ADVERTISEMENT
Pharmacotherapy Update 2009, Part II: Infectious Disease, Positive Beers Criteria, and Pharmacist Interventions
This article is part II of a two-part series update on pharmacotherapy, and it focuses on infectious disease, positive Beers criteria, and pharmacist interventions. Part I appeared in the December issue of the Journal and focused on cardiology, neurology, and psychiatry.
Introduction
This article is intended to provide a review of recently published literature of relevance to the care of older adults. It focuses on studies that involve pharmacotherapeutic interventions, including both risks and benefits. It is important for clinicians to decide independently how the results of these investigations should be applied to individual patients; clinicians are encouraged to refer to the original articles to assist with making decisions and applying the results to patient care.
Infectious Disease Acid-Suppressive Medications and Nosocomial Pneumonia
Previous trials have linked acid-suppressive medication use and the risk of pneumonia, both in the ambulatory care setting as well as the inpatient setting. Two recent articles have again looked at acid-suppressive medication and risk of pneumonia, with focus on the association with nosocomial pneumonia. The first of two articles was published in May 2009.1 This prospective pharmacoepidemiologic cohort study at a single institution focused on general, nonintubated hospitalized patients admitted for 3 or more days. The primary outcome was hospital-acquired pneumonia (HAP) as defined by a secondary discharge diagnosis of bacterial pneumonia, which was identified by ICD-9 codes.
A total of 64,878 admissions consisting of 43,093 unique patients with a mean age of 54 years were included in the final analysis. Of those admissions, 32,922 admissions (52%) were categorized as being exposed to acid-suppressive medication, which was defined as an order for a proton pump inhibitor (PPI) or histamine2-receptor antagonist during admission. Of those admissions exposed, 83% received a PPI. HAP, the primary outcome, occurred in 3.5% (2219) of admissions. The unadjusted and confounder adjusted incidence of HAP was higher in those admissions exposed to acid-suppression medication as compared to those admissions not exposed to acid-suppressive medication (odds ratio [OR], 2.6 [2.3-2.8]; OR, 1.3 [1.1-1.4], respectively).
When the groups were propensity-matched, a total of 16,396 patient admissions in each group were compared again, with a higher incidence of HAP in the patient admissions exposed to acid-suppressive medications (OR, 1.3 [1.1-1.4]). Overall, in this cohort study, the use of acid-suppressive medications was associated with a 0.9% attributable risk of developing HAP or a number needed to harm of 111. The second of the two articles was published in August 2009.2 This retrospective cohort analysis at a large, single institution teaching hospital included a total of 834 patients age 18 years or older (mean age, 65 yr) admitted to the cardiothoracic surgery service over a 4-year period. The patients were identified and data collected from the Society of Thoracic Surgeons database. The primary outcome of the study was the incidence of nosocomial pneumonia, including both HAP and ventilator-associated pneumonia (VAP). Of the 834 patients included, 377 patients received pantoprazole and 457 received ranitidine, with no crossover between the agents throughout the study period.
The primary outcome of nosocomial pneumonia occurred in a total of 42 admissions, with 35 in the pantoprazole group (9.3%) and 7 in the ranitidine group (1.5%; OR, 6.6 [2.9-14.9]). When the groups were propensity-adjusted, pantoprazole remained an independent risk factor for nosocomial pneumonia (OR, 2.7 [1.1-6.7]). Looking at the specific types of nosocomial pneumonia cases in the study, VAP accounted for 88.5% of the cases in pantoprazole group and 71.4% in the ranitidine group.
Although both of these trials are limited by the means of data collection via large databases, which can add numerous confounders, the investigators attempted to adjust for these confounders through the use of propensity score analysis. Both of these trials, in slightly different capacities, address the risk of nosocomial pneumonia in patients who had received acid-suppressive medications, one looking at all patients receiving acid-suppressive medications (with 83% being PPIs) and the other comparing the risk with different types of acid-suppressive medications. These two studies add to the mounting literature linking acid-suppressive medication use and the risk of pneumonia, specifically the PPI class.
References
1. Herzig SJ, Howell MD, Ngo LH, Marcantonio ER. Acid-suppressive medication use and the risk for hospital-acquired pneumonia. JAMA 2009;301(20):2120-2128.
2. Miano TA, Reichert MG, Houle TT, et al. Nosocomial pneumonia risk and stress ulcer prophylaxis: A comparison of pantoprazole vs ranitidine in cardiothoracic surgery patients. Chest 2009;136:440-447. Published Online: March 24, 2009.
Pneumonia in Elderly Nursing Home Residents
Because it is both a common and serious condition, elderly nursing home (NH) residents are more likely to die from pneumonia than any other infection. The appropriate treatment of nursing home–acquired pneumonia (NHAP) has been debated for a number of years. In 2003, the Infectious Diseases Society of America (IDSA) recommended in its community-acquired pneumonia (CAP) guidelines to treat infected NH residents with antibiotics similar to those used for the general public.3 This included a respiratory fluoroquinolone (levofloxacin or moxifloxacin) alone or with the combination of an anti-pneumococcal beta-lactam (ceftriaxone, cefotaxime, or ampicillin-sulbactam) plus an advanced macrolide (azithromycin or clarithromycin) for atypical bacteria.
In 2005, however, the American Thoracic Society and IDSA published a joint guideline for the treatment of VAP, HAP, and healthcare-associated pneumonia (HCAP) that specifically included NHAP.4 These treatment guidelines focused on the need to start initial effective therapy for methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa. This strategy has been shown repeatedly to provide a mortality benefit in critically ill patients with nosocomial pneumonia, but it is not known whether the same is true for less severe cases. Two studies have recently examined the treatment of NH residents hospitalized for pneumonia.5,6
The first compared patients treated according to the 2003 CAP guidelines to those treated with antibiotics consistent with the 2005 HCAP guidelines. This was a retrospective review performed at three study hospitals in Buffalo, NY. Patients admitted to the intensive care unit (ICU) were not included because of their increased risk of pneumonia caused by multidrug-resistant organisms. Other exclusion criteria included: patients who received more than one dose of antibiotic prior to presentation to the Emergency Department; patients who had the human immunodeficiency virus (HIV); and patients who had been hospitalized within the previous 30 days, had been transferred from another hospital, or were actively receiving chemotherapy.5
Between patients treated with antibiotics from the 2003 CAP (n = 258) and the 2005 HCAP (n = 76) guidelines, there was no significant difference in outcomes. These included time to clinical stability (3.6 vs 3.9 days; P = 0.38), hospital mortality (13.2% vs 17.1%; P = 0.49), and 30-day mortality (15.1% vs 22.4%; P = 0.19). Patients treated according to the 2003 CAP guidelines did have a faster switch to oral therapy (4.1 vs 5.8 days; P < 0.001) and shorter hospital stay (5.7 vs 6.9 days; P < 0.001). Moxifloxacin was used 71% of the time in this group, and its 100% oral bioavailability likely contributed to early switch to oral therapy and discharge.
Patients in the HCAP group most often received vancomycin plus an antipseudomonal penicillin (piperacillin-tazobactam) and antipseudomonal fluoroquinolone (ciprofloxacin). Although not statistically significant, HCAP-treated patients tended to be older (mean age, 73.5 vs 76.7 yr; P = 0.08), have end-stage renal disease (4.3% vs 10.5%; P = 0.07), and pneumonia that was more severe. Propensity score statistics were used in an attempt to correct for the potential selection bias of prescribers giving sicker patients the broad-spectrum antibiotics indicated by HCAP guidelines while reserving narrower CAP antibiotics for less ill patients.
Overall, a benefit could not be shown for using antibiotics concordant with the 2005 HCAP guidelines over those previously recommended to treat hospitalized NH residents not admitted to the ICU.5 A difference could still exist if a larger population were studied, but this study could not show that the use of multiple, broad-spectrum antibiotics improved outcomes of elderly NH residents treated for pneumonia outside of the ICU. Although resistant pathogens are known to infect NH residents more than community-dwelling elderly individuals, the rate of pneumonia for them is less than that seen in both hospitalized and mechanically ventilated patients. If prescribed, the use of multiple broad-spectrum antibiotics needs to be balanced with a strategy of de-escalation to narrower-spectrum agents when resistant pathogens are not identified (after 48-72 hr). Short treatment courses (7-8 days total) have also been shown to be effective for treating pneumonia and preventing the emergence of resistance.
A second recent article evaluated the treatment of pneumonia in an elderly population with a carbapenem antibiotic, ertapenem, which can be administered either intravenously or intramuscularly. Ertapenem has a longer half-life than other carbapenems and can be dosed once daily, much like ceftriaxone. In fact, these two drugs have been compared for CAP in several studies and shown similar efficacy. The updated 2007 CAP guidelines from IDSA included ertapenem as an anti-pneumococcal beta-lactam for treatment of select patients, such as hospitalized patients not in the ICU who have received previous therapy for CAP or are otherwise at risk of a resistant respiratory pathogen.7
Ertapenem has a narrower spectrum than the rest of the carbapenems but is broader than other anti-pneumococcal beta-lactams. Like ceftriaxone, its spectrum includes penicillin-resistant S. pneumoniae, but it also covers extended-spectrum beta-lactamase–producing enteric gram-negative organisms and anaerobes that third-generation cephalosporins do not. Unlike other carbapenems, it does not have activity against Pseudomonas aeruginosa, and is therefore not recommended as empiric therapy for patients with HAP, those who are critically ill, or patients on ventilators.
The 2007 CAP guideline update does say, “pneumonia in nonambulatory residents of long-term care facilities epidemiologically mirrors HAP and should be treated according to HCAP guidelines,” but as described above, the evidence behind this advice is weak in noncritically ill patients. None of the beta-lactam antibiotics treat atypical bacteria such as Mycoplasma pneumoniae or Legionella pneumophilia, and therefore CAP guidelines in the United States recommend combination therapy with a macrolide or doxycycline for additional coverage. Atypical bacteria, however, are less of a concern in elderly patients, especially NH residents, for whom pneumococcus and gram-negative organisms are the most common causes of pneumonia.
This retrospective study evaluated elderly patients treated with ertapenem for CAP at seven hospitals in Spain from 2002-2006.6 When possible, each patient who received ertapenem was matched with two patients of similar age, pneumonia severity, and NH residence status. Patients were excluded if they had received parenteral antibiotic therapy for more than 24 hours within the 72 hours prior to hospital admission and/or if they had the diagnosis of tuberculosis, VAP or nosocomial pneumonia, shock, immunosuppression, cystic fibrosis, neutropenia, bronchiectasis, primary lung cancer or lung metastasis, meningitis, and/or HIV (< 200 CD4/mL).
Seventy-one patients who received ertapenem were compared to 131 matched controls treated with other parenteral antibiotics.6 A total of 41 patients (20.3%) were receiving oral antibiotics prior to admission, but no comparison is given between the two groups. These included amoxicillin-clavulanate (12), macrolides (10), quinolones (9), cephalosporins (2), and unspecified combinations (9). While in the hospital, significantly more patients receiving ertapenem were treated with monotherapy as compared to the control group (83.1% vs 57.2%; P = 0.0002). Of the 12 patients who did not receive ertapenem as monotherapy, 8 also received a macrolide, 3 a quinolone, and 1 ceftazidime. In the control group, 75 received monotherapy with a quinolone (n = 31), third-generation cephalosporin (n = 20), amoxicillin-clavulanate (n = 16), piperacillin-tazobactam (n = 5), or other antibiotics (n = 3).
Fifty-six control patients received combination therapy. The most common was a beta-lactam plus quinolone in 26 patients, followed by 19 patients with beta-lactam plus macrolide combinations. Six received two beta-lactams, while five had other combinations. Over 95% of patients enrolled in this study had at least one comorbidity, and their mean age was 80.5 years. Bacteria were identified from cultures taken before antimicrobial therapy in 14.1% of patients. S. pneumoniae (10), Hemophilus influenza (10), E. coli (4), and Klebsiella pneumonia (3) were most common. There was no difference in mortality between the two arms of this study (8.5% vs 7.6%), but more patients treated with ertapenem had a clinical response as compared to those in the control group (88.7% vs 77.1%; P = 0.0465). Average length of hospital stay also tended to be shorter for patients receiving ertapenem, although this did not reach statistical significance (7 vs 10 days; P = 0.066). Seventy-one out of the 202 patients (35.1%) in this study were NH residents.
These patients had more severe pneumonia than the community-dwelling elderly individuals, but when treated with ertapenem they had better clinical response rates than with control antibiotics (95.8% vs 63.8%; P = 0.0034). Although this study has limitations such a small sample size and nonrandomized design, it showed how the once-daily use of parenteral ertapenem could effectively be used to treat pneumonia in elderly patients, especially NH residents. It adds to the literature that anti-pneumococcal antibiotics are successful at treating NHAP, and that multiple broad-spectrum agents may not be necessary.6
References
3. Mandell LA, Bartlett JG, Dowell SF, et al. Update of Practice Guidelines for the management of community-acquired pneumonia in immunocompetant adults. Clin Inf Dis 2003;37:1405-1433.
4. American Thoracic Society and Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Repir Crit Care Med 2005;171:388-416.
5. El Solh AA, Akinnusi ME, Alfarah Z, Patel A. Effect of antibiotic guidelines on outcomes of hospitalized patients with nursing home-acquired pneumonia. J Am Geriatr Soc 2009;57:1030-1035. Published Online: April 30, 2009.
6. Murcia JM, González-Comeche J, Marin A, et al; SCAPE Study Group. Clinical response to ertapenem in severe community-acquired pneumonia: A retrospective series in an elderly population. Clin Microbiol Infect 2009;15(11):1046-1050. Published Online: June 22, 2009.
7. Mandell LA, Wunderink RG, Anzueto A, et al. Infectious Diseases Society of America/American Thoracic Society Consensus Guidelines on the Management of Community-Acquired Pneumonia in Adults. Clin Infect Dis 2007;44:S27-S72.
Positive Beers Criteria
The Beers Criteria has been in existence for more than a decade and has been used extensively to help define potentially inappropriate drug use in older adults.8 Although helpful for identifying medications to avoid, it wasn’t useful for the opposite end of the spectrum— identifying preferred medications. In this article, Stefanacci et al9 completed extensive literature reviews and used a modified Delphi method (similar to that used to develop the original Beers Criteria) to identify preferred medications for older adults with four central nervous system disorders: dementia, Parkinson’s disease, depression, or psychosis.
From a starting list of 78 medications used to treat the four disorders, the eight experts reached consensus on 13 medications considered preferred for older adults. For dementia, the panel recommended donepezil, galantamine ER, and memantine (as add-on therapy only). For depression, citalopram, duloxetine, escitalopram, bupropion extended-release, and mirtazapine were recommended. Carbidopa/levodopa, ropinirole, and entacapone (as add-on therapy) were recommended for Parkinson’s disease, and risperidone and haloperidol (acute use only) were recommended for psychosis. It seems useful to have a preferred list of medications for use in older adults, but it remains unclear how the preferred criteria could or will be used.
In addition, the overall utility of the preferred criteria is limited to the drug classes addressed in this report. Will other drug classes be subject to the same process to develop a preferred list in these classes? Should the criteria be used only for patients beginning therapy for one of these disorders, rather than for someone who has already been receiving treatment and responding well to a nonpreferred medication? Also, similar to the original Beer’s criteria, the preferred criteria will require periodic updating as new information is accumulated. Furthermore, even if a preferred medication is selected for use, clinicians must consider other factors to ensure ongoing appropriateness, such as dosing, potential drug-drug or drug-disease interactions, and monitoring.
References
8. Fick DM, Cooper JW, Wade WE, et al. Updating the Beers criteria for potentially inappropriate medication use in older adults: Results of a U.S. consenus panel of experts [published correction appears in Arch Intern Med 2004;164(3):298]. Arch Intern Med 2003;163(22):2716-2724.
9. Stefanacci RG, Cavallaro E, Beers MH, Fick DM. Developing explicit positive Beers criteria for preferred central nervous system medications in older adults. Consult Pharm 2009;24:601-610.
Pharmacist Interventions
It is estimated that up to 30% of hospitalizations among older adults are related to adverse drug events. Medicare expenditures for potentially preventable rehospitalizations are estimated to be as high as $12 billion annually. Programs utilizing nurses and pharmacists at discharge have shown reductions in rehospitalization rates and costs to the healthcare system; however, this type of intervention has not been well studied in a randomized fashion involving pharmacists and acutely ill older adults. Medicare is likely to revise hospital payment policies so that hospitals with higher 30-day readmission rates receive lower average per-case payments. This creates an incentive for hospitals to develop services that attempt to reduce readmissions.
A study at a University hospital in Sweden randomized 400 consecutive internal medicine patients age 80 years or older to either pharmacist intervention or standard of care.10 The primary outcome was the frequency of hospital visits, both Emergency Department (ED) visits and hospital readmissions, during a 12-month follow-up period. The secondary outcome of the study, cost of hospital care, was also investigated. Pharmacist intervention occurred on weekdays from 8:00 AM to 4:00 PM and encompassed all aspects of the patients’ hospital stay, as well as post-hospitalization follow-up, including a 2-month follow-up phone interview with each patient.
During admissions, pharmacists would verify medication reconciliation forms through use of medical records, as well as conduct patient interviews to assess patient adherence and understanding of medication therapy. Comprehensive medication reviews were conducted throughout the inpatient stay, and medication issues were discussed with the team during rounds, with the team making the final decisions regarding any medication changes. In addition, during the inpatient stay, pharmacists would counsel patients regarding newly initiated or newly discontinued medications. Upon discharge, patients would then be counseled regarding their medications, as well as receive a letter summarizing the hospital stay. The same letter would also be sent to the patients’ primary care providers. The overall estimated pharmacist time spent on each patient was 2 hours and 20 minutes.
A total of 368 patients with a mean age of 86.6 years were followed throughout the 12-month follow-up period. The groups were relatively balanced, except for history of cerebral vascular disease and number of prescription medications, which were higher in the pharmacist intervention group. For the primary outcome, there was a 16% reduction in hospital visits in the intervention group (266 vs 316; estimate, 0.84 [0.37-0.75]). If the primary outcome is separated out into ED visits and readmissions, there was a 47% reduction in ED visits in the intervention group (49 vs 93; estimate, 0.53 [0.37-0.75]), but no significant difference in the number of readmissions (217 vs 223; estimate, 0.97 [0.81-1.17]).
When looking at reasons for admissions, the intervention group had significantly fewer readmissions due to drug-related events (9 vs 45; estimate, 0.20 [0.10-0.41]). For the secondary outcome, the estimated cost savings of the pharmacist intervention balanced against the estimated cost of the intervention, one pharmacist at 0.5 full-time equivalents for 9 months with 182 patients, calculated to $230 per patient. Extrapolating the results of this study to a larger scale, pharmacists taking a more active role in the care of older adults could result in major reductions in hospital visits and healthcare costs.
Reference
10. Gillespie U, Alassaad A, Henrohn D, et al. A comprehensive pharmacist intervention to reduce morbidity in patients 80 years or older: A randomized controlled trial. Arch Intern Med 2009;169(9):894-900.
Dr. Bergman has been on the speaker’s bureau for Pfizer and Ortho-McNeil.
The other authors report no relevant financial relationships.
Dr. Bergman is Assistant Professor, Dr. Ronald and Dr. Gonzalez are Clinical Assistant Professors, and Dr. Ruscin is Professor, Department of Pharmacy Practice, Southern Illinois University Edwardsville School of Pharmacy; and Drs. Bergman, Ronald,Gonzalez, and Ruscin are all Adjunct Clinical Assistant Professors, Department of Internal Medicine, Southern Illinois University School of Medicine, Springfield.
