Antimicrobial Salvage Therapy for Persistent Staphylococcal Bacteremia Using Daptomycin Plus Ceftaroline

Purpose

Guidelines recommend daptomycin combination therapy as an option for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia after vancomycin failure. Recent data suggest that combining daptomycin with a β-lactam may have unique benefits; however, there are very limited clinical data regarding the use of ceftaroline with daptomycin.

Methods

All 26 cases from the 10 medical centers in which ceftaroline plus daptomycin was used for treatment of documented refractory staphylococcal bacteremia from March 2011 to November 2012 were included. In vitro (synergy studies, binding assays, cathelicidin LL-37 killing assays), and in vivo (virulence assays using a murine subcutaneous infection model) studies examining the effects of ceftaroline with daptomycin were also performed.

Findings

Daptomycin plus ceftaroline was used in 26 cases of staphylococcal bacteremia (20 MRSA, 2 vancomycin-intermediate S aureus, 2 methicillin-susceptible S aureus [MSSA], 2 methicillin-resistant S epidermidis). Bacteremia persisted for a median of 10 days (range, 3–23 days) on previous antimicrobial therapy. After daptomycin plus ceftaroline was started, the median time to bacteremia clearance was 2 days (range, 1–6 days). In vitro studies showed ceftaroline synergy against MRSA and enhanced MRSA killing by cathelicidin LL-37 and neutrophils. Ceftaroline also induced daptomycin binding in MSSA and MRSA to a comparable degree as nafcillin. MRSA grown in subinhibitory concentrations of ceftaroline showed attenuated virulence in a murine subcutaneous infection model.

Implications

Ceftaroline plus daptomycin may be an option to hasten clearance of refractory staphylococcal bacteremia. Ceftaroline offers dual benefit via synergy with both daptomycin and sensitization to innate host defense peptide cathelicidin LL37, which could attenuate virulence of the pathogen.     

Vancomycin and Piperacillin-Tazobactam Against Methicillin-Resistant Staphylococcus aureus and Vancomycin-Intermediate Staphylococcus aureus in an In Vitro Pharmacokinetic/Pharmacodynamic Model

Purpose

Synergy between β-lactams and vancomycin against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-intermediate Staphylococcus aureus (VISA) has been observed in vitro and in vivo. However, studies investigating piperacillin-tazobactam with vancomycin against MRSA and VISA are limited despite broad clinical use of these antibiotics in combination. This study evaluated vancomycin and piperacillin-tazobactam against MRSA and VISA by using an in vitro pharmacokinetic/pharmacodynamic model.

Methods

Two clinical MRSA strains (M3425 and M494) and one VISA strain (Mu50) were tested in duplicate by using a 72-hour, 1-compartment pharmacokinetic/pharmacodynamic model with the following exposures: growth control, vancomycin only, piperacillin-tazobactam only, and vancomycin with piperacillin-tazobactam. Vancomycin 1 g every 12 hours (free trough concentration, 8.75 mg/L; C_min, 17.5 mg/L) and piperacillin-tazobactam 13.5 g per 24 hours’ continuous infusion (free steady-state concentration, 27 mg/L) were simulated. Time–kill curves were constructed, and reductions in log₁₀ CFU/mL at all time points were compared between regimens tested.

Findings

Vancomycin and piperacillin-tazobactam MICs for M494, M3425, and Mu50 were 1, 1, and 4 and 1.5, 32, and >256 mg/L, respectively. All isolates had an oxacillin MIC ≥4 mg/L. Against all 3 isolates, vancomycin with piperacillin-tazobactam achieved a significant reduction in inoculum at 72 hours compared with vancomycin alone (all, P ≤ 0.015). The superiority of vancomycin with piperacillin-tazobactam compared with vancomycin alone became detectable at 8 hours for M3425 (P < 0.001) and at 24 hours for M494 and Mu50 (both, P ≤ 0.008). Although vancomycin with piperacillin-tazobactam achieved enhanced antibacterial activity at 72 hours against M3425 compared with vancomycin alone, bacterial regrowth occurred. Reduced susceptibility to vancomycin at 72 hours for M3425 was confirmed by using population analysis profile/AUC analysis. At 72 hours, M3425 had a PAP/AUC ratio of 0.77 compared to 0.51 at baseline.

Implications

Vancomycin with piperacillin-tazobactam demonstrated enhanced antimicrobial activity against MRSA and VISA compared with vancomycin alone. These results further enhance existing data that support using vancomycin in combination with a β-lactam for invasive MRSA infections. Combination therapy with vancomycin and a β-lactam against MRSA warrants clinical consideration.     

Effectiveness of the antibiotic lock therapy for the treatment of port-related enterococci,Gram-negative,or Gram-positive bacilli bloodstream infections

Objective

The purpose of this study is to evaluate the efficacy of antibiotic lock therapy to treat port-related enterococci, Gram-negative, or Gram-positive bacilli bloodstream infections.

Patients and Methods

We conducted a prospective observational study including all patients with port-related bacteremia diagnosed at the Clinica Universitaria de Navarra, Pamplona, Spain. During a 36-month period, 110 patients were diagnosed with port-related bacteremia. Of these patients, 18 met criteria to be enrolled in the study. They were treated with a combination of systemic and antibiotic lock therapy (12–24 h/day during 7–14 days). Treatment effectiveness was assessed by clinical and microbiologic criteria.

Results

Treatment was associated with clinical and microbiologic success in 88.8% of our patients (2/2 of the Propionibacterium acnes, 5/5 of the Corynebacterium spp., 6/7 of the Gram-negative bacillus, and 3/4 of the Enterococcus faecium port-related bloodstream infections). Mean increase of port life span for all patients after bacteremia was 288 days (range, 0–1403 days).

Conclusion

Antibiotic lock therapy combined with systemic antibiotics appears to be a safe and effective treatment of port-related bacteremia caused by enterococci, Gram-negative, or Gram-positive bacilli if the patient is stable and no septic syndrome is associated.     

Primary sternal osteomyelitis with bacteremia and distal seeding

Background

Primary sternal osteomyelitis is a rare disease, whereas secondary sternal osteomyelitis is relatively well known as a complication in post-sternotomy patients.

Objective

Describe a case of primary Staphylococcus aureus sternal osteomyelitis in an immunocompetent man and its diagnostic challenges, treatment, and complications.

Case Report

A 46-year-old man presented with prolonged sternal pain and swelling, fatigue, and fever. He is diagnosed with primary sternal osteomyelitis with concurrent bacteremia and complicated by local and distant abscess formation. The diagnosis was aided by computed tomography, and treatment consisted of incision and drainage and long-term antibiotics.

Conclusion

Primary sternal osteomyelitis is uncommon and often difficult to diagnose. Complications include abscess formation and distal seeding. Diagnosis can be aided by a detailed history and radiography, and treatment may consist of a prolonged course of antibiotics and incision and drainage.     

Combination Therapy With Vancomycin and Ceftaroline for Refractory Methicillin-resistant Staphylococcus aureus Bacteremia: A Case Series

Purpose

Although vancomycin has been the mainstay of therapy for methicillin-resistant Staphylococcus aureus (MRSA) infections, its effectiveness has been challenged. Combination therapy may be used for patients with persistent MRSA bacteremia refractory to initial therapy. Studies have reported in vitro synergy between vancomycin and ceftaroline; however, clinical experience with this therapy is limited. Here, we report our experience with 5 cases of vancomycin-refractory MRSA bacteremia treated with the combination of vancomycin and ceftaroline.

Acute Bacterial Skin Infections: Developments Since the 2005 Infectious Diseases Society of America (IDSA) Guidelines

Background

Patients with acute bacterial skin and skin structure infections (ABSSSI) commonly present to Emergency Departments (EDs) where physicians encounter a wide spectrum of disease severity. The prevalence of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) has increased in the past decade, and CA-MRSA is now a predominant cause of purulent ABSSSI in the United States (US).

Objectives

This article reviews significant developments since the most recent Infectious Diseases Society of America (IDSA) guidelines for the management of ABSSSI in the CA-MRSA era, focusing on recent studies and recommendations for managing CA-MRSA, newer antimicrobials with improved MRSA activity, new diagnostic technologies, and options for outpatient parenteral antimicrobial therapy (OPAT).

Discussion

The increasing prevalence of CA-MRSA has led the IDSA and other organizations to recommend empiric coverage of CA-MRSA for purulent ABSSSI. The availability of rapid MRSA detection assays from skin and soft tissue swabs could potentially facilitate earlier selection of targeted antimicrobial therapy. Several newer intravenous antibiotics with expanded MRSA coverage, including ceftaroline fosamil, daptomycin, linezolid, and telavancin, may be utilized for treatment of ABSSSI. OPAT may be an option for intravenous administration of antibiotics in selected patients and may prevent or shorten hospitalizations, decrease readmission rates, and reduce nosocomial infections and complications.

Conclusion

The growing prevalence of CA-MRSA associated with ABSSSI in the US has a significant impact on clinical management decisions in the ED. Recent availability of new diagnostic testing and therapeutic options may help meet the demand for effective antistaphylococcal agents.     

Addition of Gentamicin or Rifampin Does Not Enhance the Effectiveness of Daptomycin in Treatment of Experimental Endocarditis Due to Methicillin-Resistant Staphylococcus aureus

This study evaluated the activity of daptomycin combined with either gentamicin or rifampin against three methicillin-resistant Staphylococcus aureus (MRSA) clinical isolates in vitro and one isolate in vivo against a representative strain (MRSA-572). Time-kill experiments showed that daptomycin was bactericidal against these strains at concentrations over the MIC. Daptomycin at sub-MIC concentrations plus gentamicin at 1× and 2× the MIC yielded synergy, while the addition of rifampin at 2 to 4 μg/ml resulted in indifference (two strains) or antagonism (one strain). The in vivo activity of daptomycin (6 mg/kg of body weight once a day) was evaluated ± gentamicin (1 mg/kg intravenously [i.v.] every 8 h [q8h]) or rifampin (300 mg i.v. q8h) in a rabbit model of infective endocarditis by simulating human pharmacokinetics. Daptomycin plus gentamicin (median, 0 [interquartile range, 0 to 2] log₁₀ CFU/g vegetation) was as effective as daptomycin alone (0 [0 to 2] log₁₀ CFU/g vegetation) in reducing the density of bacteria in valve vegetations (P = 0.83), and both were more effective than daptomycin plus rifampin (3 [2 to 3.5] log₁₀ CFU/g vegetation; P < 0.05) for the strain studied. In addition, daptomycin sterilized a ratio of vegetations that was similar to that of daptomycin plus gentamicin (10/15 [67%] versus 9/15 [60%]; P = 0.7), and both regimens did so more than daptomycin plus rifampin (3/15 [20%]; P = 0.01 and P = 0.02, respectively). No statistical difference was noted between daptomycin plus gentamicin and daptomycin alone for MRSA treatment. In the combination arm, all isolates from vegetations remained susceptible to daptomycin, gentamicin, and rifampin. Sixty-one percent of the isolates (8/13) acquired resistance to rifampin during monotherapy. In the daptomycin arm, resistance was detected in only one case, in which the daptomycin MIC rose to 2 μg/ml among the recovered bacteria. In conclusion, the addition of gentamicin or rifampin does not enhance the effectiveness of daptomycin in the treatment of experimental endocarditis due to MRSA.Staphylococcus aureus is a common cause of infective endocarditis (IE), with methicillin-resistant S. aureus (MRSA) strains found in up to one-third of all cases (11, 28). Due to multidrug resistance among many strains, vancomycin is the standard therapy for IE caused by MRSA (1). However, vancomycin therapy has been associated with poor outcomes that may be explained by the drug''s slow bactericidal activity and insufficient diffusion into valve vegetations (5, 10, 23).Daptomycin is a cyclic lipopeptide that is rapidly bactericidal against gram-positive pathogens such as MRSA, including strains that exhibit resistance to vancomycin. It is approved for the treatment of skin and soft tissue infections, S. aureus bacteremia, and right-sided native valve endocarditis (6). However, there is limited information regarding the efficacy of daptomycin in the treatment of left-sided native valve IE caused by MRSA. In a randomized clinical trial (10), none of the patients with left-sided endocarditis treated with daptomycin at 6 mg/kg of body weight/day were cured, and postmarketing registry data (24) revealed a successful clinical outcome in only 9 out of 15 cases (60%). Therefore, given the lack of efficacy data with daptomycin monotherapy in left-sided MRSA endocarditis, the continued evaluation of methods to enhance the activity of daptomycin is warranted. It is unknown whether daptomycin''s activity against MRSA may be improved by combining it with one or more additional antibiotics to produce a potentially additive or synergistic effect. Gentamicin has been shown to augment daptomycin''s activity against strains of MRSA in vitro (4, 20, 35). The combination of daptomycin plus rifampin has demonstrated additive activity against MRSA in vitro (4) and has enhanced activity against MRSA in vivo (4, 32). The aim of this study was to evaluate the in vitro activity of daptomycin combined with gentamicin or rifampin against MRSA and compare treatment with daptomycin alone to treatment with both combinations in experimental MRSA aortic valve endocarditis using a human-adapted pharmacokinetic model.(This work was previously presented at the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy [ICAAC], Chicago, IL, 17 to 20 September 2007 [29a] and at the 48th Annual ICAAC-IDSA Annual Meeting, Washington, DC, 25 to 28 October 2008 [29b].)     

Predictors of Clinical Success Among a National Veterans Affairs Cohort With Methicillin-Resistant Staphylococcus aureus Pneumonia

Background

The treatment of methicillin-resistant Staphylococcus aureus (MRSA) pneumonia is exceedingly complicated, which is concerning because of the high mortality rate associated with the infection. Identification of independent predictors of clinical success can optimize patient care by assisting clinicians in treatment decisions.

Objectives

Our goal was to identify independent predictors of clinical success in a national Veterans Affairs (VA) cohort of patients with MRSA pneumonia.

Methods

A nested case-control study was conducted among a cohort of VA patients with MRSA pneumonia receiving linezolid or vancomycin between January 2002 and September 2010. Cases included those demonstrating clinical success, defined as discharge from the hospital or intensive care unit by day 14 after treatment initiation, in the absence of death, therapy change, or intubation by day 14. Control subjects represented nonsuccess, defined as therapy change, intubation, intensive care unit admission, readmission, or death between treatment initiation and day 14. The potential predictors assessed included treatment, patient demographic and admission characteristics, previous health care and medication exposures, comorbidities, and medical history. Odds ratios (ORs) and 95% CIs were calculated from logistic regression.

Results

Our study included 2442 cases of clinical success and 1290 control subjects. Demographic characteristics varied between the clinical success and nonsuccess groups, including age, race, and region of facility. A current diagnosis of chronic respiratory disease (46% vs 42%) and diagnosis of pneumonia in the year before the MRSA pneumonia admission (37% vs 32%) were both more common in the clinical success group. Despite these significant differences, only 2 predictors of clinical success were identified in our study: previous complication of an implant or graft, including mechanical complications and infections, in the year before the MRSA pneumonia admission (adjusted OR, 1.55 [95% CI, 1.17–2.06]) and treatment with linezolid (adjusted OR, 1.53 [95% CI, 1.12–2.10]). Predictors of nonsuccess (adjusted OR [95% CI) included diagnosis of concomitant urinary tract infection (0.82 [0.70–0.96]), intravenous line (0.76 [0.66–0.89]), previous coagulopathy (0.74 [0.56–0.96]), previous amputation procedure (0.72 [0.53–0.98]), current coagulopathy diagnosis (0.71 [0.53–0.96]), dialysis (0.54 [0.38–0.76]), multiple inpatient procedures (0.53 [0.45–0.62]), inpatient surgery (0.48 [0.41–0.57]), and previous endocarditis (0.24 [0.07–0.81]).

Conclusions

MRSA pneumonia tends to affect patients with complex care, and identification of the predictors of clinical success is useful when considering different therapeutic approaches. In this national cohort of VA patients with MRSA pneumonia, treatment was the only modifiable variable predicting clinical success.     

Efficacy of Daptomycin in Implant-Associated Infection Due to Methicillin-Resistant Staphylococcus aureus: Importance of Combination with Rifampin

Limited treatment options are available for implant-associated infections caused by methicillin (meticillin)-resistant Staphylococcus aureus (MRSA). We compared the activity of daptomycin (alone and with rifampin [rifampicin]) with the activities of other antimicrobial regimens against MRSA ATCC 43300 in the guinea pig foreign-body infection model. The daptomycin MIC and the minimum bactericidal concentration in logarithmic phase and stationary growth phase of MRSA were 0.625, 0.625, and 20 μg/ml, respectively. In time-kill studies, daptomycin showed rapid and concentration-dependent killing of MRSA in stationary growth phase. At concentrations above 20 μg/ml, daptomycin reduced the counts by >3 log₁₀ CFU/ml in 2 to 4 h. In sterile cage fluid, daptomycin peak concentrations of 23.1, 46.3, and 53.7 μg/ml were reached 4 to 6 h after the administration of single intraperitoneal doses of 20, 30, and 40 mg/kg of body weight, respectively. In treatment studies, daptomycin alone reduced the planktonic MRSA counts by 0.3 log₁₀ CFU/ml, whereas in combination with rifampin, a reduction in the counts of >6 log₁₀ CFU/ml was observed. Vancomycin and daptomycin (at both doses) were unable to cure any cage-associated infection when they were given as monotherapy, whereas rifampin alone cured the infections in 33% of the cages. In combination with rifampin, daptomycin showed cure rates of 25% (at 20 mg/kg) and 67% (at 30 mg/kg), vancomycin showed a cure rate of 8%, linezolid showed a cure rate of 0%, and levofloxacin showed a cure rate of 58%. In addition, daptomycin at a high dose (30 mg/kg) completely prevented the emergence of rifampin resistance in planktonic and adherent MRSA cells. Daptomycin at a high dose, corresponding to 6 mg/kg in humans, in combination with rifampin showed the highest activity against planktonic and adherent MRSA. Daptomycin plus rifampin is a promising treatment option for implant-associated MRSA infections.Implants are increasingly used in modern medicine to replace a compromised biological function or missing anatomical structure. Periprosthetic infections represent a devastating complication, causing high rates of morbidity and consuming considerable health care resources. Implant-associated infections are caused by microorganisms growing adherent to the device surface and embedded in an extracellular polymeric matrix, a complex three-dimensional structure called a microbial biofilm (8). Bacterial communities in biofilms cause persistent infection due to increased resistance to antibiotics and the immune system and the difficulty with eradicating them from the implant (6).Staphylococcus aureus is one of the leading pathogens causing implant-associated infections. Successful treatment requires the use of bactericidal drugs acting on surface-adhering microorganisms, which predominantly exist in the stationary growth phase. Previous in vitro, experimental, and clinical studies demonstrated that rifampin (rifampicin)-containing antimicrobial regimens were able to eradicate staphylococcal biofilms and cure implant-associated infections (23, 25). Quinolones are often used in combination with rifampin in order to prevent the emergence of rifampin resistance (4, 19, 21). However, methicillin (meticillin)-resistant S. aureus (MRSA) strains are often resistant to quinolones. In addition, MRSA strains were recently shown to have decreased susceptibility to vancomycin, reducing the efficacy of this drug. Therefore, alternative drugs for use in combination with rifampin against implant-associated infections are needed (12, 20).Daptomycin is a negatively charged cyclic lipopeptide with bactericidal activity against gram-positive organisms, including MRSA (17). The drug inserts into the bacterial cytoplasmic membrane in a calcium-dependent fashion, leading to rapid cell death without lysis, and causing only minimal inflammation (15). Daptomycin has been well tolerated in healthy volunteers dosed with up to 12 mg/kg of body weight intravenously for 14 days (2). Only limited data on the use of daptomycin in combination with rifampin against staphylococcal implant-associated infections are available.In this study, we investigated the activity of daptomycin against MRSA ATCC 43300 in vitro. In addition, we evaluated the activity of daptomycin in combination with rifampin in a cage-associated infection model in guinea pigs and compared the efficacy of the treatment with the efficacies of three other antibiotics commonly used against MRSA, vancomycin, linezolid, and levofloxacin (alone and in combination with rifampin).(Part of the results of the present study were presented at the 48th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, DC, 24 to 29 October 2008 [abstr. B-1000].)     

Short Versus Long Course of Antibiotics for Catheter-Associated Urinary Tract Infections in Patients With Spinal Cord Injury: A Randomized Controlled Noninferiority Trial

Objective

To assess the applicability of a short-course regimen of antibiotics for managing catheter-associated urinary tract infection (CA-UTI) in patients with spinal cord injury (SCI).

Design

Randomized, controlled, noninferiority trial.

Setting

Medical center.

Participants

Patients with SCI who had CA-UTI (N=61).

Interventions

Patients were randomized to receive either a 5-day regimen of antibiotics after catheter exchange (experimental group) or a 10-day regimen of antibiotics with catheter retention (control group). Noninferiority was prespecified with a margin of 10%.

Main Outcome Measure

Clinical cure at the end of therapy.

Results

Of the 61 patients enrolled in this study, 6 patients were excluded because of bacteremia or absence of urinary symptoms. All patients (100%) achieved clinical cure at the end of therapy. The rates of microbiologic response were 82.1% in the experimental group and 88.9% in the control group (upper boundary 95% confidence interval (CI) for difference, 26%). The rates of resolution of pyuria were 89.3% in the experimental group and 88.9% in the control group (upper boundary 95% CI for difference, 16%). Patients in the experimental group had higher rates of CA-UTI recurrence than the control group. The rates of new CA-UTI, diarrhea, and Clostridium difficile colitis were similar in the 2 treatment arms.

Conclusions

The primary endpoint of the study was met, indicating that the 5-day regimen with catheter exchange was noninferior to the 10-day regimen with catheter retention on the basis of clinical cure. Criteria for noninferiority on the basis of microbiologic response and resolution of pyuria were not met.     

Activities of Daptomycin and Vancomycin Alone and in Combination with Rifampin and Gentamicin against Biofilm-Forming Methicillin-Resistant Staphylococcus aureus Isolates in an Experimental Model of Endocarditis

The findings of clinical and in vitro research support the theory that infective endocarditis (IE)-causing bacteria form biofilms and that biofilms negatively affect treatment outcomes. The purpose of the present study was to quantify the biofilm formation of methicillin (meticillin)-resistant Staphylococcus aureus (MRSA) isolates obtained from patients with IE and to evaluate the in vitro activities of daptomycin and vancomycin alone and in combination with rifampin (rifampicin) or gentamicin while monitoring the isolates for the development of resistance. A high-inoculum, stationary-phase infection model of IE was used to simulate the pharmacokinetics in humans of daptomycin at 6 mg/kg of body weight/day, vancomycin at 1.25 g every 12 h (q12h) alone and in combination with rifampin at 300 mg every 8 h, and gentamicin at 1.3 mg/kg q12h. Two randomly selected clinical MRSA isolates were obtained from patients with IE; both MRSA isolates quantitatively produced biofilms. The time to bactericidal activity in the presence of daptomycin was isolate dependent but was achieved by 24 h for both MRSA isolates. Vancomycin did not achieve bactericidal activity throughout the experiment. At 24, 48, and 72 h, daptomycin-containing regimens had significantly more activity (greater declines in the mean number of CFU/g) than any of the vancomycin-containing regimens (P = 0.03). Rifampin and gentamicin antagonized or delayed the bactericidal activity of daptomycin (against MRSA B346846 for rifampin and against both isolates for gentamicin) in the first 24 h. Increases in the daptomycin and vancomycin MICs were not observed. We conclude that in an IE model of biofilm-forming MRSA, daptomycin monotherapy has better in vitro activity than daptomycin in combination with rifampin or gentamicin or any vancomycin-containing regimen studied within the first 24 h. Further investigations are needed to understand the initial delay in bactericidal activity observed when gentamicin or rifampin is combined with daptomycin.Biofilm-forming Staphylococcus aureus isolates are frequently found on prosthetic devices and in deep tissue infections (21, 43), and both prosthetic devices and deep tissue infections serve as common sources for bacteremia. Clinical research supports the theory that infective endocarditis (IE)-causing bacteria form biofilms (14, 19) and that S. aureus isolates recovered from the blood of patients with IE tend to produce biofilms at a high inoculum and during the stationary phase of growth (24, 43). These isolates also typically carry accessory gene regulator (agr) groups I and II, which regulate the production of autolysins that promote biofilm formation (21, 43, 44). Despite this information, there are limited data about the biofilm-forming capabilities of S. aureus isolates that cause IE (SAIE).Until recently, effective antimicrobial therapy for methicillin (meticillin)-resistant S. aureus (MRSA) bacteremia and IE was limited to vancomycin. Although vancomycin has commonly been used since the 1980s for the treatment of MRSA infections, including endocarditis, several published studies indicate that it has limited efficacy because of bacterial resistance, bacterial tolerance, and poor tissue penetration (8, 22, 36). Patients with SAIE treated with vancomycin alone may still be bacteremic (as indicated by positive blood cultures) after 7 to 10 days of therapy (25, 26). Guidelines for the treatment of SAIE recommend the use of combination therapy with vancomycin plus gentamicin or rifampin (rifampicin) (2, 3, 41). However, these combinations can be problematic because gentamicin increases the risk of nephrotoxicity and rifampin increases the potential for drug interactions via its induction of cytochrome P450 metabolism. In addition, this recommendation is based on limited clinical data.Daptomycin, a novel lipopetide antimicrobial agent, received FDA approval in May 2006 for the treatment of bacteremia and right-sided SAIE caused by methicillin-susceptible and -resistant strains (12). The FDA indication is for monotherapy against gram-positive pathogens; however, the guidelines recommend combination therapy for SAIE. Data to support the optimal dose of daptomycin required for it to have activity when it is combined with commonly used synergistic agents such as gentamicin and rifampin are lacking. In addition, limited information about the activity of daptomycin in the presence of biofilm-forming S. aureus has been published (23, 32, 35, 37).The purpose of this study was to quantify the biofilm formation of S. aureus isolates obtained from patients with SAIE, to assess the in vitro activities of daptomycin and vancomycin alone and in combination with rifampin or gentamicin, and to evaluate the development of resistance in a high-inoculum, stationary-phase bacterial (biofilm) model of IE.(This work has been presented in part at the 108th General Meeting of the American Society for Microbiology, Boston, MA, 1 to 5 June 2008 [abstr. A-076].)     

Antibiotic resistance in Staphylococcus aureus–containing cutaneous abscesses of patients with HIV

Purpose

The aim of this study was to document the resistance patterns found in exudates from cutaneous abscesses of HIV-infected persons.

Basic Procedures

Patient records were reviewed on 93 culture and sensitivity tests performed on exudates taken from incised and drained abscesses of HIV-infected persons.

Main Findings

Of the specimens, 84.6% were Staphylococcus aureus. Of these, 93.5% were penicillin resistant, 87% oxacillin resistant, 84.4% cephazolin resistant, 84.4% erythromycin resistant, 52.2% ciprofloxacin resistant, and 15.6% tetracycline resistant. Fifty-eight specimens were tested for clindamycin with 29.3% found resistant; 85.7% were methicillin-resistant S aureus (MRSA) (defined as resistant to both penicillin G and oxacillin). All specimens were resistant to multiple antibiotics including antimicrobials that might be considered for use in MRSA. No specimens were resistant to trimethoprim-sulfamethoxazole, rifampin, or vancomycin.

Conclusions

Empiric antimicrobial therapy of HIV-infected persons with cutaneous abscesses must be tailored to the high frequency of antimicrobial drug resistance including MRSA in this population.     

Instability of Gait as an Extrapulmonary Sequela in Acute Legionella Pneumonia: A Case Report

Background

Legionnaires disease is a potentially fatal infection often associated with permanent pulmonary fibrosis in survivors. Although neurological complications are not infrequent, chronic peripheral neuropathy in the absence of pulmonary abnormalities is an uncommon consequence of Legionnaires disease.

Case Report

A 51-year-old woman was admitted to the Emergency Department due to acute respiratory failure. Chest computed tomographic (CT) scan revealed bilateral consolidation shadows suggestive of acute respiratory disease syndrome (ARDS). Urine culture was evaluated and empiric therapy was administered due to a clinical suspicion of acute legionella pneumonia. Acute flaccid paralysis of the limbs and cutaneous rash complicated the clinical course. Treatment with appropriate antibiotics and steroids resulted in complete recovery of pulmonary damage, whereas mild ataxic gait was present at 1-year follow-up.

Conclusions

The outcome of this case confirms that the early exudative phase of ARDS in the absence of bronchial dilatation on chest CT scan is not always related to pulmonary fibrosis in survivors at follow-up. It also demonstrates that peripheral neuropathy can persist despite tailored treatment.     

Early Response Assessment to Guide Management of Methicillin-Resistant Staphylococcus aureus Bloodstream Infections With Vancomycin Therapy

Background

A subset of vancomycin-treated patients with methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infection (BSI) developed persistent positive blood cultures. Treatment eventually failed.

Methods

A retrospective study was conducted to determine whether early response on day 3 after initiation of vancomycin therapy for MRSA BSI was associated with reduced rates of persistent bacteremia, end-of-treatment failure, and infection-related mortality. Patients’ medical charts were reviewed. Susceptibility testing and molecular characterization of bacterial isolates were performed.

Results

In this elderly cohort (n = 111; median age 70 years, interquartile range: 57–80 years), early response was observed in 62% of patients and was significantly (P < 0.0001) associated with lower rates of end-of-treatment failure (19% vs 57%) and infection-related death (1% vs 29%), but not with persistent bacteremia (17% vs 29%, P = 0.23). Nearly half (46%; 46 of 100 patients) remained on vancomycin therapy for the entire treatment course; those who continued despite lack of early response had a trend toward a higher risk of death than those who were switched to alternative therapy (38% vs 10%, P = NS). Most (68%) isolates had vancomycin MIC of >1 µg/mL, whereas 10% showed heterogeneous glycopeptide-intermediate Staph aureus (hGISA) phenotype. Nearly half (47%) were typed with staphylococcal cassette chromosome mec IV or V. In a multivariate logistic regression model, lack of response at day 3 was the strongest predictor for end-of-treatment failure, after adjustment for confounders such as age, Acute Physiology And Chronic Health Evaluation II score, intensive care unit admission, vancomycin MIC >1 µg/mL, unbound trough concentration <4 to 5× MIC, and continued vancomycin therapy without change.

Conclusions

Early response assessment after initiation of vancomycin therapy appeared to be useful for considering further diagnostic workup or a switch to alternative therapy to affect a positive outcome in patients with MRSA BSI.     

Predictors of bacteremia in emergency department patients with suspected infection

Objectives

The goal of this study is to identify clinical variables associated with bacteremia. Such data could provide a rational basis for blood culture testing in emergency department (ED) patients with suspected infection.

Methods

This is a secondary analysis of a prospective cohort of ED patients with suspected infection. Data collected included demographics, vital signs, medical history, suspected source of infection, laboratory and blood culture results and outcomes. Bacteremia was defined as a positive blood culture by Centers for Disease Control criteria. Clinical variables associated with bacteremia on univariate logistic regression were entered into a multivariable model.

Results

There were 5630 patients enrolled with an average age of 59.9 ± 19.9 years, and 54% were female. Blood cultures were obtained on 3310 (58.8%). There were 409 (12.4%) positive blood cultures, of which 68 (16.6%) were methicillin-resistant Staphylococcus aureus (MRSA) and 161 (39.4%) were Gram negatives. Ten covariates (respiratory failure, vasopressor use, neutrophilia, bandemia, thrombocytopenia, indwelling venous catheter, abnormal temperature, suspected line or urinary infection, or endocarditis) were associated with all-cause bacteremia in the final model (c-statistic area under the curve [AUC], 0.71). Additional factors associated with MRSA bacteremia included end-stage renal disease (odds ratio [OR], 3.9; 95% confidence interval [CI], 1.9-7.8) and diabetes (OR, 2.0; 95% CI, 1.1-3.6) (AUC, 0.73). Factors strongly associated with Gram-negative bacteremia included vasopressor use in the ED (OR, 2.8; 95% CI, 1.7-4.6), bandemia (OR, 3.5; 95% CI, 2.3-5.3), and suspected urinary infection (OR, 4.0; 95% CI, 2.8-5.8) (AUC, 0.75).

Conclusions

This study identified several clinical factors associated with bacteremia as well as MRSA and Gram-negative subtypes, but the magnitude of their associations is limited. Combining these covariates into a multivariable model moderately increases their predictive value.     

Impact of inappropriate empirical antibiotic therapy on outcome of bacteremic adults visiting the ED

Objectives

To investigate the clinical impact of inappropriate empirical antibiotics on patient outcome and determine the risk factors for mortality in bacteremic adults who visited the emergency department (ED).

Methods

Bacteremic adults visiting the ED from January 2007 to June 2008 were identified retrospectively. Demographic characteristics, clinical conditions, bacteremic pathogens, antimicrobial agents, and outcomes were determined from chart records.

Results

The total of 454 eligible bacteremic adults were included in the analysis; excluded from the study were another 261 patients with contaminated blood cultures and 64 patients with ED stays of less than 24 hours. Among the included individuals, the mean age was 64.6 years, with a small predominance of males (230 patients, 50.7%). Of a total 494 bacteremic isolates, Escherichia coli (206, 41.7%) and Klebsiella species (81, 16.4%) were the most frequently encountered microorganisms. A lower 28-day mortality rate was demonstrated in bacteremic patients treated with appropriate antibiotics than that in those with inappropriate antibiotics or that in those with no antibiotic therapy, as judged by Kaplan-Meier survival curves (P = .01). Moreover, the differences among these three groups achieved higher significance (P = .002) in critically ill patients (Pittsburgh bacteremia scores of ≥4 points). In multivariate analyses, inappropriate antibiotic therapy in the ED was associated independently with mortality at 28 days (odds ratio, 2.26; 95% confidence interval, 1.01-5.13; P = .04).

Conclusions

For bacteremic adults visiting the ED, their outcomes were favorable following appropriate antibiotics, compared to treatment with inappropriate antibiotics or no antibiotics.     

Group A Streptococcal Necrotizing Fasciitis in the Emergency Department

Background

Group A Streptococcal (GAS) necrotizing fasciitis is a critical emergency. Patients with necrotizing fasciitis principally present to emergency departments (EDs), but most studies are focused on hospitalized patients.

Objective

An ED patient-based retrospective study was conducted to investigate the clinical characteristics, associated factors, and outcomes of GAS necrotizing fasciitis in the ED.

Methods

Patients visiting the ED from January 2005 through December 2011 with the diagnosis of GAS necrotizing fasciitis were enrolled. All patients with the diagnosis of noninvasive skin and soft-tissue infections caused by GAS were included as the control group.

Results

During the study period, 75 patients with GAS necrotizing fasciitis were identified. Males accounted for 84% of patients. The most prevalent underlying disease was diabetes mellitus (45.3%). Bullae were recognized in 37.3% of patients. One third of cases were complicated by bacteremia. Polymicrobial infections were found in 30.7% of patients. Overall mortality rate for GAS necrotizing fasciitis was 16%. Patients aged >60 years with diabetes mellitus, liver cirrhosis, and gout were considerably more likely to have GAS necrotizing fasciitis than noninvasive infections. Patients presenting with bacteremia, shock, duration of symptoms/signs <5 days, low white blood cell count, low platelet count, and prolonged prothrombin time were associated with increased mortality. Surgery is a significantly negative factor for mortality of patients with GAS necrotizing fasciitis (odds ratio = 0.16; 95% confidence interval 0.002−0.16; p < 0.001).

Conclusions

A better understanding of the associated factors and initiation of adequate treatments will allow for improved survival after GAS necrotizing fasciitis.