Infection Consult

From the UC Davis Health System’s 27th Annual Infectious Diseases Conference

Educational Objectives

The goals of this program are to prevent the development and iatrogenic spread of antimicrobial-resistant infections and to improve outcomes after total joint arthroplasty. After hearing and assimilating this program, the clinician will be better able to:

1.   Discuss the impact of antimicrobial resistance on length of stay and cost of care.

2.   Identify factors that increase risk for antimicrobial resistance.

3.   Select antimicrobial agents that reduce risk for adverse drug events, including Clostridium difficile-associated diarrhea.

4.   Educate patients about signs and symptoms that indicate infection after total joint arthroplasty.

5.   Diagnose early, delayed, and late infections related to total joint arthroplasty.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any per­sonal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the faculty and plan­ning committee reported nothing to disclose.

Acknowledgments

Drs. Guglielmo and Melcher were recorded at 27th Annual Infectious Diseases Conference, sponsored by University of California, Davis, Health System, and held January 30-31, 2009, in Sacramento, CA. The Audio-Digest Founda­tion thanks the speakers and the UC Davis Health System for their cooperation in the production of this program.

Antibacterial-resistant Infections and Superinfections: Adverse Drug Events?

B. Joseph Guglielmo, PharmD, Professor and Chair, Department of Clinical Pharmacy, School of Pharmacy, University of California, San Francisco

Emergence of antimicrobial resistance: changes in resistance parallel changes in antimicrobial use; resistance more common with health care-associated bacterial infections than with those acquired in community; past antimicro­bial therapy increases likelihood of harboring resistant pathogens; increasing frequency or duration of use in­creases risk for resistance and superinfection

Hypervirulent Clostridium difficile: study by Centers for Disease Control and Prevention showed past use of antibi­otics (especially fluoroquinolones) increases risk

Multidrug-resistant (MDR) Pseudomonas aeruginosa: risk factors  —  immunocompromised state; length of hospi­tal stay; mechanical ventilation; prolonged use of antibacterials; number of antibacterial agents; use of fluoroqui­nolones or carbapenems

Duration of therapy: study of patients with ventilator-associated pneumonia (VAP) showed short course (8 days) as effective as long course (15 days), with exception of infection with nonfermenting gram-negative rods (eg, Pseudo­monas, Acinetobacter; long course more effective in these cases); long course significantly increased risk for rein­fection

Candida infection: risk increases with use of antibacterial agents; pathogen commonly associated with bloodstream infections; antimicrobial pressure  —  as use of fluconazole increases, incidence of Candida albicans infections may decrease and incidence of Candida glabrata may increase

Adverse drug events (ADEs): “unexpected, unintended, undesired, or excessive response to drug,” requiring addi­tional care; serious consequences include hospitalization, life-threatening events, and death

Cost and length of stay (LOS): all ADEs  —  multivariate analysis showed average LOS increased by >2 days and cost increased substantially; preventable ADEs  —  average LOS increased by almost 5 days; cost almost doubled; antimicrobial-resistant organisms  —  studies show LOS and cost significantly increase with methicillin-resistant Staphylococcus aureus (MRSA) infections (eg, surgical site infections, bacteremia, VAP), compared to infections with susceptible isolates; duration of mechanical ventilation also increases with MRSA; other studies show LOS and cost significantly increase with fluoroquinolone-resistant P aeruginosa infections, postoperative infections with MDR gram-negative rods, and C difficile superinfection; associated costs approximately double

Reimbursement: Medicare no longer pays for cost of care associated with preventable errors; private insurers fol­lowing suit; non-reimbursable conditions  —   catheter-associated urinary tract infection (UTI); intravenous catheter-associated vascular infection; pressure ulcers; objects unintentionally left during surgery; air embolism; blood in­compatibility; mediastinitis; falls; conditions under consideration  —  S aureus bacteremia; all incidents of VAP; C difficile-associated diarrhea

Pharmaceutical development: few antibacterial agents in development; return on investment relatively low (com­pared to, eg, anticancer drugs, antidepressants, anti-arthritic agents); major pharmaceutical companies developing more agents for treating depression, anxiety, bladder problems, and osteoporosis than antibacterial agents

Antimicrobial intervention programs: Infectious Diseases Society of America and Society for Healthcare Epidemi­ology of America have developed guidelines for developing institutional programs to enhance antimicrobial stewardship; guidelines focus on antibiotic use and cost savings, not clinical outcomes; core members of stew­ardship team should include infectious diseases (ID) physician and clinical pharmacist with ID training; opti­mally, team should include clinical microbiologist, information systems specialist, infection control professional, and epidemiologist; team members should be compensated for participation; core strategies  —  education; usage guidelines; antimicrobial cycling (questionable efficacy); use of antibiotic order forms; combination therapy; de-escalation of therapy; dose optimization; conversion from parenteral to oral delivery

Outcomes: literature review showed decreased cost number one outcome associated with strategies; decreased re­sistance and superinfection next most common associations; pathogens  —  study (Rahall et al, JAMA 1998) showed intervention decreased use of target antibiotics (cephalosporins); incidence of infection with ceftazidime-resistant Klebsiella species decreased; however, use of imipenem increased, as did incidence of imipenem-resis­tant P aeruginosa; another study (Rice et al, 1996) restricted use of cefotaxime, clindamycin, and vancomycin and encouraged use of b-lactamase inhibitor combinations; results included decreased prevalence of vancomy­cin-resistant enterococci (VRE) and decreased incidence of C difficile infection

Focus on C difficile: recent study (Muto et al, 2007) looked at effect of “bundle” approach (ie, education, greater use of case findings, expanded measures for infection control, development of control team, and antimicrobial manage­ment targeting clindamycin, ceftriaxone, and levofloxacin) on incidence of hypervirulent C difficile infections; ap­proach resulted in decreased use of targeted antibiotics and lower infection rates (with all C difficile and with hypervirulent isolates); choice of antibiotics  —  observational study showed correlation between reduced use of ce­fepime, ceftazidime, and ceftriaxone and reduced incidence of C difficile infection; no relationship found with use of b-lactamase inhibitor combinations

University of California, San Francisco, Medical Center experience: guidelines for antimicrobial use included limiting use of vancomycin, carbapenems, 2-drug coverage for gram-negative infections, and addition of metroni­dazole to b-lactamase inhibitor therapy (use of any of these required microbiologic confirmation of appropriate use); in absence of microbiologic documentation of infection, all antimicrobial agents discontinued; initially, use patterns did not improve because guidelines not enforced; inappropriate use of some agents increased, as did inci­dence of C difficile infection; to improve results, medical center implemented antimicrobial stewardship program, which gave final decision about antibiotic usage to ID specialist; results forthcoming

Infections of Prosthetic Orthopedic Devices

Gregory P. Melcher, MD, Professor, Division of Infectious Diseases, Department of Internal Medicine, Univer­sity of California, Davis, School of Medicine, Sacramento

Impact: »400  000 total hip and »250  000 total knee arthroplasties performed each year in United States; most in­fected joints result in functional failure, requiring revision arthroplasty; economic consequences include costs of di­agnosis and treatment, hospitalization, procedures, devices, and lost work; infection rates for total joint arthroplasties  —  hip, £1%; knee, 1% to 2%; shoulder, £1%; elbow, 1% to 2%

Contributing factors: foreign-body reactivity  —  foreign body remains in place for (potentially) decades; inflamma­tory response leads to tissue liquefaction and necrosis, resulting in acute inflammation; lysosomal enzymes and ox­ygen free radicals (toxic to healthy tissues) released in response to necrosis; small numbers of bacteria and particulate debris (from device) potentiate inflammatory process; local host defenses  —  contact with implant mate­rials impairs neutrophil activities (eg, phagocytosis, production of superoxides), decreasing microbiocidal capacity; bacterial sequestration  —  fibrin sequesters small numbers of bacteria near implant, allowing evasion of early in­flammatory processes and increasing risk for late infections with less virulent organisms; biofilm  —  extracellular slime substance (glycocalyx) produced by some organisms (eg, S aureus, Staphylococcus epidermidis, Streptococ­cus viridans, and sometimes P aeruginosa) allows bacteria to adhere to implant surface and evade immune pro­cesses; fibronectin and collagen  —  involved in scar formation; increase bacterial adherence to implant

Clinical presentation: early  —  <3 mo after implantation; acute onset of joint pain, effusion (easier to see in knee than in hip), and fever; cellulitis or dehiscence may occur at surgical site; sinus tract formation suggests infection; infection usually results from contamination with S aureus or gram-negative bacilli at time of implantation or in perioperative period; delayed  —  3 to 24 mo after implantation; joint pain persists, despite healed wound; signs of prosthesis loosening may occur; difficult to distinguish from mechanical failure; contamination with less virulent organisms (eg, coagulase-negative staphylococci, Propionibacterium acnes) generally occurs at time of implanta­tion; late  —  >24 mo after implantation; usually results from hematogenous infections (eg, S aureus, S viridans, Streptococcus pneumoniae, gram-negative organisms); sources include dental infections, pneumonia, skin or soft-tissue infections, and UTIs; relative incidence  —  29% early; 41% delayed; 30% late

Diagnosis: early and late infections present with acute inflammatory response (easier to diagnose than delayed infec­tions); wound dehiscence, sinus tract formation, and abrupt onset of joint pain suggest infection; pain persisting for months after surgery may indicate mechanical failure or infection; early  —  important to distinguish superficial from deep infections; surgical debridement and tissue culture important for diagnosis; most imaging not helpful in early postoperative period (acute inflammation reduces specificity of nuclear medicine scans and produces artifacts on computed tomography [CT] and magnetic resonance imaging; too early to detect changes on plain radiographs); delayed  —  x-rays may show radiolucent lines at interface between bone and cement (indicating loosening due to mechanical failure or infection); complete blood cell count, erythrocyte sedimentation rate, and C-reactive protein levels often normal; arthrography (preferred imaging study) may show “pocketing” of radiopaque material and per­mits sampling of synovial fluid for Gram stain and culture; indium-111 labeled white blood cell scan useful for sus­pected infection without acute inflammation (more sensitive than bone and gallium scans; look for asymmetry between joints); metal prosthesis interferes with CT; gold standard is culture (with susceptibility testing) from sy­novial fluid aspirate

Culture: skin flora may contaminate specimen during aspiration; presence of inflammatory cells and/or large num­bers of colony-forming units increases likelihood of true infection; taking multiple samples from different locations improves sensitivity

Microbiology: S aureus and coagulase-negative staphylococci most common pathogens; gram-positive organisms re­sponsible for 75% of deep infections; presence of open draining wound increases suspicion for gram-negative or­ganisms

Goals of therapy: pain-free functional joint (primary goal); eradication of infection (secondary goal; often requires removal of prosthesis, followed by directed antimicrobial therapy for 4-6 wk); for fractures, goal is union at frac­ture site (may necessitate leaving fixation hardware in place; chronic osteomyelitis and/or chronically draining si­nus tract often preferable over amputation)

Device exchange: one-stage  —  implantation of new device (using antimicrobial-impregnated cement) immediately follows excision of contaminated device; study of hip arthroplasties showed 77% eradication of infection; some or­ganisms (eg, S aureus, P aeruginosa) associated with 50% rate of recurrence over 10 yr; careful selection of pa­tients (those with no sinus tract drainage or gross purulence in wound or deep tissue) reduces recurrence rate to 5.4%; decision to perform one-stage revision arthroplasty sometimes made at time of explantation (based on infec­tion status); two-stage  —  device removed; tissue debrided and irrigated; pathogen identified; parenteral antimicro­bial therapy given for 6 wk, then (optional) oral therapy; additional cultures often taken at time of revision arthroplasty; if infection persists, appropriate antimicrobial therapy for 6 wk after reimplantation; study showed rate of recurrence »26.5% when delay <1 yr and »7% when delay >1 yr; revision arthroplasty of knee  —  must be performed within 6 to 8 wk to prevent excessive formation of scar tissue (limits functional outcome)

Directed antimicrobial therapy: S aureus  —  nafcillin for susceptible isolates; vancomycin or daptomycin for MRSA; linezolid sometimes used; streptococci  —penicillin or ceftriaxone generally effective; penicillin may be given as infusion; gram-negative organisms  —susceptibility testing required

Oral agents: avoid rifampin monotherapy (promotes resistance); consider long-term (lifetime) suppressive therapy with oral agents when device explantation not feasible or patient refuses revision arthroplasty; choose agents with good bioavailability (eg, fluoroquinolones, trimethoprim-sulfamethoxazole, clindamycin, doxycycline)

Preventive measures: intraoperative  —  use of laminar airflow and ultra-clean operating suites has reduced infection rate to 0.3%; perioperative  —  antimicrobial therapy with cefazolin or vancomycin (speaker prefers vancomycin be­cause of high rate of methicillin resistance) has reduced infection rate from »3.5% to <1%

Suggested Reading

Bolon MK et al: Improved surveillance for surgical site infections after orthopedic implantation procedures: extending applications for automated data. Clin Infect Dis 48:1223, 2009; Chastre J et al: Comparison of 8 vs 15 days of antibiotic therapy for ventilator-associated pneumonia in adults: a randomized trial. JAMA 290:2588, 2003; Cordero-Ampuero J et al: Oral antibiotics are effective for highly resistant hip arthroplasty infections. Clin Orthop Relat Res Mar 31, 2009 [Epub ahead of print]; Dellit TH et al: Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis 44:159, 2007; Evans HL et al: Cost of gram-negative resistance. Crit Care 35:89, 2007; Ghanem E et al: Periprosthetic infec­tion: Where do we stand with regard to Gram stain? Acta Orthop 80:37, 2009; Jamsen E et al: Risk factors for infection after knee arthroplasty. A register-based analysis of 43,149 cases. J Bone Joint Surg Am 91:38, 2009; Loo VG et al: A predominantly clonal multi-institutional outbreak of Clostridium difficile-associated diarrhea with high morbidity and mortality. N Engl J Med 353:2442, 2005; Mendez MN et al: Impact of a piperacillin-tazobactam shortage on antimicro­bial prescribing and the rate of vancomycin-resistant enterococci and Clostridium difficile infections. Pharmacotherapy 26:61, 2006; Muto CA et al: Control of an outbreak of infection with hyperviurulent Clostridium difficile B1 strain in a university hospital using a comprehensive “bundle” approach. Clin Infect Dis 45:1266, 2007; Rahall JJ et al: Class re­striction of cephalosporin use to control total cephalosporin resistance in nosocomial Klebsiella. JAMA 280:1233, 1998; Rice LB et al: Ceftazidime-resistant Klebsiella pneumoniae isolates recovered at the Cleveland Department of Veterans Affairs Medical Center. Clin Infect Dis 23:118, 1996; Shorr AF et al: Morbidity and cost burden of methicillin-resistant Staphylococcus aureus in early onset ventilator-associated pneumonia. Crit Care 10:R97, 2006; Trampuz A et al: Soni­cation of removed hip and knee prostheses for diagnosis of infection. N Engl J Med 357:654, 2007.