Treatment Considerations for Common Infections Caused by (or Likely to be Caused by) Gram-Positive Bacteria Infectious Diseases Section, VA Greater Los Angeles Healthcare System February 2013 Outline: I. When vancomycin therapy can be safely de-escalated II. Suitable oral de-escalation options according to underlying syndrome III. In-depth discussion of specific infections: a. Staphylococcus aureus bacteremia b. Skin and soft tissue infection (excluding diabetic foot infection) c. Diabetic foot infection d. Intravascular catheter-associated infection e. Pneumonia I. WHEN VANCOMYCIN THERAPY CAN BE SAFELY DE-ESCALATED: Patients can be safely considered for de-escalation of vancomycin therapy if all of the following criteria are met (NOTE: These criteria are not intended to be a comprehensive list of all situations in which vancomycin can be escalated but rather should serve as a guide to where available literature and national policy clearly suggest that de-escalation from vancomycin therapy is likely to not have untoward consequences): I. II. The patient is identified as low-risk for MRSA infection as defined by: a. Absence of presumed or confirmed infection where MRSA may be present, including serious skin and soft tissue infections (SSTI), prosthetic joint and other orthopedic surgery-related infections, osteomyelitis, septic arthritis, and epidural or visceral abscesses. NOTE: Vancomycin de-escalation and conversion to non-MRSA antimicrobials should be considered for these above infections that are proven to be caused by organisms sensitive to β-lactams such as MSSA. b. Absence of prior MRSA infection or colonization within the past 12 months as indicated by lack of a Clinical Warning note or flag in CPRS. c. Absence of MRSA on all surveillance test results obtained upon admission and during hospitalization. d. Absence of MRSA in all clinical culture(s) obtained upon admission and during the hospitalization. Note that cultures should not be considered negative until at least 4872 hours after specimen collection. NOTE: If cultures are not obtained, clinical judgment, in conjunction with other objective criteria, should be utilized to identity appropriate patients for vancomycin de-escalation. Such judgment may be necessary in cases of diffuse non-culturable cellulitis without underlying induration or fluctuance, thus suggesting a streptococcal etiology of infection, which does not require treatment with vancomycin. The patient exhibits normal vital signs, or has an alternative explanation to Gram-positive infection for abnormal vital signs. a. Normal vital signs are defined as: i. Temperature < 100 degrees Fahrenheit or < 37.8 degrees Celsius ii. Systolic Blood Pressure > 99 mm Hg iii. Heart Rate < 100 beats per minute iv. Respiratory Rate < 20 breaths per minute III. IV. Patient does not have a documented serious infection by a β-lactam resistant CoagulaseNegative Staphylococcus, Enterococcus, Streptococcus pneumoniae, or other organism that warrants treatment with vancomycin. The patient does not require empirical or definitive coverage of Gram-positive organisms in the settting of a documented allergy or adverse reaction to β-lactam antimicrobials. Discussion/Background: Clinical practice guidelines recommend prompt and broad empiric coverage including anti-MRSA therapy for severely ill patients at high risk for MRSA infection [1-4]. The Surviving Sepsis campaign suggests empiric antimicrobial therapy including one or more antimicrobial agents with activity against all likely pathogens for patients with severe sepsis [1]. Initial broad-spectrum antimicrobial therapy is emphasized for critically ill patients as it is associated with decreased morbidity and mortality; however, guidelines also recommend that the antimicrobial regimens be assessed daily to ensure appropriate antimicrobial utilization. Similarly, health care-associated pneumonia (HCAP) and skin and soft tissue infection (SSTI) guidelines call for broad empiric antimicrobial therapy depending on patient-specific risk factors for multi-drug resistant organisms [2,3]. Of note, guidelines recommend de-escalation of empiric MRSA coverage based on clinical improvement and culture results. As a result of widespread adoption of consensus guidelines and use of initial broad empiric antimicrobial coverage in severely ill patients with risk factors for MRSA, vancomycin days of therapy exceeded all other antimicrobials within the VHA from 2006-2010 [5]. Similar high rates of vancomycin utilization outside the VHA as a result of substantial utilization for empiric coverage have also been reported [6]. Increased use of an antimicrobial agent with a narrow therapeutic index, such as vancomycin, is associated with the potential for adverse drug reactions and requires extensive therapeutic drug monitoring. Additionally, MSSA infections treated with β-lactam antimicrobials are associated with better outcomes than those treated with vancomycin [7,8]. Appropriate antimicrobial de-escalation is an essential component of a successful antimicrobial stewardship program. The Infectious Diseases Society of America (IDSA)/Society of Healthcare Epidemiology of America (SHEA) Guidelines for Developing an Institutional Program to Enhance Antimicrobial Stewardship recommend de-escalation of empirical antimicrobial therapy on the basis of culture results and other clinical findings [9]. While de-escalation from empiric vancomycin to a β -lactam antimicrobial is appropriate and strongly recommended once MRSA infection has been ruled out based upon clinical culture results, direction for vancomycin de-escalation in patients without clinical cultures is less clear. Aforementioned consensus guidelines recommend collection of clinical cultures to direct anti-MRSA therapy; however, occasionally clinical cultures are not obtained. Limited data from HCAP suggests that these patients may be deescalated to regimens that do not provide microbial activity against MRSA [10,11]. Assessment of the potential for anti-MRSA therapy de-escalation for patients where clinical cultures were not obtained requires further clinical judgment based upon criteria such as the source of infection, stability of the patient, and risk for MRSA infection. A relatively recent observation suggests that nares surveillance cultures may be used to identify patients at low-risk for clinical MRSA infection and subsequently guide vancomycin de-escalation [12-15]. Harris et al conducted a prospective cohort study of 29,978 non-ICU admissions [12]. Absence of MRSA colonization upon admission in patients at low risk for MRSA infection was associated with a high negative predictive value (NPV) for clinical MRSA infection. Similarly, Jinno et al developed prediction rules to assess clinical risk factors for MRSA infection and the potential need for vancomycin therapy in a single VAMC. The findings indicated a 95.7 % NPV for negative nares surveillance results alone. When negative surveillance results were combined with the absence of other established risk factors for MRSA, the NPV for MRSA infection improved to almost 100% [13]. The estimated potential reduction in vancomycin use depending on which risk models were used to select candidates for empirical vancomycin therapy ranged from 18 -79 %. A smaller study conducted by Stano et al in an ICU population implemented a policy of vancomycin de-escalation based upon a NPV of > 99% for negative MRSA PCR surveillance results [14]. However, it is important to recognize that nares surveillance results may not be as useful in identifying MRSA infection patients presenting with skin and soft tissue infections [13, 15]. A fine balance exists between providing appropriate empiric coverage for severely ill patients and utilizing antimicrobial therapy judiciously. Each patient must be assessed individually with culture results and clinical judgment used to guide de-escalation as appropriate. Benefits of antimicrobial de-escalation include reduction of antimicrobial-associated toxicity, minimization of antimicrobial resistance, and cost savings. References: 1. Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med. 2008;36:296-327. 2. American Thoracic Society Documents: Guidelines for the management of adults with hospitalacquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005;171:388-416. 3. Stevens DL, Bisno AL, Chambers HF, et al. Practice guidelines for the diagnosis and management of skin and soft-tissue infections. Clin Infect Dis. 2005;41:1373-1406. 4. Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis. 2011;52:1-38. 5. Jones M, Huttner B, Mayer JM, Rubin M, Madaras-Kelly K, Samore M. Variation of Inpatient Antibiotic Use in Acute Care Facilities of the Veterans Health Administration between 2005 and 2009. Presented at the Society of Health Care Epidemiology annual meeting. April, 2011. Abstract #377. 6. Pakyz AL, MacDougall C, Oinonen M, Polk RE. Trends in antimicrobial use in US academic health centers: 2002 to 2006. Arch Intern Med. 2008;168(20):2254-2260. 7. Schweizer ML, Furuno JP, Harris AD, et al. Comparative effectiveness of nafcillin or cefazolin versus vancomycin in methicillin-susceptible Staphylococcus aureus bacteremia. BMC Infectious Diseases. 2011;11:279-285. 8. Kim SH, Kim HB, Kim NJ, et al. Outcome of vancomycin treatment in patients with methicillinsusceptible Staphylococcus aureus bacteremia. Antimicrob Agents Chemother. 2008;52(1):192197. 9. Dellit TH, Owens RC, McGowan JE, 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. 2007;44:159-177. 10. Schleuter M, James C, Dominquez A, Tsu L, Seymann G. Practice patterns for antibiotic deescalation in culture-negative healthcare-associated pneumonia. Infection. 2010;38(5):357-362. 11. Labelle AJ, Arnold H, Reichley RM, Micek ST, Kollef MH. A comparison of culture-positive and culture-negative health-care-associated pneumonia. Chest. 2010;137(5):1130-1137. 12. Harris AD, Furuno JP, Roghmann M, et al. Targeted surveillance of methicillin-resistant staphylococcus aureus and its potential use to guide empiric antibiotic therapy. Antimicrob Agents Chemother. 2010;54:3143-3148. 13. Jinno S, Change S, Donskey CJ. A negative nares screen in combination with absence of clinical risk factors can be used to identify patients with very low likelihood of methicillin-resistant Staphylococcus aureus infection in a Veterans Affairs hospital. Am J Infect Control. 2012:1-5. 14. Stano P, Avolio M, Rosa R. An antibiotic care bundle approach based on results of rapid molecular screening for nasal carriage of methicillin-resistant Staphylococcus aureus in the intensive care unit. In vivo.2012;26:469-472. 15. Robicsek A, Suseno M, Beaumont JL, Thomson RB Jr, Peterson LR. Prediction of methicillinresistant Staphylococcus aureus involvement in disease sites by concomitant nasal sampling. J Clin Microbiol. 2008;46:588-592. II. SUITABLE ORAL DE-ESCALATION OPTIONS ACCORDING TO UNDERLYING SYNDROME*: SYNDROME MRSA COVERAGE WARRANTED MRSA COVERAGE NOT WARRANTED Skin and soft tissue infection Doxy/minocycline; TMP-SMX; Cephalexin (suspect MRSA if induration, clindamycin; linezolid** fluctuance, or purulence is present; diffuse cellulitis suggests a streptococcal etiology) Diabetic foot infection Mild to moderate infection: Cephalexin, amoxicillin(suspect MRSA if prior history of Doxy/minocycline or TMP-SMX ± clavulanate infection or colonization with optional anaerobic coverage with MRSA) amoxicillin-clavulanate or metronidazole Pneumonia Linezolid** or doxy/minocycline Doxy/minocycline; (consider continuation of anti+ levofloxacin; clindamycin (for azithromycin; moxifloxacin; MRSA therapy past 3d only in cases lung abscess/empyema) amoxicillin-clavulanate (if where lower respiratory cultures aspiration/abscess/empyema have grown MRSA or MRSA is present) otherwise strongly suspected) *: Please corroborate with antimicrobial susceptibility testing. **: Requires approval of the Infectious Diseases service. III. IN-DEPTH DISCUSSION OF SPECIFIC INFECTIONS: 1. Staphylococcus aureus Bacteremia: As the management of Staphylococcus aureus bacteremia can be complex and can result in serious long-term complications when not managed appropriately, identification of S. aureus from a blood culture will, per hospital policy, prompt automatic consultation from Infectious Diseases. Assessment and initial management Search for focus Other interventions Role of echocardiography S. aureus Treatment guidelines – general principles Over 50% of S. aureus bacteremia is caused by MRSA. Vancomycin is the drug of choice for treatment of MRSA bacteremia; vancomycin troughs should be maintained at 15-20 µg/mL for bloodstream infections. In addition, proper management of S. aureus bacteremia requires removal of infected devices, debridement and abscess drainage. Blood cultures should be repeated every 24 hours until the blood is sterile. Four to six weeks of intravenous antibiotic therapy should be considered for S. aureus bacteremia unless there is convincing evidence that a shorter course of therapy is appropriate. S. aureus bacteremia is most often due to skin/soft tissue infection, which may be trivial or clinically inapparent, infective endocarditis (IE), infected peripheral or central venous catheters (CVC), and/or pneumonia. Persistent S. aureus bacteremia, despite apparently effective treatment, is common; this occurs most often with MRSA, but is occasionally seen with MSSA. Difficult-to-eradicate (DTE) sites of infection include endovascular infection, infected prosthetic devices (including indwelling vascular catheters) and deep tissue infection (bone, muscle and visceral abscess). Persistent bacteremia (defined as positive blood cultures while on effective treatment for >48 hours) suggests either an endovascular infection or infection at another DTE site. DTE sites of infection due to S. aureus often require intravenous antimicrobial therapy for 4-6 weeks. Assessment and initial management of S. aureus bacteremia: The assessment & initial management of patients with documented S. aureus bacteremia should consist of a search for a focus of infection that may either have led to bacteremia, or be a consequence of bacteremia: Evaluate for possible infective endocarditis (EKG to assess for new conduction abnormalities and TTE to assess for vegetations) Infected skin entrance sites/tunnels of vascular catheters (physical exam) Skin/soft tissue infection (physical exam) Bone infection, particularly axial skeleton (CT/MRI, if clinically significant back or neck pain is present) Deep abscesses, including kidney, spleen and psoas muscle (consider abdominal/pelvic CT + IV contrast) Recovery of S. aureus from urine may an important clue (reflecting seeding of the kidneys and urine) to subclinical S. aureus bacteremia, or it may as a consequence of GU tract manipulation with ascending infection. Other interventions: Repeat blood cultures: Obtain 2 sets of follow-up blood cultures every 24 hours until the blood is sterile, beginning with notification by the laboratory of “gram positive cocci in clusters; on “effective” treatment, blood cultures may not become positive until 2-3 days after they were collected. Remove all intravascular catheters that were present around the time of onset of bacteremia. Do NOT change central vascular catheters (CVCs) over a guide wire—select a new site for CVC insertion, if a central catheter is warranted. Role of echocardiography: Transthoracic echocardiography (TTE) versus transesophageal echocardiography (TEE): ALL cases of S. aureus bacteremia should prompt echocardiography to evaluate for endocarditis. TTE may be an appropriate initial evaluation in most patients, but a TTE that is negative for evidence of endocarditis should be used as evidence to shorten intravenous antibiotic therapy to ≤ 14 days only if all of the following criteria are met: o TTE is judged by Cardiology to be of high quality: all valves are clearly visualized o No valvular abnormalities (including valve thickening, bicuspid aortic valve, stenosis or regurgitation greater than “trace”) are noted o Patient has no prior history of endocarditis or intravenous drug use o Patient has no prosthetic heart valves or intracardiac devices (pacemaker, ICD, etc.) o Febrile illness was not present for more than 2 days prior to first blood culture yielding S. aureus o Bacteremia clears within 48 hours of the onset of appropriate antibiotic therapy o Fever resolves within 72 hours of the onset of appropriate antibiotic therapy o There is no evidence for metastatic spread of bacteremia or other clinical reasons to suspect IE TEE is more sensitive than TTE and should be done to evaluate for endocarditis in the following situations: o All cases of S. aureus bacteremia with negative TTE that do not meet all of the “negative” criteria above o To evaluate for myocardial abscess or pathology requiring valve replacement in patients with IE as diagnosed by TTE o Patients with prosthetic valve-associated IE o Absent indications for earlier TEE, test is performed preferably at 5 – 10 days of therapy. [TOP] Treatment of S. aureus bacteremia: general principles: An increase in the relative resistance of MRSA to vancomycin has developed over the past several years and has been particularly noted at GLA; this translates into a need for more aggressive treatment and diagnostic approaches. Proper management of S. aureus bacteremia requires removal of infected devices and debridement or drainage of abscesses. Occasionally, the use of use of agents adjunctive to vancomycin (e.g. rifampin) or use of other agents in place of vancomycin (e.g., daptomycin, ceftaroline, or linezolid) may be considered to clear bacteremia in difficult cases. When MSSA is identified, betalactam therapy is preferred (oxacillin, or cefazolin in patients with non-anaphylactic penicillin allergies). Short course therapy: In RARE cases of MSSA bacteremia, in which there is rapid defervescence (<48h), removal of source of infection, and rapid (<48h) clearance of bacteremia, a 7-10 day treatment course of intravenous antibiotics may be considered. Such short course therapy should be done ONLY in consultation with Infectious Diseases. Intermediate course therapy (i.e. 14 days of intravenous antibiotics): S. aureus bacteremia that clears promptly (i.e., within 24 – 48 hours) with institution of treatment can be treated for 14 days of intravenous antibiotics if all the following conditions are satisfied: No metastatic foci of infection are present (e.g. multiple nodular-cavitating pulmonary lesions, splenic abscess, etc.) No other evidence of endocarditis is present with negative echocardiography as above Low risk for endocarditis or other site of endovascular infection, including absence of prosthetic intravascular materials [e.g., prosthetic valve, pacemaker, ICD, arteriovenous dialysis graft or femoral-popliteal bypass graft] and absence of purulent phlebitis at the site of a recently removed central venous catheter No recent implantation of intravascular stents, prosthetic joint or other significant surgical hardware A primary removable focus of infection (e.g., infected vascular catheter, abscess) has been identified and removed or debrided Febrile illness was not present for more than 2 days prior to first blood culture yielding S. aureus, and Fever has resolved within 72 hours of the onset of appropriate antibiotic therapy. Failure to satisfy all of these conditions indicates the need for more prolonged parenteral therapy (i.e., 4 weeks or more). Longer course therapy (i.e. 4-6 weeks of intravenous antibiotics) Persistent bacteremia (positive blood cultures for >48 hours on effective therapy) is suggestive of endovascular infection and warrants treatment for at least 4 weeks and an aggressive workup for potential occult source of bacteremia. Longer therapy may be warranted if there is metastatic infection [TOP] 2. Skin and Soft Tissue Infection (Cellulitis and Complicated Soft Tissue Infection) NOTE: Diabetic foot infection is addressed separately in the next section. General statements: If the patient is febrile, obtain two sets of blood cultures Obtain wound culture of drainage or purulence to determine if MRSA is present and tailor therapy accordingly. If isolated, S. aureus (MSSA or MRSA) almost always requires therapy Treatment of gram negative and anaerobic pathogens is most important in the setting of devitalized, necrotic or ischemic tissues Cefazolin should replace vancomycin if MRSA is not recovered from purulent wound drainage Fluoroquinolones have very little activity against MRSA isolates at the VA Greater Los Angeles Healthcare System Beta-lactam antibiotics are uniformly active against beta-hemolytic streptococci and inactive against MRSA (with the exception of ceftaroline) Doxycycline (100mg po bid) and trimethoprim-sulfamethoxazole (typically 1 DS tab bid) have very good activity against mild-moderate infections caused by MRSA that are suitable for oral therapy, but do not cover beta-hemolytic streptococci well. Clindamycin (300mg po tid) provides excellent activity against beta-hemolytic streptococci, but is effective against only about 80% of MRSA at GLA. Diffuse cellulitis without underlying fluctuance, induration, or abscess is typically caused by beta-hemolytic streptococci and can be treated with beta-lactam therapy if clinically stable. [TOP] 3. Diabetic Foot Infection Diabetic foot infection should be classified upon presentation as mild, moderate, or severe, with corresponding considerations for treatment, as follows: Mild infection: Mild diabetic foot infection is defined as local infection involving only the skin and the subcutaneous tissue (without involvement of deeper tissues and WITHOUT signs of systemic inflammatory response, including temperature > 38° C or < 36°C, heart rate > 90/min, respiratory rate > 20/min or PaCO2 < 32 mm Hg, and WBC > 12,000 or < 4000 cells/uL or ≥ 10% immature (band) forms). Mild diabetic foot infection is typically be treated with oral agents, with inclusion of MRSA coverage if the patient has a current or recent wound culture positive for MRSA (deep wound cultures are preferable to superficial cultures). Options include amoxicillin-clavulanate 875mg po bid or cephalexin 500mg po qid x 10-14d if no MRSA coverage is warranted, or doxycycline 100mg po bid, TMP-SMX 1 DS tab po bid, or clindamycin 300mg po tid x 10-14d can be considered. Moderate infection: Moderate diabetic foot infection is defined as local infection involving the skin and subcutaneous tissue with erythema > 2 cm, or involving deeper structures (e.g. abscess, osteomyelitis, septic arthritis, fasciitis) AND WITHOUT signs of systemic inflammatory response, including temperature > 38° C or < 36°C, heart rate > 90/min, respiratory rate > 20/min or PaCO2 < 32 mm Hg, and WBC > 12,000 or < 4000 cells/uL or ≥ 10% immature (band) forms). Ongoing moderate diabetic foot infection may be treated with initial intravenous antimicrobial therapy with rapid transition to oral agents, depending on whether the patient has had resolution of local signs of infection (i.e. erythema, warmth, tenderness, pain, and induration). Duration of treatment will depend on whether or not osteomyelitis is present. MRSA coverage is indicated if the patient has a current or recent wound culture positive for MRSA (deep wound cultures are preferable to superficial cultures). Consider podiatry consultation for assistance in surgical management and/or debridement and infectious diseases consultation for advice regarding antimicrobial management. Severe infection: Severe diabetic foot infection is defined as local infection involving the skin and subcutaneous tissue and/or involving deeper structures (e.g. abscess, osteomyelitis, septic arthritis, fasciitis) WITH signs of systemic inflammatory response, including temperature > 38° C or < 36°C, heart rate > 90/min, respiratory rate > 20/min or PaCO2 < 32 mm Hg, and WBC > 12,000 or < 4000 cells/uL or ≥ 10% immature (band) forms). Severe diabetic foot infection should be treated empirically with vancomycin PLUS broad-spectrum therapy targeting Gram-negative organisms and anaerobes pending the results of wound cultures (deep wound cultures are preferable to superficial cultures). At GLA, empiric therapy with vancomycin plus ertapenem is recommended except in patients with necrotizing fasciitis where vancomycin plus piperacillin/tazobactam is preferred. Podiatry consultation for assistance in surgical management and/or debridement and infectious diseases consultation for advice regarding antimicrobial management are highly recommended. [TOP] 4. Intravascular catheter-associated infection The primary consideration in the management of catheter-associated infection is to define the extent and type of infection, using the following guide: Phlebitis: Induration or erythema, warmth, and pain or tenderness around catheter exit site Exit site infection: o Microbiologic definition: Exudate at catheter exit site yields a microorganism with or without concomitant bloodstream infection o Clinical definition: Erythema, induration, and/or tenderness within 2cm of the catheter exit site; may be associated with other signs and symptoms of infection, such as fever or pus emerging from the exit site, with or without concomitant bloodstream infection Tunnel infection: Tenderness, erythema, and/or induration >2cm from the catheter exit site, along the subcutaneous tract of a tunneled catheter, with or without concomitant bloodstream infection Pocket infection: Infected fluid in the subcutaneous pocket of a totally implanted intravascular device; often associated with tenderness, erythema, and/or induration over the pocket; spontaneous rupture and drainage, or necrosis of the overlying skin, with or without concomitant bloodstream infection, may also occur Catheter-related bloodstream infection (CRBSI): Bacteremia or fungemia in a patient who has an intravascular device and ≥1 positive result of culture of blood samples obtained from the peripheral vein, clinical manifestations of infection (e.g. fever, chills, and/or hypotension), and no apparent other source for bloodstream infection. The following algorithms for the management of CRBSI associated with removable versus tunneled central venous catheters are from the IDSA guidelines on the management of intravascular catheterrelated infections: [TOP] 5. Pneumonia Anti-MRSA therapy is typically not necessary for most cases of community-acquired pneumonia. IDSA guidelines recommend inclusion of antimicrobial therapy directed against MRSA for severe communityacquired pneumonia, as defined by a) requirement for ICU admission, b) necrotizing or cavitary infiltrates, or c) empyema, pending sputum and/or blood culture results. The role of anti-MRSA therapy in the management of healthcare-associated pneumonia (HCAP), hospital-associated pneumonia (HAP), or ventilator-associated pneumonia (VAP) is more controversial. At GLA, due to our relatively low rates of true HCAP/HAP/VAP caused by MRSA, we only recommend empiric addition of anti-MRSA therapy for HCAP/HAP/VAP requiring ICU admission, with discontinuation of anti-MRSA therapy if lower respiratory cultures are negative for MRSA. [TOP]