What recent changes may influence pharmacotherapy of community-acquired pneumonia?
Community-acquired pneumonia (CAP) is the leading cause of infection-related death in the US, and carries a mortality rate of 30% to 40%.1,2 As one of the most common conditions encountered in adults in both community and hospital practice, CAP accounts for over 4.5 million visits annually in both settings.3 The economic burden of CAP is substantial, with estimates of annual costs of care in the US ranging from $10.6 to $17 billion, which are projected to increase because of an aging population.2
Guidelines for diagnosis and treatment of CAP in the US have been issued by the American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA), and were last published in 2007.4 Since then, a variety of changes have occurred in resistance patterns and pharmacological treatment options that could meaningfully impact pharmacotherapy of CAP. For example, in recent years, several new antibiotics received Food and Drug Administration (FDA) approval for treatment of CAP and a revised ATS/IDSA guideline was issued in 2019. Major drug-related changes in treatment of CAP are summarized in this review.
CAP microbiology & resistance patterns
The bacterial pathogen most commonly responsible for CAP in otherwise healthy adults is Streptococcus pneumoniae, which accounts for up to 35% of all cases.5 Other common pathogens include Haemophilus influenzae, Mycoplasma pneumoniae, Moraxella catarrhalis, Chlamydophila pneumoniae, and Legionella species.6 Empiric treatment of CAP is targeted toward these likely pathogens, and has commonly included antibacterial therapy with a macrolide, respiratory fluoroquinolone, or a combination of a beta-lactam with a macrolide or doxycycline. Notably, resistance to first-line empiric antibiotic regimens for CAP is expanding, with rates of S. pneumoniae resistance to macrolides exceeding 25% in all major regions of the US, and resistance to doxycycline approximating 20%.5,7,8
Major changes in 2019 guidelines
Several major drug-related changes were introduced with the 2019 revision to the ATS/IDSA guideline for diagnosis and treatment of CAP.9 Additionally, some changes to the guideline process occurred since the 2007 guideline that influenced the presentation of recommendations. In line with other IDSA guidelines, the 2019 CAP guideline now follows the Grading of Recommendations, Assessment, and Evaluation (GRADE) format, which provides ratings for the strength of each recommendation (strong or conditional) and the quality of the supporting literature (very low, low, moderate, or strong). These ratings distinguish confidence in recommendations for some notable drug-related changes in CAP pharmacotherapy, which are summarized below.
Macrolide monotherapy in outpatients
Macrolide monotherapy in empiric treatment of CAP in healthy outpatients without comorbidities or risk factors for resistant pathogens is now only conditionally recommended in areas where pneumococcal resistance to macrolides is below 25% of isolates.9 This downgrading of the recommendation for macrolide monotherapy compared with 2007 guidelines is rooted in studies documenting failure of macrolides in this population, as well as the notable rates of macrolide-resistant S. pneumoniae in all major regions of the US.7 Macrolide monotherapy may remain appropriate only in settings where resistance is low and patients have contraindications to other therapy. Amoxicillin 1 gram three times daily (strong recommendation) and doxycycline 100 mg twice daily (conditional recommendation) remain options in outpatient empiric treatment of CAP in healthy outpatients.
Whereas the 2007 CAP guideline did not provide explicit recommendations on use of corticosteroids, the 2019 guideline recommends against their routine use in adults with CAP that is non-severe (strong recommendation) and severe (conditional recommendation).4,9 No data have demonstrated benefit of corticosteroid therapy in patients with non-severe CAP in outcomes related to mortality or organ failure, and only limited data have shown benefit in patients with severe CAP. The guideline endorses recommendations of the Surviving Sepsis Campaign, which recommend use of corticosteroids in patients with CAP and refractory septic shock.10 The guideline notes that this recommendation should not override clinical judgment in determinations regarding treatment of comorbid conditions with corticosteroids.9 Uncertainty remains regarding which subpopulations of patients with CAP, if any, may experience particular benefit or harm from corticosteroid therapy.
Beta-lactam combination regimens in severe CAP
For inpatient adults with severe CAP without risk factors for MRSA or P. aeruginosa, the 2019 guideline strongly recommends empiric therapy with either combination beta-lactam plus macrolide or beta-lactam plus fluoroquinolone regimens; however the level of evidence was moderate and strong for these recommendations, respectively.9 Previous literature has described improved mortality in critically ill patients with CAP who were treated with macrolide- vs non-macrolide-containing regimens.11,12
Sputum and blood cultures to curtail use
Pretreatment blood and sputum culture are now recommended in patients with CAP managed in the hospital setting who have severe CAP, are being empirically treated for or have prior infection with MRSA or P. aeruginosa, or have been hospitalized and treated with parenteral antibiotics within the previous 90 days.9 These recommendations are strong for all subgroups except for patients with prior infection or recent hospitalization and antimicrobial therapy, in whom recommendations are conditional. The quality of evidence for these recommendations was rated very low; however, these changes are intended to curtail the overuse of agents with activity against Pseudomonas and methicillin-resistant Staphylococcus aureus (MRSA), as well as to generate data quantifying the local prevalence and resistance of these pathogens.9,13
Anaerobic coverage in aspiration pneumonia
The 2007 CAP guideline did not make explicit recommendations regarding the need for additional anaerobic coverage in patients with aspiration pneumonia, although it did describe the generally overestimated need for this treatment.4 The 2019 guideline now conditionally recommends that routine anaerobic coverage for suspected aspiration pneumonia is unneeded unless lung abscess or empyema is suspected.9 This recommendation is based on very low quality evidence, and further research is warranted, as no clinical trials have compared treatment regimens with vs without anaerobic coverage for hospitalized patients with suspected aspiration.
Newly approved drugs for treatment of CAP
Since 2017, three new antibiotics have been approved by the FDA for treatment of CAP – delafloxacin, lefamulin, and omadacycline.14-16 While these agents offer expanded options for treatment of CAP, they were largely unmentioned in the guideline update because of a dearth of literature. The 2019 CAP guideline states that further research on lefamulin and omadacycline in the outpatient setting is warranted and does not comment on delafloxacin. All three agents demonstrated noninferiority to moxifloxacin in phase 3 trials supporting their approval in this indication (Table 1). However, as summarized below, their distinct characteristics may influence selection of these agents in appropriate patients with CAP.
Table 1. Phase 3 trials of new antibiotics approved for CAP. Heading link
|Table 1. Phase 3 trials of new antibiotics approved for CAP.|
|Trial||N||Antibiotic regimens||Early clinical response (%) a||CI for difference|
|DEFINE-CABP17,18, b||860||Delafloxacin 300 mg IV every 12 hours||88.9%||‑4.4% to 4.1%c, d|
|Moxifloxacin 400 mg every 24 hours, with potential switch to IV linezolid for confirmed MRSA||89.0%|
|LEAP-119, b||551||Lefamulin 150 mg IV every 12 hours, with added placebo if MRSA was suspected||87.3%||‑8.5% to 2.8%c, e|
|Moxifloxacin 400 mg IV every 24 hours, with added linezolid if MRSA was suspected||92.0%|
|LEAP-220||738||Lefamulin 600 mg orally every 12 hours||90.8%||‑4.4% to ∞e, f|
|Moxifloxacin 400 mg orally every 24 hours||90.8%|
|Stets et al21, b||774||Omadacycline 100 mg IV every 12 hours, followed by 100 mg IV every 24 hours||81.1%||‑7.1% to 3.8%c, e|
|Moxifloxacin 400 mg IV every 24 hours||82.7%|
|Abbreviations: CAP = community-acquired pneumonia; CI = confidence interval; IV = intravenous; MRSA = methicillin-resistant Staphylococcus aureus.
aEarly clinical response was measured at day 3 to 5 and is reported for the intention-to-treat population.
bConversion from IV to oral administration was permitted at day 3 of treatment.
c95% CI for difference.
dNoninferiority was defined as ‑12.5% difference.
eNoninferiority was defined as ‑10% difference.
f97.5% one-sided CI for difference.
Delafloxacin is a fluoroquinolone with broad activity against aerobic gram-positive and gram-negative bacteria, including fluoroquinolone-susceptible P. aeruginosa.14,22 Compared with other fluoroquinolones, delafloxacin appears to have greater activity against gram-positive organisms, including multidrug-resistant S. pneumoniae. It is the first fluoroquinolone approved for treatment of MRSA; however, this is only currently applicable to the indication for treatment of acute bacterial skin and skin structure infections (ABSSSI), not CAP. Notably, there does not appear to be risk for QT prolongation with delafloxacin, unlike with other fluoroquinolones.23 Delafloxacin is available in both oral and intravenous (IV) formulations, and the product labeling indicates treatment for CAP may be initiated with oral tablets.14 Delafloxacin requires dosage adjustment when administered IV in patients with renal impairment because of a product vehicle that accumulates in these patients.
Lefamulin, a pleuromutilin antibacterial agent, inhibits bacterial protein synthesis through interactions with peptidyl transferase centers of ribosomal subunits.15,24 Lefamulin is active against S. pneumoniae, H. influenzae, M. pneumoniae, C. pneumoniae, Legionella pneumophila, and methicillin-sensitive S. aureus. It does not have activity against P. aeruginosa and has only shown in vitro activity against MRSA. Lefamulin is available in IV and oral formulations, and like delafloxacin, product information suggests initiation with oral tablets is possible. Neither lefamulin formulation requires dosage adjustment in patients with renal impairment. However, when administered IV, lefamulin requires dosage adjustment in patients with severe hepatic impairment, and lefamulin tablets are not recommended in patients with moderate or severe hepatic impairment.
Omadacycline is a broad-spectrum tetracycline with activity against gram-positive, gram-negative, atypical, and anaerobic pathogens.6,25,26 It possesses activity against penicillin- and macrolide-resistant S. pneumoniae and the ability to overcome resistance against doxycycline, although it is not active against Pseudomonas species. Similar to delafloxacin, the activity of omadacycline against MRSA is only reflected in its approval for use in ABSSSI, not CAP. Omadacycline is available in both IV and oral formulations, although its approved oral regimen for CAP includes an initial IV loading dose prior to transition to an oral maintenance dose. Omadacycline does not require dose adjustment in renal or hepatic impairment.
The 2019 revised guideline for diagnosis and treatment of CAP updated several drug-related recommendations that could change practice in the coming years. These changes may usher in lower usage of some treatment practices, including empiric macrolide monotherapy in healthy outpatients, beta-lactam fluoroquinolone regimens for inpatients with severe CAP, use of corticosteroids, and added anaerobic coverage in aspiration pneumonia. While the place in therapy of CAP for delafloxacin, lefamulin, and omadacycline is not characterized by the 2019 CAP guideline, these new agents may have a role in treatment of patients who have resistant infection or contraindications to other antibiotics, and in shortening the length of hospital stay for patients transitioning from IV to oral therapy.27
- Ramirez JA, Wiemken TL, Peyrani P, et al. Adults hospitalized with pneumonia in the United States: incidence, epidemiology, and mortality. Clin Infect Dis. 2017;65:1806-1812.
- Kim Y, Sanjay KC, Sharma R. Community-acquired pneumonia. Pharmacy Times website. https://www.pharmacytimes.com/publications/health-system-edition/2018/january2018/communityacquired-pneumonia. Published January 23, 2018. Accessed November 22, 2019.
- Ramirez JA, File TM, Bond S. Overview of community-acquired pneumonia in adults. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate; 2019. https://www.uptodate.com/contents/overview-of-community-acquired-pneumonia-in-adults?search=community acquired pneumonia&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1. Accessed November 22, 2019.
- 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):S27-72.
- Zasowski EJ, Blackford MG. Lower respiratory tract infections. In: DiPiro JT, Yee GC, Posey LM, Haines ST, Nolin TD, Ellingrod V, eds. Pharmacotherapy: A Pathophysiologic Approach. 11th ed. New York, NY: McGraw-Hill Education; 2019. accesspharmacy.mhmedical.com/content.aspx?aid=1164176551. Accessed November 22, 2019.
- Anonymous. Omadacycline (Nuzyra)–a new tetracycline antibiotic. Med Lett Drugs Ther. 2019;61(1572):74-77.
- Haran JP, Volturo GA. Macrolide resistance in cases of community-acquired bacterial pneumonia in the emergency department. J Emerg Med. 2018;55(3):347-353.
- Jones RN, Jacobs MR, Sader HS. Evolving trends in Streptococcus pneumoniae resistance: implications for therapy of community-acquired bacterial pneumonia. Int J Antimicrob Agents. 2010;36:197-204.
- 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 Respir Crit Care Med. 2019;200(7):e45-e67.
- Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: International guidelines for management of sepsis and septic shock: 2016. Crit Care Med. 2017;45(3):486-552.
- Sligl WI, Asadi L, Eurich DT, Tjosvold L, Marrie TJ, Majumdar SR. Macrolides and mortality in critically ill patients with community-acquired pneumonia: a systematic review and meta-analysis. Crit Care Med. 2014;42(2):420-432.
- Vardakas KZ, Trigkidis KK, Falagas ME. Fluoroquinolones or macrolides in combination with beta-lactams in adult patients hospitalized with community acquired pneumonia: a systematic review and meta-analysis. Clin Microbiol Infect. 2017;23(4):234-241.
- Lesney MS. Guidelines updated for treating community-acquired pneumonia. MDedge.com website. https://www.mdedge.com/chestphysician/article/210421/pulmonology/guidelines-updated-treating-community-acquired-pneumonia. Published October 18, 2019. Accessed November 21, 2019.
- Baxdela [package insert]. Lincolnshire, IL: Melinta Therapeutics; 2019.
- Xenleta [package insert]. King of Prussia, PA: Nabriva Therapeutics; 2019.
- Nuzyra [package insert]. Boston, MA: Paratek Pharmaceuticals; 2019.
- Melinta Therapeutics. Melinta Therapeutics announces positive top-line results in phase III trial of Baxdela® (delafloxacin) for treatment of CABP. Melinta Therapeutics website. http://ir.melinta.com/news-releases/news-release-details/melinta-therapeutics-announces-positive-top-line-results-phase. Published October 29, 2018. Accessed November 21, 2019.
- Clinicaltrials.gov. Study to Compare Delafloxacin to Moxifloxacin for the Treatment of Adults With Community-acquired Bacterial Pneumonia (DEFINE-CABP). Clinicaltrials.gov website. https://clinicaltrials.gov/ct2/show/NCT02679573. Published February 10, 2016. Updated July 29, 2019. Accessed November 22, 2019.
- File TM, Jr., Goldberg L, Das A, et al. Efficacy and safety of IV-to-oral lefamulin, a pleuromutilin antibiotic, for treatment of community-acquired bacterial pneumonia: the phase 3 LEAP 1 trial. Clin Infect Dis. 2019.
- Alexander E, Goldberg L, Das AF, et al. Oral lefamulin vs moxifloxacin for early clinical response among adults with community-acquired bacterial pneumonia: the LEAP 2 randomized clinical trial [published online ahead of print September 27, 2019]. JAMA. doi: 10.1001/jama.2019.15468.
- Stets R, Popescu M, Gonong JR, et al. Omadacycline for community-acquired bacterial pneumonia. N Engl J Med. 2019;380(6):517-527.
- Anonymous. Delafloxacin (Baxdela)–a new fluoroquinolone antibiotic. Med Lett Drugs Ther. 2018;60(1543):49-51.
- Litwin JS, Benedict MS, Thorn MD, Lawrence LE, Cammarata SK, Sun E. A thorough QT study to evaluate the effects of therapeutic and supratherapeutic doses of delafloxacin on cardiac repolarization. Antimicrob Agents Chemother. 2015;59(6):3469-3473.
- Anonymous. Lefamulin (Xenleta) for community-acquired bacterial pneumonia. Med Lett Drugs Ther. 2019;61(1581):145-148.
- Barber KE, Bell AM, Wingler MJB, Wagner JL, Stover KR. Omadacycline enters the ring: A new antimicrobial contender. Pharmacotherapy. 2018;38(12):1194-1204.
- Kollef MH, Betthauser KD. New antibiotics for community-acquired pneumonia. Curr Opin Infect Dis. 2019;32(2):169-175.
- Burgos RM, Rodvold KA. Omadacycline: a novel aminomethylcycline. Infect Drug Resist. 2019;12:1895-1915.
Ryan Rodriguez, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy
The information presented is current as of November 20, 2019. This information is intended as an educational piece and should not be used as the sole source for clinical decision making.