Antimicrobial Therapy for Community-Acquired Pneumonia

ABSTRACT: Pneumonia, including community-acquired pneumonia, is a common lower respiratory tract infection associated with high rates of hospital readmission and mortality. Numerous antibiotics are approved for the treatment of pneumonia; however, the rapid rise in antibiotic resistance coupled with increased risk of adverse events such as fatal cardiac arrhythmias poses a challenge in the selection of antimicrobial therapy. Given these factors, it is imperative for pharmacists to recognize the crucial role they play in the optimal treatment selection and management of pneumonia.

Despite the availability of preventive measures, pneumonia remains one of the leading causes of hospital readmission and mortality, particularly in the elderly population.¹

Introduction

Traditionally, pneumonia was categorized into community-acquired pneumonia (CAP), hospital-acquired pneumonia (HAP), and ventilator-associated pneumonia (VAP). In 2005, the Infectious Disease Society of America (IDSA) and the American Thoracic Society (ATS) expanded the classification system of pneumonia to include healthcare-associated pneumonia (HCAP) (TABLE 1).² Prior to this expansion, HCAP was classified and treated as CAP. The inclusion of HCAP to differentiate it from CAP was the result of reports that multidrug-resistant organisms (MDRO) were being isolated more frequently in patients residing in the community who have had recent contact with the healthcare system.^3,4 In addition to being at high risk for harboring MDRO, such patients also have a greater burden of comorbidities and more severe symptoms requiring a targeted approach with broad-spectrum antibiotics.³ However, several studies have shown more frequent administration of broad-spectrum antibiotics than necessary in patients with HCAP.^3,5 A recent retrospective study also showed that isolation of MDRO was high among patients hospitalized with CAP and treated with first-line therapy.⁶

Given the rapid emergence of anti-microbial resistance, it is imperative for clinicians to appropriately select therapy based on the patient’s risk factors and underlying comorbidities. Further complicating the selection of an antimicrobial regimen are recent reports on the risk of fatal adverse events associated with the use of some antibiotics. Macrolides and fluoroquinolones, commonly used for treatment of pneumonia, have been implicated in increased risk of cardiovascular death.^7-9

It is predicted that the incidence of and cost attributed to pneumonia will rise dramatically as the proportion of the population aged ≥65 years increases.¹⁰ Given the complex classification system, economic burden, increase in antibiotic resistance, and risk of fatal cardiac events, it is imperative for pharmacists to recognize the crucial role they play in the optimal treatment selection and management of pneumonia. This article focuses on identification and current management strategies for CAP in adult patients with an emphasis on proper antibiotic selection and preventive measures to curb the incidence of pneumonia.

Antimicrobial Therapy

The etiology of CAP is variable and dependent on the site of care. TABLE 2 categorizes the most common etiologies by patient type.^11,12 Although several pathogens are identified in CAP, the etiology is confirmed only in approximately 40% of cases.^13,14 Up to 75% of all diagnosed cases acquired by healthy adults are due to Streptococcus pneumoniae (pneumococcal pneumonia). The incidence of Haemophilus influenzae (12%) increases in chronic obstructive pulmonary disease (COPD) patients and those with cystic fibrosis. Other common “atypical” bacterial such as Mycoplasma pneumoniae, Legionella species, and Chlamydophila pneumoniae account for 10% to 20% of cases. Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) and gram-negative bacteria occur in 2% and 1%, respectively.^13,14

Patients who have structural lung disease or severe COPD that has required frequent corticosteroid or antibiotic therapy or who are elderly are particularly susceptible to CAP caused by Pseudomonas species. Despite the relative infrequency of CA-MRSA infection, expanded empirical coverage is warranted when this infection is suspected. Risk factors are end-stage renal disease (on dialysis) and injection drug abuse as well as recent influenza and/or antibiotic therapy. Oral anaerobic bacteria and Streptococcus species in the oral cavity are the primary causative pathogens of aspiration pneumonia associated with swallowing of oropharyngeal or gastric contents. If a patient aspirates oral and/or gastric contents, additional coverage for gram-negative bacilli is warranted.^13,14

Patients with CAP typically present with abrupt onset of fever, chills, dyspnea, cough, and/or sputum production. It is often difficult to distinguish other respiratory tract infections like bronchitis from pneumonia based on these nonspecific findings. Moreover, an elevated white blood cell (WBC) count is not useful for distinguishing between the various causative microorganisms. However, a WBC count >12,000 cells/mm³ is typically suggestive of a bacterial infection.^13,14 Chest radiographs can help differentiate pneumonia from other infections. The presence of infiltrates on chest x-ray is usually indicative of pneumonia.^11,12

In general, it is often difficult to distinguish between bacterial and nonbacterial pathogens. However, specific findings on radiograph can guide the practitioner as to whether antimicrobial therapy is warranted upon diagnosis. Sputum examination and a culture of acceptable quality  are also useful in the initial evaluation and can help identify a causative organism. Invasive diagnostic techniques including bronchoscopy, bronchoalveolar lavage, and direct aspiration can be performed, especially in severe cases of CAP, when a sputum sample is unobtainable.¹⁴ It is recommended that patients presenting with severe CAP requiring hospital admission have blood cultures drawn. In addition, urinary antigen testing for Legionella species and S pneumoniae should be considered, and Gram stain and culture of expectorated sputum should be performed.¹¹ Blood and respiratory cultures should be drawn prior to the first antibiotic dose. TABLE 3 defines criteria for severe CAP.¹¹

Several scoring systems are currently available for assessing the severity of pneumonia, including the Pneumonia Severity Index (PSI) and CURB-65 severity score (TABLE 4).¹¹ These models are utilized to determine the patient’s mortality risk, need for hospitalization, and selection of appropriate antimicrobial therapy. Whether the PSI or the CURB-65 score is superior is unclear based on current clinical guidelines.¹¹ According to the IDSA/ATS guidelines, “When compared in the same population, the PSI classified a slightly larger percentage of patients with CAP in the low risk categories, compared with the CURB or CURB-65 criteria, while remaining associated with a similar low mortality rate among patients categorized as low risk. In contrast, the CURB-65 criteria are easily remembered.”¹¹

It was shown that the PSI has a higher discriminatory power for short-term mortality; thus, it is more accurate for low-risk patients than the CURB-65. However, the PSI is more complicated and requires arterial blood gas sampling among other tests; given this, the CURB-65 score is more easily used in primary care settings.¹¹

Early identification of causative microorganisms is essential for proper management. However, when diagnostic tests cannot identify causative organisms, broad-spectrum empirical therapy effective against most probable pathogens is often initiated.^11-14 Clinicians should remember to de-escalate therapy once cultures are available. The approach to patient care is based on classification of patients into two broad categories, outpatient and inpatient, with further division by comorbidities and location of care within the hospital.¹¹ Appropriate empirical regimens for treatment of CAP for adults are listed in TABLE 5.¹¹ Hospital antibiograms to assess predominant pathogens and their patterns should also be used to guide the clinician to the most appropriate therapy, particularly in the inpatient setting. In addition to antibiotics, supportive care often requires provision of adequate hydration plus bronchodilators for dyspnea and acetaminophen or ibuprofen for fever control.

Response to treatment is based on severity of infection, pathogens isolated, and patient comorbidities. Improvement in subjective clinical symptomatology is usually seen 3 to 5 days after antimicrobial initiation. Objective findings such as fever, leukocytosis, and chest radiograph abnormalities resolve at different time periods. Fever (≤37.8°C) generally resolves within 48 to 72 hours for most cases, with leukocytosis usually resolving by the fourth day.¹¹

The recommended duration of antibiotic therapies is usually 5 to 7 days. Two antibiotics are approved for a 5-day duration, levofloxacin and azithromycin.¹¹ Patients should be afebrile for 48 to 72 hours and be clinically stable before discontinuation of drug therapy.¹¹ Hospitalized patients receiving IV therapy should be converted to an oral equivalent regimen when improvement is noted.

Considerations in Antibiotic Selection

The majority of patients with CAP are treated with a respiratory fluoroquinolone or macrolide with or without a beta-lactam. In 2013, the FDA issued a statement linking azithromycin with increased risk for cardiovascular death from QT prolongation and the associated ventricular arrhythmia torsade de pointes.¹⁵ Fluoroquinolones have also been implicated in similar risk.⁷ All fluoroquinolone product labels carry a warning for QT prolongation. Ciprofloxacin carries the lowest risk. The risk of cardiovascular death is highest among elderly patients with cardiovascular diseases and/or preexisting risk factors for QT prolongation such as electrolyte abnormalities, particularly hypokalemia and hypomagnesemia, bradycardia, and use of drugs with QT prolonging abilities (e.g., Class IA and III antiarrhythmic agents). Clinicians should carefully evaluate risk versus benefit and consider the arrhythmogenic potential of antimicrobial therapy, especially in the elderly population with underlying cardiovascular diseases, when designing a treatment regimen for pneumonia.

Vaccination: As healthcare providers, pharmacists are uniquely positioned to advocate the prevention of diseases through promotion and administration of vaccinations. Vaccines are cost-effective preventive services that should be adequately utilized in an attempt to curb hospitalization for and mortality from pneumonia. Despite the availability of safe and effective pneumococcal vaccines, the rates of immunization in the elderly remain low.

Two types of pneumococcal vaccines are approved for use in the United States: pneumococcal conjugate vaccine (PCV13, Prevnar 13) and 23-valent pneumococcal polysaccharide vaccine (PPSV23, Pneumovax 23).¹⁶ PCV13 is indicated for all individuals aged ≥65 years. Adults ≥19 years with certain high-risk medical conditions, including cerebrospinal fluid leaks, cochlear implants, immunocompromising conditions, and functional or anatomical asplenia, should also receive a single dose. PPSV23 is indicated for all adults ≥65 years and those aged 2 to 64 years with various medical conditions, similar to those for PCV13 but also including individuals with chronic heart disease (congestive heart failure and cardiomyopathies, excluding hypertension), chronic lung disease (chronic obstructive lung disease, emphysema, asthma), chronic liver disease (including cirrhosis), alcoholism, or diabetes mellitus, as well as those aged 19 to 64 years who smoke cigarettes or reside in nursing homes or long-term care facilities.¹⁶ 

Role of the Pharmacist and Antimicrobial Stewardship

According to the 2014 World Health Organization (WHO) report, the rate of antimicrobial resistance has reached an alarming level in many parts of the world and is now a major public health concern.¹⁷ Many factors play a role in the development and spread of antibiotic resistance, which is likely accelerated by the misuse and overuse of available agents. The pipeline for new antibacterial drugs is essentially dry, and many agents that were once effective in treating infections are now ineffective. Pneumonia, which was once easy to treat, is becoming difficult to manage due to increased rates of antibiotic resistance. Thus, it is becoming increasingly important to preserve the efficacy of existing antibiotics by minimizing the development and spread of resistance.

Antimicrobial stewardship programs promote judicious use of antibiotics through implementation of diverse strategies aimed at reducing inappropriate use while optimizing antibiotic selection, dosing, and duration of therapy through application of pharmacodynamic and pharmacokinetic principles.¹⁸ Examples of antimicrobial stewardship strategies include implementation of antibiotic policies and management programs, IV-to-oral conversion for drugs with similar bioavailability, antimicrobial cycling, and formulary restriction to approved indications. Successful implementation of stewardship strategies has been shown to improve antimicrobial utilization, decrease hospital length of stay and costs, and optimize patient care and outcomes.^19-21 As more and more pharmacists are considering formal postgraduate training in infectious diseases, the increasing role of specialist pharmacists and general pharmacists in these programs has enabled hospitals to deliver on the antimicrobial stewardship agenda and provide additional opportunities to expand this role further and ensure greater multidisciplinary engagement.

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