Current Treatment Challenges

  • The rise of antibiotic resistance underlines the need for the development of new therapies to treat community-acquired pneumonia (CAP) with activity against pathogens commonly associated with this disease, including drug-resistant strains.1
  • There is a need to improve antibiotic utilization and patient outcomes.2,3
  • There is a need to increase appropriate use of oral antibiotics to reduce cost and length of hospitalization.2,4
  • The risk of C. difficile and other serious side effects should be minimized.2,5
Treatment Challenges
Antibiotic Resistance
CAP Treatment Regimens
Clinical Considerations
Oral CAP Agents
Treatment Failure

Antibiotic Resistance May Impact Treatment Outcomes

Knowledge of local or regional resistance rates and patterns is important for selecting the appropriate empiric therapy as common CAP pathogens, including Streptococcus pneumoniae, have demonstrated resistance to older oral antibiotics, with large degrees of regional variability seen.4,6 This complicates treatment in the outpatient setting, and failure of empiric therapy in patients with CAP is associated with worse clinical outcomes.7 To illustrate this point, the latest ATS/IDSA guidelines do not give a strong recommendation for use of macrolides as monotherapy for outpatients due to treatment failure in patients with macrolide-resistant S. pneumoniae.4

CAP Current treatment challenges

aCLSI breakpoints applied to all agents (US FDA)
A total of 1,038 S. pneumoniae isolates from 31 US centers (2019–2021) were included in the study.

The clinical relevance of these in vitro data is unknown. 

Learn more about antimicrobial resistance

CAP Treatment Regimens and Risk of Clostridioides difficile Infection

The emergence of C. difficile as a major cause of healthcare-associated infection is largely facilitated by antibiotic overuse and resistance.1 The use of virtually every antibiotic can lead to Clostridioides difficile infections (CDI), which can cause life-threatening disease.2,5 Antibiotic risk factors include the number of antibiotics used, duration of antibiotic use and the use of high-risk antibiotics. Elderly patients and patients with irritable bowel disease, immunocompromising conditions, renal disease or previous history of CDI are at increased risk.2,8

 

Management of respiratory tract infections accounts for 75% of all antibiotic use worldwide, and consequently plays a major role in the spread and development of CDI.9 The ATS/IDSA CAP guidelines emphasize that the choice between the various antibiotic treatment options requires a risk–benefit assessment for each individual patient, including a history of CDI.4 The IDSA Clinical Practice Guidelines for CDI recommend antibiotic stewardship measures including targeted antibiotic restrictions to control CDI rates. Antibiotics to be targeted should be based on the local epidemiology and the C. difficile strains present. Restriction of high-risk antibiotics such as fluoroquinolones, clindamycin, and cephalosporins should be considered.5

 

A meta-analysis of comparative observational studies was performed to determine the association between antibiotic class and the risk of CDI in the community setting. This study found that clindamycin (odds ratio [OR] 16.8), fuoroquinolones (OR 5.5) and cephalosporins (OR 5.7) were associated with the highest risk of CDI, whereas tetracyclines were low risk (OR 0.92).10 These findings are consistent with other published meta-analyses and case studies that examined the risk of CDI associated with antibiotic use.11-13

Variation in Risk of CDI Associated with Different Antimicrobial Classes10

 

CAP Current treatment challenges risk of CDI

A simple 4-point index summarizing the meta-analysis results was developed in a post-hoc exploratory analysis: the index was equal to 1 for tetracyclines; 2 for sulfonamides, macrolides, and penicillins; 3 for cephalosporins, monobactams, carbapenems and fluoroquinolone; and 4 for clindamycin. Each 1- point increase in the index was associated with a 2.4-fold increase in the odds of acquiring C. difficile.10

Clinical Considerations for the Treatment of CAP

The ATS/IDSA CAP guidelines recommend multiple antibiotic treatment options without specifying a preference order. The choice between these options requires a risk–benefit assessment for each individual patient, weighing local epidemiological data against specific risk factors that increase the risk of individual choices, such as documented β-lactam or macrolide allergy, cardiac arrhythmia (macrolides), and vascular disease (fluoroquinolones).3 Treatment may be complicated in patients with serious allergies to β-lactams and/or macrolides as alternative treatment options are limited.14-16

 

Another factor to consider in drug selection is the impact of the known pharmacokinetics of a particular drug/class on the individual patient. Many patients with CAP have comorbidities and are older, which may affect drug pharmacokinetics and increases the risk for potential drug-drug interactions (DDIs).17,18

Alternative Oral CAP Agents May Improve Transition of Care

The IDSA Guideline on the Implementation of an Antimicrobial Stewardship Program recommends implementation of programs to increase both appropriate use of oral antibiotics for initial therapy and the timely transition of patients from intravenous (IV) to oral antibiotics. The findings of many studies, including those focused on patients with CAP, have shown that programs aimed to increase the use of oral antibiotics are associated with reduced drug costs and length of hospital stay without compromising efficacy or safety.2 The ATS/IDSA CAP treatment guideline recommends patients receive the same class of antibiotic when transitioning from IV to oral therapy.4

New agents with both IV and oral formulation may help with transition of care at hospital discharge. This may reduce cost and hospitalizations.2

Implications of Antibiotic Treatment Failure

Antibiotic treatment failure contributes to the economic and humanistic burdens of CAP by increasing morbidity, mortality, and healthcare costs. The incidence of treatment failure in patients with CAP can range from approximately 10% to 20% of patients. Risk factors for treatment failure include older age (>65 years), high-risk pneumonia, liver disease, leukopenia, and discordant antimicrobial therapy.19 Inappropriate choice of empiric therapy has been linked to worse outcomes, including treatment failure, increased length of stay, hospital readmission, and mortality.20-22

 

Treatment failure and poor outcomes have been documented in CAP patients treated in the outpatient setting. A retrospective claims-based analysis of 251,947 adults with CAP treated as outpatients, found that 22% of patients failed antibiotic therapy, defined as any of the following within 30 days of initial antibiotic: refill of initial antibiotic, switch to a new antibiotic, emergency room visit for CAP, and/or hospitalization for CAP.22

 

Patients with treatment failure also had higher all-cause mortality compared to patients with CAP who did not fail their antibiotic therapy (18.1% vs. 4.6%, respectively). The differences in 30-day mortality between antibiotic failure groups increased as a function of age.22 This study had several limitations. Diagnosis codes and pharmacy data were used to identify patients with CAP in the outpatient setting. Based on the nature of the data authors were unable to determine reasons for which patients received a new prescription, required a refill or subsequent outpatient or inpatient care. Based on the results of this study, the authors concluded that improvements in clinical management programs and therapeutic options are needed.22

Mortality by Treatment Failure and Age22 

CAP Current treatment challenges mortality

Figure adapted from Tillotson G, Lodise T, Classi P, et al. Antibiotic Treatment Failure and Associated Outcomes Among Adult Patients With Community-Acquired Pneumonia in the Outpatient Setting: A Real-world US Insurance Claims Database Study. Open Forum Infect Dis. 2020;7(3):ofaa065.

References

  1. Centers for Disease Control and Prevention. Antibiotic Resistance Threats in the United States. Available from: https://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-threats-report-508.pdf (accessed October 24 2020)
  2. 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):e51–77.
  3. Centers for Disease Control and Prevention. Core elements of antibiotic stewardship. August 15, 2019. Available from: https://www.cdc.gov/antibiotic-use/healthcare/pdfs/hospital-core-elements-H.pdf (accessed October 09 2020)
  4. 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.
  5. McDonald LC, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis. 2018;66(7):e1–e48.
  6. Lalitagauri M Deshpande, Michael D Huband, Sarah Charbon, Mariana Castanheira, Rodrigo E Mendes, 2139. High Rates of Non-Susceptibility to Common Oral Antibiotics Among Streptococcus pneumoniae Clinical Isolates from the United States (2019-2021), Open Forum Infectious Diseases, Volume 10, Issue Supplement_2, December 2023, ofad500.1762, https://academic.oup.com/ofid/article/10/Supplement_2/ofad500.1762/7446724 
  7. Kollef MH, Betthauser KD. New antibiotics for community-acquired pneumonia. Curr Opin Infect Dis. 2019;32(2):169–175.
  8. Leffler DA, Lamont JT. Clostridium difficile infection. N Engl J Med. 2015;372(16):1539–1548.
  9. Bruns AH, Oosterheert JJ, Kuijper EJ, et al. Impact of different empirical antibiotic treatment regimens for community-acquired pneumonia on the emergence of Clostridium difficile. J Antimicrob Chemother. 2010;65(11):2464–2471.
  10. Brown KA, Khanafer N, Daneman N, et al. Meta-analysis of antibiotics and the risk of community-associated Clostridium difficile infection. Antimicrob Agents Chemother. 2013;57(5):2326–2332.
  11. Brown KA, Langford B, Schwartz KL, et al. Antibiotic prescribing choices and their comparative C. difficile infection risks: a longitudinal case-cohort study. Clin Infect Dis. 2021;72(5):836–844.
  12. Deshpande A, Pasupuleti V, Thota P, et al. Community-associated Clostridium difficile infection and antibiotics: a meta-analysis. J Antimicrob Chemother. 2013;68(9):1951–1961.
  13. Tariq R, Cho J, Kapoor S, et al. Low Risk of Primary Clostridium difficile Infection With Tetracyclines: A Systematic Review and Meta-analysis. Clin Infect Dis. 2018;66(4):514–522.
  14. Blumenthal KG, Peter JG, Trubiano JA, et al. Antibiotic allergy. Lancet. 2019;393(10167):183–198.
  15. Sakoulas G, Geriak M, Nizet V. Is a Reported Penicillin Allergy Sufficient Grounds to Forgo the Multidimensional Antimicrobial Benefits of betaLactam Antibiotics? Clin Infect Dis. 2019;68(1):157–164.
  16. Salkind AR, Cuddy PG, Foxworth JW. The rational clinical examination. Is this patient allergic to penicillin? An evidence-based analysis of the likelihood of penicillin allergy. JAMA. 2001;285(19):2498–2505.
  17. Giarratano A, Green SE, Nicolau DP. Review of antimicrobial use and considerations in the elderly population. Clin Interv Aging. 2018;13:657–667.
  18. 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(11):1806–1812.
  19. Hess G, Hill JW, Raut MK, et al. Comparative antibiotic failure rates in the treatment of community-acquired pneumonia: Results from a claims analysis. Adv Ther. 2010;27(10):743–755.
  20. Micek ST, Lang A, Fuller BM, et al. Clinical implications for patients treated inappropriately for community-acquired pneumonia in the emergency department. BMC Infect Dis. 2014;14:61.
  21. Welte T. Managing CAP patients at risk of clinical failure. Respir Med. 2015;109(2):157–169.
  22. Tillotson G, Lodise T, Classi P, et al. Antibiotic Treatment Failure and Associated Outcomes Among Adult Patients With Community-Acquired Pneumonia in the Outpatient Setting: A Real-world US Insurance Claims Database Study. Open Forum Infect Dis. 2020;7(3):ofaa065.
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