Clearance Of Bacteremia Research Articles

Infective endocarditis due to multidrug resistant gram-negative bacilli: Single centre experience over 5 years

BackgroundInfective endocarditis (IE) due to gram-negative (GN) bacilli is uncommon. Although multi- and extensively-drug resistant (MDR/XDR) GN infections are emerging, very few data are available on IE due to these microrganisms. MethodsIn this study, we describe the clinical characteristics, course and outcome of five contemporary, definite, MDR/XDR GNIE cases seen at our centre. ResultsAll patients had been admitted to a hospital during the 6months before IE onset, 2 were on hemodialysis and 3 on intravenous medications. Three of the 5 cases were hospital-acquired. Intracardiac prosthetic devices were present in all cases (3 central venous lines, 2 prosthetic heart valves, 2 pacemakers). Mean Charlson comorbidity index was 5.8. Causative pathogens were XDR Pseudomonas aeruginosa (2 cases), XDR Acinetobacter baumannii, MDR Burkolderia cepacia and MDR Escherichia coli (1 case each). Concomitant pathogens with a MDR/XDR phenotype were isolated in 4 patients. Both valves and intracardiac devices and left and right sides of the heart were involved. The rate of complications was high. Antibiotic treatment hinged on the use of colistin, a carbapenem or both. Cardiovascular surgical procedures were performed in 3 patients. Despite aggressive therapeutic regimens, outcomes were poor. Clearance of bacteremia was obtained in 3 patients, in-hospital death occurred in 3 patients, only 1 patient survived during follow up. ConclusionsMDR/XDR GN are emerging as a cause of IE in carriers of intracardiac prostheses with extensive healthcare contacts and multiple comorbidities. Resistant GNIE has a complicated course and shows a dismal prognosis.

Efficient B Cell Responses to Borrelia hermsii Infection Depend on BAFF and BAFFR but Not TACI

T cell-independent antibody responses develop rapidly, within 3 to 4 days, and are critical for preventing blood-borne pathogens from evolving into life-threatening infections. The interaction of BAFF, also known as BLyS, with its receptors BAFFR and TACI on B cells is critical for B cell homeostasis and function. Using a synthetic polysaccharide antigen, it has previously been shown that TACI is critical for T cell-independent antibody responses. To examine the role of BAFFR and TACI in T cell-independent antibody responses to an active infection, we utilized the Borrelia hermsii infection system. In this infection system, T cell-independent responses mediated by the B1b cell subset are critical for controlling bacteremia. We found that B1b cells express BAFFR and TACI and that the surface expression of both receptors is upregulated on B1b cells following exposure to whole B. hermsii cells. Surprisingly, we found that TACI(-/-) mice are not impaired either in specific antibody responses to B. hermsii or in controlling B. hermsii bacteremia. In contrast, TACI-deficient mice immunized with heat-killed type 3 serotype pneumococcus cells are impaired in generating pneumococcal polysaccharide-specific responses and succumb to challenge with live type 3 serotype pneumococcus, indicating that TACI is required for T cell-independent antibody responses to bacterial-associated polysaccharides. Although we have found that TACI is dispensable for controlling B. hermsii infection, mice deficient in BAFFR or BAFF exhibit impairment in B. hermsii-specific IgM responses and clearance of bacteremia. Collectively, these data indicate a disparity in the roles for TACI and BAFFR in primary T cell-independent antibody responses to bacterial pathogens.

High-Dose Daptomycin Therapy for Left-Sided Infective Endocarditis: a Prospective Study from the International Collaboration on Endocarditis

The use of daptomycin in Gram-positive left-sided infective endocarditis (IE) has significantly increased. The purpose of this study was to assess the influence of high-dose daptomycin on the outcome of left-sided IE due to Gram-positive pathogens. This was a prospective cohort study based on 1,112 cases from the International Collaboration on Endocarditis (ICE)-Plus database and the ICE-Daptomycin Substudy database from 2008 to 2010. Among patients with left-sided IE due to Staphylococcus aureus, coagulase-negative staphylococci, and Enterococcus faecalis, we compared those treated with daptomycin (cohort A) to those treated with standard-of-care (SOC) antibiotics (cohort B). The primary outcome was in-hospital mortality. Time to clearance of bacteremia, 6-month mortality, and adverse events (AEs) ascribable to daptomycin were also assessed. There were 29 and 149 patients included in cohort A and cohort B, respectively. Baseline comorbidities did not differ between the two cohorts, except for a significantly higher prevalence of diabetes and previous episodes of IE among patients treated with daptomycin. The median daptomycin dose was 9.2 mg/kg of body weight/day. Two-thirds of the patients treated with daptomycin had failed a previous antibiotic regimen. In-hospital and 6-month mortalities were similar in the two cohorts. In cohort A, median time to clearance of methicillin-resistant S. aureus (MRSA) bacteremia was 1.0 day, irrespective of daptomycin dose, representing a significantly faster bacteremia clearance compared to SOC (1.0 versus 5.0 days; P < 0.01). Regimens with higher daptomycin doses were not associated with increased incidence of AEs. In conclusion, higher-dose daptomycin may be an effective and safe alternative to SOC in the treatment of left-sided IE due to common Gram-positive pathogens.

Central Line–associated Bloodstream Infection in Children

Central Line–associated Bloodstream Infection in Children

Addition of Rifampin to Vancomycin for Methicillin-Resistant Staphylococcus aureus Infections: What Is the Evidence?

To evaluate evidence supporting efficacy and safety of the combination of vancomycin and rifampin for treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections. MEDLINE (1946-February 2013), EMBASE (1974-February 2013) and Cochrane Database of Systematic Reviews were searched. All human prospective trials and retrospective studies evaluating clinical outcomes of vancomycin-rifampin combinations were included. Case reports, case series, and in vitro or animal data were excluded. Full-text articles were included and abstracts excluded; 43 of 421 references were reviewed. Five articles met inclusion and were evaluated. A nonrandomized prospective trial reported complete clearance of MRSA bacteremia at 24 hours in all 14 burn patients receiving vancomycin-rifampin therapy. In a case-control study of 42 patients with MRSA endocarditis, adding rifampin prolonged bacteremia (5.2 vs 2.1 days, p < 0.001), decreased survival rates (79% vs 95%, p = 0.048), resulted in drug interactions (52% of cases), and increased hepatic transaminases (21% vs 2%, p = 0.014). In a retrospective analysis of 28 patients with persistent MRSA bacteremia requiring salvage therapy, switching from vancomycin-based to linezolid-based treatment was associated with better salvage success than adding rifampin (88% vs 0%, p < 0.001). In a randomized open-label trial of 42 patients with MRSA endocarditis, addition of rifampin to vancomycin did not affect cure rates (90% combination vs 82% monotherapy, p > 0.20), but increased duration of bacteremia (9 vs 7 days, p > 0.20) compared with vancomycin monotherapy. Another randomized open-label trial of combination versus monotherapy for MRSA pneumonia in 93 intensive care unit patients reported higher clinical successes (53.7% vs 31.0%, p = 0.047), similar 30-day mortality rates, and more adverse events with combination therapy (11 vs 6). Limited evidence exists to support the adjunctive use of rifampin to treat MRSA infections. The combination may increase drug interactions, adverse effects, and rifampin resistance. Further studies are needed to define the role of rifampin adjunct therapy.

Dose-Related Clinical Efficacy of Polymyxin B in a Critically Ill Patient

In Brief Published dosing schemes call for reduced dosage of polymyxin B for patients with renal insufficiency. However, recent evidence suggests that clearance of polymyxin B is not affected by renal function. We report a patient with renal insufficiency who had microbiological failure when adjusted dosing was administered but clearance of bacteremia when the dose was increased to that recommended for a patient with normal renal function. Even though polymyxins are being used more commonly with the emergence of resistant gram negative bacteria, appropriate dosing of Polymyxin B especially in patients with renal insufficiency remains unknown. This reported case indicates that dosage of polymyxin B adjusted for renal insufficiency may be inadequate.

Activity of doripenem versus comparators in subjects with baseline bacteraemia in six pooled phase 3 clinical trials

An analysis of subjects with concurrent bacteraemia and either nosocomial pneumonia, complicated intra-abdominal infection or complicated urinary tract infection from six phase 3 clinical trials demonstrated similar cure rates and clearance of bacteraemia in patients treated with doripenem and comparator agents.

Improving the management of Staphylococcus aureus bacteraemia, including MRSA.

Staphylococcus aureus bacteraemia is a serious infection associated with significant complications, including recurrence of bacteraemia, endocarditis and metastatic foci of infection. The management of these patients is often complex, involving appropriate source control, a thorough review and investigations to exclude metastatic foci and infective endocarditis. Additionally, a prolonged course of intravenous antibiotics is often required.As part of our quality improvement project, the following five aspects were evaluated in 56 patients with S. aureus bacteraemia at two District General Hospitals: 1) adequate and timely removal of the source of bacteraemia, 2) echocardiography to exclude endocarditis, 3) repeat blood culture to prove clearance of bacteraemia, 4) adequate duration and choice of antibiotics and 5) documentation of bacteraemia in the discharge summary.After an initial review revealed several areas for improvement, we instituted five Plan-Do-Study-Act learning cycles which involved: teaching microbiology trainees and junior doctors, improving clinical liaison and communication between the microbiology team and clinicians, as well as a clinical review of patients by the microbiology team where appropriate.The post-intervention review evaluated 24 patients with S. aureus bacteraemia between November 2012 and May 2013. The proportion of patients undergoing an echocardiogram improved from 49% to 88%. Another marked improvement was seen in the timely obtaining of clearance blood cultures, with 88% of patients having clearance blood cultures within the 2-4 day window, compared to 56% pre-intervention. 70% of patients with uncomplicated S. aureus bacteraemia received an appropriate antibiotic course post-intervention, compared with 59% pre-intervention. Documentation of the S. aureus bacteraemia in the discharge summary improved from 65% to 75%. The support of the entire microbiology team was pivotal in the successful outcome of the quality improvement project.

Transient Staphylococcus aureus Bacteremia in an Urban Teaching Hospital

In Brief Background Transient Staphylococcus aureus bacteremia (TSAB) is frequently encountered in hospitalized patients, yet physicians lack guidance in the management of these patients. Methods We retrospectively reviewed all cases of S. aureus bacteremia at Detroit Receiving Hospital from January 1, 2006 to December 31, 2006 and compared patients with TSAB to patients with persistent S. aureus bacteremia (PSAB). Results There were 112 patients in the study: 35 patients with TSAB and 77 patients with PSAB. Injection drug use was less common among patients with TSAB than those with PSAB (P = 0.001). More patients with TSAB had surgical wounds (P = 0.033); metastatic infection was more common among patients with PSAB (P < 0.001). The time to positivity for blood cultures was longer for TSAB (27.03 hours) than for PSAB (18.42 hours; P = 0.014) and patients with TSAB were more likely to become bacteremic more than 48 hours after admission (P = 0.046). Vascular catheters and skin/soft tissue/bone infection were the most frequent portals of entry of bacteremia for patients with TSAB; primary bloodstream infection was more common in PSAB (P < 0.001). The rates of readmission, relapse/recurrence of SAB and death were similar for the 2 groups. Conclusion Compared to patients with PSAB, patients with TSAB are more likely to develop TSAB as a hospital-acquired infection and are at very low risk of metastatic infection. In addition, the prolonged time for their blood cultures to become positive and their rapid clearance of bacteremia make endovascular infection unlikely. Our findings suggest that physicians faced with patients with TSAB may be confident in providing a relatively short course of antibiotic therapy. Summary: Patients with transient Staphylococcus aureus bacteremia have different characteristics from patients with persistent S. aureus bacteremia. These differences may be used to help identify patients who might benefit from relatively short courses of therapy.

A Neonatal Model of Intravenous Staphylococcus epidermidis Infection in Mice &lt;24 h Old Enables Characterization of Early Innate Immune Responses

Staphylococcus epidermidis (SE) causes late onset sepsis and significant morbidity in catheterized preterm newborns. Animal models of SE infection are useful in characterizing disease mechanisms and are an important approach to developing improved diagnostics and therapeutics. Current murine models of neonatal bacterial infection employ intraperitoneal or subcutaneous routes at several days of age, and may, therefore, not accurately reflect distinct features of innate immune responses to bacteremia. In this study we developed, validated, and characterized a murine model of intravenous (IV) infection in neonatal mice <24 hours (h) old to describe the early innate immune response to SE. C57BL/6 mice <24 h old were injected IV with 106, 107, 108 colony-forming units (CFU) of SE 1457, a clinical isolate from a central catheter infection. A prospective injection scoring system was developed and validated, with only high quality injections analyzed. Newborn mice were euthanized between 2 and 48 h post-injection and spleen, liver, and blood collected to assess bacterial viability, gene expression, and cytokine production. High quality IV injections demonstrated inoculum-dependent infection of spleen, liver and blood. Within 2 h of injection, SE induced selective transcription of TLR2 and MyD88 in the liver, and increased systemic production of plasma IL-6 and TNF-α. Despite clearance of bacteremia and solid organ infection within 48 h, inoculum-dependent impairment in weight gain was noted. We conclude that a model of IV SE infection in neonatal mice <24 h old is feasible, demonstrating inoculum-dependent infection of solid organs and a pattern of bacteremia, rapid and selective innate immune activation, and impairment of weight gain typical of infected human neonates. This novel model can now be used to characterize immune ontogeny, evaluate infection biomarkers, and assess preventative and therapeutic modalities.

Bacillus Bloodstream Infections in a Tertiary Perinatal Centre: An 8-Year Study

Isolates of nonanthrax Bacillus species in clinical samples are frequently considered as contaminants. However, there were case reports describing Bacillus sepsis among infants, associated with high mortality and morbidity. We performed a retrospective review of the clinical and epidemiological features of Bacillus bacteremia at our neonatal intensive care unit from January 2002 to December 2009. Bacillus bacteremia was considered to be clinically significant in 11 infants. The median gestational age was 30 weeks. All had either central catheters or peripherally inserted arterial lines in situ. The mean neutrophil and lymphocyte counts were 6.73 × 10(9)/L (0.78 to 12.56 × 10(9)/L) and 2.75 × 10(9)/L (0.82 to 6.15 × 10(9)/L), respectively. All 11 infants received intravenous vancomycin, with an average duration of 12.4 days. In general, the earlier the catheter was removed, the quicker the clearance of bacteremia was achieved. All infants survived and were discharged from the hospital. The growth of Bacillus species in blood cultures cannot simply be regarded as a contaminant. Hematologic parameters are frequently unremarkable at the disease onset. Increased vigilance, early diagnosis, and effective therapy in conjunction with prompt catheter removal are the keys to successful management of Bacillus bacteremia.

Timing of Toll-Like Receptor 9 Agonist Administration in Pneumococcal Vaccination Impacts Both Humoral and Cellular Immune Responses as Well as Nasopharyngeal Colonization in Mice

Synthetic oligodeoxynucleotides (ODN) containing unmethylated CpG motifs, CpG ODN, are Toll-like receptor 9 agonists (TLR9a), which have been used as adjuvants in pneumococcal vaccines to improve antibody responses in immunodeficient patients. Here, we examined whether the coadministration of TLR9a with pneumococcal CRM(197)-conjugate vaccine enhances protection against pneumococcal colonization, the levels of antipolysaccharide antibodies, and the CD4(+) T-cell responses. Wild-type BALB/c mice and B-cell-deficient BALB/c Igh-J(tm1Dhu) mice were immunized twice with the following: (i) PCV alone; (ii) simultaneous PCV and TLR9a; (iii) PCV and then TLR9a, after a 48-h delay; (iv) TLR9a alone; and (v) phosphate-buffered saline. Nasopharyngeal protection, serum antibodies, CD4(+) T-cell responses, and clearance of bacteremia after intraperitoneal challenge with Streptococcus pneumoniae 6B were evaluated. We found decreased nasopharyngeal protection against S. pneumoniae 6B colonization after simultaneous immunization with PCV and TLR9a compared to immunization with PCV alone in wild-type BALB/c mice (P = 0.037). A similar trend was observed in B-cell-deficient BALB/c Igh-J(tm1Dhu) mice. Simultaneous administration did not enhance antibody levels and lowered the CRM(197)-specific cytokine release of gamma interferon, interleukin-2 (IL-2), IL-5 and IL-13. Immunization with PCV and then TLR9a, after a 48-h delay, significantly improved nasopharyngeal protection compared to simultaneous administration (P = 0.011). Furthermore, delaying TLR9a delivery increased antibody titers compared to both simultaneous administration (P = 0.001) and PCV immunization alone (P = 0.026). In conclusion, the immunological and clinical impact of adjuvanting a pneumococcal conjugate vaccine (Prevnar; Pfizer) with a TLR9a is highly depended on timing of the adjuvant administration. Thus, careful timing of adjuvant administration may improve novel vaccine formulations.

Protection Against Staphylococcus aureus by Antibody to the Polyglycerolphosphate Backbone of Heterologous Lipoteichoic Acid

Type 1 lipoteichoic acid (LTA) is present in many clinically important gram-positive bacteria, including enterococci, streptococci, and staphylococci, and antibodies against LTA have been shown to opsonize nonencapsulated Enterococcus faecalis strains. In the present study, we show that antibodies against E. faecalis LTA also bind to type 1 LTA from other gram-positive species and opsonized Staphylocccus epidermidis and Staphylcoccus aureus strains as well as group B streptococci. Inhibition studies using teichoic acid oligomers indicated that cross-reactive opsonic antibodies bind to the teichoic acid backbone. Passive immunization with rabbit antibodies against E. faecalis LTA promoted the clearance of bacteremia by E. faecalis and S. epidermidis in mice. Furthermore, passive protection also reduced mortality in a murine S. aureus peritonitis model. The effectiveness of rabbit antibody against LTA suggests that this conserved bacterial structure could function as a single vaccine antigen that targets multiple gram-positive pathogens.

B1b lymphocyte-derived antibodies control Borrelia hermsii independent of Fcα/μ receptor and in the absence of host cell contact

The critical role of IgM in controlling pathogen burden has been demonstrated in a variety of infection models. In the murine model of Borrelia hermsii infection, IgM is necessary and sufficient for the rapid clearance of bacteremia. Convalescent, but not naïve, B1b cells generate a specific IgM response against B. hermsii, but the mechanism of IgM-mediated protection is unknown. Here, we show that neither Fcα/μR, a high-affinity receptor for IgM, nor IgM-dependent complement activation is required for controlling B. hermsii. Bacteria in diffusion chambers with a pore size impermeable to cells were killed when diffusion chambers were implanted into either convalescent or passively immunized mice. Furthermore, adoptively transferred convalescent B1b cells in Rag1(-/-) mice produced specific IgM that also cleared B. hermsii in diffusion chambers independent of complement. These results demonstrate that IgM-mediated clearance of B. hermsii does not require opsonophagocytosis and indicate that a mechanism for in vivo B1b cell-mediated protection is through the generation of bactericidal IgM.

Campylobacter Bacteremia

Campylobacter is a very rare cause of bloodstream infection, although it has been found relatively frequently in patients infected with human immunodeficiency virus (HIV). The impact of highly active antiretroviral therapy (HAART) and new forms of immunosuppression on the incidence of Campylobacter bacteremia has not been sufficiently assessed. In this study we analyzed the incidence and microbiologic and clinical characteristics of Campylobacter bacteremia over 23 years.We reviewed the clinical records of all patients who had Campylobacter bacteremia from 1985 to 2007. Available strains were reidentified using universal polymerase chain reaction (PCR).During the study period, there were 71 episodes of Campylobacter bacteremia in 63 patients (0.24% of all bloodstream infections), and the incidence remained stable (mean, 0.06/1000 admissions per year and 0.47/100,000 inhabitants per year). Median age was 52 years (interquartile range, 31.25-72.5 yr), and 82% of patients were male. The underlying conditions included liver disease (21/64, 32.8%), HIV infection (15/64, 23.4%), malignancy (7/64, 10.9%), solid organ transplantation (2/64, 3%), hypogammaglobulinemia (10/64, 15.6%), and other (18/64, 31.2%). Twelve patients shared more than 1 underlying condition. Campylobacter bacteremia was community acquired in 81% of the episodes. The origin of the bloodstream infection was abdominal (43.5%), primary (26%), or extraintestinal (31%: respiratory 15%, cellulitis 4.8%, urinary 8%, other 3%). C jejuni was recovered in 66% of cases, C fetus in 19%, and C coli in 12%.Universal PCR was performed on 14 available strains. Molecular and conventional identification matched in 8 isolates. In contrast, molecular methods classified as C fetus (n = 2) and C jejuni (n = 1) 3 strains formerly identified only to genus level as Campylobacter species. In another 3 isolates, molecular identification was not consistent with the phenotypic identification (C fetus identified as C jejuni).Complications appeared in 23.9% of patients. Quinolone resistance was observed in 50% of the isolates. Only 37.8% of patients received appropriate empirical therapy. Mortality was 16.4%, although it was higher in HIV-infected patients than uninfected patients (33% vs. 10%; p = 0.04), in cases of hospital-acquired Campylobacter bacteremia compared with community-acquired cases (38.5% vs. 9.4%; p = 0.02), and in the presence of complications compared with patients without complications (100% vs. 0%; p < 0.001). The incidence of recurrence was 5% (3 patients with humoral immunodeficiency). There was a higher proportion of HIV-infected patients among patients with Campylobacter bacteremia in the pre-HAART era (1985-1996) than in the HAART era (1997-2007)-27.5% (11/40) vs. 14.3% (4/28)-although the difference was not statistically significant. Debilitating diseases such as chronic obstructive pulmonary disease emerged as predisposing conditions in the HAART era (0% before HAART era vs. 14.3% in HAART era; p = 0.032).Campylobacter bacteremia is no longer a significant disease of HIV-positive patients on HAART, but often affects other immunocompromised patients as well. Campylobacter bacteremia has an extraintestinal origin in as many as 31% of cases, and humoral immunodeficiency must be sought in patients with recurrent episodes. Quinolones should not be considered for empirical therapy.

TLR2 Mediates Recognition of Live Staphylococcus epidermidis and Clearance of Bacteremia

Background Staphylococcus epidermidis (SE) is a nosocomial pathogen that causes catheter-associated bacteremia in the immunocompromised, including those at the extremes of age, motivating study of host clearance mechanisms. SE-derived soluble components engage TLR2; but additional signaling pathways have also been implicated, and TLR2 can play complex, at times detrimental, roles in host defense against other Staphylococcal spp. The role of TLR2 in responses of primary blood leukocytes to live SE and in clearance of SE bacteremia, the most common clinical manifestation of SE infection, is unknown.Methodology/Principal FindingsWe studied TLR2-mediated recognition of live clinical SE strain 1457 employing TLR2-transfected cells, neutralizing anti-TLR antibodies and TLR2-deficient mice. TLR2 mediated SE-induced cytokine production in human embryonic kidney cells, human whole blood and murine primary macrophages, in part via recognition of a soluble TLR2 agonist. After i.v. challenge with SE, early (1 h) cytokine/chemokine production and subsequent clearance of bacteremia (24–48 h) were markedly impaired in TLR2-deficient mice.Conclusions/SignificanceTLR2 mediates recognition of live SE and clearance of SE bacteremia in vivo.

Factors Influencing Time to Vancomycin‐Induced Clearance of Nonendocarditis Methicillin‐ResistantStaphylococcus aureusBacteremia: Role of Platelet Microbicidal Protein Killing andagrGenotypes

Vancomycin susceptibility, the accessory gene global regulator (agr) genotype and function, staphylococcal cassette chromosome (SCC) mec type, and susceptibility to cationic thrombin-induced platelet microbicidal protein 1 (tPMP-1) have been individually predictive of duration of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. This investigation evaluated the interrelationship of these factors with time to clearance of MRSA bacteremia during vancomycin therapy in patients without endocarditis. Vancomycin minimum inhibitory concentration and in vitro killing, agr function (delta-hemolysin activity), agr group, SCCmec type, and survival in tPMP-1 killing assays were determined for 29 MRSA bacteremia isolates. Increased resistance to tPMP-1 killing was observed with agr group III MRSA (P = .025) and MRSA with reduced or absent agr function (P = .023). The median time to clearance of MRSA bacteremia was earlier for agr group III (3 days) versus group I (10.5 days) or II (15 days) (P = .001). In multivariate analysis, agr group II, reduced tPMP-1 killing in vitro, and prior vancomycin exposure were significant independent predictors of longer MRSA bacteremia duration. Specific genotypic, phenotypic, and clinical parameters appear to correlate with persistent MRSA bacteremia. The interrelationship of these and other factors probably contributes to vancomycin-mediated clearance of MRSA bacteremia.

Daptomycin versus vancomycin plus gentamicin for treatment of bacteraemia and endocarditis due to Staphylococcus aureus: subset analysis of patients infected with methicillin-resistant isolates

ObjectivesIn a prospective, randomized trial, daptomycin was non-inferior to standard therapy for Staphylococcus aureus bacteraemia and right-sided endocarditis. Since rates of infection due to methicillin-resistant S. aureus (MRSA) infection are increasing and treatment outcomes for bacteraemia caused by MRSA are generally worse than those observed with methicillin-susceptible S. aureus bacteraemia, clinical characteristics and treatment results in the trial’s pre-specified subset of patients with MRSA were analysed.MethodsClinical characteristics and outcomes of patients receiving daptomycin were compared with those receiving vancomycin plus low-dose gentamicin. Success was defined as clinical improvement with clearance of bacteraemia among patients who completed adequate therapy, received no potentially effective non-study antibiotics and had negative blood cultures 6 weeks after end of therapy.ResultsTwenty of the 45 (44.4%) daptomycin patients and 14 of the 43 (32.6%) vancomycin/gentamicin patients were successfully treated (difference 11.9%; confidence interval −8.3 to 32.1). Success rates for daptomycin versus vancomycin/gentamicin were 45% versus 27% in complicated bacteraemia, 60% versus 45% in uncomplicated bacteraemia and 50% versus 50% in right-sided MRSA endocarditis. Cure rates in patients with septic emboli and in patients who received pre-enrolment vancomycin were similar between treatment groups. However, in both treatment groups, success rates were lower in the elderly (≥75 years). Persisting or relapsing bacteraemia occurred in 27% of daptomycin and 21% of vancomycin/gentamicin patients; among these patients, MICs of ≥2 mg/L occurred in five daptomycin and four vancomycin/gentamicin patients. The clinical course of several patients may have been influenced by lack of surgical intervention.ConclusionsDaptomycin was an effective alternative to vancomycin/gentamicin for MRSA bacteraemia or right-sided endocarditis.

Addition of Rifampin to Standard Therapy for Treatment of Native Valve Infective Endocarditis Caused byStaphylococcus aureus

Staphylococcus aureus is a common cause of native valve infective endocarditis (IE). Rifampin is often added to traditional therapy for the management of serious S. aureus infections. There are no large, prospective studies documenting the safety and efficacy of adjunctive therapy with rifampin for treatment of native valve S. aureus IE. We reviewed all cases of definite native valve S. aureus IE confirmed by modified Duke criteria in a large urban hospital between 1 January 2004 and 31 December 2005. A retrospective cohort analysis was used to assess the impact of the addition of rifampin to standard therapy. There were 42 cases of S. aureus IE treated with the addition of rifampin and 42 controls. Cases received a median of 20 days of rifampin (range, 14 to 48 days). Rifampin-resistant S. aureus isolates developed in nine cases who received rifampin before clearance of bacteremia (56%), while significant hepatic transaminase elevations also occurred in nine cases, all of whom had hepatitis C infection. Unrecognized significant drug-drug interactions with rifampin occurred frequently (52%). Cases were more likely to have a longer duration of bacteremia (5.2 versus 2.1 days; P < 0.001) and were less likely to survive (79% versus 95%; P = 0.048) than controls. Our results suggest that the potential for hepatotoxicity, drug-drug interactions, and the emergence of resistant S. aureus isolates warrants a careful risk-benefit assessment before adding rifampin to standard antibiotic treatment of native valve S. aureus IE until further clinical studies are performed.

Vancomycin In Vitro Bactericidal Activity and Its Relationship to Efficacy in Clearance of Methicillin-Resistant Staphylococcus aureus Bacteremia

We examined the relationship between the time to clearance of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia while patients were receiving vancomycin therapy and the in vitro bactericidal activity of vancomycin. Vancomycin killing assays were performed with 34 MRSA bloodstream isolates (17 accessory gene regulator group II [agr-II] and 17 non-agr-II isolates) from 34 different patients with MRSA bacteremia for whom clinical and microbiological outcomes data were available. Vancomycin doses were prospectively adjusted to achieve peak plasma concentrations of 28 to 32 mug/ml and trough concentrations of 8 to 12 microg/ml. Bactericidal assays were performed over 24 h with approximately 10(7) to 10(8) CFU/ml in broth containing 16 microg/ml vancomycin. The median time to clearance of bacteremia was 6.5 days for patients with MRSA isolates demonstrating > or =2.5 reductions in log(10) CFU/ml at 24 h and >10.5 days for patients with MRSA isolates demonstrating <2.5 log(10) CFU/ml by 24 h (P = 0.025). The median time to clearance was significantly longer with MRSA isolates with vancomycin MICs of 2.0 microg/ml compared to that with MRSA isolates with MICs of < or =1.0 microg/ml (P = 0.019). The bacteremia caused by MRSA isolates with absent or severely reduced delta-hemolysin expression was of a longer duration of bacteremia (10 days and 6.5 days, respectively; P = 0.27) and had a decreased probability of eradication (44% and 78%, respectively; P = 0.086). We conclude that strain-specific microbiological features of MRSA, such as increased vancomycin MICs and decreased killing by vancomycin, appear to be predictive of prolonged MRSA bacteremia while patients are receiving vancomycin therapy. Prolonged bacteremia and decreased delta-hemolysin expression may also be related. Evaluation of these properties may be useful in the consideration of antimicrobial therapies that can be used as alternatives to vancomycin for the treatment of MRSA bacteremia.