Here is an overview of the key Issues for hospital pharmacists.
Community-acquired pneumonia (CAP) is a common serious illness that is associated with considerable costs, morbidity, and mortality.1 In the EPIC study, a contemporary, large, population-based, and recent study performed in the United States, the annual incidence of CAP requiring hospitalization was estimated to be 24.8 cases per 10,000 adults.2 A leading cause of hospitalization among adults in the United States, CAP is associated with total estimated costs in excess of $17 billion, with hospital and outpatient costs accounting for $8 billion and $9 billion, respectively.1 Moreover, in the United States, readmission to hospital with a diagnosis of pneumonia within 30 days of discharge incurs a reimbursement penalty, according to the terms of Medicare’s Hospital Readmission Reduction Program.3
Recommendations for the management of CAP are detailed in the Infectious Diseases Society of America (IDSA)/American Thoracic Society (ATS) guidelines.4 These guidelines were last updated in 2007, and an update is expected within the next year. It is expected that the upcoming guidelines will address a number of key issues, including new developments in diagnostics that may facilitate rapid identification of the causative pathogen. The guidelines will likely also provide updates on appropriate empiric antibiotic selection, as several antibiotics have been approved for the treatment of CAP since the publication of the previous guidelines. In addition, updated recommendations for preventative measures for CAP, including vaccine options may be addressed. A detailed discussion of pneumococcal vaccines is beyond the scope of this review. However, recommendations of the Advisory Committee on Immunization Practices, adopted by the CDC and published in the Morbidity and Mortality Weekly Report, are available on the CDC website.5 The updated CAP guidelines may also address the issue of differentiation among various pneumonia classifications, particularly CAP and health care-associated pneumonia (HCAP). This distinction has become less clear in recent years, leading to a dilemma in the empiric management of patients. Another important challenge that may be addressed is the identification of patients at risk for community-acquired methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. A recent study found that though the prevalence of Staphylococcus aureus and specifically MRSA CAP was low, the use of empirical anti-MRSA antibiotics was common.6 There was substantial overlap in the clinical presentation of MRSA CAP and pneumococcal CAP, highlighting the difficulty of identifying patients at risk for S. aureus CAP and the need for new diagnostic strategies.6 In addition, the duration of treatment is a factor that requires continuous re-evaluation, as we aim to identify the shortest courses to reduce unnecessary antibiotic exposure and the emergence of resistance while optimizing efficacy.
Here, we review the management of CAP, including its diagnosis, initial (empiric) antibiotic regimen, duration of therapy, and de-escalation and step-down of therapy, highlighting key topics that may be of interest to hospital pharmacists.
Diagnosis and Identification of Pathogen(s)
Diagnostic tests play an important role at different stages of the clinical care of patients with suspected infectious diseases, including the identification of specific pathogens and appropriate treatment options, and monitoring response to the selected treatment.7
Misdiagnosis of CAP is a significant problem that can lead to patients receiving care that is suboptimal. For example, patients may remain untreated for alternative diagnoses or receive inappropriate, ineffective, or potentially harmful treatment.8 It may also result in patients receiving treatment that could mask another infection.9 Over diagnosis of CAP is also an issue, which may have been driven by regulatory pressure to reduce the time to first antibiotic dose, leading to errors in diagnosis and unnecessary use of antibiotics in patients who do not have CAP.8,10 For example, patients presenting with chronic obstructive pulmonary disease exacerbations, congestive heart failure exacerbations, or upper respiratory viral infections, are often misclassified as having CAP and therefore receive CAP therapy. However, this must be balanced by the harm associated with missing the diagnosis of CAP in these patients. These issues may be alleviated with better use of rapid diagnostics, as discussed below.
Considerable advances have been made in the field of infectious-diseases diagnostics, from advances in automation, chemistry, engineering, immunology, molecular biology, and nucleic acid amplification. For example, newer diagnostics may aid in the selection of empiric antibiotic regimens based on rapid detection of resistance mechanisms or specific pathogens. Other tests may facilitate the decision to treat with antibiotics based on the likelihood of a bacterial versus viral infection. However, in an IDSA policy paper published in 2013, it was noted that these developments are slow to be adopted into practice to assist with decision making. As such, patients may still receive antibiotics, despite a test result pointing to an alternative explanation for their signs/symptoms, resulting in the overuse of the limited available armamentarium of effective antibiotics.7 It is essential that the results of diagnostic tests are effectively communicated to the prescribing physician in a timely manner, which may require the involvement of a clinical microbiologist or an infectious-diseases specialist.
The IDSA/ATS CAP guidelines recommend that, in addition to clinical features, a diagnosis of pneumonia require demonstrable infiltrate by chest x-ray or other imaging technique, with or without microbiological data. The guidelines comment that recommendations for the extent of diagnostic tests for etiology remain controversial, with the most clear-cut argument in favor of extensive diagnostic testing for the critically ill patient with CAP.4 The low pathogen detection rate in the EPIC study has further highlighted the need for more sensitive and innovative diagnostic methods. Pathogens were detected in 38% of the patients: viruses in 27% and bacteria in 14%, of which Streptococcus pneumoniae was the most commonly detected bacterium.2
In addition to blood culture and respiratory tract specimen Gram stain and culture, other tests, such as antigen tests, polymerase chain reaction (PCR) and serologic testing, might be needed to identify a specific pathogen.4 Urinary antigen tests are available for the detection of S. pneumoniae and L. pneumophila serogroup 1 and appear to have a higher yield in patients with more severe illness.4 Antigen tests for S. pneumoniae are simple, specific, can be performed rapidly, and can be used when samples cannot be obtained for culture in a timely fashion or when antibiotic therapy has already been started. A number of urinary antigen assays are available for L. pneumophila serogroup 1, and these have been reported to have a specificity of about 99% and a sensitivity of 70% to 90%.4 Acute- and convalescent-phase serologic testing are the standard for the diagnosis of infection with most atypical pathogens (a single acute phase titer is considered unreliable as a basis for patient management), and PCR tests are also being increasingly used for detection of atypical pathogens.4
Distinguishing between patients with CAP and HCAP is becoming more difficult, and discerning patients who are at high risk for MDR pathogens is even more challenging. Patients with HCAP have been found to have increased mortality compared with CAP patients, which may be because of patient factors, such as severity of underlying diseases and co-morbidities.15
A study by Shindo and colleagues has indicated that it is possible to predict drug resistance in patients with either CAP or HCAP by looking at the cumulative number of risk factors in each patient.16 The results of their study suggest that the threshold for empirical coverage of MDR pathogens should be set higher than the presence of a single risk factor that is recommended by the 2005 HAP, HCAP, and VAP guidelines.13,16 Based on the results of this study, Wunderink has proposed an algorithm for the management of patients at risk for the usual CAP drug-resistant pathogens (CAP-DRP) and MRSA-specific risk factors (Figure).16 It has been suggested that for patients with 0 to 1 risk factor for CAP-DRP, usual CAP regimens would be appropriate. For those with 2 risk factors for CAP-DRP, the patients should also be evaluated for the MRSA risk factors. Those without MRSA risk factors would be provided usual CAP regimens.
Figure. Risk Factors for Drug-Resistant Pathogens in CAP16
Independent risk factors for pneumonia secondary to CAP-DRP:
Independent risk factors for pneumonia secondary to MRSA:
MRSA-specific risk factors
Those with MRSA risk factors would receive the usual CAP regimens with the addition of MRSA coverage, pending culture and susceptibility results. Finally, for those patients with 3 or more risk factors for CAP-DRP, broad spectrum regimens are suggested for empiric coverage, with culture results then dictating the need for continuing the broad agents or de-escalating to the usual CAP agents.17 Although these findings still require validation, they suggest that traditional CAP treatment may be adequate in many patients previously classified as having HCAP.16,17
Other scoring systems have also been developed to assist prescribers in rapid identification of patients at risk of pneumonia secondary to MDR pathogens.18 Falcone and colleagues compared some existing scoring systems and proposed a new prediction rule for the early identification of patients with MDR-pneumonia.18 The ARUC score (Assessment of Risk of multidrUg resistant pathogens in Community-onset pneumonia) includes HCAP criteria (at least 1 of the following: dialysis; hospitalization in the previous 3 months; intravenous (IV) therapy in the previous 30 days; and/or residence in a nursing home or LTC facility) plus 1 points; bilateral pulmonary infiltration +0.5 points, pleural effusion +0.5 points; and PaO2/FiO2 <300 +1.5 points).18
These scoring systems still require validation and confirmation of how they should be applied in clinical practice.
Initial Empiric Antibiotic Therapy for CAP
The CAP guidelines recommend that patients admitted through the emergency department (ED) should receive the first dose of antibiotic while still in the ED.4 Guideline-recommended empiric antibiotic therapy options by clinical setting, such as hospitalized non-intensive care unit (ICU), ICU, or outpatient, are summarized in the Table.4 Other treatment considerations are also detailed in the guidelines, including the management of patients with persistent septic shock, hypotension or hypoxemia, and the management of non-responding pneumonia.4
Table. Guideline-Recommended Empiric Antibiotic Therapy Options for CAP in Adults4
In the case of a patient who is hospitalized with pneumonia, it will be important to review his or her history carefully to see if there are any factors that may warrant treatment for HAP/HCAP/VAP rather than CAP. This information will be needed to guide the selection of the most appropriate empiric antibiotic regimen. In certain patients, there may be additional risk factors to consider, including treatments such as chemotherapy and dialysis. For example, immunosuppression has been identified as an independent risk factor for pneumonia secondary to CAP-DRP, while chronic hemodialysis in the previous 30 days has been identified as an independent risk factor for pneumonia secondary to MRSA.16,17 It is important to consider additional factors that affect the decision-making process for antibiotic selection. Collateral damage, such as adverse drug reactions, the risk of Clostridium difficile infection, and the selection of resistance should be considered. For example, fluoroquinolone and third-generation cephalosporins are associated with a higher risk of C. difficile infection, because of a hypervirulent BI/NAP1/027 strain, and doxycycline may protect against C. difficile infection.21-23 The potential for collateral damage must also be weighed against the efficacy data that are available for each agent, and the risk-to-benefit ratio should be considered. In July 2016, the FDA approved changes to the safety labeling for fluoroquinolones, enhancing warnings about their adverse effects and limiting their use in patients with less serious bacterial infections.24 Although the FDA drug safety communication does not specifically mention pneumonia or CAP, it reminds clinicians to weigh the benefits versus the risks when choosing antibiotic regimens. An FDA news release about the safety labeling changes for fluoroquinolones stated: “Because the risk of these serious side effects generally outweighs the benefits for patients with acute bacterial sinusitis, acute exacerbation of chronic bronchitis and uncomplicated urinary tract infections, the FDA has determined that fluoroquinolones should be reserved for use in patients with these conditions who have no alternative treatment options. For some serious bacterial infections, including anthrax, bacterial pneumonia, and plague, among others, the benefits of fluoroquinolones outweigh the risks, and it is appropriate for them to remain available as a therapeutic option.”25
Drug shortages have become a real and increasing challenge in the hospital setting.26,27 The shortages may involve agents that are considered the standard of care, and shortages of agents used to treat infections due to MDR pathogens are of particular concern, as there may be few alternative treatment options. The antimicrobial stewardship team should develop a conservation strategy for use in these situations, for example, reserving available stocks of alternative antibiotics, such as aztreonam and fluoroquinolones, for beta-lactam-allergic patients. If non-formulary drugs are not available in an institution, the prescriber should outline the rationale for a non-formulary treatment choice. This would be reviewed by an antimicrobial stewardship representative, who may seek advice from an infectious-diseases specialist, if needed.
Among these, Streptococcus pneumoniae, which is the leading cause of bacterial pneumonia in the United States, has developed resistance to members of the macrolide and penicillin classes, in addition to less commonly used drugs.28 An increase in the incidence of S. pneumoniae resistant to commonly used antibiotics, including beta-lactams, macrolides, and tetracyclines, is making the selection of empiric antimicrobial therapy more challenging.29 Pneumococcal macrolide resistance in the United States has been reported to be close to 50%, which is of concern, while the level of susceptibility to fluoroquinolones remains high.29
Staphylococci, including MRSA, cause a range of illnesses, including pneumonia. They can be the cause of infections in both the community- and in health care-associated infections. Resistance to methicillin and related antibiotics, such as nafcillin and oxacillin, and to cephalosporins, is of concern.28 Although Enterobacteriaceae are less frequent causes of CAP, the resistance rates for these organisms are on the rise. Nearly 20% of health care-associated Enterobacteriaceae infections are caused by organisms producing extended-spectrum beta-lactamase (ESBL), which allows bacteria to become resistant to a wide variety of cephalosporins and penicillins.28 Other gram negatives, such as Acinetobacter spp. and Pseudomonas aeruginosa, may also be identified in patients who present from the community. For example, P. aeruginosa may be seen in IV drug abusers, patients who are on chronic immunosuppressive medications, or those with structural lung disease. Some strains of P. aeruginosa, a common cause of health care-associated infections, have been found to be resistant to nearly all or all antibiotics, including aminoglycosides, carbapenems, cephalosporins, fluoroquinolones, and penicillins.28 The CAP guidelines note the emergence of CAP because of MRSA and P. aeruginosa as exceptions.4 Data describing risk factors for MDR organisms in CAP and HCAP in the United States are limited. Available evidence indicates local etiology of CAP and specific risk factors for MDR organisms should be integrated into therapeutic decision-making to prevent empirical overprescribing of antibiotics for MRSA and P. aeruginosa.30
De-escalation and Sequential Antibiotic Therapy
Antimicrobial stewardship program interventions have been associated with improvements in a number of areas that may affect treatment costs, as well as clinical outcomes, including shorter time to appropriate therapy, shorter therapy duration, shorter length of hospital stay, and lower rates of readmission and Clostridium difficile infections.20, 31-34
The 2016 IDSA/SHEA Antimicrobial Stewardship guidelines recommend that de-escalation of antibiotics be considered, once culture and susceptibility results are available and according to the patient’s clinical response.20 De-escalation is also recommended in the 2007 IDSA/ATS guidelines on CAP management, where it is referred to as “pathogen-directed therapy.”4 Sequential antibiotic therapy, including IV to oral switching, is also recommended in current guidelines. Implementation of programs to increase the appropriate use of oral antibiotics and timely switching from IV to oral therapy is recommended in the 2016 IDSA/SHEA Antimicrobial Stewardship guidelines, with a comment that such programs should be integrated routinely into pharmacy activities.20 The guidelines state that antibiotic stewardship programs should review patients and switch from IV to oral antibiotics when appropriate, based on pre-determined clinical criteria, such as the ability to tolerate oral medication, clinical improvement, clinical improvement, having signs of a functioning gastrointestinal tract, and hemodynamic stability.4,20
A retrospective cohort study of adult patients hospitalized at a single institution in Colorado found that management of CAP was often inconsistent with IDSA/ATS guideline recommendations. The findings identified a number of potential opportunities for antibiotic and health care resource stewardship. For example, two-thirds of patients initially treated with azithromycin and ceftriaxone were discharged on a new drug class, most often a fluoroquinolone. Guidelines recommend the use of the same drug or class of drug when switching to oral antibiotics, to avoid unnecessary exposure to another drug class and contribution to overuse of fluoroquinolones.38
Audit and feedback intervention have been shown to increase adherence to local best practice treatment algorithms. Among a group of hospitalists in the Regina Qu’Appelle Health Region in Saskatchewan, Canada, adherence to treatment algorithms was just 10% in the pre-intervention audit, and this increased to 38% in the post-intervention audit, resulting in a nonsignificant trend toward a reduction in treatment duration post-intervention.39
When choosing between different IV-to-oral sequential therapy options recommended in CAP treatment guidelines, it is important to consider not only efficacy and safety outcomes but also bacterial eradication rates in order to minimize the risk of the development of MDR pathogens. For example, in a randomized trial, patients with CAP received IV treatment with either ceftriaxone plus azithromycin or levofloxacin, and patients who showed clinical improvement were switched to oral follow-up therapy with either azithromycin or levofloxacin.40 Although both treatments were well tolerated, and favorable clinical outcomes were reported in similar proportions of patients in the 2 treatment groups, bacteriological eradication rates for S. pneumoniae were 100% of isolates with ceftriaxone plus azithromycin compared with 44% with levofloxacin.40
To make the transition to outpatient oral therapy as smooth and efficient as possible, it is essential to counsel the patient regarding the discharge medication regimen. CAP guidelines recommend using the same antibiotic class when converting from IV to oral therapy.4 Convenience is an important factor, influencing adherence with treatment in select patients. Once-daily treatment options, such as fluoroquinolones, are convenient for select patients and are likely to lead to improved adherence and better outcomes.41 However, as discussed, a recent safety warning issued by the FDA in July 2016 recommends limiting the use of fluoroquinolones. In some serious bacterial infections, their benefits may outweigh their risks.
Duration of Antibiotic Therapy
The IDSA/ATS guidelines recommend that CAP should be treated for a minimum of 5 days, patients should be afebrile for 48 to 72 hours, and should have no more than 1 CAP-associated sign of clinical instability before discontinuing therapy.4 A recent randomized controlled trial has shown that these guidelines can safely be implemented in patients hospitalized with CAP.42 In this study, patients assigned to an intervention group received antibiotics for a minimum of 5 days, and the antibiotic treatment was stopped at this point if they had a body temperature of 37.8°C or less for 48 hours and no more than 1 CAP-associated sign of clinical instability, including hypoxia, hypotension, tachycardia, or tachypnea). The duration of antibiotic treatment in a control group was determined by physicians. The results of this study indicate that withdrawing antibiotic treatment based on clinical stability after a minimum of 5 days of treatment resulted in clinical success that was non-inferior compared with traditional treatment schedules. Clinical cure rates at day 30 since admission were 94.4% in the intervention group and 92.7% in the control group.42
CAP is a common serious illness, associated with considerable costs, morbidity, and mortality, and the selection of antibiotic therapy for CAP involves consideration of multiple factors. Differentiating between CAP and HCAP has become increasingly difficult, leading to a dilemma in the empiric management of patients and several scoring systems developed to predict the risk of DRP in patients presenting from the community and outpatient health care settings. Pharmacist intervention and sequential therapy can reduce antibiotic costs and the length of the hospital stay. The 2016 IDSA/SHEA guidelines on antimicrobial stewardship recommend that programs to increase appropriate use of oral antibiotics and timely switching from IV to oral therapy should be integrated routinely into pharmacy activities. Updated IDSA/ATS guidelines on CAP management are expected to discuss HCAP as well as new developments in diagnostics that may facilitate rapid identification of causative pathogens and recommendations for sequential antibiotic therapy and the optimal duration of treatment.
This article was co-authored by Dimple Patel, PharmD, BCPS-AQ ID, clinical pharmacist for infectious diseases in the pharmacy department at Morristown Medical Center in New Jersey.