Optimizing Antibiotic Therapy

Switch Therapy, Step-Down Therapy and Prevention

In our current health care environment, hospitals and health care providers are challenged to provide a high standard of care in a more efficient way. Multiple evidence-based practice guidelines support the concept that hospitalized patients with community-acquired pneumonia (CAP) should be treated with an empiric antibiotic regimen that treats infection of multiple etiologies; this has been discussed in other sections of this module. The issues of timeliness and, to a lesser extent, duration of antibiotic therapy along with timing of switch from intravenous (IV) to oral medications have been addressed in these guidelines.

Timeliness of Antibiotic Therapy

As the pressures of cost containment have increased, the appropriate duration of IV antibiotics and hospital stay and the cost of antibiotic therapy have come under scrutiny. Early administration of antibiotics, either at home, in the clinician’s office, or in the emergency department, has been associated with improved survival in pneumonia. A large retrospective study concluded that antibiotic administration within 4 hours of hospital arrival was associated with decreased mortality and length of stay among older inpatients with CAP. Empiric treatment with antimicrobial therapy should be initiated preferably within the first 4 hours of presentation, but at a minimum within the first 8 hours of admission; this is considered an important parameter to assess the process of care in pneumonia. While there has been some discussion regarding the possibility that imperative for early treatment will result in “over treatment,” this recommendation remains at the core of emergency management of CAP with the caveat that the pneumonia diagnosis should be confirmed by chest x-ray (CXR).

Definitions

The 2009 British Thoracic Society (BTS) guidelines underline how parenteral treatment is often unnecessary in management of hospitalized patients and that only 30% to 50% of the patients admitted with CAP will require parenteral antibiotics. It is clear that a substantial portion of hospitalized CAP patients can be safely switched to oral antibiotics earlier in their hospital course without any untoward events. Replacing IV antibiotics with effective oral antibiotics in the treatment of serious infections (e.g., CAP, hospital-acquired pneumonia (HAP), or health care–associated pneumonia (HCAP), urinary tract infections) is known as switch therapy. If the change is accomplished with the same antibiotic as the IV antibiotic (e.g., azithromycin), it is labeled step-down therapy. If a different drug is used (e.g., switching from an IV third-generation cephalosporin to an oral fluoroquinolone), this approach is defined as sequential therapy. The clinical concept is identical, however: switching to oral antibiotics with similar or identical antibacterial spectra.

Several studies have shown that the institution of switch therapy is both safe and associated with economic benefits. The common theme that links these is the identification of patients who are responding clinically to IV therapy.

Switch therapy has several established and potential benefits. The main established benefit is economic; switch therapy reduces both the cost of antimicrobial therapy and hospitalization-related costs. From the patient’s perspective, switch therapy may have clinical and psychological benefits including comfort, lower risk of hospital-acquired infection and earlier discharge. From the physician’s point of view, switch therapy may allow for a more focused approach to patient care with an emphasis on clearly definable clinical end points. Health care organizations may benefit from switch therapy by allowing the care of CAP patients to be standardized and streamlined. Discharge is often feasible at the time of switch, benefiting patient and provider. Clinical practice guidelines may be formulated that facilitate management of CAP at reduced cost. Other potential benefits of switching to oral antimicrobials for CAP include decreased complications of IV therapy, such as thrombophlebitis, line sepsis and decreased incidence of hospital-acquired infections.

Factors That Influence Antimicrobial Therapy

Determining the type, duration and switch to oral therapy is complicated by the fact that in the majority of patients with CAP, no pathogen is identified. Even when carefully sought, a putative pathogen is documented in 50% or fewer of cases of CAP. Therefore, in most instances, a specific microbiologic diagnosis is not established and the physician uses empiric antibiotics based on epidemiologic data. When an etiologic pathogen is identified (either initially or at a later time), the antibiotic spectrum can be narrowed. When no pathogen is discovered, empiric antibiotics are continued. However, it is important to note that therapy is very rarely (<1%) changed in the face of microbiologic confirmation.

Several factors play a role in deciding when to switch from IV to oral antibiotics in CAP. These include:

• Patient factors
• Pathogen characteristics
• Antibiotic properties.

Patient Factors

Patient factors that have traditionally influenced antibiotic decisions include:

• Severity of illness
• Clinical characteristics:
  • Patient age
  • Comorbid medical illness
  • Medical status
  • Vital sign abnormalities
  • Ability to take oral medication
  • Pulmonary and nonpulmonary organ dysfunction
• Laboratory abnormalities:
  • WBC count
  • Arterial blood gas abnormalities
  • Elevated BUN levels
  • Bacteremia
• Radiographic patterns:
  • Parapneumonic effusion
  • Abscess formation.

Multilobar infiltrates or radiographic progression must also be taken into account in making this decision.

Pathogen Characteristics

Pathogen characteristics that impact on the route and duration of therapy include:

• Virulence patterns
• Resistance patterns
• Whether the pathogen is intracellular or extracellular.

For example, a virulent and resistant pathogen causing CAP, such as methicillin-sensitive Staphylococcus aureus (MSSA), usually necessitates a more prolonged course of IV antibiotics as compared with pneumonia caused by the less virulent and more antibiotic-sensitive M pneumoniae.

Antibiotic Properties

Antibiotic properties that allow initiation of switch therapy include:

• Antimicrobial spectrum
• Dosing schedule
• Bioavailability
• Patient tolerance of the antibiotic
• Expense.

All of these listed properties influence compliance. The characteristics of the ideal oral antibiotic used in switch therapy would be one that has:

• Identical antimicrobial spectrum to that of the IV antibiotic
• Once- or twice-a-day dosing to improve compliance
• High level of bioavailability
• Minimal adverse side effects
• Low acquisition cost
• Few drug/drug interactions.

Approach to Switch Therapy

Several studies have evaluated the safety and efficacy of switch therapy in CAP. One study applied a switch-therapy practice guideline retrospectively to 503 hospitalized patients with CAP. The practice guideline was based upon three criteria that were used to categorize patients as being low risk on hospital day 3. These three criteria were:

• No obvious reason for continued hospitalization (e.g., hypoxia)
• Absence of a high-risk pneumonia pathogen (e.g., S aureus)
• No life-threatening complications during hospitalization (e.g., acute myocardial infarction).

Based on this practice guideline, these investigators reported that only 33% of patients met their criteria retrospectively at day 3 for switch to oral antibiotics. The authors reported that the quality of care would not have been affected in 98.2% of the patients had they been switched to oral therapy on day 3. If these same patients were discharged from the hospital on day 4, 93.4% of them would have had no change in their quality of care.

Other investigators defined a set of criteria for an early switch from IV to oral therapy that included improved cough and dyspnea, fever <38°C for at least 8 hours, normalized white blood cell (WBC) count, oral intake and adequate intestinal function. In a prospective clinical study, the clinical cure rate with switch therapy was 99%, and mean length of hospital stay was reduced by >2 days. Early switch, coupled with hospital discharge, may be possible in nearly half of all CAP patients. The authors predicted that universal use of switch therapy in the United States could result in the total reduction of about 440,000 hospital days annually and an overall savings of $400 million.

In fact, even in the presence of pneumococcal bacteremia, changing to oral therapy can be safely done once clinical stability is achieved and prolonged IV therapy is not needed. However, bacteremic patients in general take longer (approximately 0.5 days more) to become clinically stable as compared with non­bacteremic patients. The various criteria for clinical stability proposed over the years by international societies are presented in Table 8-1.

The benefits of in-hospital observation after changing to oral therapy were also examined by Rhew and colleagues. They found that this practice was not associated with the need for any medical intervention and therefore did not provide any clinical benefit. However, it did add to the length of stay by 1 day and added $550 to the cost of care.

In summary, a body of evidence suggests that patients hospitalized for CAP can be switched to oral antimicrobials when there is clinical improvement on IV antibiotics and when patients have no associated risk factors for increased morbidity and mortality (Table 8-2). However, several caveats are worth considering. Patients hospitalized for CAP have varying concomitant medical diseases and are managed by physicians with different practice patterns. There is inherent variability in the patient-physician interaction, resulting in a wide range of diagnostic approaches and initial antibiotic regimens. Further, in many instances, the practical aspect of switch therapy is connected with discharge from hospital, and therefore patients at risk for poor compliance (e.g., inability to self-supervise due to dementia or other cognitive impairment) may benefit from continued parenteral antibiotic administration. It is therefore impossible to establish a set formula for switch therapy. This concept is further complicated by the fact that not all patients are created equal. Patients respond to therapy at different rates as influenced by the interaction of types and severity of preexisting morbidities, age, severity of pneumonia and pathogen virulence. Factors that contribute to slowly resolving or nonresolving pneumonia are also important since they impact on response to therapy (Table 8-3). It seems likely that response assessment must be ongoing rather than attempting to set predetermined time intervals for conversion to oral therapy. This hypothesis, however, remains to be tested.

Based on the current data, switch therapy may be instituted if certain criteria are met (Table 8-4). Similarly, hospital discharge can occur the day the patient reaches clinical stability if there is no need to treat comorbidity, conduct further diagnostic workup, or attend to social needs.

Thus there are three treatment options available for patients hospitalized with CAP. The first option, the traditional one, is to initiate therapy with par­enteral antibiotics and continue them for the entire course. The second option is the switch-therapy option, starting with IV antibiotics and then changing to oral therapy to complete treatment. Finally, physicians may use oral antibiotics from the outset, depending on the initial severity of the infection. Also, many patients with nonsevere CAP are hospitalized primarily to treat de­compensated comorbidities or because of social reasons. These patients can be treated with oral antibiotics at the time of hospitalization.

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Antibiotic Principles

In most patients with CAP, no pathogen is identified even after extensive diagnostic testing. In this common clinical situation, empiric antibiotics are continued. If the pathogen is identified, the antibiotic regimen can be narrowed. In either scenario, the patient should be evaluated for switch to oral antibiotics once clinical improvement and factors associated with increased morbidity and mortality are absent (Table 8-2).

The oral antibiotic chosen for switch therapy should encompass the same antibacterial spectrum as the IV agent. In addition, the oral regimen should have a good dosing schedule and a low adverse-reaction profile to ensure completion of therapy. The dosing schedule is of particular importance since this affects patient compliance. Using an oral antibiotic with a frequent dosing schedule is associated with reduced compliance and potential medication error compared to using one with a once- or twice-a-day dosing regimen.

No one antibiotic regimen has yet been shown to have definitive superiority to another in switch therapy. Knowledge of local epidemiology and resistance patterns should guide both the initial IV empiric therapy and the subsequent oral antibiotic. Fluoroquinolone antibiotics available in both IV and oral formulations (e.g., levofloxacin, moxifloxacin, delafloxacin) are particularly useful in switch and step-down therapy. Another example is if a patient is treated with an IV second- or third-generation cephalosporin and no pathogen is identified, switch therapy may be initiated with an oral second- or third-generation cephalosporin. If the patient is treated initially with an IV β-lactam/β-lactamase–inhibitor combination and no pathogen is identified, switch therapy may be initiated with an oral β-lactam/β-lactamase–inhibitor combination (e.g., amoxicillin/clavulanate). In the case of a patient initially treated with an IV macrolide, switch therapy can be with an oral macrolide (usually azithromycin or clarithromycin since erythromycin is associated with significant gastrointestinal (GI) side effects that may impair compliance) that has less complex dosing regimens. Studies evaluating newer macrolides suggest better compliance, fewer side effects and similar clinical cure rates. In clinical practice, doxycycline is often used to complete antibiotics after hospital discharge.

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Duration of Therapy

Generally, the duration of therapy in patients with CAP is 7 (in mild cases) to 10 days (in more severe cases), but patients infected with atypical pathogens or intracellular organisms such as Legionella spp should receive longer treatment, usually 10 to 14 days. Treatment should be prolonged (14 to 21 days) also in the case of gram-negative pathogens or S aureus infections. Data suggest that patients can be treated with a shorter duration of antibiotics (minimum 5 days) as long as they are afebrile by that time and are otherwise clinically stable. The benefits of short-duration therapy in CAP include early eradication of pathogens and the reduction of selective pressure, which often leads to the development of resistance. Further positive consequences include a decreased impact on endogenous flora, improved patient adherence, the potential for decreased adverse events, and cost savings. There is no precise recommendation about duration of therapy that can be made and decisions must be individualized to the patient’s situation and clinician judgment. A useful tool that has emerged for this purpose is procalcitonin, a biomarker elevated in bacterial infections and certain other inflammatory conditions. While its utility as a diagnostic biomarker is controversial (see, Diagnosis of Pneumonia), its use as a biomarker to stop antibiotic treatment is now an important option. The recommended procalcitonin level thresholds for discontinuing antibiotic therapy are <0.25 µg in low-risk patients and <0.5 µg (or a decrease in procalcitonin level of ≥80%) in critically ill patients with suspected sepsis; in the latter group, the criteria should only be used once the patient achieves clinical stability.

Prevention of CAP

All hospitalized patients with CAP should be evaluated for pneumococcal vaccine, vaccination for common viral causes of pneumonia (influenza, respiratory syncytial virus (RSV) and COVID-19), and smoking cessation. Pneumococcal vaccination is indicated. Pneumococcal vaccination is also indicated for adults aged 65 and older and adults of any age who are at risk for CAP.

There are two types of pneumococcal vaccines: the pneumococcal polysaccharide vaccine (PPV) and the pneumococcal conjugate vaccine (PCV). The PPV contains 23 serotypes (PPSV23) based on capsular polysaccharides, while the PCV is also based on capsular polysaccharides but these are conjugated to a carrier protein, allowing the PCV to overcome certain limits of the PPV (e.g., poor immunogenicity in children and inability to generate immune memory). The pneumococcal vaccines have been shown to prevent pneumococcal pneumonia in young adults and to prevent more severe disease in the elderly. Similarly, influenza vaccine is effective for the prevention of respiratory illness, including influenza pneumonia, and the secondary bacterial pneumonia that occurs in the setting of influenza A and B infection. In hospitalized patients with CAP, there is no contraindication for the simultaneous administration of the pneumococcal vaccine and influenza vaccine given at two different sites. As smoking is a risk factor for acquisition of pneumonia, smokers who are hospitalized with CAP should be enrolled in a smoking-cessation program to prevent future episodes of pneumonia. Data have suggested that conjugate vaccines may offer better protection, particularly in high-risk patients with HIV, where polysaccharide efficacy is suboptimal. The Centers for Disease Control (CDC) currently recommends routine vaccination with PCV (15-valent or 20-valent) for all children younger than 5 years of age and for all adults 65 years of age or older who have never received a pneumococcal vaccine. The specific recommendations are presented in Table 8-5. A new 21-valent pneumococcal vaccine (PCV21) received Food and Drug Administration (FDA) approval in June 2024. The serotypes covered by this vaccine (8 of which are not included in any other available pneumococcal vaccines) contribute to 74-94% of invasive pneumococcal infections in older adults. With the approval of PCV21, the CDC voted to recommend PCV21 “as an option for adults aged ≥19 years who currently have a recommendation to receive a dose of PCV.”

Many types of vaccine against influenza have been developed, and a decision is made each year on which influenza strains to include in the seasonal vaccines in the US based on factors such as the strains that are circulating prior to the season and their epidemiological dynamics, as well as how effective the vaccines from the previous year are expected to be. Currently, all influenza vaccines in the US are tetravalent and protect against an influenza A(H1) virus, an A(H3) virus, a B/Yamagata lineage virus and a B/Victoria lineage virus. Routine annual influenza vaccination is recommended for all individuals ≥6 months of age, unless contraindicated. The key recommendations from the 2023/2024 season are shown in Table 8-5, and updated recommendations will be released in fall of 2024.

For prevention of RSV-associated disease in infants and young children, the following immunization products are available: two injectable monoclonal antibody products (nirsevimab and palivizumab), which are intended for direct administration to the child; and one vaccine (Abrysvo, Pfizer) intended for administration to pregnant individuals to protect their infants. For adults 60 years of age and older, three vaccines are available for prevention of RSV-associated disease: Abrysvo (which can be used in this group as well as in pregnant individuals), Arevxy (GSK), and mRESVIA (Moderna). Abrysvo and Arexvy contain the pre-fusion conformation of the RSV F protein, a critical mediator of cell entry for RSV, while mRESVIA contains an mRNA encoding a stabilized version of the pre-fusion F protein. The recommendations for RSV immunization of infants/children and older adults are presented in Table 8-5. Note that, while Arexvy received FDA approval in June 2024 for vaccination of adults 50-59 years of age who are at increased risk of RSV disease, the CDC made the decision to wait until more data becomes available before issuing a vaccination recommendation for this age group.

Updated vaccines for COVID-19 are formulated every year to counter the continuing evolution of the SARS-CoV-2 virus. For the 2024-2025 season, updated mRNA-based vaccines from Pfizer and Moderna and an updated subunit vaccine from Novavax will be made available. The CDC recommends an updated COVID-19 vaccine be administered to all individuals 6 months of age and older (Table 8-5); more detailed recommendations will be released in fall of 2024.

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Improving the Process of Care

The primary processes of care that need to be improved are prevention, diagnosis and treatment. Continuous quality improvement can improve these processes at the local hospital level. The methodology can be summarized in three steps:

Collection of data on process-of-care or performance indicators

Evaluation of variance from recommended care

Development of local interventions for process of care (e.g., clinical pathways, health-provider education, reminders regarding IV to oral switch for antibiotics and vaccination, etc.).

Computerized physician-order entry has been shown to enhance adherence to guidelines by systematizing prompts and alerts as reminders and suggestions. Collaboration with nursing staff has been shown to enable successful switch therapy. When interventions are successful, process of care will be improved and local variance from the standard guidelines will be minimized.

Summary

Clinical and economic outcomes in hospitalized patients with CAP are directly related to the way certain processes of care are executed for hospitalized CAP patients. Step-down therapy is an important step toward improving the process of care leading to improved outcomes in hospitalized patients with CAP. Appropriate candidates must be identified and timing ascertained for the changeover. Predetermining conversion time (i.e., the convention: switch on day 3) should be replaced with the practice of ongoing evaluation (Figure 8-1 and Figure 8-2). It is important to note that many patients are good candidates for switch or step-down therapy before the third day of hospitalization. Clinical pathways and appropriate multidis­ciplinary communication are keys to optimal timely evaluation for switch readiness (Table 8-4).

Optimal management of patients with CAP requires further research and continuous reevaluation, as new medications become available. However, several interventions already mentioned, including early administration of antibiotics, appropriate antibiotic use following clinical practice guidelines, use of a critical pathway, a switch to oral therapy and early discharge, can help improve clinical outcomes in a cost-effective manner.

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