Presentation on theme: "Surgical Site Infection: New Solutions to a Continuing Problem"— Presentation transcript:
1 Surgical Site Infection: New Solutions to a Continuing Problem R. Lawrence Reed, II, MD, FACS, FCCMProfessor of SurgeryLoyola University Medical CenterDirector, SICU, Hines VA Medical CenterMaywood, IL
2 Surgical Site Infections (SSI) Third most common nosocomial infection (14%–16%)Most common nosocomial infection among surgical patients (38%)2/3 incisional1/3 organs or spaces accessed during surgery7.3 additional postoperative days at cost of $3,152 in extra chargesSurgical site infections are the third most common type of nosocomial infection accounting for 14% to 16% of all infections.Among surgical patients, however, SSIs are the most common nosocomial infection, observed in 38% of cases. Two-thirds of these infections are due to the incision, whereas one-third are due to infection of the organs or spaces during surgery.Surgical site infections result in an additional 7.3 postoperative days at an added cost of $3,152.Mangram AJ et al. Infect Control Hosp Epidemiol. 1999;20:
3 Colonization vs Contamination – Definitions Bacteria present in a wound with no signs or symptoms of systemic inflammationUsually less than 105 cfu/mLContaminationTransient exposure of a wound to bacteriaVarying concentrations of bacteria possibleTime of exposure suggested to be < 6 hoursSSI prophylaxis best strategyColonization is defined as bacterial presence in a wound without signs or symptoms of inflammation, usually less than 105 cfu/mL.Contamination is defined as a transient exposure of a wound to bacteria of varying concentrations. Exposure to the bacteria is less than 6 hours. In this case surgical site infection prophylaxis is the best strategy.
4 SSI – Definitions Infection Surgical wound infection is SSI Systemic and local signs of inflammationBacterial counts ≥ 105 cfu/mLPurulent versus nonpurulentLOS effectEconomic effectSurgical wound infection is SSISurgical sites are considered infected when there are signs of systemic and local inflammation and bacterial counts are 105 cfu/mL or higher. Infections are also differentiated by purulence or nonpurulence.The length of stay for the patient and economic effects of the hospital stay are important factors to consider in SSIs.It is important to note is that a surgical wound infection is a surgical site infection.LOS=length of stay.
5 Superficial Incisional SSI Infection occurs within 30 days after the operation and involves only skin or subcutaneous tissue of the incisionSuperficial incisional SSISkinSubcutaneous tissueThe first type of surgical site infection is the superficial incisional surgical infection which occurs within 30 days post-op and involves only the skin or subcutaneous tissue.Mangram AJ et al. Infect Control Hosp Epidemiol. 1999;20:
6 Deep Incisional SSIInfection occurs within 30 days after the operation if no implant is left in place or within 1 year if implant is in place and the infection appears to be related to the operation and the infection involves the deep soft tissue (e.g., fascia and muscle layers)Deep incisional SSISuperficial incisional SSIA more serious SSI is a deep incisional surgical infection, which extends past the superficial layer. The infection occurs within 30 days post-op only if no implant is left in place or within 1 year if implant is in place and the infection appears to be related to the operation and the infection involves the deep soft tissue, which include the fascia and muscle layers.Deep soft tissue (fascia & muscle)Mangram AJ et al. Infect Control Hosp Epidemiol. 1999;20:
7 Organ/Space SSIInfection occurs within 30 days after the operation if no implant is left in place or within 1 year if implant is in place and the infection appears to be related to the operation and the infection involves any part of the anatomy, other than the incision, which was opened or manipulated during the operationSuperficial incisional SSIDeep incisional SSIThe most extensive of these surgical infections involves the organs and the space surrounding the organs. These infections can occur within 30 days post-op if no implant is left in place or within 1 year if an implant is in place and the infection appears to be related to the operation and the infection involves any part of the anatomy, other than the incision, which was opened or manipulated during the operation.Organ/space SSIOrgan/spaceMangram AJ et al. Infect Control Hosp Epidemiol ;20:
8 SSI – Risk Factors Operation Factors Foreign material at surgical siteSurgical drainsSurgical techniquePoor hemostasisFailure to obliterate dead spaceTissue traumaDuration of surgical scrubMaintain body tempSkin antisepsisPreoperative shavingDuration of operationAntimicrobial prophylaxisOperating room ventilationInadequate sterilization of instrumentsBoth operation factors and patient characteristics may influence the risk of surgical site infection.Depending on the conditions of the operation a patient can be at an even greater risk of infection. These factors can include duration of surgical scrub, maintenance of body temperature, the use of skin antisepsis, preoperative shaving, duration of the operation, antimicrobial prophylaxis, ventilation of the operating room, inadequate sterilization of instruments, the presence of foreign material at the surgical site, surgical drains, and surgical technique. Poor surgical technique includes poor hemostasis, failure to obliterate dead space, and tissue trauma.Mangram AJ et al. Infect Control Hosp Epidemiol. 1999;20:
9 SSI – Risk Factors Patient Characteristics AgeDiabetesHbA1C and SSIGlucose > 200 mg/dL postoperative period (<48 hours)Nicotine use: delays primary wound healingSteroid use: controversialMalnutrition: no epidemiological associationObesity: 20% over ideal body weightProlonged preoperative stay: surrogate of the severity of illness and comorbid conditionsPreoperative nares colonization with Staphylococcus aureus: significant associationPerioperative transfusion: controversialCoexistent infections at a remote body siteAltered immune responseThis slide shows risk factors for patients who are considered to be at a higher risk for surgical site infection.High-risk characteristics include advanced age, diabetes, smoking, poor nutritional status, obesity, coexisting infections at a particular body site, and altered immune response, among other factors.Prolonged preoperative stay is also a risk, depending on the severity of illness and comorbid conditions. There is also a significant association between preoperative nares colonization with Staphylococcus aureus and surgical site infection. Perioperative transfusion remains a controversial issue.Mangram AJ et al. Infect Control Hosp Epidemiol. 1999;20:
10 Risk of Infection Bacterial dose Virulence Impaired host resistance In a nonsurgical infection, the virulence of the pathogen, bacterial dose, and impaired host resistance are all equivalent to one another. However, in a surgical infection, the bacterial dose and impaired host resistance play the major roles in infection, while virulence is less of a factor.
11 Risk of Infection Bacterial dose Virulence Impaired host resistance In a nonsurgical infection, the virulence of the pathogen, bacterial dose, and impaired host resistance are all equivalent to one another. However, in a surgical infection, the bacterial dose and impaired host resistance play the major roles in infection, while virulence is less of a factor.
12 Risk of Surgical Infection Risk of InfectionBacterial doseVirulenceImpairedhost resistanceBacterial doseVirulenceImpairedhost resistanceIn a nonsurgical infection, the virulence of the pathogen, bacterial dose, and impaired host resistance are all equivalent to one another. However, in a surgical infection, the bacterial dose and impaired host resistance play the major roles in infection, while virulence is less of a factor.
13 SSI – Wound Classification Class 1 = CleanClass 2 = Clean contaminatedClass 3 = ContaminatedClass 4 = Dirty infectedProphylactic antibiotics indicatedTherapeutic antibioticsSurgical site infections are categorized into four classes depending on wound type. Class 1 is a clean wound, class 2 is a clean contaminated wound, class 3 is a contaminated wound, and class 4 is a dirty infected wound.Mangram AJ et al. Infect Control Hosp Epidemiol. 1999;20:
14 SSI – Risk Stratification NNIS Project 3 independent variables associated with SSI riskContaminated or dirty/infected wound classificationASA > 2Length of operation > 75th percentile of the specific operation being performedThree independent variables have been shown to be associated with surgical skin infection risk through the National Nosocomial Infections Study.These include an ASA greater than 2, classification of the wound as contaminated or dirty, and length of operation being longer than the 75th percentile of the specific operation being performed.NNIS=National Nosocomial Infections Surveillance.NNIS. CDC. Am J Infect Control. 2001;29:
15 SSI – Wound Class vs NNIS Class Wound Class All NNIS 0 NNIS 1 NNIS 2 NNIS 3Clean % % % % N/AClean contaminated % % % % N/AContaminated % N/A % % %Dirty infected % N/A % % %All % 1.5% % % %This chart compares the wound class for surgical site infections with the NNIS classes.Although the risk of infection increases within the wound classification, it has been shown to be also dependant within each wound class on the NNIS classification.NNIS. CDC. Am J Infect Control. 2001;29:
16 Campaign to Prevent Antimicrobial Resistance Centers for Disease Control and PreventionNational Center for Infectious DiseasesDivision of Healthcare Quality PromotionThe Campaign to Prevent Antimicrobial Resistance was developed by the Centers for Disease Control and Prevention (CDC) and other national organizations with the aim to prevent antimicrobial resistance in healthcare settings. The campaign centers on four main strategies: prevent infection, diagnose and treat infection, use antimicrobials wisely, and prevent transmission. Multiple programs have been developed for specific patient populations, including hospitalized adults, dialysis patients, surgical patients, hospitalized children, and long-term care patients.Clinicians hold the solution!Link to: Campaign to Prevent Antimicrobial Resistance OnlineLink to: Federal Action Plan to Combat Antimicrobial Resistance
17 12 Steps to Prevent Antimicrobial Resistance Among Surgical Patients Step 1 – Prevent SSIsMonitor and maintain normal glycemiaMaintain normothermiaPerform proper skin preparation using appropriate antiseptic agent and, when necessary, hair removal techniquesThink outside the wound to stop surgical site infectionsThe CDC has developed guidelines to help prevent antimicrobial resistance among surgical patients.The first step is to prevent surgical site infections by monitoring and maintaining normal glucose levels, especially in diabetic patients; maintaining normal body temperature; proper skin preparation using appropriate antiseptic agents and when necessary, hair removal techniques; and thinking outside of the wound in order to prevent surgical site infections.CDC. Available at Accessed July 16, 2004.
18 Opportunity to Prevent SSI An estimated 40%–60% of SSIs are preventableOveruse, underuse, improper timing, and misuse of antibiotics occurs in 25%–50% of operationsIt is estimated that 40% to 60% of surgical site infections are preventable. The overuse, underuse, improper timing, or misuse of antibiotics occurs in 25% to 50% of operations.Mangram AJ et al. Infect Control Hosp Epidemiol. 1999;20:
19 Principles of Antibiotic Prophylaxis Preop administration, serum levels adequate throughout procedure with a drug active against expected microorganisms.High Serum LevelsPreop timingIV routeHighest dose of drugDuring ProcedureLong half-lifeLong procedure–redoseLarge blood loss–redoseDurationNone after wound closed24 hours maximumMangram AJ et al. Infect Control Hosp Epidemiol. 1999;20:
20 Surgical Site Infection (SSI) Challenges that make surgical site infections difficult to avoid include resistant pathogens, advanced age, chronic diseases, a state of immunocompromise, prostheses, and transplants.Because patients with these conditions are more susceptible to infection, prophylaxis is necessary.Preventive measures include antimicrobial prophylaxis, proper ventilation of operating rooms, sterilization methods, use of barriers, and proper surgical techniques.These simple steps can help the body defend itself against pathogens.Mangram AJ et al. Infect Control Hosp Epidemiol. 1999;20:
22 National Data Collection State-level baseline description from random sample of 788 cases per stateData collected from records by two professional clinical data abstraction centersAbstraction tool for hospitals is available….Is JCAHO compatible
23 Surgical Infection Prevention Preliminary Results 34,133 (87.3)Cases eligible for analysis205 (0.52)1,817 (4.7)2 (0.01)1,461 (3.74)1,432 (3.66)36 (0.09)General ExclusionsSurgery of interest not performedInfection present pre-operativelyMissing antibiotic dates and timesPatient on antibiotics prior to admissionPatient on antibiotics for more than 24 hours pre-opOther39,086 (100)Number of cases reviewedN (%)
24 Discontinuation of Antibiotics Patients were excluded from the denominator of this performance measure if there was any documentation of an infection during surgery or in the first 48 hours after surgery.
25 Relative Percentage by Site of Infection Most Common Pathogens Associated With Nosocomial Infections (NNIS 1989–1998) Medical & Surgical CombinedRelative Percentage by Site of InfectionPathogen All Sites BSI Pneumonia SSI n=235,758 n=50,091 n=64,056 n=22,043Coag-neg StaphS aureusEnterococci sppP aeruginosaEnterobacter sppE coliC albicansK pneumoniaeOthersExamination of data from the NNIS from 1989 through 1998 documents that Gram-positive organisms are the most common pathogens associated with nosocomial infections in the intensive care unit. This study, which evaluated more than 235,000 isolates in both medical and surgical ICU patients, demonstrated that coagulase-negative Staphylococcus and S aureus were the two most common pathogens isolated from all nosocomial infections. These two organisms also accounted for the majority of bloodstream and surgical site infections in the ICU.BSI=bloodstream infection; SSI=surgical site infection.Fridkin SK et al. Clin Chest Med. 1999;20:
26 Predominance of S aureus in Skin and Skin Structure Infections (SSSIs) SENTRY – US and Canada 2000 10.8%P aeruginosaEnterococci 8.2%E coli %Enterobacter 5.8%Other %MSSA 30.9%MRSA ~15%Klebsiella 5.1%In the SENTRY Antimicrobial Surveillance Program, S aureus was found to be the predominant pathogen in nosocomial SSSIs. MRSA was more prevalent than any other organism, excluding methicillin-susceptible S aureus.S aureus accounted for 45.9% of isolates recovered from SSSIs among hospitalized patients at 24 sites in the United States and 5 sites in Canada between October and December Notably, approximately 30% of S aureus isolates were methicillin (oxacillin)-resistant.Other common pathogens isolated from SSSIs were P aeruginosa (10.8%), Enterococcus spp (8.2%), E coli (7.0%), Enterobacter spp (5.8%), and Klebsiella spp (5.1%). The same rank order of pathogens in SSSIs was observed in both the United States and Canada.N=1,404 isolatesRennie RP et al. Diagn Microbiol Infect Dis. 2003;45:
27 Progression of Methicillin Resistant S aureus – United States 13%57.1%55.3%MRSA was first described in the United Kingdom in MRSA rates were low in US hospitals, reported at < 2% in the 1970s and early 1980s.Examination of the rates of methicillin resistance in S aureus isolates in the United States by the CDC documents that rates have increased steadily over the past decade, with a dramatic 40% increase during the last 5-year historical mean. In 2000, 55.3% of the S aureus isolates associated with a hospital-acquired infection in ICU patients were resistant to methicillin, reflecting a further 31% increase in resistant S aureus isolates during the past year. More recently in 2002, 57.1% of S aureus isolates were MRSA, accounting for an increase of 13% from the previous year.CDC. MMWR. 1997;46: , 635. (1975 data); Lowy FD. N Engl J Med. 1998;339: ( data); CDC. NNIS System Report, January–November (1998 data); CDC. NNIS System Report, January 1990–May 1999, issued June Am J Infect Control. 1999;27: (1999 data); CDC. NNIS System Report, January 1992–June Am J Infect Control. 2001;29: (2000 data); NNIS. CDC. Am J Infect Control. 2003;31:
28 Impact of MRSA on SSI Median Hospital Charges N=479 patients 29,45552,97192,36310,00020,00030,00040,00050,00060,00070,00080,00090,000100,000ControlMSSAMRSAMedian Hospital ChargesN=479 patientsMRSA greater 90-d mortality vs MSSA (adjusted odds ratio, 3.4; 95% CI: 1.5–7.2)MRSA longer LOS after infection (median additional days=5; P<0.001)MRSA associated with greater hospital charges (1.19-fold increase in hospital charges, P=0.03)The graph here shows that MRSA is associated with significantly higher hospital charges, a 1.19-fold increase. The hospital charges for MRSA were $92,363 compared with $52,971 for MSSA. Compared with MSSA, MRSA was associated with a higher 90-day mortality rate and a longer length of stay after infection (an average of 5 additional days).Engemann JJ et al. Clin Infect Dis. 2003;36:
29 Vascular SSI Retrospective review (1993–2000) Leicester Royal Infirmary, United Kingdom172 patients MRSA-positive (4.4% of total)75 infected, 97 colonizedProportion of wound/graft infections caused by MRSA has increased4% in 1994, increased to 63% in 2000All patients with aortic graft infection diedAll patients with infected prosthetic infrainguinal bypass required amputationsIn a retrospective review of vascular surgical site infections from 1993 through 2000 at Leicester Royal Infirmary in the United Kingdom researchers evaluated 172 MRSA-positive patients. Of the 172 patients, 75 were infected and 97 were colonized.The proportion of wound/graft infections caused by MRSA increased from 4% in 1994 to 63% in All the patients with aortic infection died, and all patients with infected prosthetic infrainguinal bypass required amputation.Nasim A et al. Eur J Vasc Endovasc Surg. 2001;22:
30 MRSA in Orthopedic SSI Prospective study, London, United Kingdom 12-month study, January through December 2000Total of 1,879 patients admitted, 121 screened1.6% of total with MRSA infection/colonizationHigher risk for MRSA infectionHip surgeryEmergency surgery for femoral neck fracturePresence of woundMRSA infection – increased hospital LOS (88 vs 11 days)41% of positive patients still carried MRSA on dischargeIn a prospective study conducted in London, United Kingdom between January and December 2000, investigators evaluated MRSA surgical skin infections among orthopedic patients. They found that 1.6% of patients were infected or colonized with MRSA. Patients at highest risk for MRSA had had hip surgery, emergency surgery for femoral neck fracture, or presence of a wound.MRSA infection was associated with a longer length of hospital stay (88 days versus 11 days for patients without MRSA). On discharge, 41% of positive patients still carried the infection.Tai CC et al. Int Orthop. 2004;28:32-35.
31 MRSA in Cardiac Surgery 3,443 CABG patients, all received antimicrobial prophylaxisJune 1997 through December 2000Sternal SSI developed in 122 (3.5%)71 (58.2%) were superficial SSI51 (41.8%) were deep SSIGram-positive cocci were most frequently recovered (81%)S aureus was the most frequently isolated pathogen (49%)S aureus bacteremia occurred in 18% and was significantly associated with deep SSI (P=0.002)From June 1997 through December 2000, 3,443 CABG patients received antimicrobial prophylaxis for MRSA. Sternal surgical site infections developed in 3.5% of these patients; 58.2% were superficial infections and about 42% were deep.Gram-positive cocci were recovered in 81% of the infections, with S aureus the most frequently isolated pathogen (accounting for 49%). S aureus was implicated in most cases and was significantly associated with deep surgical site infections.Need to get this paper to determine the number of MRSA infections – not stated in the abstract.CABG=coronary artery bypass grafting.Sharma M et al. Infect Control Hosp Epidemiol. 2004;25:
32 Impact of MRSA in Cardiac Surgery Retrospective review (41 patients)Poststernotomy S aureus mediastinitisMRSA: 15 patientsMSSA: 26 patientsLogistic regression analysis: MRSA was the only independent risk factor for increased mortality, P=0.04Survival RatesIn a retrospective review of 41 patients with poststernotomy S aureus, MRSA was identified in 15 patients and MSSA in 26 patients. MRSA was found to be an independent risk factor for increased mortality of cardiac surgical patients with poststernotomy S aureus mediastinitis.As is depicted in the graph, MRSA survival rates were significantly lower compared with those for MSSA at 1 month, 1 year, and 3 years.Mekontso-Dessap A et al. Clin Infect Dis. 2001;32:
33 Nasal Mupirocin and SSI Percent of patients with S aureus (%)47.7MupirocinPlaceboP=0.02All postoperative S aureus Infections4,030 patients enrolled, 3,864 ITT patientsPRDBPCT, intranasal mupirocin891 patients (23.1%) had S aureus in anterior nares444 mupirocin,447 placeboS aureus SSI:2.3% mupirocin2.4% placeboA total of 4,030 patients were enrolled in a prospective, randomized, double-blind placebo-controlled trial evaluating intranasal mupirocin for treating S aureus surgical site infection. Of 891 patients who had S aureus in their anterior nares, 444 were given mupirocin and 447 received placebo.The graph shows that 4% of mupirocin-treated patients had S aureus infections compared with 7.7% of placebo patients.ITT=intent-to-treat; PRDBPCT=prospective, randomized, double-blind placebo-controlled trial.Perl TM et al. N Engl J Med. 2002;346:
34 Surgical Wound Management SSI Prophylaxis in MRSA-Colonized Patient Must use same principlesDrug choice differenceMRSA drugsVancomycinQuinupristin/dalfopristin*LinezolidDaptomycinWhen managing an MRSA surgical site infection several important points should be considered and the same principles should be applied in all cases.Consider drug choice differences among MRSA drugs which include vancomycin, Quinupristin/dalfopristin, linezolid, or daptomycin and how this may affect outcome.*Not FDA approved for MRSA.
35 Vancomycin Bactericidal glycopeptide Introduced clinically in 1958 Discovered in 1956Produced by Streptococcus orientalis, an actinomycete isolated from soil samples from Indonesia & IndiaIntroduced clinically in 1958Quickly overshadowed by less toxic anti-staphylococcal penicillins and cephalosporinsRe-emergence as an important antibiotic in 1980s & 1990sVancomycin is a bactericidal glycopeptide that was discovered in The drug is produced by Streptococcus orientalis, which is an actinomycete isolated from soil samples from Indonesia and India.Vancomycin was introduced clinically in 1958, but was quickly overshadowed by less toxic antistaphylococcal penicillins and cephalosporins.But in the 1980s and 1990s, vancomycin re-emerged as an important antibiotic.
36 Historical Yearly Usage of Vancomycin 2001: 1.8 million courses of vancomycin annually in U.S.30 million doses of vancomycin estimatedThis graph shows the historical yearly usage of vancomycin. Estimates are that in million courses and 30 million doses of vancomycin were used in the United States.From the mid-1970s to the early 1980s vancomycin was rarely used. However, by the mid-1990s, vancomycin, especially the injectable form, was used extensively.Kirst HA et al. Antimicrob Agents Chemother. 1998;42: ; NNIS. Am J Infect Control. 2001;29:
37 12 Steps to Prevent Antimicrobial Resistance Among Surgical Patients Step 9. Know when to say “no” to vancoVanco should be used to treat known infections, not for routine prophylaxisTreat staphylococcal infection, not contaminants or colonizationConsider other antimicrobials in treating MRSAThe CDC has developed guidelines to help prevent antimicrobial resistance among surgical patients.The first step is to prevent surgical site infections by monitoring and maintaining normal glucose levels, especially in diabetic patients; maintaining normal body temperature; proper skin preparation using appropriate antiseptic agents and when necessary, hair removal techniques; and thinking outside of the wound in order to prevent surgical site infections.CDC. Available at Accessed July 16, 2004.
38 Vancomycin Tissue Penetration 33 open-heart surgery patients, mean vancomycin concentrations after 15 mg/kg IV doseBelow the mean MICs for many strains of staphylococciThis graph shows vancomycin tissue penetration in the cardiac valve, myocardium, and fat in 33 patients who underwent open-heart surgery. Patients were given 15 mg/kg IV vancomycin, which resulted in less than the mean minimum inhibitory concentration for many strains of staphylococci as depicted in the graph.Cardiac valve tissue showed to have the highest penetration of vancomycin and myocardial tissue had the least amount of penetration.MIC=minimum inhibitory concentration.Daschner FD et al. J Antimicrob Chemother. 1987;19:
39 Vancomycin Penetration CNS: <10%Epithelial lining fluid3: 18%Sternal Bone1: 57% Heart Valve4:12%Lung tissue2: 17%–24%Vancomycin PenetrationThis slide demonstrates vancomycin tissue penetration. As you can see vancomycin penetrates poorly into various types of tissue.Fat4: 14%Muscle4: 9%Bone5: 7%–13%1. Massias L et al. Antimicrob Agents Chemother. 1992;36: ; 2. Cruciani M et al. J Antimicrob Chemother. 1996;38: Lamer C et al. Antimicrob Agents Chemother. 1993;37: ; Daschner FD et al. J Antimicrob Chemother. 1987;19: ; 5. Graziani AL et al. Antimicrob Agents Chemother. 1988;32:
40 Quinupristin/Dalfopristin (Synercid®) Streptogramin class related to macrolide-lincosamidesQuinupristin is a Group B streptograminDalfopristin is a Group A streptograminActivity against:MSSA – potently bactericidalStreptococcus pneumoniae (including PRSP) – potently bactericidalMRSA – moderately activeE faecium – moderately active against most E faecium strainsNO activity against E faecalisQuinupristin/dalfopristin is classified as a streptogramin related to macrolide-lincosamides. Quinupristin is a Group B streptogramin and dalfopristin is a Group A streptogramin.Quinupristin/dalfopristin has activity against MSSA, against which it is potently bactericidal; Streptococcus pneumoniae, including penicillin-resistant Streptococcus pneumoniae; and moderate activity against some strains of MRSA and most Enterococcus faecium strains. The combination is not active against Enterococcus faecalis.PRSP=penicillin-resistant Streptococcus pneumoniae.Synercid® IV (quinupristin/dalfopristin for injection) [package insert]. Bristol, Tenn: Monarch Pharmaceuticals, Inc; 2002.
41 Quinupristin/Dalfopristin (Synercid®) Central line access used to decrease incidence of infusion-related venous irritation3%–30% incidence of severe myalgias and arthralgiasResistance has already been reportedBacteriostaticDoes not have indication for pneumoniaDid not perform as well as vancomycinQuinupristin/dalfopristin must be administered through a central line and has a reported 3% to 30% incidence of severe myalgias and arthralgias. Resistance has been reported with this bacteriostatic agent. Finally, it is not indicated for pneumonia, and did not perform as well as vancomycin.Synercid® IV (quinupristin/dalfopristin for injection) [package insert]. Bristol, Tenn: Monarch Pharmaceuticals, Inc; 2002.
42 Daptomycin (Cubicin™) Lipopeptide natural productActivity in Gram-positive organismsDistinct mechanism of actionRapidly bactericidal in vitro and in vivoNo mechanisms of resistance identifiedNo cross-resistance with other antibioticsSafety profile similar to comparatorsOnce-daily IV dosingDaptomycin is a lipopeptide with activity against Gram-positive organisms. Daptomycin has a distinct mechanism of action and is rapidly bactericidal in vitro and in vivo. No mechanisms of resistance have been identified and there has been no cross-resistance with other antibiotics. Its safety profile is similar to its comparators and the agent is dosed once daily intravenously.Cubicin™ (daptomycin for injection) [prescribing information]. Lexington, MA: Cubist Pharmaceuticals; September 2003.
43 Linezolid (ZYVOX®) An oxazolidinone: a novel antimicrobial class 100% oral bioavailabilityEquivalent dosing oral/IVNo dose adjustment in renal failureBacteriostaticNo cross-resistance with other antibioticsReversible thrombocytopenia with prolonged useBinds selectively to the 50S ribosomal subunitInhibits the formation of a functional initiation complexLinezolid is an antimicrobial that belongs to a novel class known as oxazolidinones. Linezolid is 100% orally bioavailable and has equivalent dosing with both the oral and IV forms. Dose adjustments are not required for patients with renal failure. Linezolid is bacteriostatic with no cross-resistance with other antibiotics and rarely can cause reversible thrombocytopenia with prolonged use.Linezolid binds selectively to the 50S ribosomal subunit where it inhibits the formation of a functional initiation complex.ZYVOX® (linezolid injection, tablets, and oral suspension) [package insert]. Kalamazoo, Mich: Pharmacia & Upjohn, a Pfizer Company; revised June 2004.
44 Average Steady-State Plasma Linezolid Concentrations After Oral Administration of 400 or 600 mg Twice Daily600 mg BID400 mg BIDMIC-90 StaphMIC-90 EnteroMIC-90 StrepLinezolid concentration (μg/mL)This graph shows the average steady-state plasma concentrations of linezolid following oral administration of 400 or 600 mg twice daily.Concentrations were more than the MIC of 4 mcg/mL for as long as 9–10 hours for 400 mg and for more than 15 hours for 600 mg.Time After Last Dose (hours)Linezolid Research Update. Denver, Colo: Infectious Diseases Society of America; November 13, 1998.
45 Linezolid Penetration CNS1: 70%*Epithelial lining fluid4: 450%Saliva2: 120%Alveolar cells4: 15%Linezolid PenetrationBone3: 40%–60%Sweat2: 55%Skin Blister Fluid5: 100%This slide demonstrates the amount of linezolid penetration into various tissues of the body.The most important for surgical patients are bone with 40% to 50% penetration, sweat with 55%, and skin blister fluid with 100%.1. Cottagnound et al. J Antimicrob Chemother. 2000;46: ; 2. ZYVOX® (linezolid injection, tablets, and oral suspension) [package insert]. Kalamazoo, Mich: Pharmacia & Upjohn, a Pfizer Company; revised 2003; 3. Lovering AM et al. J Antimicrob Chemother. 2002, 50:73-77; 4. Conte JE et al. Antimicrob Agents Chemother. 2002;46: ; 5. Gee T. Antimicrob Agents Chemother. 2001;45:
46 Comparison of Tissue Concentrations (% Tissue/Serum) VancomycinLinezolidBone7%–13%160%8Cerebral Spinal Fluid0%–18%2,370%9Epithelial Lining Fluid (Lung)11%–17%4,5450%9Inflammatory Blister Fluid----104%10Muscle~30%694%8Peritoneal dialysis fluid~20%761%11This chart is a comparison of linezolid and vancomycin penetration in various tissues.As you can see, linezolid has a significantly greater penetration into all tissue compartments when compared to vancomycin, with at least 60% penetration in all tissue compartments.1. Graziani AL et al. Antimicrob Agents Chemother. 1988;32: ; 2. Matzke et al. Clin Pharmacokinet. 1986;11: ; 3. Albanese J et al. Antimicrob Agents Chemother. 2000;44: ; 4. Georges H et al. Eur J Clin Microbiol Infect Dis. 1997;16: ; 5. Lamer C et al. Antimicrob Agents Chemother. 1993;37: ; 6. Daschner FD et al. J Antimicrob Chemother. 1987;20: ; 7. Blevins RD et al. Antimicrob Agents Chemother. 1984;25: ; 8. Lovering AM et al. J Antimicrob Chemother. 2002;50:73-77; 9. Conte JE et al. Antimicrob Agents Chemother. 2002;46: ; 10. Gee T et al. Antimicrob Agents Chemother. 2001;45: ; 11. Gendjar SR et al ASN/ISN World Congress of Nephrology; 2001; San Francisco, Calif. Abstract
47 Complicated Skin and Soft Tissue Infection (cSSTI) Treatment Staph most common causeStaph resistance continues to increase57.1% in 2002Treatment for MRSA cSSTI prior to 2000VancomycinQuinupristin/dalfopristin*New alternatives for treatment of MRSA cSSTILinezolidDaptomycinStaphylococcus remains to be the most common cause of complicated skin and soft tissue infections (cSSTIs). Resistance to Staph is on the rise, with resistance reported to be 57.1% in 2002.The treatment for MRSA in cSSTI prior to 2000 consisted of vancomycin or quinupristin/dalfopristin.More recently new alternatives for treatment of MRSA cSSTI have emerged, including linezolid and daptomycin.*Not FDA approved for MRSA.NNIS. CDC. Am J Infect Control. 2003;31:
48 Quinupristin/Dalfopristin† (Q/D) Efficacy Design: 2 randomized, open-label, controlled clinical trials in cSSSIStudy 1: Q/D (7.5 mg/kg q12h IV) vs oxacillin (2 g q6h IV)*Study 2: Q/D (7.5 mg/kg q12h IV) vs cefazolin (1 g q8h IV)*Q/D (n=450)Comparator (n=443)Study 1 (US)49.5%51.9%Study 2 (International)66.4%64.2%Postoperative infections‡14/38 (36.8%)24/42 (57.1%)Traumatic wound infections‡33/55 (60.0%)Efficacy in the Clinically Evaluable Population†A total of 450 patients were enrolled in 2 randomized, open-label, controlled clinical trials of complicated skin and skin structure infections (cSSSIs). Study 1 compared Q/D with oxacillin and Study 2 compared Q/D with cefazolin. For postoperative infections the comparator was more effective than Q/D and for traumatic wound infections Q/D was equally effective. Q/D is not indicated for MRSA infections.*Vancomycin 1 g q12h IV could be substituted if the pathogen was suspected or confirmed methicillin-resistant Staphylococcus or the patient was allergic to penicillin, cephalosporins, or carbapenems. †Patients cured or improved. ‡Results are combined from the 2 clinical trials. Statistical conclusions could not be reached due to the small number of patients in the subsets.†Not FDA approved for MRSA.Synercid® IV (quinupristin/dalfopristin for injection) [package insert]. Bristol, Tenn: Monarch Pharmaceuticals, Inc; 2002.
49 Quinupristin/Dalfopristin† (Q/D) Efficacy Design: 2 randomized, open-label, controlled clinical trials in cSSSISummary of Clinical and Microbiologic Results*Q/D(n=450)Comparator(n=443)Clinical efficacy†68.2%70.7%Microbiologic eradication‡66.6%77.7%MSSA64.3%76.6%MRSA77.8%50.0%Gram-positive cocci only56.3%69.7%This chart provides a summary of the clinical and microbiologic results from 2 randomized, open-label, controlled clinical trials in cSSSI.The comparator was slightly more efficacious in clinical efficacy, microbiologic eradication, MSSA, and Gram-positive cocci, while quinupristin/dalfopristin was more efficacious than the comparator in eradicating MRSA.*Results are combined from the 2 clinical trials. †Patients cured or improved in the clinically evaluable population. ‡Overall and by-pathogen bacteriologic eradication rates in the microbiologically evaluable population.cSSSIs=complicated skin and skin structure infections.Nichols RL et al. J Antimicrob Chemother. 1999;44:†Not FDA approved for MRSA.
50 Linezolid vs Vancomycin for cSSTI Presumed or Known to Be Caused by MRSA Study design: Open-label, randomized, comparator-controlled, multicenter, multinational clinical studyPopulation: 1,200 hospitalized adult patients with cSSTITreatment arms:Linezolid (oral or IV) 600 mg every 12 hoursVancomycin (IV only) 1 g every 12 hoursORIf MSSA, vancomycin could be switched to oxacillin/nafcillin/flucloxacillin (IV only) –2 g q6h or dicloxacillin (oral) 500 mg q6hIn an open-label, randomized, comparator controlled, multicenter, and multinational clinical study, we evaluated 1,200 hospitalized adult patients with cSSTI who were randomized to receive either linezolid (oral or IV) 600 mg every 12 hours or vancomycin (IV only) 1 gram every 12 hours, with doses adjusted to maintain therapeutic levels.Patients with documented methicillin-susceptible S aureus (MSSA) could remain on vancomycin therapy or be switched to oxacillin sodium/nafcillin/flucloxacillin (IV only) 1 to 2 grams every 6 hours or dicloxacillin sodium (oral) 500 mg every 6 hours.Treatment was for 4 to 14 days.4- to 14-day treatment durationWeigelt JA et al. Infectious Diseases Society of America, 2003, poster 314. San Diego, CA.
51 Linezolid vs Vancomycin for cSSTI Clinical Cure Rates in Clinically Evaluable Subset P=0.023Clinical cure rates in the clinically evaluable subset showed a 94% cure rate for linezolid versus 90% for the vancomycin group which was statistically significant (P=0.023)Weigelt JA et al. Infectious Diseases Society of America, 2003, poster 314. San Diego, CA.
52 Linezolid vs Vancomycin for cSSTI Clinical Cure Rates in MRSA Subgroup In cSSTIs caused by MRSA, clinical cure rates were 94% in the linezolid arm and 84% in the vancomycin arm which was statistically significant (P=0.011).126/134112/134Weigelt JA et al. Infectious Diseases Society of America, 2003, poster 314. San Diego, CA.
53 Linezolid Reduces LOS vs Vancomycin in cSSTI due to MRSA Mean LOS (days)Study Sample (linezolid/vancomycin)LinezolidVancomycinP ValueITT (592/588)7.49.8<0.0001CE (491/472)9.9ME (349/334)7.6MRSA (143/146)8.110.70.0026This chart shows that linezolid significantly reduces the length of stay versus vancomycin in cSSTI due to MRSA.The average length of stay for MRSA-infected patients given linezolid was 8.1 days compared with 10.7 days for patients receiving vancomycin.This study confirms that empiric therapy with linezolid in hospitalized patients with cSSTI significantly reduces LOS when compared with vancomycin. These reductions in LOS may result in a reduction of resource utilization and costs.CE=clinically evaluable; ITT=intent-to-treat; LOS=length of stay; ME=microbiologically evaluable.Weigelt JA et al. Infectious Diseases Society of America; 2003, poster San Diego, CA.
54 Linezolid vs Vancomycin for cSSTI IV Antibiotic Treatment Days Duration of IV treatment (days)This graph shows IV antibiotic treatment days of linezolid versus vancomycin in cSSTI. Duration of treatment for linezolid, which is in red, was significantly shorter than for vancomycin. The duration of treatment for linezolid was not more than 2 days, while the duration of treatment for vancomycin was at least 9 days.In the MRSA population, the treatment duration for linezolid was an average of 1.8 days, while the treatment duration for vancomycin averaged 12.6 days.CE=clinically evaluable; ITT=intent-to-treat; ME=microbiologically evaluable; MITT=modified intent-to-treat.Weigelt JA et al. Infectious Diseases Society of America, 2003, poster 315. San Diego, CA.
55 Cost Effectiveness of Linezolid vs Vancomycin in cSSTI $5,187CI (4,691–5,714)$4,143CI (3,750–4,576)COST($)This graph shows that linezolid is more cost effective than vancomycin for managing cSSTI, with linezolid costing $4,143 compared to vancomycin at $5,187.LinezolidVancomycin2003 Per diem hospital cost, administration of IV therapy, wholesale acquisition costFleming T, ed. Red Book edition. Montvale NJ: Thompson PDR;2004.
56 Linezolid vs Vancomycin for Surgical Site Infection (SSI ) Total Patients With cSSTI1,200Total Patients With SSI135Linezolid66Vancomycin69Of the 1,200 patients with complicated skin and soft tissue infections, 135 had surgical site infections. Of these 135 patients, 66 were treated with linezolid while 69 were treated with vancomycin. All demographics and risk factors were equal among the two populations.-Weigelt J et al.: Am J Surg 2004;188:
57 Linezolid vs Vancomycin in SSI Study Population All patients66 (100)69 (100)MRSA34 (52)31 (45)Baseline demographics:No significant differenceBaseline comorbidities/MRSA risk factors:In the study population, 52% of the 66 linezolid patients were MRSA infected, and 44% of the 69 vancomycin patients had MRSA. No significant differences were found in the baseline demographics, co-morbidities, or MRSA risk factors.-Weigelt J et al.: Am J Surg 2004;188:
58 Linezolid vs Vancomycin in SSI: Clinical Cure Rates at TOC P=0.06In cSSTIs caused by MRSA, clinical cure rates were 94% in the linezolid arm and 84% in the vancomycin arm which was statistically significant (P=0.011).-Weigelt J et al.: Am J Surg 2004;188:
59 Linezolid vs Vancomycin in SSI: Microbiological Cure Rates at TOC P=0.007In cSSTIs caused by MRSA, clinical cure rates were 94% in the linezolid arm and 84% in the vancomycin arm which was statistically significant (P=0.011).-Weigelt J et al.: Am J Surg 2004;188:
60 Linezolid vs Vancomycin in SSI: Microbiological Cure Rates at TOC in MRSA Pts. In cSSTIs caused by MRSA, clinical cure rates were 94% in the linezolid arm and 84% in the vancomycin arm which was statistically significant (P=0.011).-Weigelt J et al.: Am J Surg 2004;188:
61 Daptomycin for cSSSIsPhase III: 2 international, multicenter, randomized, double-blind (evaluator blinded) studies (Studies 9801 & 9901):Daptomycin (4 mg/kg IV qd) vs 1 of 2 comparators:Vancomycin (1 g q12h)Synthetic penicillin (4–12 g/d in 4 daily doses)Primary endpoint was safety and efficacyBoth studies demonstrated equivalence of daptomycin to the comparatorTwo international, multicenter, randomized, double-blind (evaluator blinded) phase III studies were conducted to determine the efficacy of daptomycin for complicated skin and skin structure infections.Daptomycin 4 mg/kg IV daily was compared with either vancomycin 1 g every 12 hours or synthetic penicillin 4–12 g in 4 daily doses. The primary endpoint was clinical signs and symptoms.Both studies showed that daptomycin was equivalent to the comparator.Arbeit RD et al. Clin Infect Dis. 2004;38:
62 Daptomycin Efficacy Clinical Success Rate: CE Population Design: 2 randomized, multinational, multicenter investigator-blinded studiesDaptomycin 4 mg/kg IV q24h or vancomycin 1 g IV q12h or a semisynthetic penicillin (nafcillin, oxacillin, cloxacillin, flucloxacillin)Clinical Success Rate: CE PopulationType of InfectionDaptomycinNo. of Pts (Success rate %)Comparator*Wound infection169 (84%)180 (87%)Major abscess102 (92%)92 (88%)Ulcer infection47 (66%)56 (70%)Other infection†47 (79%)58 (83%)This chart shows the efficacy of daptomycin in the different types of infections treated. Daptomycin 4 mg/kg IV every 24 hours was slightly more efficacious for major abscesses than wound, other infections (complicated cellulitis, major abscess, or traumatic wound infection) and ulcer infections, in which the comparator showed to be more efficacious.*Comparator was vancomycin or a semisynthetic penicillin.†Other infections included complicated cellulitis, major abscess, or traumatic wound infection.Arbeit RD et al. Clin Infect Dis. 2004;38:
63 Comparison of MRSA Antimicrobials VancomycinQuinupristin/ DalfopristinDaptomycinLinezolidMultipleFDA approved for MRSAcSSSI (not MRSA)cSSSIcSSSI and pneumoniaParenteralRoute(s)Parenteral (central?)ParenteralParenteral, oralVariable depending upon renal functionDosingq8-12hQDBID“Cheap”Sales pitch“Works when vancomycin won’t”“Faster cure” (rapidly cidal)“Gets patients home”Toxicity, resistance (VRE, VISA, VRSA)DisadvantagesThis chart compares the different antimicrobials used for the treatment of MRSA.Vancomycin IV is FDA approved for MRSA. The dose of vancomycin is variable depending on renal function. But vancomycin is a familiar drug and is known to be “cheap” so it is commonly used. Toxicity and resistance are disadvantages associated with vancomycin.Quinupristin/dalfopristin is approved for cSSSI, but NOT MRSA. Quinupristin/dalfopristin is administered parenterally every 8–12 hours. Disadvantages of the drug include infusion site inflammation, myalgias, arthralgias, and resistance. This agent can be used as an alternative to vancomycin and is known as the drug that “works when vanco won’t.”Daptomycin is FDA approved for cSSSI MRSA. It is administered parenterally once a day. Daptomycin is known to have a “faster cure” because it is rapidly bactericidal. The disadvantages include its limited indication use, acquisition cost, risk of myalgia, and lack of effectiveness for pneumonia. But daptomycin does have the potential for less resistance.Linezolid is FDA approved for MRSA infections associated with cSSSI and pneumonia. This agent can be given as either a parenteral or oral dose twice a day. It is known as the drug that “gets patients home.” The disadvantages of linezolid include unfamiliarity, cost, reversible hematologic abnormalities, and potential for resistance. Advantages of linezolid include an equivalent oral dosing and formulation, early discharge, and evidence of superiority to vancomycin in cSSTIs.Infusion site inflammation, myalgias, arthralgias, and resistanceLimited indications, acquisition cost, myalgia, not effective for pneumoniaUnfamiliarity and cost, reversible hematologic abnormalities, resistance (ie, VRE with prolonged use)FamiliarityAdvantagesAlternative to vancomycinPotential for less resistanceOral dosingremoval of catheters, early discharge, evidence of superiority to vancomycin in cSSTI
64 Summary SSI is a preventable morbidity Gram-positive organisms are the primary pathogensMRSA increasingTreatment alternatives in MRSA SSIs and cSSTIsVancomycinLinezolidDaptomycinQuinupristin/dalfopristin*As a summary, surgical site infections are a preventable. Gram-positive organisms are the primary pathogens, with MRSA rapidly on the rise. This development has lead to treatment alternatives for MRSA surgical site infections and complicated skin and soft tissue infections, including vancomycin, quinupristin/dalfopristin, linezolid, and daptomycin.*Not FDA approved for MRSA.