The Parsimonious Use of Antibiotics To Treat Common Infections in the Elderly

Robin McKenzie, M.D.Associate Professor of MedicineDivision of Infectious DiseasesJohns Hopkins University

Therapeutics Initiative: Best Evidence for CliniciansNanaimo Division of Family Practice

10/20/2017

Disclosures

• No financial disclosures

The Parsimonious Use of Antibiotics To Treat Two Common Infections in the Elderly: Objectives

• Discuss why we should be stingy with antibiotics• For treatment of common infections, discuss the following

• How can we focus (narrow) our treatment?• When can we use a short course of antibiotics?• Should we suppress the inflammatory response?

Why not use broad-spectrum antibiotics for a long course (to be safe)?

Reasons not to overuse antibiotics:The world-wide view

Overuse of antibiotics is wasteful

In 2009 antibiotic prescription costs: $11 billion• $6.5 billion in the community

• 50% unnecessary

Antibiotic resistance is an international public health emergency.

Each year in the US, antibiotic-resistant bacteria cause• 2 million illnesses • 23,000 deaths• $30 billion

CDC. Antibiotic Resistance Threats in the United States, 2013 (http://www.cdc.gov/drugresistance/threat-report-2013/ )

• 50% reduction in inappropriate antibiotic use in doctor's offices and

• 20% reduction in hospital use by 2020.

Reasons not to overuse antibiotics:The individual patient view

Z-PAK?

Effect of macrolide therapy on pharyngeal carriage of macrolide-resistant streptococci

• a randomized, double-blind, placebo-controlled study

• 224 healthy volunteers given azithromycin 500 mg Q day x 3 days or clarithromycin 500 mg BID x 7 days or placebo

• Swab of tonsils and posterior pharynx taken to isolate strep

Malhotra-Kumar, The Lancet, 2007

Vitamin L?

• 126 episodes of C. difficile infection• 93 patients (74%), had taken at least one preceding course

of antibiotics that was inappropriate.

Is lack of knowledge the problem?

JAMA Intern Med, 2016

“The overuse of antibiotics is not a knowledge problem or a diagnostic problem: it is largely a psychological problem.”

Linder, JAMA Intern Med, 2014

“I want to do right, just not right now.”

Linder, JAMA Intern Med, 2014

71 yo women with DM-2• Admitted on Mon

• pain, redness, swelling x 1 day • T-38.3, WBC-16K.• Vancomycin started

• Wed: • Erythema has not receded• Afebrile, but WBC 13K

Diagnosis: Nonpurulent cellulitis.

Treatment: What antibiotics should she receive? For how long?

Nonpurulent cellulitis: How to treat?

1. What are the bacterial pathogens that I should cover?2. Should I add clindamycin for its anti-toxin effect?3. Should I add ibuprofen or prednisone for an anti-inflammatory

effect?

Evaluation of Cellulitis/ Erysipelas in Adults: skin biopsy and DFA42 adults with erysipelas (27) or cellulitis (15) plus fever and WBC >10K• DFA positive for streptococcus in 29 of 42 (70%) of patients

• Group A, 22 pts• Group B, 2• Group C, 1• Droup G, 4

• An additional 8 pts were found to have strep by culture or serology• Altogether, 37 of 42 (88%) had beta-hemolytic strep

Bernard, Arch Dermatol, 1986

Microbiologic Evaluation of Cutaneous Cellulitis in Adults.• 50 adults with cellulitis had cultures of the following:

• Aspirates of leading edge: 5 positive• Punch bx of leading edge: 10 positive• Blood: 2 positive

• 13 of 50 had at least one positive culture• 5/13 grew beta-hemolytic strep• 9/13 grew S. aureus

Hook, Arch Intern Med, 1986

Do we need to cover MRSA?

Acute and convalescent serology suggests that beta-strep is still the most common pathogen.

Jeng, Medicine, 2010

Two RCTs showed no benefit to adding MRSA coverage (with TMS) to cephalexin.

Palin, CID, 2013Moran, JAMA, 2017

Nonpurulent cellulitis: How to treat?

1. What are the bacterial pathogens that I should cover?2. Should I add clindamycin for its anti-toxin effect?3. Should I add ibuprofen or prednisone for an anti-inflammatory

effect?

Nonpurulent cellulitis: How to treat?

1. What are the bacterial pathogens that I should cover?2. Should I add clindamycin for its anti-toxin effect?3. Should I add ibuprofen or prednisone for an anti-inflammatory

effect?

Brindle R, et al. BMJ Open 2017;7:e013260.

Design: randomized, double-blind, placebo-controlled. 410 patients.Conclusions:

The addition of a short course of clindamycin to flucloxacillin early on does not improve outcome. doubles the likelihood of diarrhea

Uncomplicated Cellulitis: How broad an antibiotic?

Data supporting narrow-spectrum antibiotics to cover beta-hemolytic strep and MSSA (not MRSA)1. Serology and DFA show that beta-strep is the main pathogen2. Response to beta-lactam antibiotics remains high3. Adding TM-S to cephalexin did not improve the cure rate.4. Adding clindamycin for anti-toxin effects was not beneficial.

NONPURULENT SSTIsnecrotizing infection/cellulitis/erysipelas

ORAL Rx:• Penicillin VK• Cephalosporin• Dicloxacillin• Clindamycin

MILD

INTRAVENOUS Rx:• Penicillin• Ceftriaxone• Cefazolin• Clindamycin

SEVERE

• Emergent surgical inspection/debridement

• Vanc + pip/tazo• Additional abx based on

cultures

MODERATE

Guidelines for the Diagnosis and Management of Skin and Soft Tissue Infections: 2014 Update by IDSACID, June 2014

Cellulitis: when special antibiotics are needed

Risk Organism Antibiotic coverageSeawater, raw oysters Vibrio vulnificus Ceftriaxone + doxyCat or dog bites Pasteurella multocida Amox/clav or

amp/sulbactamFresh water contamination; leeches

Aeromonas Ceftriaxone or FQ (adjust based on sensitivities)

Immunocompromise, cirrhosis

Gram-negative rods Broader coverage

71 yo women with DM-2• Mon. admitted

• pain, redness, swelling x 1 day • T-38.3, WBC-16K.• Vancomycin started

• Wed: • Erythema has not receded• Afebrile, but WBC 13K

Why hasn’t her cellulitis improved?

Cellulitis: the inflammatory response

“Treating the inflammation in these infections by combining antimicrobial therapy with either an NSAID (ibuprofen 400 mg qid x 5 days) or systemic corticosteroids significantly hastens clinical improvement compared with antimicrobial therapy alone [60, 62].”

Practice Guidelines for the Diagnosis and Management of Skin and Soft Tissue Infections: 2104 Update by the IDSA

V. Should Anti-inflammatory Agents Be Used to Complement Antibiotic Treatment of Cellulitis?

Recommendation19. Systemic corticosteroids (eg, prednisone 40 mg daily for 7 days) could be considered in nondiabetic adult patients with cellulitis (weak recommendation, moderate-quality evidence).

(Ensure that necrotizing fasciitis is not present.)

64 patients in the ED with cellulitis (quasi-)randomized to receive • Antibiotics for 10 days (ceftriaxone 1 g q day cephalexin 500 mg qid)

or• Antibiotics for 10 days + ibuprofen 400 mg q 6h for 5 days

Exclusions: Immunocompromise, creatinine >1.5

Percent of patients with cellulitis regression

• Double-blind, randomized trial of 51 pts getting outpt IV cefazolin for cellulitis• Pts received ibuprofen 400 mg TID or placebo for 5 days.• 48 pts in the mITT population. • Endpoint: regression of superior margin of inflammation in 48 h

20 (80%) in ibuprofen group15 (65%) in the placebo group; difference = 15% (95 CI -10 to +40, p=>0.05)

2017

David, Clin Micro Infect, 2017

71 yo women with DM-2• Mon. admitted

• pain, redness, swelling x 1 day • T-38.3, WBC-16K.• Vancomycin started

• Wed: • Erythema has not receded• Afebrile, but WBC 13K

Why hasn’t she improved???

Raff, JAMA, 2016

Raff, JAMA, 2016

MAJ MJ Hepburn, MC, et al., Brooke Army Medical Ctr, San Antonio, TX

• Double-blind RCT of 121 patients with uncomplicated cellulitis• All treated with levofloxacin 500 mg x 5 days, then evaluated• On Day 5 if no progression of disease, no abscess or other source of infection, pts

randomized to 5 more days of • levofloxacin x 5 more days or • Placebo x 5 more days

• “The continued presence of the clinical indicators of cellulitis … did not exclude subjects from randomization if … even minimal improvement had occurred.”

Arch Intern Med. 2004

5 vs 10 days of antibiotics for cellulitis: results

• 121 subjects enrolled. Most were outpts with no fever or leukocytosis. • 34 not randomized at Day 5

• 6 abscess, 5 persistent ulcer, 3 bursitis, 2 alternate dx, 1 + blood cultures• 5 worse at 72 hours• 4 not improved at Day 5• 8 protocol nonadherence: missed apt, med intolerance

• 87 randomized

Clinical scores in pts receiving 5 or 10 days of levofloxacin for uncomplicated cellulitis

98% in both groups had resolution of infection Day 14 without relapse Day 28

The case for short-course treatment of cellulitis1. The bacterial burden is low2. The inflammatory response is strong3. Short-course antibiotics work4. The IDSA says so.

“The recommended duration of antimicrobial therapy is 5 days, but treatment should be extended if the infection has not improved within this time period (strong, high).”

71 yo women with DM-2• Mon. admitted

• pain, redness, swelling x 1 day • T-38.3, WBC-16K.• Vancomycin started

• Wed: • Erythema has not receded• Afebrile, but WBC 13K

Should we broaden her antibiotics?No, narrow. (cefazolin, cephalexin or ampicillin/sulbactam)

How long should we treat? Evaluate at Day 5 and stop if improved.

Nonpurulent cellulitis: parsimonious treatment

• For most patients choose a beta-lactam (eg. cefazolin amox/clav)• Exceptions: penetrating trauma, bites, IDU, MRSA elsewhere, severely ill,

immunocompromised.

• Keep the extremity elevated!• When improved, switch to oral antibiotics. • For most patients, treat with antibiotics for 5 days

• Evaluate at Day 5

• [Consider steroid or NSAID treatment for some pts when more data are available]

Clinical trials comparing short vs long courses of antibioticsCondition Duration, days ReferenceVAP 8 vs 15 Chastre, 2003CAP 3 vs 5 Moussaoui, 2006Cellulitis 5 vs 10 Hepburn, 2004Women, uncomplicated pyelo 7 vs 14 Talan, 2000Women, pyelo 7 vs 14 Sandberg, 2012Spontaneous bacterial peritonitis 5 vs 10 Runyon, 1991Vertebral osteomyelitis 42 vs 84 Bernard, 2015Intraabdominal infections 4 vs < 10 Sawyer, 2015

Barlam, Clin Infect Dis, 2016