Expert Review of Anti-infective Therapy ISSN: 1478-7210 (Print) 1744-8336 (Online) Journal homepage: http://www.tandfonline.com/loi/ierz20 Treatment of community-acquired pneumonia Young R Lee, Coovi Houngue & Ronald G Hall To cite this article: Young R Lee, Coovi Houngue & Ronald G Hall (2015) Treatment of community-acquired pneumonia, Expert Review of Anti-infective Therapy, 13:9, 1109-1121, DOI: 10.1586/14787210.2015.1060125 To link to this article: http://dx.doi.org/10.1586/14787210.2015.1060125 Published online: 19 Jun 2015. Submit your article to this journal Article views: 86 View related articles View Crossmark data Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ierz20 Download by: [Texas Tech University Libraries], [Ronald Hall] Date: 18 September 2015, At: 10:18 Review Treatment of community- acquired pneumonia Expert Rev. Anti Infect. Ther. 13(9), 1109–1121 (2015) Young R Lee1, Community-acquired pneumonia is the sixth leading cause of death in the USA. Adherence Coovi Houngue2 and to the 2007 Infectious Diseases Society of America/American Thoracic Society Ronald G Hall*3 community-acquired pneumonia guidelines has been associated with improved clinical outcomes. However, choice between guideline-recommended treatments is at the discretion 1 Texas Tech University Health Sciences of the prescribing clinician. This review is intended to discuss the characteristics of these Center, School of Pharmacy, 1718 Pine Street, Abilene, TX 79601, USA treatment options including dosing frequency, dose adjustment for renal/hepatic dysfunction, 2Texas Tech University Health Sciences serious/common adverse events, drug interactions, lung penetration, pharmacokinetic- Center, School of Pharmacy, 5920 Forest pharmacodynamic target and effect of obesity to help guide antimicrobial selection. An Park Rd, Suite 400, Dallas, TX 75235, USA increasing portion of patients are receiving expanded empiric coverage for methicillin-resistant 3Dose Optimization and Outcomes Staphylococcus aureus as recommended by the American Thoracic Society and Infectious Research (DOOR) program, Texas Tech Diseases Society of America for healthcare-associated pneumonia. However, this expanded University Health Sciences Center, coverage may not be achieving the desired improvements in clinical outcomes. We expect School of Pharmacy, 5920 Forest Park Rd, Suite 400, Dallas, TX 75235, USA this increasingly diverse spectrum of patients with pneumonia to eventually result in the *Author for correspondence: merger of these two guidelines to include all patients with pneumonia. Tel.: +1 214 358 9009 Fax: +1 214 654 9707 KEYWORDS: dose optimization . empiric therapy . lung penetration . obesity . pharmacodynamics . pharmacokinetics [email protected] Community-acquired pneumonia (CAP) on a general medicine ward typically receive affects 5.6 million Americans and 915,900 antimicrobial coverage for Streptococcus pneu- Americans aged 65 and over per year [1,2].Itis moniae, Haemophilus influenzae and atypical the sixth leading cause of death in the USA pathogens (Chlamydophila pnuemoniae, Myco- and is responsible for 600,000 hospitalizations plasma pnuemoniae, Legionella) [3]. of geriatric patients. The Infectious Diseases Society of America Previously healthy & have not used (IDSA) and American Thoracic Society (ATS) antimicrobials within 3 months provide numerous guideline-recommended ther- Treatment options for these patients include: apeutic options for the treatment of CAP [3]. While the selection of agent has not been associ- 1. Azithromycin, clarithromycin or erythromy- ated with clinical success or mortality, the provi- cin (strong recommendation) sion of guideline-recommended therapy has been 2. Doxycycline (weak recommendation) linked to improved clinical outcomes [4–6]. This review will provide a summary of the IDSA/ATS Macrolides/ketolide Downloaded by [Texas Tech University Libraries], [Ronald Hall] at 10:18 18 September 2015 guideline recommendations for adults with CAP Drug characteristics: Drug characteristics for emphasizing factors associated with patient- and antimicrobials used in the treatment of CAP are drug-specific factors. Patient factors to be dis- shown in TABLE 1. Erythromycin is rarely used for cussed include allergy history, concomitant CAP due to its frequent dosing, inhibition of medications and disease states as well as kidney/ CYP450 3A4 and gastrointestinal side effects. liver function. Drug-specific factors will focus on Clarithromycin is favored by some clinicians factors affecting antimicrobial pharmacokinetics due to its potency against S. pneumoniae. How- (PK) and pharmacodynamics (PD) with an ever, it also inhibits CYP450 3A4 and is associ- emphasis on lung penetration and obesity. ated with metallic taste. Therefore, azithromycin is the most commonly used macrolide. Reasons Outpatient treatment of CAP for this include its once-daily dose, shortened The IDSA/ATS guidelines recommend that duration of treatment due to its extended half- patients with CAP in the outpatient setting or life and relative lack of CYP450 3A4 inhibition. informahealthcare.com 10.1586/14787210.2015.1060125 Ó 2015 Informa UK Ltd ISSN 1478-7210 1109 Review Lee, Houngue & Hall Telithromycin is a ketolide that was designed to overcome Lung penetration: Doxycycline is a lipophilic agent with excel- the low- (efflux) and high-level (alteration of the 50S ribosomal lent lung penetration. The drug concentration ratio in sputum/ binding site) macrolide resistance. The appeal of its in vitro plasma ranged from 0.33 to 1.2 (mean 0.71) with 100–200 mg potency and once-daily dosing have been diminished by the after 14–28 days therapy in patients with cystic fibrosis [11]. reports of hepatotoxicity that have resulted in removal of Effect of obesity: We were unable to find any data describing telithromycin’s indications for acute sinusitis and acute exacer- the impact of obesity on the PK, effectiveness or safety of bations of chronic bronchitis [7]. Telithromycin’s use can also doxycycline. be limited by its potent inhibitor of CYP450 3A4 and lack of Dose optimization: Tetracyclines are optimized with a an intravenous formulation. T>MIC ‡50% and an AUC/MIC of 2–4 times the MIC Lung penetration: Macrolides are lipophilic agents and have value [12]. A 200 mg intravenous (iv.) or per os (p.o.) q12h is high concentrations in the lungs (epithelial lining fluid [ELF] recommend in CAP since 100 mg iv. or p.o. q12h will take to plasma concentration ratio >1) [8]. This will be beneficial; 5 days to achieve optimal concentrations [13]. At higher concen- especially in extracellular microorganisms (i.e., S. pneumonia, trations (8- to 16-times the MIC), doxycycline exhibits Moraxella catarhalis, H. influenzae) since ELF is the likely concentration-dependent killing and post-antibiotic effect. infection site for these pathogens [8]. Effect of obesity: To our knowledge, the only data come Presence of comorbidities or recent use of antimicrobials/ from a study of patients with Helicobacter pylori [9].Two immunosuppressive agents groups of non-diabetic naı¨ve H. pylori-positive patients, a con- According to the IDSA/ATS guidelines, people with diabetes trol group (BMI <25 kg/m2) and study group (BMI ‡25 kg/ mellitus, asplenia, alcoholism, cancer or those with heart, lung, m2), received pantoprazole 40 mg for 2 weeks plus amoxicillin liver, renal or immunosuppressive comorbidities should receive 1 g three times a day, and clarithromycin 250 mg three times expanded antimicrobial coverage [3]. The receipt of antimicro- a day, for the first week. H. pylori eradication was less com- bials within 3 months or immunosuppressive drugs also places mon for BMI ‡25 kg/m2 than BMI <25 kg/m2 (55 vs 85%, a person into this category. These patients can be treated with p < 0.005). However, it is difficult to extrapolate these find- one of two recommended regimens. ings as it is unknown which drug(s) was/were affected by 1. Monotherapy with moxifloxacin, gemifloxacin or levofloxa- patient weight. cin 750 mg Dose optimization: Macrolides are as concentration- 2. An oral b-lactam (or ceftriaxone administered intramuscu- independent antibiotics [10]. The percentage of time above the larly) plus a macrolide minimal inhibitory concentration (MIC), also known as T>MIC, is the PK-PD parameter best associated with microbial a. Oral b-lactam: killing for erythromycin and clarithromycin, whereas the ratio (i) Preferred: High-dose amoxicillin or amoxicillin- of the area under curve (AUC) to the MIC (AUC/MIC) best clavulanate ’ correlates with azithromycin s activity [10]. Mechanisms to (ii) Alternatives: cefpodoxime and cefuroxime improve the PK-PD target for an oral formulation of T>MIC include using more frequent daily dosing or an extended-release Fluoroquinolones formulation. Mechanism to improve T>MIC for intravenous Drug characteristics: Fluroquinolones are commonly used agents formulations will be discussed later as most data supporting the for CAP as their ability to be used as monotherapy, relative approaches used come from b-lactams. Clarithromycin is the lack of CYP450 3A4 inhibition and direct iv. to p.o. conver- only macrolide with a commercially available extended-release sion. Gemifloxacin is not commonly used due to the current formulation. Drugs whose activity is best associated with the lack of an intravenous formulation approved for use in the AUC/MIC ratio should be dosed as infrequently as possible to USA as