Archive for November, 2010
MMWR Nov 30, 2010 V.59 Early Release
IV testing and linkage to care are essential to identify persons early in their course of infection to prevent progression to AIDS and death and to reduce transmission. CDC used 2001–2009 data from the National Health Interview Survey to estimate percentages of persons aged 18–64 years who reported ever being tested for HIV in the United States. The results of that analysis indicate that the number of persons in the United States who report ever being tested for HIV is increasing, and fewer persons are being diagnosed late in their infection. However, nearly one third of diagnoses still occur late. Increased testing efforts are needed, particularly among populations that account for most HIV diagnoses.
Journal of Antimicrobial Chemotherapy November 2010 V.65 Suppl 4
The problem of complicated skin and skin structure infections: the need for new agents
Robert C. Moellering Jr
Harvard Medical School and Department of Medicine, Beth Israel Deaconess Medical Center, 110 Francis Street, Suite 6A, Boston, MA 02215, USA
Complicated skin and skin structure infections (cSSSIs) continue to pose a significant clinical challenge. The most frequent cause of these infections is Staphylococcus aureus, although other organisms, including Streptococcus pyogenes and, in certain circumstances, Enterobacteriaceae, are also involved. The relentless increase in methicillin resistance among S. aureus isolated in hospitals throughout the world has made it important to provide coverage for these organisms when treating cSSSIs in hospitals. More recently, however, there has been a striking increase in methicillin resistance among staphylococci isolated from infections acquired in the community, particularly in the USA. As a result, previous recommendations for empirical therapy of these important infections are now outdated. The papers in this Supplement detail the properties of a new broad-spectrum cephalosporin that has activity against MRSA and is, thus, an outstanding candidate for empirical therapy of cSSSIs. The papers included provide data on the in vitro activity, pharmacokinetics and pharmacodynamics as well as the clinical efficacy of ceftaroline fosamil, which is a welcome addition to our therapeutic armamentarium against cSSSIs.
Ceftaroline fosamil: a novel broad-spectrum cephalosporin with expanded anti-Gram-positive activity
Donald Biek1,*, Ian A. Critchley1, Todd A. Riccobene2 and Dirk A. Thye1
1Cerexa, Inc., 2100 Franklin St, Ste 900, Oakland, CA 94612, USA
2Forest Research Institute, Inc., Jersey City, NJ 07311, USA
Ceftaroline fosamil is a novel cephalosporin with broad-spectrum activity against Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Streptococcus pneumoniae, and common Gram-negative organisms. The activity of ceftaroline against MRSA is attributed to its ability to bind to penicillin-binding protein (PBP) 2a with high affinity and inhibit the biochemical activity of PBP 2a more efficiently than other presently available β-lactams. The activity of ceftaroline against MRSA and the β-haemolytic streptococci makes it an attractive monotherapy agent for the treatment of complicated skin and skin structure infections (cSSSIs). Recent profiling and surveillance studies have shown that ceftaroline is active against contemporary skin pathogens collected from US and European medical centres in 2008. The mean free drug %T > MIC (percentage of time the drug concentration remains above the MIC) needed for stasis ranged from 26% for S. aureus to 39% for S. pneumoniae in the murine thigh infection model. Pharmacokinetic and pharmacodynamic target attainment predictions for 600 mg of ceftaroline fosamil every 12 h showed that the mean %T > MICs for which plasma free-drug concentrations exceeded an MIC of 1 and 2 mg/L were 71% and 51% of the dosing interval, respectively. For a 40% T > MIC target, the predicted attainments for infections due to pathogens for which ceftaroline MICs were 1 or 2 mg/L were 100% and 90%, respectively. Clinical and microbiological successes of ceftaroline fosamil in treating cSSSIs were demonstrated in two Phase III clinical studies, in which 96.8% of all baseline cSSSI isolates from the microbiologically evaluable population were inhibited by ceftaroline at ≤2 mg/L. Ceftaroline fosamil is a promising broad-spectrum agent for the treatment of cSSSIs.
Ceftaroline activity against pathogens associated with complicated skin and skin structure infections: results from an international surveillance study
Ronald N. Jones1,2,*, Rodrigo E. Mendes1 and Helio S. Sader1
1JMI Laboratories, 345 Beaver Kreek Centre, Suite A, North Liberty, IA 52317, USA
2Tufts University School of Medicine, Boston, MA 02111, USA
To assess the spectrum and potency of ceftaroline, a novel anti-methicillin-resistant staphylococcal cephalosporin, against a 2008 surveillance collection of clinical isolates from patients in the USA and Europe.
A collection of 14 169 isolates of various bacterial species from complicated skin and skin structure infections (cSSSIs) was tested for susceptibility to ceftaroline and 19 comparator agents in a central reference laboratory using CLSI broth microdilution methods. Organisms were received from 55 medical centres; 27 in the USA and 28 in Europe (12 countries, including Israel). The clonality of isolates of Staphylococcus aureus with elevated ceftaroline MICs (4 mg/L) was determined by PFGE and single and multilocus sequence typing, and the mechanism of ceftaroline non-susceptibility was assessed by molecular methods (PCR amplification and sequencing).
Ceftaroline, the active component of the parenteral prodrug ceftaroline fosamil, was active against 2988 methicillin-resistant S. aureus (MRSA) isolates, with an MIC90 of 1 mg/L. The MIC90 for methicillin-susceptible strains was 0.25–0.5 mg/L. Ceftaroline was additionally active against coagulase-negative staphylococci (MIC90, 0.5–1 mg/L), Enterococcus faecalis (MIC50, 2 mg/L), β-haemolytic and viridans group streptococci (MIC90, 0.015–0.25 mg/L) and three commonly isolated Enterobacteriaceae (Escherichia coli, Klebsiella spp. and Proteus mirabilis; MIC90 values of 0.25 to >16 mg/L). All but four isolates of MRSA (0.13%) had ceftaroline MIC values of ≤2 mg/L. The isolates for which ceftaroline MICs were 4 mg/L were clonal (single Greek hospital) and had detectable mecA mutations (N146K, N204K, E150K and H351N).
The ceftaroline yearly (2008) surveillance for the USA and Europe documented low MIC50/90 values for MRSA isolates at 1/1 and 1/2 mg/L, respectively. Ceftaroline demonstrated promising potency and coverage against Gram-positive and -negative pathogens known to cause cSSSIs, including MRSA and β-haemolytic streptococci.
Pharmacodynamics of ceftaroline fosamil for complicated skin and skin structure infection: rationale for improved anti-methicillin-resistant Staphylococcus aureus activity
George L. Drusano
Ordway Research Institute, 150 New Scotland Avenue, Albany, NY 12208, USA
Ceftaroline fosamil is a new β-lactam antibiotic with an altered 3′ side chain that allows it to interact with penicillin-binding protein (PBP) 2a, resulting in lower MIC values for methicillin-resistant Staphylococcus aureus (MRSA). Large MRSA collections repeatedly demonstrate MIC90 values of 1 mg/L. The pharmacokinetics for ceftaroline fosamil are straightforward and reminiscent of many other cephalosporin antibiotics, with a terminal half-life of ∼2.6 h. Pharmacodynamic evaluation demonstrates that relatively short free drug T > MIC results in stasis or 1 log10 cfu/g bacterial kill (mean values for four S. aureus isolates of 26% and 33% of the dosing interval, respectively). Monte Carlo simulation demonstrated high expected target attainment rates (>97%) and clinical trial data showed clinically evaluable and microbiologically evaluable cure rates (96.7%) that are highly concordant with the pharmacodynamic analyses. Clinical trial data for ceftaroline fosamil are in excellent concordance with the pharmacodynamic analysis. Ceftaroline fosamil at a dose of 600 mg administered intravenously every 12 h is highly likely to be successful in clinical practice for treatment of complicated skin and skin structure infections.
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Journal of the American Academy of Dermatology 12/Oct/2010
Margot Whitfeld FACD, MBBSa, b, , , Nishmi Gunasingam MBBSa, Liang Joo Leow MBBSc, Kyoko Shirato MBBSd and Veronica Preda MBBS BSc (Hons)a, b
a Department of Dermatology, St Vincent’s Hospital, Darlinghurst, Sydney, Australia
b Skin and Cancer Foundation of Australia, Darlinghurst, Sydney, Australia
c Peter McCallum Institute Melbourne, Australia
d Royal Adelaide Hospital, Adelaide, Australia
Rosacea is a common skin and ocular disease. Cutaneous rosacea is characterized by facial flushing, telangiectasia, papules, and pustules. It is generally regarded as inflammatory in nature. We believed that the role of bacteria as a contributory factor in pustular and ocular rosacea needed to be revisited.
We sought to ascertain whether there is an increase in the bacteria isolated from the (1) pustules of rosacea; and (2) eyelid margins of persons with cutaneous pustular rosacea.
Bacterial swabs were taken and cultured from an incised rosacea pustule, the ipsilateral cheek skin, and the eyelid margin of 15 patients with pustular rosacea. Swabs were also taken from the cheek skin and ipsilateral eyelid margin of 15 matched control subjects.
A pure growth of Staphylococcus epidermidis was isolated from a pustule of 9 of 15 patients with pustular rosacea, and no pure growth of S epidermidis was isolated from their ipsilateral cheek skin. This was a highly statistically significant increase (P = .0003). A pure growth of S epidermidis was isolated from the eyelid margins of 4 of 15 patients with pustular rosacea, and no pure growth was isolated from the eyelids of age- and sex-matched control subjects. This was a statistically significant increase (P = .05).
This study focuses on the microbial basis of rosacea.
Our findings suggest S epidermidis may play a role in pustular and ocular rosacea.
Rebound of plasma viremia following cessation of antiretroviral therapy despite profoundly low levels of HIV reservoir: implications for eradication.
AIDS. 2010 Nov 27 V.24 N.18 p.2803-8.
Chun TW, Justement JS, Murray D, Hallahan CW, Maenza J, Collier AC, Sheth PM, Kaul R, Ostrowski M, Moir S, Kovacs C, Fauci AS.
aNational Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA bDepartment of Medicine, University of Washington School of Medicine, Seattle, Washington, USA cDepartment of Medicine, University of Toronto, Toronto, Ontario, Canada.
Sustained suppression of plasma viremia in HIV-infected individuals is attainable with antiretroviral therapy (ART); however, eradication of virus that would allow discontinuation of ART has been hampered by the persistence of HIV reservoirs. It is of great interest to identify individuals who had received ART for prolonged periods of time with extremely low or undetectable HIV reservoirs and monitor plasma viremia following discontinuation of therapy.
We measured the size of HIV reservoirs in CD4 T cells of individuals on long-term ART and monitored plasma viremia following cessation of ART in one individual with an exceptionally low viral burden after a decade of therapy.
We demonstrated undetectable levels of HIV DNA in the blood of eight of 45 infected individuals on long-term ART. Among those eight individuals, the frequency of cells carrying infectious virus was significantly lower in those who initiated ART during the early versus the chronic phase of infection. One individual with undetectable HIV DNA in both blood and tissue and a profoundly low level of infectious virus experienced plasma viral rebound 50 days following discontinuation of ART.
Our data suggest that a significant reduction in the size of viral reservoirs may be achievable in selected individuals who initiate standard ART early in infection. However, given re-emergence of plasma viremia in an individual with an extraordinarily low viral burden, therapeutic strategies aimed at specifically targeting these extremely rare HIV-infected cells with novel interventions may be necessary in order to achieve eradication of virus.
Role of primary prophylaxis for pneumocystis pneumonia in patients treated with systemic corticosteroids or other immunosuppressive agents for immune-mediated dermatologic conditions.
J Am Acad Dermatol. 2010 Nov V.63 N.5 p.815-23.
Lehman JS, Kalaaji AN.
Department of Dermatology, Mayo Clinic, Rochester, Minnesota 55905, USA.
The incidence of pneumocystis pneumonia (PCP), an opportunistic infection caused by Pneumocystis jiroveci, in patients taking immunosuppressive medications for dermatologic indications is unknown.
We sought to define the incidence of PCP in patients with dermatologic conditions, to characterize risk factors for PCP development in these patients, to examine PCP prophylaxis practices among dermatologists, and to document adverse effects of PCP prophylaxis medications.
We reviewed the medical records of patients taking immunosuppressive medications for longer than 1 month who were treated for dermatologic conditions between 1998 and 2007 at Mayo Clinic, Rochester, MN.
Of 198 patients meeting inclusion criteria (150 [75.8%] of whom received no PCP prophylaxis), one patient (0.5% and 0.7%, respectively) had PCP that developed during the follow-up period. In this patient, a 94-year-old woman with bullous pemphigoid, severe interstitial pulmonary fibrosis, aortic stenosis, and hypoalbuminemia, PCP developed within 7 months of diagnosis and was treated with methotrexate and prednisone. She had not received PCP prophylaxis. Only 6 patients (3%) with dermatology as their primary service received PCP prophylaxis. Overall, rates of adverse effects with PCP prophylaxis were low.
The study design was retrospective. Low rates of PCP precluded our development of concrete PCP prophylaxis guidelines.
Results did not support routine administration of PCP prophylaxis in all patients taking immunosuppressive medications. When prescribing immunosuppressive medications for dermatologic indications, physicians should consider PCP prophylaxis on a case-by-case basis.