethoprim/sulfamethoxazole, azithromycin, clindamycin, doxycycline, fluconazole, linezolid, metronidazole, and fluoroquinolones.

However, not all infectious diseases are amenable to oral antimicrobial therapy. Historically, “deep-seated” infections — such as bacteremia, infective endocarditis, and osteomyelitis — were contraindicated until findings from recent data suggested favorable outcomes were possible with oral antimicrobial therapy with good bioavailability and comparable serum concentrations. Having an interdisciplinary hospital committee approve a formulary-specific hospital IV to PO policy is encouraged, and often is led by the Department of Pharmacy to auto-convert patient regimens if meeting the set of outlined criteria correlating to clinical response and appropriateness given infective diagnosis.

Gram-Negative Bacteremia

Patients with gram-negative bacteremia are typically treated with 14 days of IV antimicrobial therapy to ensure adequate bloodstream concentrations.¹⁹ However, many oral antimicrobial agents are highly bioavailable and provide sustained bloodstream concentrations, achieving pharmacodynamic targets and similar outcomes compared with patients treated exclusively with IV antimicrobial therapy.

A retrospective cohort study of 241 patients with Enterobacterales (e.g., Escherichia coli) bacteremia from a urinary source found no statistically significant difference in the rate of treatment failure between patients treated only with IV antimicrobial therapy compared with those who were transitioned from IV to oral antimicrobial therapy.²⁰ More than 75% of patients were infected with Escherichia coli or Klebsiella pneumoniae, and patients in the oral group were most often transitioned to oral ciprofloxacin after 4 days of IV antimicrobial therapy.

While these data support transitioning patients with Enterobacterales bacteremia secondary to a urinary source to oral antimicrobial therapy, Tamma and colleagues set out to compare the efficacy and safety of oral-step down therapy in patients with uncomplicated gram- negative bacteremia due to urinary, intra-abdominal, IV catheters, pulmonary, and skin and soft tissue infections in a multicenter retrospective study.²¹ A 1:1 propensity score–matched cohort produced 739 patients in both the IV only group and oral-step down group. Thirty-day mortality was not different between groups, but the length of hospitalization was 2 days shorter in the oral-step down group. While all patients underwent source control and received at least 7 days of antimicrobial therapy, those in the oral step-down group were transitioned to oral therapy after a median of 3 days. Almost 85% of patients in the oral step-down group were transitioned to trimethoprim/sulfamethoxazole or a fluoroquinolone, while the remainder received oral β-lactams, but the study was not powered to detect a difference between antimicrobial therapies. β-lactams are not frequently used for patients with Enterobacterales bacteremia due to lack of consistent therapeutic bloodstream concentrations.²²

Sutton et al. compared oral β-lactams to fluoroquinolones or trimethoprim/sulfamethoxazole for patients with E. coli, Klebsiella spp., or Proteus spp. bacteremia from a urinary source.²³ No significant difference in 30-day recurrent bacteremia or 30-day mortality was observed between groups. Median time to transition to oral fluoroquinolones or trimethoprim/sulfamethoxazole was 5 days compared with 4 days for those receiving oral β-lactams, which was most commonly amoxicillin/clavulanate, cephalexin, and cefpodoxime proxetil.

Based on these data, patients with uncomplicated Enterobacterales bacteremia may be safely transitioned to oral antimicrobial therapy after approximately 3 days of IV antimicrobial therapy. While most data support fluoroquinolones or trimethoprim/sulfamethoxazole due to their high bioavailability and sustained bloodstream concentrations, oral β-lactams may represent a reasonable option in patients with urinary tract-related Enterobacterales bacteremia and individuals with average weight.

Infective Endocarditis

Prolonged IV antimicrobial therapy has been the mainstay for treating patients with infective endocarditis in the inpatient and outpatient setting.²⁴ However, not all patients are ideal candidates for outpatient IV antimicrobial therapy.²⁵ The partial oral treatment of endocarditis (POET) trial compared IV and oral antimicrobial therapy in 400 patients with left-sided native or prosthetic valve infective endocarditis caused by Streptococcus spp., Enterococcusfaecalis, Staphylococcusaureus, or coagulase-negative Staphylococcus spp. with no indications for valve replacement.²⁶ After at least 10 days of IV antimicrobial therapy, patients were randomized to continue IV antimicrobial therapy in the hospital or transition to 2-drug oral therapy (moxifloxacin, amoxicillin, clindamycin, rifampicin, dicloxacillin, fusidic acid, or linezolid) and receive treatment with intensive follow-up in outpatient clinics. The primary outcome was a composite of all-cause mortality, unplanned cardiovascular surgery, clinically significant embolic events, or recurrent bacteremia within 6 months. The primary composite outcome occurred in 12% and 9% of patients in the IV and oral groups, respectively, thus satisfying criteria for noninferiority. No significant differences in adverse events were noted between groups. Patients in the oral group were transitioned from IV antimicrobial therapy 17 days after diagnosis of infective endocarditis.

Findings from this study support the use of oral antimicrobial therapy in stable patients with left-sided infective endocarditis, but the results were limited in terms of generalizability. Only 5 patients enrolled were persons who inject drugs (PWIDs), fewer than one-fourth of patients had infective endocarditis caused by S. aureus, and none were methicillin-resistant S. aureus (MRSA). Furthermore, the study did not compare outcomes among specific antimicrobial therapies.

Bone and Joint Infections

Similar to infective endocarditis, bone and joint infections are most often treated with prolonged courses of IV antimicrobial therapy coupled with surgical management.²⁷ The oral versus intravenous antibiotics for bone and joint infection (OVIVA) trial compared 1-year outcomes in 1,015 patients with chronic osteomyelitis treated with IV or oral antimicrobial therapy.²⁸ Patients were randomized to IV or oral antimicrobial therapy within 7 days after surgery or initiation of antimicrobial therapy if no surgery was performed. Treatment failure occurred in 15% of patients in the IV group versus 13% in the oral group, which demonstrated noninferiority between the groups. S. aureus, coagulase-negative Staphylococcus spp., and Streptococcus spp. were the most frequently identified pathogens. Median duration of therapy was similar in the 2 groups (78 and 71 days, respectively), but length of hospitalization was significantly longer in the IV group, as was early discontinuation and IV catheter-related complications. Glycopeptides and cephalosporins the most common IV antimicrobial therapies, whereas fluoroquinolones were most often administered to patients in the oral group. However, the study did not compare outcomes between specific antimicrobial agents.

While the aforementioned studies support the use of oral antimicrobial therapy in certain complicated infectious diseases, guidance on specific antimicrobial agents is lacking.

SHORTENING DURATION OF THERAPY IS POSSIBLE

Antimicrobial stewardship is focused on improving patient outcomes while minimizing the risks of antimicrobial use.²⁹ Optimizing antimicrobial use requires a multifaceted approach to limit the use of unnecessary antimicrobial therapy while selecting the most appropriate agent, dose, route of administration, and duration of therapy in those with ongoing infectious diseases. Perhaps one of the most critical components of improving antimicrobial therapy is centered around using the shortest, but most effective duration of therapy.

Prolonged, excessive treatment durations increase the risk for antimicrobial-related adverse events, multidrug resistant organisms, and Clostridioidies difficile infections. Dr. Brad Spellberg, an infectious diseases physician and the Chief Medical Officer at the Los Angeles County + University of Southern California Medical Center, coined the phrase “The New Antibiotic Mantra — ‘Shorter Is Better’” to emphasize the evidence supporting shorter durations of therapy.³⁰

Community-Acquired Pneumonia

Although the 2007 Infectious Diseases Society of America (IDSA) and American Thoracic Society (ATS) community-acquired pneumonia (CAP) guideline recommended a minimum treatment duration of 5 days,³¹ data to support this recommendation were relatively weak and most clinicians continued to prescribe prolonged treatment durations.³² In fact, the median length antibacterial therapy was 9.5 days in a retrospective cohort study of 152,874 patients with uncomplicated CAP hospitalized throughout the United States in 2012 to 2013.³³

In an effort to validate guideline-based recommendations, Uranga and colleagues studied 312 patients hospitalized with CAP who were randomized after 5 days of treatment to stop antimicrobial therapy (short course) or continue at the discretion of their prescriber (long course). Median treatment duration was 5 days in the short course and 10 days in the long course, and similar rates of clinical success were noted at 10 days and 30 days (50% vs. 60% and 93% vs. 94%, respectively).³⁴

As a result of these findings, the 2019 IDSA and ATS CAP guideline continued to recommend 5 days of treatment for patients with either nonsevere or severe CAP who achieve clinical stability within 48 to 72 hours.³⁵ However, treatment duration may be extended to 7 days in patients with CAP caused by methicillin-resistant S. aureus or Pseudomonas aeruginosa or longer in those with CAP complicated by meningitis, infective endocarditis, or other deep-seated infections such as empyema.

Vaughn and colleagues conducted a retrospective study of 6,400 patients with CAP or health care-associated pneumonia from 43 hospitals in the Michigan Hospital Medicine Safety Consortium to identify factors associated with excess treatment duration. Median treatment duration was 8 days; 68% of patients received a longer duration of therapy than indicated, and 93% of excess treatment days resulted from antimicrobial prescriptions at discharge. Excess antimicrobial therapy was not associated with an increased mortality rate, but each additional day of antimicrobial therapy was associated with an increased risk of antimicrobial-related adverse events.³⁶

Gram-Negative Bacteremia

Uncomplicated gram-negative bacteremia — defined as a bloodstream infection without evidence of central nervous system, cardiovascular, osteoarticular, or other deep-seated infection — is associated with high rates of morbidity and mortality.³⁷ Traditionally, patients with uncomplicated gram-negative bacteremia received 14 days of IV antibacterial therapy, but data are unavailable to validate this practice.

Yahav and colleagues conducted a randomized trial comparing a short course (7 days) to a long course (14 days) of antibacterial therapy in 604 patients with uncomplicated gram-negative bacteremia. The most common primary sources of bacteremia included the urinary tract (68%) and intra-abdominal (12%) infections, while the most common organisms isolated were Enterobacterales, such as E. coli (90%). The primary outcome was a composite of bacteremia-related complication, prolonged hospitalization, re-admission, or 90-day all-cause mortality; it occurred in 46% of patients in the 7-day group compared with 48% of patients in the 14-day group, with no significant differences in 14-day or 28-day mortality between the 2 groups (2.3% and 5% vs. 1.3% and 4.4%, respectively).³⁸

A multicenter, observational, propensity-score–weighted cohort study was conducted to compare shorter versus longer durations of antimicrobial therapy in 249 patients with uncomplicated Pseudomonasaeruginosa bacteremia. Approximately two-thirds of patients were immunocompromised, with conditions such as absolute neutrophil counts (ANC) ˂500 cells/μL, receiving chemotherapy, living with HIV, or prior solid organ or stem cell transplantation. IV catheters (31%) and urinary tract (30%) infections were the most common primary sources of bacteremia. The median duration of bacteremia was 1 day, and almost all patients in both groups underwent source control. Twenty-eight percent of patients received a short duration of therapy (median 9 days); 72% received a long duration of therapy (median 16 days). The primary outcome, a composite of recurrent P. aeruginosa infection or mortality within 30 days of antimicrobial cessation, occurred in 14% of the short-course group compared with 13% of the long-course group.³⁹

The results from the CAP^34,36 and uncomplicated gram-negative bacteremia^38,39 studies are similar to those observed with multiple other infectious diseases^30,40, including nosocomial pneumonia,^41,42 acute bacterial skin and soft tissue infections,^43,44 chronic osteomyelitis,⁴⁵ diabetic foot osteomyelitis⁴⁶, and intra-abdominal infections (Table 2).^47,48 In summary, these data suggest that shorter durations of antimicrobial therapy do not result in harmful clinical outcomes.

RAPID DIAGNOSTICS: NECESSARY FOR ANTIMICROBIAL STEWARDSHIP

Significant progress has been made in recent years with new rapid molecular technologies that have allowed much quicker diagnosis of a number of pathogens within various clinical infectious disease syndromes such as pneumonia, meningitis, or gastrointestinal infections. Furthermore, rapid diagnostic technologies can identify both the most common pathogens for a number of infectious syndromes and also resistance genes specific to commonly used agents, such as the mecA gene, which correlates with MRSA.

Only one platform (Accelerate Pheno) performs comprehensive identification and susceptibility testing to date. Other platforms allow for identification of the organism along with resistance genes of clinical value, especially with gram-positive bacteria. With traditional culture and susceptibility methods, turnaround times historically have been several days; rapid diagnostic technology has now reduced this time to hours or minutes. However, no matter how quickly a test can be completed, it is only valued when results are communicated to the ordering provider who can make an appropriate antimicrobial change(s). This may include initiating new antibiotics, discontinuing antibiotics, or changing antibiotic therapy.

These technologies have allowed faster diagnoses, which in turn decrease the time to appropriate treatment and in many circumstances to optimized or “best” treatment.⁴⁹ The faster time to optimized therapy has resulted in decreased morbidity and mortality, primarily in patients with bloodstream infections. Narrowing therapy also allows for decreased usage of broader antimicrobials, leading to less adverse effects and potential for C. difficile infection.

A number of FDA-approved rapid diagnostic platforms from multiple manufacturers are approved and available for use.⁵⁰ Table 3 displays some of the common technologies with details on specifications.

A number of factors go into determining which platform would be best for an individual institution. Most of the platforms listed are not only approved by FDA but have been demonstrated in multiple outcomes studies as effective.^50,51 Some facilities have implemented multiple platforms depending on syndromes requiring testing. Individual factors affecting the ultimate choice of platform(s) include laboratory workflow, expertise required, hands-on time needed, total cost of the platform, the cost of the individual test, and the feasibility of batch testing. For example, a platform such as MALDI-TOF may cost significantly more upfront, but the individual costs of tests are much less compared with other platforms. Therefore, in large institutions that run large numbers of daily tests, this platform may be more cost effective.

Cost-effective analyses are needed to help make these decisions in what is quickly becoming a competitive market. These decisions should be made in a multidisciplinary manner similar to a hospital pharmacy, nutrition, and therapeutics committee, where key stakeholders in the microbiology laboratory and on the antimicrobial stewardship team can collaborate regarding the selection and ultimate implementation of assays that will optimize treatment outcomes.⁵²

An important factor in implementation of rapid diagnostics, irrespective of platform chosen, is that antimicrobial stewardship should be integrally involved upfront and sustained long-term. Data show clearly that rapid diagnostic technology by itself is not cost effective; it requires an antimicrobial steward (often a pharmacist) to integrate that information into the normal workflow, communicate the patient-specific diagnostic information to the ordering provider, and facilitate the change required to improve outcomes.⁵³ In addition, the pharmacist can organize effective educational and interventional strategies that best fit often-variable institutional practices. Initial implementation and continued education to all stakeholders is important, especially provision of information to other pharmacists who lack specialized training in infectious diseases.⁵⁴

Future directions for rapid diagnostic stewardship include implementation in the outpatient or clinic setting. This would be ideal for rural settings where traditional culture and susceptibility testing may be logistically difficult due to time required to transport media to centralized testing centers. Initial outpatient rapid diagnostic platforms provide identification of antibiotic-resistance genes along with identification of the organism(s). A high number of patients with respiratory tract illnesses, including influenza, could potentially benefit from rapid diagnostic technology to decrease overall antimicrobial use and subsequent adverse effects, especially in the era of a global COVID-19 pandemic due to SARS-CoV-2. Population studies demonstrate that more than 30% of antimicrobial prescribing is inappropriate, driven by viral respiratory infections such as bronchitis. Additional opportunities would involve management of sexually transmitted infections as well as urinary tract infections, one of the most common bacterial infections inappropriately treated in the outpatient setting. By identifying not only the organism but also the antibiotic-resistance genes present, antimicrobial therapy could be optimized earlier in the course, potentially avoiding side effects from ineffective antimicrobial therapy.

While the CDC and accreditation bodies such as The Joint Commission have mandated outpatient antimicrobial stewardship programs, guidance is limited on efficacy of rapid diagnostics in this setting due to limited, poor quality data. Potential barriers and roadblocks to implementation include logistics of short office visits, determination of optimal population to test, and lack of a dedicated clinical position (such as a pharmacist) to integrate new antimicrobial stewardship policies and procedures into this setting.⁵⁵ An increase in telemedicine prescribing of antibiotics, especially for upper respiratory tract infections, during the COVID-19 pandemic pose an additional added complexity to ensure appropriate antibiotic prescribing. Outpatient treatment guidelines and algorithms integrating use of rapid diagnostic tools are needed to guide appropriate antibiotic prescribing for common infections.

In summary, rapid diagnostics are continually being developed and integrated into clinical practice, primarily in the inpatient setting but also gradually into ambulatory care clinics. Pharmacists and physicians co-responsible for antimicrobial stewardship programs should be highly involved at each step of implementation to ensure these technologies are managed appropriately, leading to improved patient morbidity and mortality from infectious diseases.

UPDATE ON NEWER ANTIMICROBIALS

Research and development into newer antimicrobials has continually decreased in recent decades. Several newer antimicrobials — including a few oral agents — are now approved by FDA. Select antimicrobials are highlighted below that are novel or may have a unique place in therapy. Table 4 summarizes the optimal place in therapy for these agents.

Lefamulin (Xenlet)

Lefamulin is a first-in-class semisynthetic pleuromutilin antibiotic for systemic administration. It was approved in August 2019 for the treatment of adults with community-acquired bacterial pneumonia. It inhibits bacterial protein synthesis through the 50s subunit of ribosomal RNA. This antibiotic has activity against Streptococcus pneumoniae, methicillin-sensitive Staphylococcus aureus, Haemophilus influenzae, Legionella pneumophila, Mycoplasma pneumoniae, and Chlamydophila pneumoniae. This activity includes macrolide-resistant strains of M. pneumoniae. Lefamulin 150 mg is infused intravenously over 1 hour twice daily or taken orally at a dose of 600 mg twice daily (1 hour before or 2 hours after a meal).

Severe hepatic impairment necessitates an intravenous dose adjustment to once daily administration. The oral dosage form is not recommended for patients with moderate-to-severe hepatic impairment due to lack of patients with these clinical criteria included in the registry trials.

Lefamulin has several notable adverse effects, including QTc prolongation, fetal toxicity, and C. difficile–associated diarrhea. The potential for fetal toxicity and significant concentrations found in animal breast milk make this medication unsafe for women who are pregnant or breast feeding. Interestingly, lefamulin is both a CYP3A4 and PGP substrate; however, only oral administration inhibits CYP3A4, not the IV formulation.⁵⁶

Imipenem/Cilastatin/Relebactam (Recarbri)

Imipenem/cilastatin/relebactam is a new antimicrobial initially approved by FDA in July 2019 for complicated urinary tract infections, including pyelonephritis, and complicated intra-abdominal infections. In June 2020, the product was approved for the additional indication: of treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia.

The component drugs in this product act through different mechanisms. Imipenem is a carbapenem antibacterial that inhibits cell wall synthesis by binding to penicillin binding proteins; cilastatin has antibacterial activity and is instead a renal dehydropeptidase inhibitor, limiting the renal metabolism of imipenem; and relebactam is a novel beta-lactamase inhibitor that protects imipenem from degradation by a wide variety of beta-lactamases. Unlike meropenem/vaborbactam, this medication affords activity against multidrug-resistant Pseudomonas species as well as is active against carbapenem-resistant Enterobacterales, specifically those strains that produce K. pneumoniae carbapenemase. The recommended dose of imipenem/cilastatin/relebactam is 1.25 g (imipenem 500 mg, cilastatin 500 mg, and relebactam 250 mg) infused over 30 minutes every 6 hours. This medication is renally cleared and requires a dose adjustment for creatinine clearance (CrCL) <90 mL/min and should not be administered to patients with a CrCL <15 mL/min unless hemodialysis is initiated within 48 hours.

The most notable adverse effects reported in clinical studies include hypersensitivity reactions, seizures and other central nervous system reactions, and C. difficile–associated diarrhea. Imipenem/cilastatin/relebactam does not interact with other medications in any appreciable way except for increased seizure risk in patients also taking ganciclovir or valproic acid.⁵⁶ While the exact mechanism is unknown, carbapenems decrease valproic acid concentrations significantly through what is postulated to be hydrolysis inhibition of valproic acid’s glucuronide metabolite back to the parent drug.⁵⁷Administering higher doses of valproic acid in patients receiving imipenem/cilastatin/relebactam will not increase concentrations appropriately, and co-administration should therefore be avoided. If administration of a carbapenem-like imipenem/cilastatin/relebactam is required in patients on valproic acid for seizure management, an additional antiepileptic drug such as levetiracetam should be initiated.

Baloxavir (Xofluza)

Baloxavir marboxil is a novel antiviral drug initially approved in October 2018. It is a polymerase acidic endonuclease inhibitor indicated for the treatment of acute uncomplicated influenza A or B in patients 12 years of age and older who have been symptomatic for no more than 48 hours. It is additionally approved for postexposure prophylaxis in patients 12 years of age and older following contact with a patient with confirmed influenza. This agent’s novel mechanism is different from those of other influenza antivirals; baloxavir marboxil inhibits viral replication rather than decreasing the spread of the virus to uninfected cells.

Baloxavir is administered in single-dose, weight-based regimens for treatment or prophylaxis: 80 mg tablet for patients weighing 80 kg or more or a 40 mg tablet for those weighing more than 40 kg and under 80 kg. A prodrug, baloxavir is converted to the active metabolite via hydrolysis and had no clinically significant interactions when co-administered with CYP enzyme inhibitors or inducers.

In clinical studies, baloxavir shortened influenza symptoms by approximately 1 day compared with placebo. This reduction is similar to that of oseltamivir. Adverse effects are rare, mainly consisting of diarrhea, bronchitis, nausea, and nasopharyngitis, occurring in similar or fewer numbers of patients than with placebo. This drug should not be coadministered with multivalent cations such as calcium, selenium, zinc, iron, or magnesium, as these may decrease absorption and potentially decrease efficacy. There is also a theoretical risk of decreased efficacy of the live influenza vaccine when co-administered with baloxavir.⁵⁸

Reports of significant number of anaphylactic shock episodes by health care professionals, including some fatal cases, have signaled a hypersensitivity reaction associated with baloxavir that deserves close monitoring, as this medication will potentially be used more frequently in upcoming influenza seasons in an era after the COVID-19 pandemic. Compared with oseltamivir, baloxavir has similar efficacy and tolerability with the advantage of a one-dose treatment or prophylaxis regimen.

Omeprazole/Amoxicillin/Rifabutin (Talicia)

Omeprazole/amoxicillin/rifabutin is a newer combination medication approved in November 2019 for the treatment of Helicobacter pylori infection in adults. The 3-drug combination contains omeprazole, a proton pump inhibitor, amoxicillin, a penicillin-class antibacterial, and rifabutin, a rifamycin antibacterial. This medication, developed in an attempt to provide an alternative to clarithromycin-based therapies, is the only rifabutin-based H. pylori therapy. Macrolide resistance to H. pylori has been increasing in recent years necessitating evaluation of alternative therapies.

Each delayed-release capsule contains rifabutin 12.5 mg, amoxicillin 250 mg, and omeprazole 10 mg. The treatment dose is 4 tablets every 8 hours with food for 14 days. Omeprazole/amoxicillin/rifabutin is not recommended in patients with renal or hepatic impairment.

In a phase 3 study of 455 patients with dyspepsia, eradication rates were 84% with this combination, compared with 58% with dual therapy (proton pump inhibitor/amoxicillin). Adverse events for this medication include hypersensitivity reactions, C. difficile–associated diarrhea, acute interstitial nephritis, cutaneous and systemic lupus erythematosus, rash in patients with mononucleosis, and uveitis.

Several drug interactions involving the individual ingredients are of concern. Rifabutin is a substrate and inducer of CYP3A4 enzymes that overall offers fewer drug interactions (less potent CYP inducer) in comparison with rifampin, another commonly used rifamycin. Omeprazole is a substrate and an inhibitor of CYP2C19 and substrate of CYP3A4. Based on reproductive studies, use of omeprazole/amoxicillin/rifabutin is not recommended during pregnancy. Additionally, simultaneous use of both rifabutin and amoxicillin may reduce efficacy of hormonal contraceptives due to reduced estrogen reabsorption and decreased ethinyl estradiol and norethindrone concentrations.⁵⁹

PENICILLIN ALLERGY INTERVENTION STRATEGIES WITH SUBSEQUENT DELABELING

In September 1928, Alexander Fleming noticed the absence of Staphylococcus aureus growth around the common mold Penicillum notatum on an old culture plate. More than a decade after this discovery, penicillin began to be used to treat infections of susceptible organisms such as staphylococci, streptococci, and pneumococci.⁶⁰ Although many organisms have developed resistance to penicillin, it remains the drug of choice for a number of infections such as syphilis caused by Treponema pallidum, including neurosyphilis.⁶¹

Penicillin and its derivatives belong to a class of antibiotics with a characteristic beta-lactam ring in their molecular structure. These beta-lactam antibiotics have cross-reactivity. meaning that allergic reactions to 1 agent may imply allergic reactions to others.⁶² Because of this allergy and cross-reactivity, many patients labeled allergic to penicillin are not prescribed other beta-lactam agents.

Allergic reactions reported due to penicillin can manifest as any of the four types of the Gell and Coombs allergic reactions (Table 5). Immediate reactions typically occur within 1 hour of administration and are the results of an IgE-mediated type I reaction.⁶³ The incidence of reported penicillin allergies ranges from 1% to 10%, but the incidence of life-threatening, anaphylactic reactions is only 0.004% to 0.015%.⁶⁴

Interestingly, despite a reported penicillin allergy, more than 95% of patients evaluated for such allergy are found penicillin and cephalosporin tolerant. At 5 and 10 years, respectively, after experiencing a true IgE-mediated allergy to penicillin, 50% and 80% of antibodies are no longer present. These patients may be unnecessarily receiving alternative non-beta-lactam antibiotics. These alternative antibiotics are often less effective, more toxic, costlier, and generally have a broader-than-necessary antimicrobial spectrum. When a beta-lactam antibiotic is the preferred antibiotic, but not administered because of the labeled allergy, patients experience more treatment failures and adverse events. Patients reporting penicillin allergy have increased risk of acquiring an infection with antibiotic-resistant organisms, such as MRSA and vancomycin-resistant Enterococcus.⁶⁵ Therefore, if clinicians can prove that a patient with a reported penicillin allergy can safely receive a beta-lactam and avoid these alternative antibiotics, outcomes would significantly improve.

Various intervention strategies can be used to reconcile a penicillin allergy including penicillin skin testing, graded challenges, and direct challenge with amoxicillin. These strategies all involve an initial patient interview to determine the nature and timeline of the supposed allergic reaction as well as inquiring if the patient received any other beta-lactam since the reaction. Using of brand names of beta-lactam antibiotics may trigger patient’s memory, and calling the patient’s pharmacy and/or searching the hospital’s electronic medical record archives can also help clarify past tolerances of beta-lactam antibiotics. The goal is to use the intervention that is the least invasive and time consuming with the ultimate goal of delabeling the patient record when that is clinically appropriate.

Penicillin skin testing is an increasingly common practice to ascertain penicillin allergy, but this is also the most time and resource intensive and thus is done primarily in patients with high-risk features, such as anaphylaxis. This test involves the application of drops of several penicillin-derived reagents onto the skin, along with a positive and negative control. The personnel administering the test punctures the skin at the center of each drop to allow systemic immune effects appear (usually 15–30 minutes). If a negative reaction is seen, the clinician can move forward to the intradermal portion of the test. If this is negative, then the patient does not have an IgE-mediated penicillin allergy. An optional oral amoxicillin challenge may be administered after the intradermal test if the provider or patient wishes. This optional oral challenge is most often done in an outpatient setting where the patient may not be receiving antibiotic therapy at the time of skin testing.^66,67

A less invasive option of determining whether a patient has penicillin allergy is the graded challenge. Historically, in the absence of commercially available penicillin skin testing and in patients who were labeled as allergic to penicillin, graded challenges were used to determine the legitimacy of the labeled allergy. In this challenge, the clinician may choose to administer 1/100^th to 1/10^th of the required antibiotic dose every 30–60 minutes with escalation based on tolerance; beta-lactams antibiotics may be administered either orally or intravenously. This method may be preferred in patients with a recent history (£5 years) of a moderate IgE-mediated reaction such as hives without features of anaphylaxis.⁶⁸ Often graded challenges are built into the electronic health record as an order set available for each drug to ensure the appropriate dosing, frequency, and availability of as-needed rescue medications with administration instructions.

For the lowest-risk patients, a direct oral challenge with a therapeutic dose of amoxicillin with close monitoring for adverse reactions is appropriate. These are often patients with features such as nonallergic reactions (e.g., headache or gastrointestinal complaints), family history alone, or nonurticarial rash from 10 or more years previously. Studies have confirmed that direct oral amoxicillin challenges are safe and effective in these low-risk patients, with a tolerability rate upon direct challenge of 95% or more.⁶⁹

Pharmacists can serve an active role or take the lead in implementing penicillin allergy record reconciliation or delabeling using these intervention strategies.⁷⁰ Several studies have successfully demonstrated how a trained pharmacist can assess the allergy, perform the challenge or test, and interpret the results.^71,72 With each of these intervention strategies described, pharmacists can discuss the results with the patient and ensure the patient’s health record is delabeled when appropriate and with the patient’s consent. Every pharmacist with proper education and training can perform a number of activities described. An example of a continuing education program specifically created to develop skills within beta-lactam allergy assessment and skin testing is available on the South Carolina College of Pharmacy website.

CONCLUSION

Despite the substantial focus on COVID-19 for the past year, many notable advances have occurred in infectious diseases during this time. The topics presented in this review represent practice-changing recommendations aimed at optimizing antimicrobial selection and duration therapy. Given their expanding role in various health care settings, pharmacists are well situated to incorporate these literature updates into their evidence-based recommendations to improve patient outcomes..

REFERENCES

1. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents living with HIV. Department of Health and Human Services. 2020. Accessed October 20, 2020. http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf
2. Saag MS, Gandhi RT, Hoy JF, et al. Antiretroviral drugs for treatment and prevention of HIV infection in adults: 2020 recommendations of the International Antiviral Society-USA Panel. JAMA. 2020;324:1651–1669.
3. Cahn P, Madero JS, Arribas JR, et al. Dolutegravir plus lamivudine versus dolutegravir plus tenofovir disoproxil fumarate and emtricitabine in antiretroviral-naive adults with HIV-1 infection (GEMINI-1 and GEMINI-2): week 48 results from two multicentre, double-blind, randomised, non-inferiority, phase 3 trials. Lancet. 2019;393(10167):143-155.
4. Cahn P, Madero JS, Arribas JR, et al. Durable efficacy of dolutegravir plus lamivudine in antiretroviral treatment-naive adults with HIV-1 infection: 96-week results from the GEMINI-1 and GEMINI-2 randomized clinical trials. J Acquir Immune Defic Syndr. 2020;83(3):310-318.
5. U.S. Department of Health and Human Services. Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission. Recommendations for the use of antiretroviral drugs in pregnant women with HIV infection and interventions to reduce perinatal HIV transmission in the United States. 2020. Accessed October 22, 2020. https://clinicalinfo.hiv.gov/sites/default/files/inline-files/PerinatalGL.pdf
6. Zash R, Makhema J, Shapiro RL. Neural-tube defects with dolutegravir treatment from the time of conception. N Engl J Med. 2018;379(10):979–981.
7. Zash R, Holmes L, Diseko M, et al. Neural-tube defects and antiretroviral treatment regimens in Botswana. N Engl J Med. 2019;381(9):827–840.
8. U.S. Food and Drug Administration. FDA approves new HIV treatment for patients with limited treatment options. 2020. Accessed October 21, 2020. https://www.fda.gov/news-events/press-announcements/fda-approves-new-hiv-treatment-patients-limited-treatment-options
9. Kozal M, Aberg J, Pialoux G, et al. Fostemsavir in adults with multidrug-resistant HIV-1 infection. N Engl J Med. 2020;382(13):1232–1243.
10. Bavinton BR, Pinto AN, Phanuphak N, et al. Viral suppression and HIV transmission in serodiscordant male couples: an international, prospective, observational, cohort study. Lancet HIV. 2018;5(8):e438–e447.
11. Rodger A, Cambiano V, Bruun T, et al. Risk of HIV transmission through condomless sex in MSM couples with suppressive ART: the PARTNER2 study extended results in gay men. Abstract No: WEAX0104LB. Paper presented at: 22nd International AIDS Conference; 2018; Amsterdam.
12. Rodger AJ, Cambiano V, Bruun T, et al. Sexual activity without condoms and risk of HIV transmission in serodifferent couples when the HIV-positive partner is using suppressive antiretroviral therapy. JAMA. 2016;316(2):171–181.
13. Cohen MS, Chen YQ, McCauley M, et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med. 2011;365(6):493–505.
14. U.S. Centers for Disease Control and Prevention. Preexposure prophylaxis for the prevention of HIV infection in the United States—2017 update. 2017. https://www.cdc.gov/hiv/pdf/risk/prep/cdc-hiv-prep-guidelines-2017.pdf
15. Owens DK, Davidson KW, Krist AH, et al. Preexposure prophylaxis for the prevention of HIV infection: US Preventive Services Task Force recommendation statement. JAMA. 2019;321(22):2203–2213.
16. Mayer KH, Molina JM, Thompson MA, et al. Emtricitabine and tenofovir alafenamide vs emtricitabine and tenofovir disoproxil fumarate for HIV pre-exposure prophylaxis (DISCOVER): primary results from a randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial. Lancet. 2020;396(10246):239–254.
17. U.S. Centers for Disease Control and Prevention. Core elements of hospital antibiotic stewardship programs. 2019. Accessed October 26, 2020. https://www.cdc.gov/antibiotic-use/core-elements/hospital.html
18. Barlam TF, Cosgrove SE, Abbo LM, et al. Implementing an antibiotic stewardship program: guidelines by the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America. Clin Infect Dis. 2016;62(10):e51–e77.
19. Mermel LA, Allon M, Bouza E, et al. Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis. 2009;49(1):1–45.
20. Rieger KL, Bosso JA, MacVane SH, et al. Intravenous-only or intravenous transitioned to oral antimicrobials for Enterobacteriaceae-associated bacteremic urinary tract infection. Pharmacotherapy. 2017;37(11):1479–1483.
21. Tamma PD, Conley AT, Cosgrove SE, et al. Association of 30-day mortality with oral step-down vs continued intravenous therapy in patients hospitalized with Enterobacteriaceae bacteremia. JAMA Intern Med. 2019;179(3):316–323.
22. Mogle BT, Beccari MV, Steele JM, et al. Clinical considerations for oral beta-lactams as step-down therapy for Enterobacteriaceae bloodstream infections. Expert Opin Pharmacother. 2019;20(8):903–907.
23. Sutton JD, Stevens VW, Chang NN, et al. Oral β-lactam antibiotics vs fluoroquinolones or trimethoprim-sulfamethoxazole for definitive treatment of Enterobacterales bacteremia from a urine source. JAMA Netw Open. 2020;3(10):e2020166.
24. Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications: a scientific statement for healthcare professionals from the American Heart Association. Circulation. 2015;132(15):1435–1486.
25. Norris AH, Shrestha NK, Allison GM, et al. 2018 Infectious Diseases Society of America clinical practice guideline for the management of outpatient parenteral antimicrobial therapy. Clin Infect Dis. 2019;68(1):e1–e35.
26. Iversen K, Ihlemann N, Gill SU, et al. Partial oral versus intravenous antibiotic treatment of endocarditis. N Engl J Med. 2019;380(5):415–424.
27. Schmitt SK. Osteomyelitis. Infect Dis Clin North Am. 2017;31(2):325–338.
28. Li H-K, Rombach I, Zambellas R, et al. Oral versus intravenous antibiotics for bone and joint infection. N Engl J Med. 2019;380(5):425–436.
29. Barlam TF, Cosgrove SE, Abbo LM, et al. Implementing an antibiotic stewardship program: guidelines by the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America. Clin Infect Dis. 2016;62(10):e51–e77.
30. Spellberg B. The new antibiotic mantra — "shorter is better." JAMA Intern Med. 2016;176(9):1254–1255.
31. Mandell LA, Wunderink RG, Anzueto A, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community–acquired pneumonia in adults. Clin Infect Dis. 2007;44(suppl 2):S27–S72.
32. Aliberti S, Giuliani F, Ramirez J, Blasi F. How to choose the duration of antibiotic therapy in patients with pneumonia. Curr Opin Infect Dis. 2015;28(2):177–184.
33. Yi SH, Hatfield KM, Baggs J, et al. Duration of antibiotic use among adults with uncomplicated community–acquired pneumonia requiring hospitalization in the United States. Clin Infect Dis. 2017;66(9):1333–1341.
34. Uranga A, España PP, Bilbao A, et al. Duration of antibiotic treatment in community-acquired pneumonia: a multicenter randomized clinical trial. JAMA Intern Med. 2016;176(9):1257–1265.
35. Metlay JP, Waterer GW, Long AC, et al. Diagnosis and treatment of adults with community–acquired pneumonia. an official clinical practice guideline of the American Thoracic Society and Infectious Diseases Society of America. Am J Resp Crit Care Med. 2019;200(7):e45–e67.
36. Vaughn VM, Flanders SA, Snyder A, et al. Excess antibiotic treatment duration and adverse events in patients hospitalized with pneumonia: a multihospital cohort study. Ann Intern Med. 2019;171(3):153–163.
37. Mermel LA, Allon M, Bouza E, et al. Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis. 2009;49(1):1–45.
38. Yahav D, Franceschini E, Koppel F, et al. Seven versus 14 days of antibiotic therapy for uncomplicated gram-negative bacteremia: a noninferiority randomized controlled trial. Clin Infect Dis. 2019;69(7):1091–1098.
39. Fabre V, Amoah J, Cosgrove SE, Tamma PD. Antibiotic therapy for Pseudomonas aeruginosa bloodstream infections: how long is long enough? Clin Infect Dis. 2019;69(11):2011–2014.
40. Spellberg B. The maturing antibiotic mantra: "shorter is still better." J Hosp Med. 2018;13(5):361 362.
41. Chastre J, Wolff M, Fagon JY, et al. Comparison of 8 vs 15 days of antibiotic therapy for ventilator-associated pneumonia in adults: a randomized trial. JAMA. 2003;290(19):2588–2598.
42. Kalil AC, Metersky ML, Klompas M, et al. Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis. 2016;63(5):e61–e111.
43. Moran GJ, Fang E, Corey GR, et al. Tedizolid for 6 days versus linezolid for 10 days for acute bacterial skin and skin-structure infections (ESTABLISH-2): a randomised, double-blind, phase 3, non-inferiority trial. Lancet Infect Dis. 2014;14(8):696–705.
44. Prokocimer P, De Anda C, Fang E, et al. Tedizolid phosphate vs linezolid for treatment of acute bacterial skin and skin structure infections: the ESTABLISH-1 randomized trial. JAMA. 2013;309(6):559–569.
45. Bernard L, Dinh A, Ghout I, et al. Antibiotic treatment for 6 weeks versus 12 weeks in patients with pyogenic vertebral osteomyelitis: an open-label, non-inferiority, randomised, controlled trial. Lancet. 2015;385(9971):875–882.
46. Gariani K, Pham TT, Kressmann B, et al. Three versus six weeks of antibiotic therapy for diabetic foot osteomyelitis: a prospective, randomized, non-inferiority pilot trial. Clin Infect Dis. 2020 Nov 26: ciaa1758. doi: 10.1093/cid/ciaa1758
47. Sawyer RG, Claridge JA, Nathens AB, et al. Trial of short-course antimicrobial therapy for intraabdominal infection. N Engl J Med. 2015;372(21):1996–2005.
48. Montravers P, Tubach F, Lescot T, et al. Short-course antibiotic therapy for critically ill patients treated for postoperative intra-abdominal infection: the DURAPOP randomised clinical trial. Intens Care Med. 2018;44(3):300–310.
49. Porter AM, Bland CM, Young HN, et al. Comparison of pharmacist-directed management of multiplex PCR blood culture results with conventional microbiology methods on effective and optimal therapy within a community hospital. Antimicrob Agents Chemother. 2018;63(1):e01575–18.
50. Timbrook TT, Spivak ES, Hanson KE. Current and future opportunities for rapid diagnostics for antimicrobial stewardship. Med Clin North Am. 2018;102(5):899–911.
51. Timbrook TT, Morton JB, McConeghy KW, et al. The effect of molecular rapid diagnostic testing on clinical outcomes in bloodstream infection: a systematic review and meta-analysis. Clin Infect Dis. 2017;64(1):15–23.
52. Wenzler E, Timbrook TT, Wong JR, et al. Implementation and optimization of molecular rapid diagnostic tests for bloodstream infections. Am J Health-Syst Pharm. 2018;75(16):1191–1202.
53. Holtzman C, Whitney D, Barlam T, et al. Assessment of impact of peptide nucleic acid fluorescence in situ hybridization for rapid identification of coagulase-negative staphylococci in the absence of antimicrobial stewardship intervention. J Clin Microbiol. 2011;49(4):1581–1582.
54. Foster RA, Kuper K, Lu ZK, et al. Pharmacists’ familiarity with and institutional utilization of rapid diagnostic technologies for antimicrobial stewardship. Infect Control Hosp Epidemiol. 2017;38(7):863–866.
55. Fong K, Timbrook TT. The changing antimicrobial landscape: rapid diagnostic testing and biomarkers affecting stewardship. Infect Dis Spec Ed. Accessed October 27, 2020. https://www.idse.net/Review-Articles/Article/03-20/The-Changing-Antimicrobial-Landscape/58033
56. Xenleta [package insert]. Nabriva Therapeutics Inc; 2019.
57. Recarbrio [package insert]. Merck and Co. Inc; 2019.
58. Xofluza [package insert]. Genentech Inc; 2018.
59. Talicia [package insert]. RedHill Biopharma Ltd; 2019.
60. Hare R. New light on the history of penicillin. Med Hist. 1982;26(1):1–24.
61. Mahoney JF, Arnold RC, Harris A. Penicillin treatment of early syphilis—a preliminary report. Am J Public Health Nations Health. 1943;33(12):1387–1391.
62. Solensky R. Hypersensitivity reactions to beta-lactam antibiotics. Clin Rev Allerg Immunol. 2003;24(3):201–220.
63. Arroliga ME, Pien L. Penicillin allergy: consider trying penicillin again. Cleve Clin J Med. 2003;70(4), 313–314, 317–318, 320–321.
64. Lee CE, Zembower TR, Fotis MA, et al. The incidence of antimicrobial allergies in hospitalized patients: implications regarding prescribing patterns and emerging bacterial resistance. Arch Intern Med. 2000;160(18):2819–2822.
65. Blumenthal KG, Wickner PG, Hurwitz S, et al. Tackling inpatient penicillin allergies: assessing tools for antimicrobial stewardship. J Allergy Clin Immunol. 2017;140(1):154–161.e6.
66. Jones BM, Avramovski N, Concepcion, AM, et al. Clinical and economic outcomes of penicillin skin testing as an antimicrobial stewardship initiative in a community health system. Open Forum Infect Dis. 2019;6(4):ofz109.
67. King EA, Challa S, Curtin P, et al. Penicillin skin testing in hospitalized patients with β-lactam allergies: effect on antibiotic selection and cost. Ann Allergy Asthma Immunol. 2016;117(1):67–71.
68. Unger NR, Gauthier TP, Cheung LW. Penicillin skin testing: potential implications for antimicrobial stewardship. Pharmacotherapy. 2013;33(8):856–867.
69. Macy E, Vyles D. Who needs penicillin allergy testing? Ann Allergy Asthma Immunol. 2018;121(5):523–529.
70. Bland CM, Bookstaver PB, Griffith NC, et al. A practical guide for pharmacists to successfully implement penicillin allergy skin testing. Am J Health Syst Pharm. 2019;76(3):136–147.
71. Wall GC, Peters L, Leaders CB, Wille JA. Pharmacist-managed service providing penicillin allergy skin tests. Am J Health-Syst Pharm. 2004;61:1271–1275.
72. Chen JR, Tarver SA, Alvarez KS, et al. A proactive approach to penicillin allergy testing in hospitalized patients. J Allergy Clin Immunol Pract. 2017;5(3):686–693.

Back to Top