Polly Jen, PharmD, BCPS-AQ ID, AAHIVP

The management of infectious diseases is constantly changing as new diagnostic strategies and therapeutic options become available. Clinicians must be aware of the most recent recommendations issued by professional organizations to provide the latest evidence-based highlights recent updates to practice guidelines for three commonly encountered infections: infective endocarditis, hospital-acquired pneumonia, and ventilator-associated pneumonia.

On October 13, 2015, the American Heart Association published updated practice guidelines for the management of infective endocarditis (IE) in adult patients.

 These guidelines are endorsed by the Infectious Diseases Society of America (IDSA) and incorporate recent evidence-based recommendations for the diagnosis and treatment of IE available after the last published iteration in 2005.

 Although the incidence of IE is relatively low (three to ten cases per 100,000 individuals annually), the condition is associated with significant morbidity, mortality, and use of healthcare resources.

The diagnosis of IE remains based on the modified Duke criteria of clinical, pathological, and echocardiographic findings. A minimum of three sets of blood cultures should be drawn from different venipuncture sites over the course of at least one hour.

is the leading causative organism responsible for native and prosthetic valve IE, with both community-acquired and healthcare-associated cases frequently encountered.

 Transthoracic echocardiography (TTE) should be performed initially in all patients with suspected IE. Transesophageal echocardiography may be necessary if the TTE images are negative or inadequate in patients with a strong suspicion for IE, or if there is a positive TTE and a concern for intracardiac complications.

The roles of newer imaging modalities, such as three-dimensional echocardiography, computed tomography, and magnetic resonance imaging, have yet to be determined.

 Antibiotic treatment of IE is determined by multiple factors, including the causative pathogen, susceptibility profile, involvement of native or prosthetic valve, and patient allergy history. Based on results from recent clinical studies, significant changes in the recommended antibiotic therapies for IE caused by 

species were made. Gentamicin is no longer recommended as part of the treatment regimen for native valve staphylococcal IE. Monotherapy with either an anti-staphylococcal ß-lactam (for methicillin-susceptible 

) or vancomycin (for methicillin-resistant 

 The removal of gentamicin for native valve staphylococcal IE follows evidence demonstrating little to no clinical benefit and increased risk of nephrotoxicity compared to treatment with a single, effective, first-line antibiotic.

For native or prosthetic valve IE caused by penicillin-susceptible 

, the combination regimen of ampicillin plus ceftriaxone has been added as a preferred treatment option. This double ß-lactam regimen is particularly useful in cases where aminoglycoside-related nephrotoxicity is a concern or if the 

species isolated is resistant to aminoglycosides (a growing observation in clinical practice). An international, multicenter study comparing ampicillin plus ceftriaxone with the previous standard of care, ampicillin plus gentamicin, demonstrated that dual ß-lactam therapy was associated with clinical and microbiological cure rates similar to those in the comparator group, with a significantly lower incidence of nephrotoxicity.

Specific antibiotic recommendations by IE category can be found in the recently published guidelines.

As recommended in both the 2005 and 2015 guidelines of the American Heart Association, surgical management should be considered in conjunction with medical therapy for patients with severe and complicated cases of IE. While the decision for surgical intervention is case-specific, early surgery (prior to completion of antibiotic therapy) is recommended for infections caused by fungi or multidrug-resistant bacteria, not responsive to appropriate antibiotic therapy, associated with severe valve dysfunction or myocardial involvement, and/ or involving recurrent emboli. Anticoagulation is not recommended as part of the treatment plan for native valve IE. For patients with mechanical prosthetic valve IE who develop a central nervous system embolic event, all anticoagulation agents should be discontinued for at least two weeks after the embolic event to minimize the risk of acute hemorrhagic transformation of embolic lesions.

HOSPITAL-ACQUIRED PNEUMONIA AND VENTILATOR-ASSOCIATED PNEUMONIA 

The long-awaited update to the IDSA’s hospital-acquired pneumonia (HAP)/ventilator-associated pneumonia (VAP) guidelines was finally revealed in summer 2016.

 Similar to the last version released in 2005, the update was co-endorsed by the American Thoracic Society and covers a range of topics from diagnosis to treatment.

 The new guidelines also provide additional remarks, “Rationale for the Recommendation,” which describe the panel’s “Values and Preferences” for each recommendation. Given the current healthcare landscape of increasing multidrug-resistant organisms(MDROs), the panel attempted to strike a balance between appropriate broad-spectrum antimicrobial use and minimizing unnecessary antimicrobial exposure. The updated guidelines have also incorporated the now common “Grading of Recommendations Assessment, Development and Evaluation” methodology used in other recent IDSA guidelines.

Perhaps one of the largest changes is the removal of the “healthcare-associated pneumonia” terminology. It was previously thought that a subset of patients would be at increased risk of resistant pathogens by virtue of frequent contact with the healthcare system. However, increasing evidence has shown that individual patient characteristics may better predict risk for MDROs than healthcare exposure alone.

Therefore, these guidelines describe a more limited spectrum of patients compared to the prior version. The panel indicated that a forthcoming update to the Community-Acquired Pneumonia guidelines will likely incorporate a validated scoring tool to outline those who present from the community and are at risk for MDROs.

Generally, noninvasive sampling with semiquantitative cultures is recommended for a diagnosis of VAP, given insufficient evidence supporting invasive sampling methods, including protected specimen brush (PSB), blind bronchial sampling, or bronchoalveolar lavage (BAL). The value of obtaining culture data to deescalate or discontinue therapy is also addressed. For example, patients with suspected HAP should receive tailored treatment based on noninvasive respiratory sampling compared with a full course of empiric therapy (in the case that no cultures were obtained). Patients with suspected VAP and invasive quantitative culture results below the VAP diagnostic threshold (PSB <10

Colony-Forming Units(CFU)/mL; BAL <104 CFU/mL) can have their antimicrobials discontinued safely. Tracheobronchitis should not be treated to avoid unnecessary antimicrobial exposure.

The updated guidelines also highlight the importance of understanding local microbiology trends to optimize empiric therapy by minimizing exposure to unnecessary antimicrobials, such as decreasing empiric methicillin-resistant 

(MRSA) coverage and avoiding dual gram-negative coverage when possible. For example, MRSA coverage for VAP is only recommended in units where >10% to 20% of 

isolates are methicillin-resistant or if the prevalence is not known. “Double-coverage” of 

spp. is only recommended if specific criteria for MDRO are met, if there is >10% resistance of gram-negatives to the agent being considered for monotherapy, or if local gram-negative susceptibilities are unknown. Resistance thresholds are less prescriptive for HAP, with the MRSA coverage threshold set arbitrarily at >20% methicillin resistance or if the patient has “high risk of mortality,” while “double-coverage” for gram-negatives is only recommended if “high risk of mortality” or risk factors, such as structural lung disease, are present. However, modification of resistance thresholds may be considered in an individual unit with the goal of ≥95% of patients receiving empiric therapy active against likely pathogens.

 Pathogen-specific treatment is briefly reviewed, including those for MRSA, 

, extended-spectrum beta-lactamase, and carbapenemase-producing organisms. The role of newer ß-lactam/ß-lactamase combinations and older agents (eg, polymyxins) are also briefly addressed, but generally, no specific antimicrobial was shown to be more effective than others. The guidelines now advocate using pharmacokinetic/pharmacodynamic (PK/PD) data to optimize therapy when available, and advise against aminoglycoside monotherapy given poor lung penetration and clinical response, with increased adverse effects.

Regarding duration of therapy, the updated guidelines now recommend treatment for seven days for HAP/VAP, regardless of organism. Prior guidelines also advocated a duration of seven days, but excluded 

spp. and other nonglucose-fermenting, gram-negative organisms due to concerns for increased recurrence with eight versus 15 days of therapy.

 However, an updated meta-analysis did not show an association of recurrence with short-course therapy, and the panel noted that the increased recurrence rate was based only on subgroup analyses from the original Chastre study. It has also been well noted that short-course therapy led to reduction in antimicrobial exposure and MDROs, with no significant change in any clinical outcomes (including mortality) across all subgroups, including infections due to nonglucose-fermenting organisms.

In addition, the guidelines advocate de-escalation of antibiotics based on clinical experience and rationale. Unfortunately, the quality of evidence supporting the presumed benefits of de-escalation (ie, reducing antimicrobial resistance, side effects, and cost) remains poor. However, when weighing overall potential benefits and possible harms, de-escalation remains a cornerstone of antimicrobial stewardship and a method of reducing broad-spectrum empiric therapy.

Biomarkers and the Clinical Pulmonary Infection Score (CPIS) are discussed in terms of utility for diagnosis and also determining duration of therapy. At this time, it is recommended to use clinical criteria alone to diagnose HAP/VAP. Due to heterogeneous results from the studies reviewed by the panel, it is not recommended to use clinical criteria plus CPIS or clinical criteria plus any of the following biomarkers: procalcitonin (PCT), soluble triggering receptor expressed on myeloid cells, or C-reactive protein. However, PCT may have a role when used in addition to clinical criteria to guide discontinuation of antibiotics. The role of CPIS in addition to clinical criteria to shorten duration of therapy remains controversial. The panel reviewed inconsistent evidence of benefit. One study suggested use of a modified CPIS led to decreased resistance, antimicrobial cost, and superinfections,

while two other studies, which were not specifically designed to assess the use of CPIS to shorten duration, showed no effect on clinical outcomes.

Therefore, the panel indicated a preference to use clinical criteria alone to determine duration of therapy for VAP.

Polly Jen, PharmD, BCPSAQ ID, AAHIVP, is a clinical pharmacotherapy specialist in infectious diseases/ antimicrobial stewardship at New York University Langone Medical Center. She received a doctor of pharmacy degree from the Ernst Mario School of Pharmacy at Rutgers University and is a board-certified pharmacotherapy specialist with added qualifications in infectious diseases. Active member of SIDP.

Elizabeth Leung, PharmD, BCPS-AQ ID, is a clinical pharmacy specialist leader in infectious diseases/ antimicrobial stewardship, and co-leads the Antimicrobial Stewardship Program (ASP) at St. Michael's Hospital. Dr. Leung received her doctorate of pharmacy degree from Massachusetts College of Pharmacy and Health Sciences (MCPHS) in Boston, obtained double-specialty residency training (infectious diseases and critical care), and is a board-certified pharmacotherapy specialist with added qualifications in infectious diseases. Active member of SIDP.

1. Baddour LM, Wilson WR, Bayer AS, et al; American Heart Association Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in the Young, Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and Stroke Council. Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complication. A scientific statement for healthcare professionals from the American Heart Association. 

. 2015;132(15):1435-1486. doi: 10.1161/CIR.0000000000000296.

2. Baddour LM, Wilson, WR, Bayer AS, et al; Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease; Council on Cardiovascular Disease in the Young; Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia; American Heart Association; Infectious Diseases Society of America. Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications. A statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association. 

. 2005;111(23):e394-e434. doi: 10.1161/CIRCULATIONAHA. 105.165564.

3. Cahill TJ, Prendergast BD. Infective endocarditis. 

. 2016;387(10021):882-893. doi: 10.1016/S0140-6736(15)00067-7.

4. Thuny F, Grisoli D, Cautela J, Riberi A, Raolt D, Habib G. Infective endocarditis: prevention, diagnosis, and management. 

. 2014;30(9):1046-1057. doi: 10.1016/j.cjca.2014.03.042.

5. Chopra T, Kaatz GW. Treatment strategies for infective endocarditis. 

. 2010;11(3):345-360. doi: 10.1517/14656560903496430.

6. Cosgrove SE, Vigliani GA, Fowler VG, et al. Initial low-dose gentamicin for 

bacteremia and endocarditis is nephrotoxic. 

. 2009;48(6):713-721. doi: 10.1086/597031.

7. Fernández-Hidalgo N, Almirante B, Gavaldà J, et al. Ampicillin plus ceftriaxone is as effective as ampicillin plus gentamicin for treating 

s. 2013;56(9):1261- 1268. doi: 10.1093/cid/cit052.

8. Kalil AC, Metersky ML, Klompas M, et al. Management of Adults With Hospital-acquired and Ventilator-associated Pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society. 

. 2016;63(5):e61-e111. doi: 10.1093/cid/ciw353.

9. American Thoracic Society; Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator- associated, and healthcare-associated pneumonia. 

10. Chalmers JD, Rother C, Salih W, Ewig S. Healthcare-associated pneumonia does not accurately identify potentially resistant pathogens: a systematic review and meta-analysis. 

. 2014;58(3):330-339. doi: 10.1093/cid/cit734.

11. Chastre J, Wolff M, Fagon JY, et al; PneumA Trial Group. Comparison of 8 vs 15 days of antibiotic therapy for ventilator-associated pneumonia in adults: a randomized trial. 

12. Singh N, Rogers P, Atwood CP, et al. Short-course empiric antibiotic therapy for patients with pulmonary infiltrates in the intensive care unit. A proposed solution for indiscriminate antibiotic prescription. 

13. Micek ST, Ward S, Fraser VJ, et al. A randomized controlled trial of an antibiotic discontinuation policy for clinically suspected ventilator-associated pneumonia. 

14. Ibrahim EH, Ward S, Sherman G, et a. Experience with a clinical guideline for the treatment of ventilator-associated pneumonia. 

. 2001;29:1109-15.                                 

Polly Jen, PharmD, BCPS-AQ ID, AAHIVP

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