Search

Introduction: After the implementation of mitigation strategies during the COVID-19 pandemic, the incidence of respiratory viruses, including human coronaviruses (HCoV), experienced a significant decrease. The aim of this study is to characterize the epidemiology and clinical aspects of HCoV infections in ambulatory adults during COVID-19 pandemic times., Methods: descriptive, prospective, longitudinal study performed in a private hospital in La Plata, Buenos Aires, Argentina between November 2020 and October 2022; 458 outpatient adults with upper respiratory tract infections (URTI) were studied undergoing clinical and microbiological follow-up., Results: 44 (9.6%) subjects were positive by multiplex PCR for HCoV. 14 of them for 229E (31.8%), 13 for OC43 (29.5%), 11 for HKU-1 (25.1%) and 6 for NL63 (13.6%). A repeated PCR was positive for the same HCoV in 19 (57%) of 33 patients on day 3-5. No hospitalizations or deaths were reported., Discussion: Endemic HCoV caused a significant proportion of URTI among outpatient adults during COVID-19-related restrictions times. An alternating pattern of circulation between alfa-HCoV and beta-HCoV was observed.

Importance: The use of convalescent plasma (CP) could be an option for patients with severe COVID-19, especially in poor-resource countries where direct antiviral drugs are not commercially available. Currently, the U.S. Food and Drug Administration limits the CP administration for outpatients and inpatients with COVID-19 who are immunocompromised and only if high levels of anti-SARS-CoV-2 antibodies are confirmed in the CP unit. Although most of the randomized clinical trials failed to show a clear-cut benefit of CP in hospitalized patients with severe COVID-19, other studies have shown that if given early in the course of the disease, it might be a useful therapeutic option. In this retrospective study, we demonstrated that early treatment (within 3 days of hospitalization) was significantly associated with reduced 28-day mortality compared with those patients treated beyond day 3. The results from our study add up to the scientific evidence on the use of CP as a relatively safe, cheap, and possibly effective therapy in certain patients suffering from severe SARS-CoV-2 infection., Competing Interests: The authors declare no conflict of interest.

Importance: Immune dysregulation contributes to poorer outcomes in COVID-19., Objective: To investigate whether abatacept, cenicriviroc, or infliximab provides benefit when added to standard care for COVID-19 pneumonia., Design, Setting, and Participants: Randomized, double-masked, placebo-controlled clinical trial using a master protocol to investigate immunomodulators added to standard care for treatment of participants hospitalized with COVID-19 pneumonia. The results of 3 substudies are reported from 95 hospitals at 85 clinical research sites in the US and Latin America. Hospitalized patients 18 years or older with confirmed SARS-CoV-2 infection within 14 days and evidence of pulmonary involvement underwent randomization between October 2020 and December 2021., Interventions: Single infusion of abatacept (10 mg/kg; maximum dose, 1000 mg) or infliximab (5 mg/kg) or a 28-day oral course of cenicriviroc (300-mg loading dose followed by 150 mg twice per day)., Main Outcomes and Measures: The primary outcome was time to recovery by day 28 evaluated using an 8-point ordinal scale (higher scores indicate better health). Recovery was defined as the first day the participant scored at least 6 on the ordinal scale., Results: Of the 1971 participants randomized across the 3 substudies, the mean (SD) age was 54.8 (14.6) years and 1218 (61.8%) were men. The primary end point of time to recovery from COVID-19 pneumonia was not significantly different for abatacept (recovery rate ratio [RRR], 1.12 [95% CI, 0.98-1.28]; P = .09), cenicriviroc (RRR, 1.01 [95% CI, 0.86-1.18]; P = .94), or infliximab (RRR, 1.12 [95% CI, 0.99-1.28]; P = .08) compared with placebo. All-cause 28-day mortality was 11.0% for abatacept vs 15.1% for placebo (odds ratio [OR], 0.62 [95% CI, 0.41-0.94]), 13.8% for cenicriviroc vs 11.9% for placebo (OR, 1.18 [95% CI 0.72-1.94]), and 10.1% for infliximab vs 14.5% for placebo (OR, 0.59 [95% CI, 0.39-0.90]). Safety outcomes were comparable between active treatment and placebo, including secondary infections, in all 3 substudies., Conclusions and Relevance: Time to recovery from COVID-19 pneumonia among hospitalized participants was not significantly different for abatacept, cenicriviroc, or infliximab vs placebo., Trial Registration: ClinicalTrials.gov Identifier: NCT04593940.

Introduction: During the SARS-CoV-2 pandemic, Argentina population suffered from significant changes in population mobility due to non-pharmaceutical interventions. The aim of this study was to describe the impact of the mobility restrictions to the rates of positivity and diversity among different respiratory viruses., Methods: Retrospective analytical study performed at Instituto Médico Platense in La Plata that included 458 patients with nasopharyngeal swab to search for respiratory pathogens by multiplex PCR. Changes in mobility were studied using "Community Mobility Reports", data set developed by Google and publicly available., Results: Community mobility had significant correlation with the percentages of viral test positivity (p = < 0.01; R2=0.89) and viral diversity (p = 0.04; R2 = 0.78)., Discussion: Non-pharmaceutical interventions established to contain SARS-CoV-2 spread had a significant impact in the circulation patterns of other respiratory viruses.

Infections caused by methicillin-susceptible Staphylococcus aureus (MSSA) are still associated with significant morbidity and mortality. Treatment failures of cefazolin (CFZ) have been reported and probably related to the inoculum effect. New treatments for severe MSSA infections are needed and ceftaroline fosamil (CPT) could be an option. Our aim was to describe the clinical characteristics of five patients with complicated MSSA bacteremia failing CFZ and successfully treated with CPT. We performed a retrospective chart review in a Hospital in Buenos Aires, Argentina; in a 12-month period, five patients (24%) of 21 with MSSA bacteremia experienced CFZ failure and were salvaged with CPT. The median time of CFZ therapy was 10 days before changing to CPT; four patients had evidence of metastatic spread and 2 had endocarditis. All patients experienced microbiological and clinical cure with CPT, which was used as monotherapy in 4 and in combination with daptomycin in another. One patient discontinued CPT due to neutropenia on day 23 of treatment. In patients with MSSA BSI failing current therapy, CPT could be a good therapeutic option.

Background: Convalescent plasma is frequently administered to patients with Covid-19 and has been reported, largely on the basis of observational data, to improve clinical outcomes. Minimal data are available from adequately powered randomized, controlled trials., Methods: We randomly assigned hospitalized adult patients with severe Covid-19 pneumonia in a 2:1 ratio to receive convalescent plasma or placebo. The primary outcome was the patient's clinical status 30 days after the intervention, as measured on a six-point ordinal scale ranging from total recovery to death., Results: A total of 228 patients were assigned to receive convalescent plasma and 105 to receive placebo. The median time from the onset of symptoms to enrollment in the trial was 8 days (interquartile range, 5 to 10), and hypoxemia was the most frequent severity criterion for enrollment. The infused convalescent plasma had a median titer of 1:3200 of total SARS-CoV-2 antibodies (interquartile range, 1:800 to 1:3200). No patients were lost to follow-up. At day 30 day, no significant difference was noted between the convalescent plasma group and the placebo group in the distribution of clinical outcomes according to the ordinal scale (odds ratio, 0.83; 95% confidence interval [CI], 0.52 to 1.35; P = 0.46). Overall mortality was 10.96% in the convalescent plasma group and 11.43% in the placebo group, for a risk difference of -0.46 percentage points (95% CI, -7.8 to 6.8). Total SARS-CoV-2 antibody titers tended to be higher in the convalescent plasma group at day 2 after the intervention. Adverse events and serious adverse events were similar in the two groups., Conclusions: No significant differences were observed in clinical status or overall mortality between patients treated with convalescent plasma and those who received placebo. (PlasmAr ClinicalTrials.gov number, NCT04383535.)., (Copyright © 2020 Massachusetts Medical Society.)

Certain Staphylococcus aureus strains exhibit an inoculum effect (InE) with cefazolin (CFZ) that has been associated with therapeutic failures in high-inoculum infections. We assessed the i n vitro activities of ceftaroline (CPT), CFZ, and nafcillin (NAF) against 17 type A β-lactamase (βla)-producing, methicillin-susceptible S. aureus (MSSA) strains, including the previously reported TX0117, which exhibits the CFZ InE, and its βla-cured derivative, TX0117c. Additionally, we determined the pharmacokinetics of CPT in rats after single intramuscular doses of 20 and 40 mg/kg of body weight and evaluated the activities of CPT (40 mg/kg every 8 h [q8h]), CFZ, and NAF against TX0117 and TX0117c in a rat model of infective endocarditis. No InE was observed for CPT or NAF, whereas a marked InE was detected for CFZ (MIC, 8 to ≥128 μg/ml). CPT and NAF treatment against TX0117 resulted in mean bacterial counts of 2.3 and 2.1 log 10 CFU/g in vegetations, respectively, compared to a mean of 5.9 log 10 CFU/g in the CFZ-treated group (CPT and NAF versus CFZ, P = 0.001; CPT versus NAF, P = 0.9830). Both CFZ and CPT were efficacious against the βla-cured derivative, TX0117c, compared to time zero ( t 0 ) ( P = <0.0001 and 0.0015, respectively). Our data reiterate the in vivo consequences of the CFZ InE and show that CPT is not affected by this phenomenon. CPT might be considered for high-inoculum infections caused by MSSA exhibiting the CFZ InE., (Copyright © 2017 American Society for Microbiology.)

Acute bacterial skin and skin structure infections are caused mainly by Gram-positive bacteria which are often treated with intravenous vancomycin, daptomycin, or linezolid, with potential step down to oral linezolid for outpatients. Tedizolid phosphate 200mg once daily treatment for six days demonstrated non-inferior efficacy, with a favourable safety profile, compared with linezolid 600mg twice daily treatment for 10 days in the Phase 3 ESTABLISH-1 and -2 trials. The objective of the current post-hoc analysis of the integrated dataset of ESTABLISH-1 and -2 was to evaluate the efficacy and safety of tedizolid (N=182) vs linezolid (N=171) in patients of Latino origin enrolled into these trials. The baseline demographic characteristics of Latino patients were similar between the two treatment groups. Tedizolid demonstrated comparable efficacy to linezolid at 48-72h in the intent-to-treat population (tedizolid: 80.2% vs linezolid: 81.9%). Sustained clinical success rates were comparable between tedizolid- and linezolid-treated Latino patients at end-of-therapy (tedizolid: 86.8% vs linezolid: 88.9%). Tedizolid phosphate treatment was well tolerated by Latino patients in the safety population with lower abnormal platelet counts at end-of-therapy (tedizolid: 3.4% vs linezolid: 11.3%, p=0.0120) and lower incidence of gastrointestinal adverse events (tedizolid: 16.5% vs linezolid: 23.5%). Population pharmacokinetic analysis suggested that estimated tedizolid exposure measures in Latino patients vs non-Latino patients were similar. These findings demonstrate that tedizolid phosphate 200mg, once daily treatment for six days was efficacious and well tolerated by patients of Latino origin, without warranting dose adjustment., (Copyright © 2016 Elsevier Editora Ltda. All rights reserved.)

A nosocomial polyclonal outbreak associated to bacteremia caused by different Burkholderia cepacia complex (BCC) species and clones is reported. Molecular characterization identified Burkholderia stabilis, Burkholderia contaminans, and Burkholderia ambifaria among BCC isolates obtained from patients in neonatal and adult intensive care units. BCC was also isolated from an intrinsically contaminated ultrasound gel, which constituted the presumptive BCC source. Prior BCC outbreak related to contaminated ultrasound gels have been described in the setting of transrectal prostate biopsy. Outbreak caused strains and/or clones of BCC have been reported, probably because BCC are commonly found in the natural environment; most BCC species are biofilm producers, and different species may contaminate an environmental source. The finding of multiple species or clones during the analysis of nosocomial BCC cases might not be enough to reject an outbreak from a common source., (Copyright © 2015 Elsevier Editora Ltda. All rights reserved.)

Objectives: Clinical failures with cefazolin have been described in high-inoculum infections caused by methicillin-susceptible Staphylococcus aureus (MSSA) producing type A β-lactamase. We investigated the prevalence of the cefazolin inoculum effect (InE) in MSSA from South American hospitals, since cefazolin is used routinely against MSSA due to concerns about the in vivo efficacy of isoxazolyl penicillins., Methods: MSSA isolates were recovered from bloodstream (n = 296) and osteomyelitis (n = 68) infections in two different multicentre surveillance studies performed in 2001-02 and 2006-08 in South American hospitals. We determined standard-inoculum (10(5)cfu/mL) and high-inoculum (10(7) cfu/mL) cefazolin MICs. PFGE was performed on all isolates that exhibited a cefazolin InE. Multilocus sequence typing (MLST) and sequencing of part of blaZ were performed on representative isolates., Results: The overall prevalence of the cefazolin InE was 36% (131 isolates). A high proportion (50%) of MSSA isolates recovered from osteomyelitis infections exhibited the InE, whereas it was observed in 33% of MSSA recovered from bloodstream infections. Interestingly, Ecuador had the highest prevalence of the InE (45%). Strikingly, 63% of MSSA isolates recovered from osteomyelitis infections in Colombia exhibited the InE. MLST revealed that MSSA isolates exhibiting the InE belonged to diverse genetic backgrounds, including ST5, ST8, ST30 and ST45, which correlated with the prevalent methicillin-resistant S. aureus clones circulating in South America. Types A (66%) and C (31%) were the most prevalent β-lactamases., Conclusions: Our results show a high prevalence of the cefazolin InE associated with type A β-lactamase in MSSA isolates from Colombia and Ecuador, suggesting that treatment of deep-seated infections with cefazolin in those countries may be compromised.

Several reports have implicated the inoculum effect that some strains of type A beta-lactamase (Bla)-producing, methicillin-susceptible Staphylococcus aureus (MSSA) show against cefazolin as the cause for clinical failures in certain serious deep-seated infections. Here, using a previously reported MSSA strain displaying this phenotype (TX0117), we obtained a Bla-cured derivative (TX0117c) with a combination of novobiocin and high temperature. Both isolates were then used in a rat endocarditis model and treated with cefazolin, nafcillin, and daptomycin, given to simulate human dosing. Animals were treated for 3 days and either sacrificed at 24 h after the last antibiotic dose (standard group) or left untreated for an additional 3 days (relapse group). With TX0117 in the standard treatment group, daptomycin and nafcillin were both significantly better than cefazolin in reducing CFU/g of vegetations, achieving mean log 10 reductions compared to levels in untreated rats of 7.1, 5.3, and 1.8, respectively (cefazolin versus daptomycin, P < 0.0001; cefazolin versus nafcillin, P = 0.005; daptomycin versus nafcillin, P = 0.053). In addition, cefazolin was significantly more effective in reducing vegetation titers of TX0117c than of TX0117 (mean log 10 reduction of 1.4 versus 5.5, respectively; P = 0.0001). Similar results were observed with animals in the relapse group. Thus, these data show that there can be an in vivo consequence of the in vitro inoculum effect that some MSSA strains display against cefazolin and indicate a specific role for Bla production using a Bla-cured derivative strain against which cefazolin regained both in vitro and in vivo activity., (Copyright © 2013, American Society for Microbiology. All Rights Reserved.)

Treatment options for hospital-acquired pneumonia caused by Gram-positive organisms are far from ideal. The increase in vancomycin MICs among methicillin-resistant Staphylococcus aureus (MRSA) isolates, and the slow bactericidal action and poor lung penetration of vancomycin have driven the search for an alternative agent. Telavancin, a once-daily lipoglycopeptide, displays strong bactericidal activity against S. aureus. Two large Phase III randomized trials have recently compared intravenous telavancin (10 mg/kg every 24 h) with vancomycin (1 g intravenously every 12 h) for 7-21 days for the treatment of hospital-acquired pneumonia caused by Gram positives. No significant differences were observed in the cure rates in the all-treated (n = 1503), the clinically evaluable (n = 654) and the microbiologically evaluable (n =480) populations. Telavancin performed better than vancomycin in patients with monomicrobial S. aureus pneumonia (84.2 vs 74.3%; 95% CI: 0.7-19.1), with MRSA (81.8 vs 74.1%; 95% CI: -3.5 to 19.3), and with strains having vancomycin MICs ≥1 µg/ml (87.1 vs 74.3; 95% CI: 0.5-23). The rate of adverse events, including serious adverse events, was similar in both groups, with a slightly higher rate of serum creatinine increase in the telavancin-treated group. Based on these results, telavancin (already approved for this indication by the EMA) could certainly be added to the current treatment options, particularly in patients with MRSA pneumonia.

Background: Telavancin is a lipoglycopeptide bactericidal against gram-positive pathogens., Methods: Two methodologically identical, double-blind studies (0015 and 0019) were conducted involving patients with hospital-acquired pneumonia (HAP) due to gram-positive pathogens, particularly methicillin-resistant Staphylococcus aureus (MRSA). Patients were randomized 1:1 to telavancin (10 mg/kg every 24 h) or vancomycin (1 g every 12 h) for 7-21 days. The primary end point was clinical response at follow-up/test-of-cure visit., Results: A total of 1503 patients were randomized and received study medication (the all-treated population). In the pooled all-treated population, cure rates with telavancin versus vancomycin were 58.9% versus 59.5% (95% confidence interval [CI] for the difference, -5.6% to 4.3%). In the pooled clinically evaluable population (n = 654), cure rates were 82.4% with telavancin and 80.7% with vancomycin (95% CI for the difference, -4.3% to 7.7%). Treatment with telavancin achieved higher cure rates in patients with monomicrobial S. aureus infection and comparable cure rates in patients with MRSA infection; in patients with mixed gram-positive/gram-negative infections, cure rates were higher in the vancomycin group. Incidence and types of adverse events were comparable between the treatment groups. Mortality rates for telavancin-treated versus vancomycin-treated patients were 21.5% versus 16.6% (95% CI for the difference, -0.7% to 10.6%) for study 0015 and 18.5% versus 20.6% (95% CI for the difference, -7.8% to 3.5%) for study 0019. Increases in serum creatinine level were more common in the telavancin group (16% vs 10%)., Conclusions: The primary end point of the studies was met, indicating that telavancin is noninferior to vancomycin on the basis of clinical response in the treatment of HAP due to gram-positive pathogens.

Using 98 clinical methicillin-susceptible Staphylococcus aureus isolates of known beta-lactamase (Bla) type, we found a pronounced inoculum effect for cephalexin (mostly Bla type A and C strains), a mild inoculum effect for cephalothin (especially types B and C), and no inoculum effects for ceftriaxone and cefuroxime. Ceftobiprole showed the lowest MICs at a high inoculum but with a slight increase for Bla-positive versus Bla-negative strains. Since a potential therapeutic effect associated with a cephalosporin inoculum effect has been described, further studies are warranted.

Importance of the Field: A dramatic increase in infections caused by methicillin-resistant Staphylococcus aureus (MRSA) has been observed, in part as a result of the epidemic of community-associated MRSA skin and skin-structure infections (SSSIs). Simultaneously, decreasing sensitivities of S. aureus to vancomycin have been reported and invasive infections caused by these strains have been associated with worse clinical outcomes. Clearly, new agents active against MRSA are needed. Ceftaroline is a new cephalosporin active against MRSA and many Gram-negative bacteria, though it is not active against Pseudomonas spp. and extended spectrum beta-lactamase producers (ESBL)., Areas Covered in This Review: In this review we focus on the properties of ceftaroline such as in vitro activity, the pharmacokinetic and pharmacodynamic characteristics, and its efficacy and safety observed in the clinical trials of patients with SSSI. Finally, we provide an overview of the possible future role of ceftaroline and other compounds in development for the treatment of SSSIs. The literature search was based on PubMed articles plus review of the abstracts presented in the most important international conferences in the field., What the Reader Will Gain: The reader will gain clear concepts to understand the value that ceftaroline might have in the treatment of SSSIs, including those caused by MRSA., Take Home Message: Ceftaroline has shown bactericidal activity against common pathogens associated with SSSIs including MRSA, noninferiority in clinical trials of patients with complicated SSSI (cSSSI), and a favorable safety profile.

Evaluation of: Lunde CS, Hartouni SR, Janc JW, Mammen M, Humphrey PP, Benton BM: Telavancin disrupts the functional integrity of the bacterial membrane through targeted interaction with the cell wall precursor lipid II. Antimicrob. Agents Chemother. 53, 3375-3383 (2009). It has been previously demonstrated that telavancin has a dual mechanism of action: inhibition of the transglycosylation process of peptidoglycan cell wall synthesis by the formation of a complex with the D-alanyl-D-alanine precursors; and depolarization of the bacterial membrane. In this article the mechanism by which telavancin disrupts the bacterial cell membrane was studied by Lunde and colleagues using a variety of Staphylococcus aureus strains. The authors demonstrated that telavancin-induced depolarization requires both the presence of lipid II as well as an interaction between telavancin and D-alanyl-D-alanine residues. The authors were also able to show that telavancin's depolarization effect on membrane potential occurs in diverse S. aureus strains including those with decreased susceptibility to vancomycin and daptomycin. This study takes a significant step forward in our understanding of the concentration-dependent bactericidal activity of telavancin, a drug recently approved for use in skin and skin structure infections caused by Gram-positive cocci.

Methicillin (meticillin)-susceptible Staphylococcus aureus (MSSA) strains producing large amounts of type A beta-lactamase (Bla) have been associated with cefazolin failures, but the frequency and impact of these strains have not been well studied. Here we examined 98 MSSA clinical isolates and found that 26% produced type A Bla, 15% type B, 46% type C, and none type D and that 13% lacked blaZ. The cefazolin MIC(90) was 2 microg/ml for a standard inoculum and 32 microg/ml for a high inoculum, with 19% of isolates displaying a pronounced inoculum effect (MICs of >or=16 microg/ml with 10(7) CFU/ml) (9 type A and 10 type C Bla producers). At the high inoculum, type A producers displayed higher cefazolin MICs than type B or C producers, while type B and C producers displayed higher cefamandole MICs. Among isolates from hemodialysis patients with MSSA bacteremia, three from the six patients who experienced cefazolin failure showed a cefazolin inoculum effect, while none from the six patients successfully treated with cefazolin showed an inoculum effect, suggesting an association between these strains and cefazolin failure (P = 0.09 by Fisher's exact test). In summary, 19% of MSSA clinical isolates showed a pronounced inoculum effect with cefazolin, a phenomenon that could explain the cases of cefazolin failure previously reported for hemodialysis patients with MSSA bacteremia. These results suggest that for serious MSSA infections, the presence of a significant inoculum effect with cefazolin could be associated with clinical failure in patients treated with this cephalosporin, particularly when it is used at low doses.

The increase in infections caused by resistant Gram-positive organisms has led to an urgent need for new antibiotics. Telavancin is a rapidly bactericidal lipoglycopeptide with multiple mechanisms of action, including concentration-dependent inhibition of bacterial cell wall synthesis and disruption of the functional integrity of the cell membrane. Telavancin is active against a wide variety of Gram-positive organisms including Staphylococcus aureus with resistance to methicillin, reduced susceptibility to vancomycin, and full resistance to vancomycin. Telavacin is approximately 90% protein bound; it has a serum half-life of around 8 h and a prolonged postantibiotic effect, allowing once daily administration. Telavancin is eliminated principally through the urine, requiring dose adjustment in patients with renal impairment. The efficacy and safety of telavancin was demonstrated in a large program of patients with complicated skin and skin structure infections. Development of resistance has not been detected in clinical strains. Adverse events include taste disturbance, nausea and vomiting; a small proportion of patients experienced reversible increase in serum creatinine. Two large Phase III studies in patients with healthcare associated pneumonia were recently completed. Telavancin has the potential to become an important therapeutic option to treat serious infections produced by resistant Gram-positive cocci, particularly those caused by methicillin-resistant S. aureus.

In the current study, the gls24 disruption mutant TX10100, previously shown to be more sensitive to bile salts and attenuated in a mouse peritonitis model, showed an approximately fivefold higher 50% infective dose than wild-type OG1RF in a rat endocarditis model. When administered as a mixture, TX10100, unlike a downstream glsB mutant, was significantly outnumbered by OG1RF in vegetations, organs, and blood, despite being inoculated in greater numbers. These results indicate that gls24 is important in the pathogenesis of enterococcal endocarditis.

An Enterococcus faecalis gelE insertion disruption mutant (TX5128), which produces neither gelatinase (GelE) nor the cotranscribed (in the wild type) serine protease (SprE), was found to be attenuated in a rat endocarditis model with a significant decrease in the endocarditis induction rate versus wild-type E. faecalis OG1RF (GelE(+), SprE(+)). TX5266, which has a nonpolar deletion in fsrB and, like TX5128, is phenotypically GelE(-) under usual conditions, was also studied; fsrB is a homologue of agrB of staphylococci and participates in regulation of gelE-sprE expression. Unexpectedly, TX5266 approximated wild-type OG1RF in the endocarditis model and was significantly less attenuated than TX5128. This is in contrast to other models which have found fsr mutants to be as or more attenuated than TX5128. Further study found that the fsrB mutant produced very low levels of gelatinase activity after prolonged incubation in vitro versus no gelatinase activity with TX5128 and did not show the extensive chaining characteristic of TX5128. Reverse transcription-PCR confirmed that gelE was expressed in TX5266 at a very low level versus wild-type OG1RF and was not expressed at all in TX5128. Possible explanations for the increased induction of endocarditis by TX5266 versus TX5128 include the production of low levels of protease(s) or some other effect(s) of the inactivation of the E. faecalis fsr regulator. The equivalent ability of OG1RF and its fsr mutant to initiate endocarditis may explain why we did not find naturally occurring fsr mutants, which account for ca. 35% of E. faecalis isolates, unrepresented in endocarditis versus fecal isolates.

Gls24 was previously identified as a general stress protein of Enterococcus faecalis. In the present study, we found that a gls24 disruption mutant (TX10100) of E. faecalis strain OG1RF showed a considerably increased 50% lethal dose in a mouse peritonitis model, and, at high inocula, TX10100 was either not lethal or was much less so than wild-type OG1RF (P<.001). TX10100 was also more sensitive to bile salts (mean+/-SD survival rate relative to wild-type OG1RF, 9.7%+/-2.0%) at late stationary phase, as previously found by Giard et al. with another strain. Inactivation of glsB, downstream of and cotranscribed with gls24, had no effect on E. faecalis virulence but resulted in reduced bile-salts resistance (to a mean+/-SD survival rate of 28.0%+/-5.1%) relative to wild-type OG1RF. Results of complementation of TX10100 with different combinations of gls24-glsB and 2 promoters--a remote promoter (P1) and an adjacent promoter (P2)--suggested that both genes and both promoters, especially P1, are important for bile-salts resistance. Anti-Gls24 immune rabbit serum, which showed some Gls24 on the cell surface, protected mice against a lethal challenge of OG1RF in the peritonitis model (e.g., survival of 12/18 mice vs. 1/18 mice with preimmune rabbit serum; P=.008). In conclusion, the E. faecalis gls24 gene is important for virulence as well as stress response, and anti-Gls24 immune rabbit serum shows protection against E. faecalis infection in a mouse peritonitis model.

Background: In advance of a large clinical end point trial evaluating the effectiveness of subcutaneous interleukin 2 (scIL-2) for treatment of patients with human immunodeficiency virus (HIV) infection, 3 identically designed Vanguard trials were conducted in Buenos Aires, Argentina; Bangkok, Thailand; and Houston, Texas. To more precisely quantitate the effect on CD4 cell response of 3 different doses of scIL-2 that were administered twice daily for 5 days every 8 weeks, the results of these 3 trials were pooled in a meta-analysis., Methods: Two hundred eighteen HIV-1-infected subjects who were receiving antiretroviral therapy and who had a baseline CD4 cell count of > or =350 cells/mm3 were consecutively randomized to receive scIL-2 at a dose of 1.5 mIU (n=36) or a control regimen (n=36); or scIL-2 at a dose of 4.5 mIU (n=36) or a control regimen (n=36); or scIL-2 at a dose of 7.5 mIU (n=37) or a control regimen (n=37). After completion of 3 cycles of therapy, the subjects were enrolled in an extension phase (months 6-12). Subjects were encouraged to receive additional cycles of scIL-2 to maintain a CD4 cell count of more than twice the baseline count or >1000 cells/mm3., Results: After completion of 3 cycles of scIL-2, the mean CD4 cell count changes from baseline (calculated as changes from baseline in a scIL-2 group minus changes from baseline in its contemporaneous control group) were 67 (P=.14), 339 (P<.0001), and 605 cells/mm3 (P<.0001) for the 1.5, 4.5, and 7.5 mIU dose groups, respectively (P<.0001 for differences among dose groups). Between months 6 and 12, a total of 78%, 39%, and 32% of subjects assigned to the 1.5, 4.5, and 7.5 mIU dose groups, respectively, needed at least 1 additional cycle to achieve the CD4 cell count goal. At 12 months, the differences in the mean change in CD4 cell count from baseline between each scIL-2 dose group and its contemporaneous control group were 184, 369, and 432 cells/mm3, respectively (P=.01 for differences among dose groups)., Conclusions: Although CD4 cell count increases were seen in all 3 dose groups, higher scIL-2 doses resulted in greater CD4 cell count changes after 6 months, compared with control groups.

Our experience with a patient with methicillin-susceptible Staphylococcus aureus aortic native valve endocarditis, who had a relapse involving fever and positive blood culture results while receiving cefazolin, led us to evaluate this organism's ability to hydrolyze cefazolin at high inocula, a previously well-documented phenomenon. Analysis of the infecting strain disclosed a high minimum inhibitory concentration of cefazolin when a large inoculum was used, as well as rapid and complete cefazolin degradation, which was associated with regrowth in a time-kill experiment. DNA sequencing of the beta-lactamase gene showed that it was identical to that of the S. aureus type A beta-lactamase, known to efficiently inactivate cefazolin. A word of caution is given regarding the use of this antibiotic for treatment of endocarditis caused by this type of S. aureus isolate.

Fungal peritonitis in patients on continuous ambulatory peritoneal dialysis (CAPD) has been associated with high mortality and high CAPD-discontinuation rates. Most cases are due to Candida spp. while Aspergillus spp. and zygomycetes have only rarely been implicated. We report one case each of CAPD-related peritonitis caused by Aspergillus terreus and Mucor sp., which have previously been described in the literature once and twice, respectively. The former had a slowly progressive course, did not respond to amphotericin B (AB), and died; the latter improved after a prolonged course of liposomal-AB. Among reported cases of CAPD-related peritonitis due to molds (22 Aspergillus spp. and seven zygomycetes), previous bacterial peritonitis was a common event, the related mortality associated with Aspergillus and zygomycetes was 27% and 57%, respectively, prompt removal of the Tenckoff catheter was critical for survival, and most patients were not able to resume CAPD.

A novel glycylcycline agent, tigecycline (GAR-936), was evaluated in vivo in the mouse model of peritonitis against three Enterococcus faecalis and four Enterococcus faecium isolates with different susceptibilities to vancomycin and tetracyclines, all of which were inhibited by

The gut and its gut-associated lymphoid tissue serve as a preferential site for HIV1 entry, active viral replication, reservoir, and HIV-mediated CD4 cell apoptosis. The widespread use of highly active antiretroviral therapy (HAART) has resulted in a significant decrease in the incidence of opportunistic enteric pathogens as a consequence of immune recovery. Nonetheless, patients with advanced HIV1 disease who were recently diagnosed or have poor response to HAART can still suffer from opportunistic infections with pathogens such as Cryptosporidium, microsporidia, Isospora belli, Cyclospora cayetanensis, Mycobacterium avium complex, and cytomegalovirus, among others. This review describes the impact of HIV1 infection on gut immune function, the salient features of the most common opportunistic enteric pathogens and HIV-associated enteropathy, and the effects of immune reconstitution after introduction of HAART.

Execpt in patients with AIDS, disseminated MAC infection has been rare. We describe a patient with chronic lymphatic leukemia who developed disseminated cutaneous MAC lesions refractory to conventional antimycrobial therapy. The lesions responded to the addition of compounds that were recently discovered to have anti-MAC activity (linezolid, moxifloxacin) as well as GM-CSF., (Copyright 2002 The British Infection Society.)