Saira Chaudhry, PharmD, MPh

The overuse of antimicrobials is associated with antimicrobial resistance, which is now a global crisis. More than 700,000 deaths result from antimicrobial resistance each year. If this problem is left unchecked, the number of deaths will increase to an estimated 10 million per year by 2050, or 1 death every 3 seconds.

Antimicrobial stewardship involves optimizing antimicrobial use to balance the patient’s immediate need for treatment with society’s need for effective antimicrobials in the future.

 The outpatient setting is ideal for antimicrobial stewardship practices, as up to 80% of antimicrobial use occurs in this setting.

Furthermore, 30% to 60% of these prescriptions are considered suboptimal, and 30% are considered unnecessary altogether.

Much of the inappropriate use of antimicrobials in the outpatient setting is for respiratory infections, including acute bronchitis and rhinosinusitis.

 Below is a review of the treatment of acute bronchitis and rhinosinusitis in healthy adult patients who do not have chronic lung disease or who are immunocompromised.

Acute bronchitis is a self-limited lower respiratory tract infection affecting the large airways of the lung and produces a cough that typically lasts less than 3 weeks.

 It affects about 5% of adults annually and is more common in the fall and winter.

 It is caused primarily by respiratory viruses, including adenovirus, coronavirus, enterovirus, human metapneumovirus, influenza A and B parainfluenza, respiratory syncytial virus, and rhinovirus.

 Less than 10% of cases are bacterial in origin, with atypical bacteria such as 

Bordetella pertussis, Chlamydophila pneumoniae

The early course of acute bronchitis mimics that of the common 

, with symptoms including malaise, nasal congestion, rhinitis, and sore throat occurring in the first few days.

 This is followed by the onset of a cough, which becomes the dominant symptom.

 The cough associated with acute bronchitis can take 2 to 3 weeks to resolve.

The treatment of acute bronchitis involves primarily supportive care.

 Patients may benefit from symptomatic relief, with antihistamines, β-agonists, cough suppressants, decongestants, and expectorants.

 Nonpharmacologic measures, such as avoiding cigarette smoke, drinking hot tea, and using throat lozenges, may also provide symptom relief. Because this syndrome is primarily viral in origin, the American Academy of Family Physicians, the American College of Physicians, and the CDC all recommend against the empiric use of antimicrobials as treatment in most cases.

There are 2 scenarios in which antimicrobials are indicated for acute bronchitis. The first is acute bronchitis caused by seasonal 

. Treatment with neuraminidase inhibitors (

 is recommended in patients who are hospitalized, have a complicated or severe disease, or are at high risk for complications.

 The clinical benefit of treatment with neuraminidase inhibitors is greatest if treatment is initiated within 48 hours of symptom onset.

 The second scenario mandating treatment is acute bronchitis caused by pertussis. Prompt treatment with a macrolide (

) is indicated to eradicate the organism from the nasopharynx and decrease the risk of transmission to others.

Rhinosinusitis is a common condition that affects the nasal cavity and paranasal sinuses. The term 

 because inflammation of the sinuses is typically associated with inflammation of the nasal cavity.

 In a 2012 national health survey, 1 in 8 adults in the United States reported being given a diagnosis of rhinosinusitis in the previous 12 months.

 Acute rhinosinusitis (ARS) is defined as having symptoms of purulent nasal drainage accompanied by facial pain (fullness or pressure) and/or nasal obstruction for up to 4 weeks.

 Other symptoms include anosmia or hyposmia, cough, ear fullness or pressure, fatigue, fever, halitosis, and headache. This syndrome is usually viral in origin and caused less commonly by bacteria. 

Viral rhinosinusitis (VRS) is defined as symptoms of ARS that are present for fewer than 10 days and not worsening. Patients with VRS present with cough, nasal congestion, rhinorrhea, sneezing, and sore throat. VRS symptoms usually peak within 3 days and then gradually resolve within 10 to 14 days.

 Acute VRS is usually caused by the influenza virus, the parainfluenza virus, or the rhinovirus.

Acute bacterial rhinosinusitis (ABRS) is defined by one of 3 clinical scenarios: the onset of severe symptoms such as high fever (>39°C, or >102°F) and purulent nasal discharge for at least 3 to 4 consecutive days at the beginning of illness, the initial improvement of symptoms followed by worsening symptoms after 5 to 6 days (double worsening), or symptoms of ARS that do not improve within 10 days of onset.

 The most common pathogens that cause ABRS are 

Haemophilus influenzae, Moraxella catarrhalis, 

For symptomatic relief from ARS, patients can take analgesics (such as acetaminophen and nonsteroidal anti-inflammatory drugs), cough suppressants, mucolytics, nasal saline irrigation, and topical intranasal steroids. For ABRS, watchful waiting without antibiotics is recommended, unless the patient will not follow up.

 An antibiotic may be needed during watchful waiting if there is no improvement by day 7 or a worsening of symptoms.

 Amoxicillin/clavulanate is recommended as first-line treatment. See 

 for risk factors for antimicrobial resistance; duration of treatment is 5 to 7 days.

Considering the threat of antimicrobial resistance and a postantibiotic era, antimicrobials must be used prudently in acute bronchitis and ARS. It is imperative to note that both syndromes are caused most commonly by viruses and are self-limiting in nature. In most cases, the mainstays of management include symptomatic relief and watchful waiting. Nonetheless, patients should be instructed to reach out to their medical providers if they have a fever ((>38°C, >100.4°F), a prolonged duration of symptoms (>3 weeks for bronchitis, >10 days for rhinosinusitis, recurrent infections, symptoms not relieved by OTC medication, or a worsening of symptoms. If antimicrobials are prescribed, they should be taken consistently and for the entire duration. Antimicrobials are a vital nonrenewable resource and ultimately should be used judiciously.

Saira Chaudhry, PharmD, MPh, is a clinical assistant professor at the Ernest Mario School of Pharmacy at Rutgers University in Piscataway, New Jersey, and a clinical pharmacist at Jersey Shore University Medical Center in Neptune City specializing in infectious diseases.

Siddharth Swamy, PharmD, BCPS, is a clinical assistant professor at the Ernest Mario School of Pharmacy at Rutgers University and a clinical infectious diseases pharmacist at Hackensack University Medical Center in New Jersey.

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Articles

The overuse of antimicrobials is associated with antimicrobial resistance, which is now a global crisis.

Acute Bronchitis and Rhinosinusitis: Perspectives From Antimicrobial Stewardship

Combination antiretroviral therapy (ART) has greatly reduced HIV-associated morbidity and mortality and improved the quality of life for those living with HIV.

Advances, including new agents and novel strategies, continue to improve treatment options. Treatment guidelines have shifted away from long-established classes and regimens.

 Most treatment-naive patients are initiated on 2 nucleoside reverse transcriptase inhibitors (NRTIs), plus a third drug from the integrase strand transfer inhibitor (INSTI) class, because of high rates of treatment success and tolerability. In certain clinical situations, a regimen consisting of 2 NRTIs plus a boosted protease inhibitor or non-nucleoside reverse transcriptase inhibitor (NNRTI) may be preferred. The decision about which antiretroviral regimen to choose is based on its adverse effect (AE) profile, convenience, efficacy, and genetic barrier to resistance. Factors such as comorbidities, concomitant medications, and preferences, should also be considered. Single-tablet regimens, dosed once daily, have helped in adherence and overall effectiveness.

Strategies surrounding antiretroviral regimen changes have become a major part of helping people with HIV. Treatment simplification and switch strategies have largely focused on optimizing adherence and limiting long-term toxicities in patients already controlled on ART. Carrying out such changes without doing harm (development of resistance and treatment failure) has been a high priority. Evaluating the efficacy and safety of dual (2-drug) therapy, instead of the conventional 3-drug combination, has been at the forefront of changes in philosophy.

Here is a look at several antiretroviral agents and combinations that were recently approved or are late in development, including a few dual-therapy options.

BICTEGRAVIR-EMTRICITABINE— TENOFOVIR ALAFENAMIDE (BIKTARVY)

Bictegravir is the latest second-generation INSTI coformulated with the NRTIs emtricitabine and tenofovir alafenamide (with reduced bone and renal toxicity) to form Biktarvy, a single-tablet regimen approved to treat HIV-1 in treatment-naive patients or to replace ART in those virologically controlled. Like dolutegravir, bictegravir has a high invitro barrier to resistance and remains active against many resistant strains. Biktarvy can be taken with or without food and is not recommended in patients with creatinine clearance <30 mL/min.

 In 2 phase 3 clinical trials, bictegravir-emtricitabine-tenofovir once daily was compared with once-daily dolutegravir-abacavir-lami-vudine and with dolutegravir-emtricitabine—tenofovir alafenamide once daily. Bictegravir-emtricitabine- tenofovir in both trials was found to achieve viral suppression and was not inferior to both dolutegravir regimens at week 48.

 Biktarvy has minimal drug interactions, with the exception of dofetilide and rifamycins. Also, oral absorption of bictegravir is reduced when it is coadministered with polyvalent cations, such as aluminum, calcium-containing antacids, and magnesium.

To limit long-term toxicities and potential drug interactions, dual therapy has been shown to be a viable switch option for patients controlled on traditional but suboptimal triple therapy.

 The FDA recently approved the first dual-therapy combination, dolutegravir-rilpivirine (Juluca), after 2 studies found the combination was not inferior to ART therapies in maintaining HIV suppression at 48 weeks. The most common adverse effects seen in studies were nasopharyngitis and headache. Drugs that increase gastric pH and that contain polyvalent cations reduce the plasma concentrations of rilpivirine significantly and should be avoided or spaced appropriately.

DARUNAVIR-COBICISTAT-EMTRICITABINE— TENOFOVIR ALAFENAMIDE (JANSSEN THERAPEUTICS)

Darunavir-cobicistat-emtricitabine—tenofovir alafenamide (D/C/F/ TAF) is a single-tablet protease inhibitor-based regimen in development that was submitted for a new drug application (NDA) in 2017. In the AMBER and EMERALD phase 3 trials, D/C/F/TAF was found to be not inferior to the comparator regimens in both treatment-naive and -experienced patients as a switch option. Both studies showed a reduction in bone mineral density and improvements in the tubular biomarkers and proteinuria in the D/C/F/TAF group. These reductions were seen because D/C/F/TAF has the new formulation tenofovir alafenamide versus the comparator regimens that contained tenofovir disoproxil fumarate. The most common AEs seen in both studies were diarrhea, nasopharyngitis, nausea, rash, and upper respiratory infections.

In March 2018, the FDA approved ibalizumab-uiyk under an orphan drug designation to treat HIV-1 infection in treatment-experienced adult patients with documented multi-antiretroviral class resistance and whose regimens have failed.

 Ibalizumab-uiyk is the first novel monocolonal antibody for HIV-1. Ibalizumab-uiyk is a CD4-directed postattachment inhibitor, which acts by binding to CD4 and prevents the postattachment steps needed for HIV-1 to enter host cells.

Ibalizumab-uiyk is administered by a trained medical professional as an intravenous infusion over at least 30 minutes every 2 weeks. Patients must be monitored for infusion-related reactions. In a heavily treated population with multidrug-resistant HIV-1 and detectable viral load, 43% of the 40 enrolled patients who received ibalizum-ab-uiyk in conjunction with other antiretrovirals achieved treatment success.

 Although most adverse reactions were mild to moderate, 9 patients experienced serious adverse reactions.

Doravirine is an NNRTI that recently submitted an NDA, including a coformulation with tenofovir disoproxil fumarate and lamivudine as a single-tablet regimen.

 It is dosed once daily, without regard for meals, and is expected to have minimal drug interaction potential.

Doravirine, plus 2 NRTIs, was shown to be not inferior to ritona-vir-boosted darunavir- and efavirenz-based regimens at achieving virologic suppression.

Doravirine appeared to have fewer neuro-psychiatric AEs and a better lipid profile than the comparator arms. There appears to be a larger potential for doravirine in treatment-experienced patients because this agent retains antiviral activity against select strains that cause resistance to NNRTIs.

CABOTEGRAVIR-RILPIVIRINE LA (VIIV HEALTHCARE)

The pharmacokinetic and pharmacodynamic properties of rilpivir-ine and the INSTI cabotegravir allow for a long-acting injectable formulation of this combination, providing a possible alternative to daily oral therapy. Cabotegravir, a potent analogue of dolutegravir, plus rilpivirine is being studied as an intermittent intramuscular injection, with an oral tablet lead-in to ensure tolerability.

Phase 2b data demonstrated good efficacy as maintenance therapy through 96 weeks as both a monthly and bimonthly injection.

 Treatment was well tolerated across all 3 arms, with minimal complaints of injection-site reactions, and 88% of patients receiving interactive metronome therapy were happy to continue with the therapy, compared with 43% of those in the oral therapy arm. Phase 3 trials continue both monthly and bimonthly.

DOLUTEGRAVIR-LAMIVUDINE (VIIV HEALTHCARE)

Another dual-therapy option undergoing investigation is dolutegravir-lamivudine. With its high potency and genetic barrier to resistance, it has shown promising efficacy and safety data when combined with lamivudine.

 Studies are evaluating this combination for both switch strategies among patients already on ART and as initial therapy for treatment-naive patients.

 The hope is that dolutegravir-lamivudine will demonstrate efficacy and safety comparable to those of the current standard of care (triple-drug therapy), potentially reducing exposure to antiretrovirals and cutting costs in the United States and worldwide.

Another promising option in development for patients heavily experienced in treatment is fostemsavir, a novel, orally administered entry inhibitor. This agent binds to the viral envelope protein gp120, preventing attachment to the CD4+ glycoprotein and subsequent entry into the cell.

Fostemsavir, a prodrug of temsavir, received a breakthrough therapy designation from the FDA. Phase 3 data have demonstrated significantly lower HIV RNA levels from baseline than the placebo, with 54% of patients randomized to receive the study drug achieving virologic control.

 Headache and rash were the most common adverse effects, but no severe events occurred. 

Humberto R. Jimenez, PharmD, BCPS, AAHIVP, is a clinical assis- tant professor at the Ernest Mario School of Pharmacy at Rutgers University and a clinical pharmacist at St. Joseph’s University Medical Center in Paterson, New Jersey, specializing in infectious diseases.