Infection Consult

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

Educational Objectives

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

1.   Detail the factors that contribute to infection after total joint arthroplasty.

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

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

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

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

Acknowledgments

Drs. Melcher and Guglielmo were recorded at the 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.

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.

Infection After Total Joint Arthroplasty

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 microbicidal capacity; bacterial sequestration  —  fibrin sequesters small numbers of bacteria near implant, allowing evasion of early in­flammatory processes and increasing risk for late infection by less virulent organisms; biofilm  —  extracellular slime substance (glycocalyx) produced by some organisms (eg, Staphylococcus epidermidis, Staphylococcus aureus, Streptococcus viridans, and sometimes Pseudomonas 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 or reopening of healed wound considered infection until proven otherwise; 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 be present; difficult to distinguish from aseptic mechanical failure; contamination with less virulent organisms (eg, coagulase-negative staphylococci, Propionibacterium acnes) generally occurs at time of implantation; late  —  ³24 mo after implanta­tion; usually result from hematogenous infections (eg, S aureus, S viridans, Streptococcus pneumoniae, gram-nega­tive organisms); sources of bacteremia include dental infections, pneumonia, skin or soft-tissue infections, and urinary tract infections (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; deep infections not always obvi­ous (may require consultation); 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 [MRI]; too early to detect changes on plain radiographs); management directed by surgical findings and results of cultures; delayed  —  x-rays may show radiolucent lines at interface between bone and cement (indi­cate 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 analysis 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 increase likelihood of true infection; taking multiple samples from different locations improves sensitivity; sonication  —  liberates bacteria adherent to prosthesis (eg, in biofilm); may be useful when re­moval of prosthesis warranted; study showed culture from sonicate significantly more sensitive, compared to those from conventional aspiration and tissue samples, when antibiotics discontinued 4 to 14 days before procedure (no benefit when antibiotics discontinued >14 days before procedure; trend toward increased sensitivity when discon­tinued 0-3 days before procedure)

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 to 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; virulent 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) 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 oral therapy (optional); additional cultures often taken at time of revision arthroplasty; if infection per­sists, parenteral antimicrobial therapy for 6 wk after reimplantation; study showed »26.5% rate of recurrence 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 meth­icillin-resistant Staphylococcus aureus (MRSA); linezolid sometimes used; streptococci  —  penicillin or ceftriax­one generally effective; penicillin may be given as continuous 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 ultraclean 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%

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) increased risk

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

Candida infection: risk increases with use of antibacterial agents; pathogen commonly responsible for 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 discon­tinuation and/or additional care; serious consequences include hospitalization (initial or prolonged), 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 MRSA–associated infections (eg, surgical site infections, bacteremia, ventilator-associated pneumonia [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; nonreimbursable conditions  —  catheter-associated 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 pharmacologist 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 associated with strategies; pathogens  —  study (Rahal et al, 1998) showed intervention decreased use of target antibiotics (cephalosporins); incidence of infection with cef­tazidime-resistant Klebsiella species decreased; but, 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 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, increased use of early 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 antimicrobials and 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

UCSF experience: antimicrobial use guidelines 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 required consult with ID specialist (who made final decision about antibiotic usage) in certain situations; results forthcoming  

Closing remarks: difficult to isolate and assess effects of antimicrobial stewardship programs and interventions, but association between antimicrobial use and subsequent development of resistance is well established; appropriate to consider resistant infections (that result from inappropriate antimicrobial use or inadequate infection control) as ADEs

Suggested Reading

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; Ghanem E et al: Staged revision for knee arthroplasty infection: What is the role of serologic tests before re­implantation? Clin Orthop Relat Res Feb 25, 2009 [Epub ahead of print]; 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 hypervirulent 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.