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ABSTRACTSeveral 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 log10reductions 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 log10reduction 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 vivoconsequence of the in vitroinoculum 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 vitroand in vivoactivity.

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. aureusto 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 Pseudomonasspp. and extended spectrum β-lactamase producers (ESBL).Areas covered in this review:In this review we focus on the properties of ceftaroline such as in vitroactivity, 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.

ABSTRACTMethicillin (meticillin)-susceptible Staphylococcus aureus(MSSA) strains producing large amounts of type A β-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 MIC90was 2 μg/ml for a standard inoculum and 32 μg/ml for a high inoculum, with 19% of isolates displaying a pronounced inoculum effect (MICs of ≥16 μg/ml with 107CFU/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 aureuswith 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.

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 (J. C. Roberts, K. V. Singh, P. C. Okhuysen, and B. E. Murray, J. Clin. Microbiol. 42:2317-2320, 2004).

ABSTRACTAn Enterococcus faecalis gelEinsertion 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. faecalisOG1RF (GelE+, SprE+). TX5266, which has a nonpolar deletion in fsrBand, like TX5128, is phenotypically GelE−under usual conditions, was also studied; fsrBis a homologue of agrBof staphylococci and participates in regulation of gelE-sprEexpression. 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 fsrmutants to be as or more attenuated than TX5128. Further study found that the fsrBmutant 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 gelEwas 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 fsrregulator. The equivalent ability of OG1RF and its fsrmutant to initiate endocarditis may explain why we did not find naturally occurring fsrmutants, which account for ca. 35% of E. faecalisisolates, unrepresented in endocarditis versus fecal isolates (J. C. Roberts, K. V. Singh, P. C. Okhuysen, and B. E. Murray, J. Clin. Microbiol. 42:2317-2320, 2004).

ABSTRACTA novel glycylcycline agent, tigecycline (GAR-936), was evaluated in vivo in the mouse model of peritonitis against three Enterococcus faecalisand four Enterococcus faeciumisolates with different susceptibilities to vancomycin and tetracyclines, all of which were inhibited by ≤0.125 μg of tigecycline/ml. Using a single subcutaneous dose, tigecycline displayed a protective effect (50% protective dose, ≤5.7 mg/kg of body weight) against all strains tested, including two with Tn925(from the Tn916family), which contains the Tet(M) tetracycline resistance determinant, as well as VanA and VanB strains. As expected, tetracycline and minocycline were ineffective against the isolates carrying Tn925.

ABSTRACTUsing 98 clinical methicillin-susceptible Staphylococcus aureusisolates of known β-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.

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.

ABSTRACTIn the current study, the gls24disruption 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 glsBmutant, was significantly outnumbered by OG1RF in vegetations, organs, and blood, despite being inoculated in greater numbers. These results indicate that gls24is important in the pathogenesis of enterococcal endocarditis.

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.

ABSTRACTCertain Staphylococcus aureusstrains exhibit an inoculum effect (InE) with cefazolin (CFZ) that has been associated with therapeutic failures in high-inoculum infections. We assessed the in vitroactivities 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 log10CFU/g in vegetations, respectively, compared to a mean of 5.9 log10CFU/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 (t0) (P= <0.0001 and 0.0015, respectively). Our data reiterate the in vivoconsequences 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.