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LytPhage Presents at 1st Pitch Life Sciences-Philadelphia-September 16, 2014

LytPhage presented at Mid-Atlantic BioAngels 1st Pitch Life Sciences in  Philadelphia Tuesday Sept. 16, 2014.

LytPhage is a new biotech company using novel bioengineering to develop therapeutics to address the worldwide crisis of antibiotic resistant organisms.  They are developing a treatment for vancomycin resistant systemic infections with their platform, which can be adapted for other problematic organisms.  LytPhage is a spin-out form Temple University.

The overall goal is to use genetically modified bacteriophage (bacterial viruses) as an antimicrobial therapy against drug-resistant strains.  Their genetically modifed viruses are only lytic, meaning they result in cell death of the host but do not integrate in the host DNA.  In additon preliminary studies using mainly clinical isolates have shown good efficacy against most drug-resistant strains found in common hospital infections like Clostridium difficile colitis.  The presenters noted that bacteriophage therapy had successfully been used in Europe but no approved therapy in US

For more information about this meeting please see posting on this site

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High Risk of Transmissible Disease and Mortality in Cancer, Advanced Cardiovascular Disease, and Hemodialysis Patients

Curator: Larry H Bernstein, MD, FCAP

This contribution is aimed at three situations of special concern with respect to transmission and handling of episodic bacteria or virus spread in hospital and ambulatory healthcare settings, where healthcare workers may be exposed and either become ill or are potential carriers of the disease.  Not discussed is a report in the last week of an association between human papilloma virus (HPV), known to be associated with cervical cancer, and oropharyngeal cancer.   In all of these situations, the patients at highest risk of death are immune compromized, carry a heavy burden of unbalanced oxidative stress, and have mitcochondrial dysfunction from unbalanced ubiquitination and repair.

Clostridium Difficile Colitis

Faten N Aberra, MD, MSCE; Chief Editor: Julian Katz, MD
Medscape – Practice Essentials

Clostridium difficile colitis results from a disturbance of the normal bacterial flora of the colon, colonization by C difficile, and the release of toxins that cause mucosal inflammation and damage. Antibiotic therapy is the key factor that alters the colonic flora. C difficile infection primarily occurs in hospitalized patients.

Essential update: Fidaxomicin superior to vancomycin for cancer patients with C difficile

In a multicenter study including 1105 subjects with C difficile – associated diarrhea, 183 of whom had solid tumors or hematologic malignancies, fidaxomicin treatment was superior to vancomycin treatment in cancer patients, resulting in higher cure and sustained response rates, shorter time to resolution of diarrhea (TTROD), and fewer recurrences.  Cure rates were lower overall in cancer patients than in others (79.2% vs 88.6%; P < 0.001).[2Whereas cure rates for noncancer patients were approximately the same with fidaxomicin as with vancomycin (88.5% vs 88.7%), those for cancer patients were higher with fidaxomicin than with vancomycin (85.1% vs 74.0%), though the difference was not statistically significant. Median TTRODs in noncancer patients were 54 hours with fidaxomicin and 58 with vancomycin; those in cancer patients were 74 and 123 hours, respectively.  The risk of recurrence was approximately twice as high with vancomycin as with fidaxomicin, regardless of whether patients had cancer or not, but because both cure and recurrence outcomes were better with fidaxomicin than with vacomycin in cancer patients, the relative odds of sustained response at 28 days in these patients were more than 2.5-fold higher for fidaxomicin than for vancomycin.

Background

Clostridium difficile is a gram-positive, anaerobic, spore-forming bacillus that is responsible for the development of antibiotic-associated diarrhea and colitis. C difficile was first described in 1935 as a component of the fecal flora of healthy newborns and was initially not thought to be a pathogen. It was named difficile because it grows slowly and is difficult to culture. While early investigators noted that the bacterium produced a potent toxin, the role of C difficile in antibiotic-associated diarrhea and pseudomembranous colitis was not elucidated until the 1970s.
Approximately 20% of individuals who are hospitalized acquire C difficile during hospitalization, and more than 30% of these patients develop diarrhea. Thus, C difficile colitis is currently one of the most common nosocomial infections.
The diagnosis of C difficile colitis should be suspected in any patient with diarrhea who has received antibiotics within the previous 2 months and/or when diarrhea occurs 72 hours or more after hospitalization.

Pathophysiology

Colonization occurs by the fecal-oral route. C difficile forms heat-resistant spores that can persist in the environment for several months to years. Outbreaks of C difficile diarrhea may occur in hospitals and other outpatient facilities where contamination with spores is prevalent. Normal gut flora resists colonization and overgrowth with C difficile. Antibiotic use, which suppresses the normal flora, allows proliferation of C difficile.
Pathogenic strains of C difficile produce 2 distinct toxins. Toxin A is an enterotoxin, and toxin B is a cytotoxin. Both are high–molecular weight proteins capable of binding to specific receptors on the intestinal mucosal cells. Receptor-bound toxins gain intracellular entry where they catalyze a specific alteration of Rho proteins, small glutamyl transpeptidase (GTP)–binding proteins that assist in actin polymerization, cytoskeletal architecture, and cell movement. Both toxin A and toxin B appear to play a role in the pathogenesis of C difficile colitis in humans.

Epidemiology

Although the incidence of other nosocomial infections declined from 2000-2009, the number of hospitalized patients with any C difficile infection discharge diagnosis more than doubled, from approximately 139,000 to 336,600. The number of patients with a primary C difficile infection diagnosis more than tripled, from 33,000 to 111,000.
Among C difficile infections identified in the Centers for Disease Control and Prevention’s (CDC’s) Emerging Infections Program data in 2010, 94% were associated with receiving health care; of these, 75% had onset among persons not currently hospitalized, including recently discharged patients, outpatients, and nursing home residents

Diagnosis

http://img.medscape.com/pi/emed/ckb/gastroenterology/169972-186458-3532tn.jpg

Physical examination may reveal the following in patients with the disorder:
  • Fever: Especially in more severe cases
  • Dehydration
  • Lower abdominal tenderness
  • Rebound tenderness: Raises the possibility of colonic perforation and peritonitis

Laboratory studies

  • Lab tests for evaluating patients with C difficile infection include the following:
  • Electrolytes: Dehydration and electrolyte imbalance may accompany severe disease
  • Albumin: Hypoalbuminemia and anasarca may accompany severe disease
    • Transthyretin is the serum protein of choice for a rapid onset diarrhea with dehydration leading to weight loss, dehydration, anasarca and sarcopenia, as it has a serum half-life of ~ 48 hrs rather than 21 days, and it is an accurate measure of lean body mass.
  • Complete blood count: Leukocytosis may be present
  • Stool examination: Stool may be Hemoccult positive in severe colitis, but grossly bloody stools are unusual; fecal leukocytes are present in about half of cases
  • Stool assays for C difficile, from the most to the least sensitive, include the following:
  1. Stool culture: The most sensitive test (sensitivity, 90-100%; specificity, 84-100%), but the results are slow and may lead to a delay in the diagnosis if used alone
  2. Glutamate dehydrogenase enzyme immunoassay (EIA): Very sensitive (sensitivity, 85-100%; specificity, 87-98%); this test detects the presence of glutamate dehydrogenase produced by C difficile
  3. Real-time polymerase chain reaction (PCR) assay: May be used to detect C difficile gene toxin
  4. The stool cytotoxin test: Has a sensitivity of 70-100% and a specificity of 90-100%; a positive test result is the demonstration of a cytopathic effect that is neutralized by a specific antiserum
  5. Enzyme immunoassay for detecting toxins A and B: Used in most labs; the sensitivity is moderate (79-80%), and the specificity is excellent (98%)
  6. Latex agglutination technique: Another means of detecting glutamate dehydrogenase; the sensitivity of this test is poor (48-59%), although the specificity is 95-96%

Management

Treatment for C difficile infection varies according to its severity. Interventions include the following:
  • Asymptomatic carriers: No treatment necessary
  • Mild, antibiotic-associated diarrhea without fever, abdominal pain, or leukocytosis: Cessation may be the only treatment necessary
  • Mild to moderate diarrhea or colitis: Metronidazole (oral or intravenous) or vancomycin (oral) for 10 days
Severe disease: Vancomycin is considered to produce faster symptom resolution and fewer treatment failures than metronidazole; in fulminant cases, combined therapy with intravenous metronidazole and oral vancomycin may be considered

Relapse

Relapse occurs in 20-27% of patients treated with metronidazole or vancomycin. Once a patient has one relapse, the risk for a second relapse is 45%. Relapses should be treated as follows:
  • First relapse: The choice of antibiotic should be based on the severity of C difficile diarrhea/colitis
  • Subsequent relapses: For every relapse beyond the first, vancomycin (prolonged taper/pulsed regimen) is recommended to help clear persistent spores
Among various investigational therapies, fecal transplantation (fecal enemas or infusion of donor feces through a nasoduodenal tube) has been reported to repopulate the colonic flora and treat recurrent C difficile infection.

Staphylococcus Aureus Infection

Robert W Tolan Jr, MD; Chief Editor: Russell W Steele, MD
http://emedicine.medscape.com/article/971358-overview?src=wnl_ref_prac_infd&uac=62859DN

Rise of methicillin and vancomycin-resistance

Both community-associated and hospital-acquired infections with Staphylococcus aureus have increased in the past 20 years, and the rise in incidence has been accompanied by a rise in antibiotic-resistant strains—in particular, methicillin-resistant S aureus (MRSA) and, more recently, vancomycin-resistant strains.

Essential update: Universal decolonization more effective than screening and isolation in reducing rates of MRSA

Daily washing of ICU patients with chlorhexidine-impregnated cloths reduced positive cultures of MRSA by 37% and reduced bloodstream infection by any pathogen by 44%, according to a study of 74,256 patients in 74 adult ICUs.
In the study, hospitals were randomized to 18 months of either screening for MRSA followed by isolation of positive patients, targeted decolonization of MRSA-positive patients and isolation, or universal decolonization of all ICU patients without screening. Decolonization was achieved via daily cleansing with chlorhexidine-impregnated cloths and 5 days of twice-daily intranasal mupirocin treatments. At baseline, there was no significant difference in the rate of MRSA infections between the 3 groups.  However, patients who underwent universal decolonization showed a significantly larger decline between baseline and intervention periods than those in either of the targeted interventions. Universal decolonization led to a 37% drop in the rate of MRSA infections, while targeted decolonization led to a 25% decline and no significant change was seen in the screening and isolation group. There was no significant difference in outcomes between the targeted decolonization and the screening and isolation groups, while the difference between the universal decolonization and the screening and isolation groups was significant (P = .003). Universal decolonization also significantly reduced ICU-attributed bloodstream infections from any pathogen.

Management

Antibiotic regimens include the following:
  • Empiric therapy with penicillins or cephalosporins may be inadequate because of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA)
  • Combination therapy with a penicillinase-resistant penicillin or cephalosporin (in case the organism is methicillin-sensitive S aureus [MSSA]) and clindamycin or a quinolone
  • Clindamycin, trimethoprim-sulfamethoxazole (TMP-SMX), rifampin, doxycycline, or a quinolone
  • TMP-SMX and rifampin in combination, rather than singly
Clindamycin (rather than TMP-SMX) may become the preferred outpatient antibiotic therapy in regions with a relatively low incidence of clindamycin resistance
The Infectious Diseases Society of America has published treatment guidelines for MRSA infection

Bacteremia

Daptomycin, with or without beta-lactams, controls S aureus bacteremia without worsening renal dysfunction. In a cohort of patients with mild or moderate renal insufficiency, more than 80% responded to treatment, with no detrimental effect on their kidneys. Currently, the combination of daptomycin with beta-lactams is recommended only as salvage therapy for refractory MRSA bacteremia. 

New Coronavirus ‘Eerily’ Like SARS

By Michael Smith, North American Correspondent, MedPage   June 19, 2013
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco
http://www.medpagetoday.com/InfectiousDisease/GeneralInfectiousDisease/39972?xid=nl_mpt_DHE_2013-06-20

The novel coronavirus outbreak in the Middle East is eerily similar to SARS, according to Trish Perl, MD, of the Johns Hopkins University School of Medicine, part of an international team, led by Ziad Memish, MD, of the World Health Organization in Riyadh, that looked into a cluster of 23 cases in hospitals in the east of Saudi Arabia. . “The illness pattern, the incubation period — there are a lot of eerie similarities,” Perl told MedPage Today. They reported online in the New England Journal of Medicine, that the virus, MERS-CoV, is related to the virus that caused the 2002-2003 SARS outbreak.  The viruses both are coronaviruses and both lead to severe respiratory illness. Further, person-to-person transmission can take place in healthcare settings and can do so with “considerable morbidity.”  One key difference, Perl and colleagues noted, is that — at least in the cluster they investigated — the fatality rate was 65%, markedly higher than the 8% or so seen in the SARS outbreak. On the other hand, that rate may fall if a large number of milder cases is detected, they noted.  An outside expert, David Freedman, MD, of the University of Alabama at Birmingham, told MedPage Today that an open question has been whether MERS could spread within hospitals as easily as did SARS.  The current study, he said, shows “unequivocally” that it can.
The report comes as the World Health Organization is reporting a total of 64 laboratory-confirmed cases of infection with MERS-CoV, including 38 deaths. Most reported cases have either occurred in the Middle East or have involved recent travel to the region.  SARS was contained and eventually controlled by identifying cases vigorously and then isolating them to prevent transmission, Perl noted, and similar tactics — when they were applied in Saudi Arabia — appeared to have the same effect. The key in the epidemiological chain may have been Patient C, who had been undergoing long-term hemodialysis, and was admitted to hospital April 6 in the room next to Patient A.  When Patient A developed a fever April 8, Patient C was still in the same room and developed fever himself 3 days later. He also had dialysis in the hospital’s outpatient hemodialysis unit twice after the onset of symptoms. Between April 14 and April 30, MERS was confirmed in nine more patients who were undergoing hemodialysis, including six who did so at times overlapping those of Patient C. All told, Patient C appears to have transmitted MERS directly to seven people, six in the dialysis unit and one in the intensive care unit, the researchers reported, while other infected people had more limited transmission and some did not pass on the disease at all.

Related articles

Clostridium Difficile

Clostridium Difficile (Photo credit: fjbengoat)

English: Low mag. Image:Colonic pseudomembrane...

English: Low mag. Image:Colonic pseudomembranes intermed mag.jpg (Photo credit: Wikipedia)

Obtained after an outbreak this micrograph dep...

Obtained after an outbreak this micrograph depicts Gram-positive Clostridium difficile bacteria. These C. difficile organisms were cultured from a stool sample obtained during an outbreak of gastrointestinal illness, and extracted using a .1µm filter. (Photo credit: Wikipedia)

English: Clostridium difficile toxin B rendere...

English: Clostridium difficile toxin B rendered from PDB 2BVM (Photo credit: Wikipedia)

Pseudomembranous Colitis, Colectomy (Gross)

Pseudomembranous Colitis, Colectomy (Gross) (Photo credit: euthman)

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Reported by: Dr. Venkat S. Karra, Ph.D.

Oral Cephalosporins No Longer a Recommended Treatment for Gonococcal Infections: an update to CDC‘s 2010 STD guidelines.

Gonorrhea is a major cause of serious reproductive complications in women and can facilitate human immunodeficiency virus (HIV) transmission (1). Effective treatment is a cornerstone of U.S. gonorrhea control efforts, but treatment of gonorrhea has been complicated by the ability of Neisseria gonorrhoeae to develop antimicrobial resistance. This report, using data from CDC’s Gonococcal Isolate Surveillance Project (GISP), describes laboratory evidence of declining cefixime susceptibility among urethral N. gonorrhoeae isolates collected in the United States during 2006–2011 and updates CDC’s current recommendations for treatment of gonorrhea (2). Based on GISP data, CDC recommends combination therapy with ceftriaxone 250 mg intramuscularly and either azithromycin 1 g orally as a single dose or doxycycline 100 mg orally twice daily for 7 days as the most reliably effective treatment for uncomplicated gonorrhea. CDC no longer recommends cefixime at any dose as a first-line regimen for treatment of gonococcal infections. If cefixime is used as an alternative agent, then the patient should return in 1 week for a test-of-cure at the site of infection.

Infection with N. gonorrhoeae is a major cause of pelvic inflammatory disease, ectopic pregnancy, and infertility, and can facilitate HIV transmission (1). In the United States, gonorrhea is the second most commonly reported notifiable infection, with >300,000 cases reported during 2011. Gonorrhea treatment has been complicated by the ability of N. gonorrhoeae to develop resistance to antimicrobials used for treatment. During the 1990s and 2000s, fluoroquinolone resistance in N. gonorrhoeae emerged in the United States, becoming prevalent in Hawaii and California and among men who have sex with men (MSM) before spreading throughout the United States. In 2007, emergence of fluoroquinolone-resistant N. gonorrhoeae in the United States prompted CDC to no longer recommend fluoroquinolones for treatment of gonorrhea, leaving cephalosporins as the only remaining recommended antimicrobial class (3). To ensure treatment of co-occurring pathogens (e.g., Chlamydia trachomatis) and reflecting concern about emerging gonococcal resistance, CDC’s 2010 sexually transmitted diseases (STDs) treatment guidelines recommended combination therapy for gonorrhea with a cephalosporin (ceftriaxone 250 mg intramuscularly or cefixime 400 mg orally) plus either azithromycin orally or doxycycline orally, even if nucleic acid amplification testing (NAAT) for C. trachomatis was negative at the time of treatment (2). From 2006 to 2010, the minimum concentrations of cefixime needed to inhibit the growth in vitro of N. gonorrhoeae strains circulating in the United States and many other countries increased, suggesting that the effectiveness of cefixime might be waning (4). Reports from Europe recently have described patients with uncomplicated gonorrhea infection not cured by treatment with cefixime 400 mg orally (5–8).

GISP is a CDC-supported sentinel surveillance system that has monitored N. gonorrhoeae antimicrobial susceptibilities since 1986, and is the only source in the United States of national and regional N. gonorrhoeae antimicrobial susceptibility data. During September–December 2011, CDC and five external GISP principal investigators, each with N. gonorrhoeae–specific expertise in surveillance, antimicrobial resistance, treatment, and antimicrobial susceptibility testing, reviewed antimicrobial susceptibility trends in GISP through August 2011 to determine whether to update CDC’s current recommendations (2) for treatment of uncomplicated gonorrhea. Each month, the first 25 gonococcal urethral isolates collected from men attending participating STD clinics (approximately 6,000 isolates each year) were submitted for antimicrobial susceptibility testing. The minimum inhibitory concentration (MIC), the lowest antimicrobial concentration that inhibits visible bacterial growth in the laboratory, is used to assess antimicrobial susceptibility. Cefixime susceptibilities were not determined during 2007–2008 because cefixime temporarily was unavailable in the United States at that time. Criteria for resistance to cefixime and ceftriaxone have not been defined by the Clinical Laboratory Standards Institute (CLSI). However, CLSI does consider isolates with cefixime or ceftriaxone MICs ≥0.5 µg/mL to have “decreased susceptibility” to these drugs (9). During 2006–2011, 15 (0.1%) isolates had decreased susceptibility to cefixime (all had MICs = 0.5 µg/mL), including nine (0.2%) in 2010 and one (0.03%) during January–August 2011; 12 of 15 were from MSM, and 12 were from the West and three from the Midwest.* No isolates exhibited decreased susceptibility to ceftriaxone. Because increasing MICs can predict the emergence of resistance, lower cephalosporin MIC breakpoints were established by GISP for surveillance purposes to provide greater sensitivity in detecting declining gonococcal susceptibility than breakpoints defined by CLSI. Cefixime MICs ≥0.25 µg/mL and ceftriaxone MICs ≥0.125 µg/mL were defined as “elevated MICs.” CLSI does not define azithromycin resistance criteria; CDC defines decreased azithromycin susceptibility as ≥2.0 µg/mL.

Evidence and Rationale

The percentage of isolates with elevated cefixime MICs (MICs ≥0.25 µg/mL) increased from 0.1% in 2006 to 1.5% during January–August 2011 (Figure). In the West, the percentage increased from 0.2% in 2006 to 3.2% in 2011 (Table). The largest increases were observed in Honolulu, Hawaii (0% in 2006 to 17.0% in 2011); Minneapolis, Minnesota (0% to 6.9%); Portland, Oregon (0% to 6.5%); and San Diego, California (0% to 6.4%). Nationally, among MSM, isolates with elevated MICs to cefixime increased from 0.2% in 2006 to 3.8% in 2011. In 2011, a higher proportion of isolates from MSM had elevated cefixime MICs than isolates from men who have sex exclusively with women (MSW), regardless of region (Table).

The percentage of isolates exhibiting elevated ceftriaxone MICs increased slightly, from 0% in 2006 to 0.4% in 2011 (Figure). The percentage increased from <0.1% in 2006 to 0.8% in 2011 in the West, and did not increase significantly in the Midwest (0% to 0.2%) or the Northeast and South (0.1% in 2006 and 2011). Among MSM, the percentage increased from 0.0% in 2006 to 1.0% in 2011.

The 2010 CDC STD treatment guidelines (2) recommend that azithromycin or doxycycline be administered with a cephalosporin as treatment for gonorrhea. The percentage of isolates exhibiting tetracycline resistance (MIC ≥2.0 µg/mL) was high but remained stable from 2006 (20.6%) to 2011 (21.6%). The percentage exhibiting decreased susceptibility to azithromycin (MIC ≥2.0 µg/mL) remained low (0.2% in 2006 to 0.3% in 2011). Among 180 isolates collected during 2006–2011 that exhibited elevated cefixime MICs, 139 (77.2%) exhibited tetracycline resistance, but only one (0.6%) had decreased susceptibility to azithromycin.

Ceftriaxone as a single intramuscular injection of 250 mg provides high and sustained bactericidal levels in the blood and is highly efficacious at all anatomic sites of infection for treatment of N. gonorrhoeae infections caused by strains currently circulating in the United States (10,11). Clinical data to support use of doses of ceftriaxone >250 mg are not available. A 400-mg oral dose of cefixime does not provide bactericidal levels as high, nor as sustained as does an intramuscular 250-mg dose of ceftriaxone, and demonstrates limited efficacy for treatment of pharyngeal gonorrhea (10,11). The significant increase in the prevalence of U.S. GISP isolates with elevated cefixime MICs, most notably in the West and among MSM, is of particular concern because the emergence of fluoroquinolone-resistant N. gonorrhoeae in the United States during the 1990s also occurred initially in the West and predominantly among MSM before spreading throughout the United States within several years. Thus, observed patterns might indicate early stages of the development of clinically significant gonococcal resistance to cephalosporins. CDC anticipates that rising cefixime MICs soon will result in declining effectiveness of cefixime for the treatment of urogenital gonorrhea. Furthermore, as cefixime becomes less effective, continued use of cefixime might hasten the development of resistance to ceftriaxone, a safe, well-tolerated, injectable cephalosporin and the last antimicrobial that is recommended and known to be highly effective in a single dose for treatment of gonorrhea at all anatomic sites of infection. Maintaining effectiveness of ceftriaxone for as long as possible is critical. Thus, CDC no longer recommends the routine use of cefixime as a first-line regimen for treatment of gonorrhea in the United States.

Based on experience with other microbes that have developed antimicrobial resistance rapidly, a theoretical basis exists for combination therapy using two antimicrobials with different mechanisms of action to improve treatment efficacy and potentially delay emergence and spread of resistance to cephalosporins. Therefore, the use of a second antimicrobial (azithromycin as a single 1-g oral dose or doxycycline 100 mg orally twice daily for 7 days) is recommended for administration with ceftriaxone. The use of azithromycin as the second antimicrobial is preferred to doxycycline because of the convenience and compliance advantages of single-dose therapy and the substantially higher prevalence of gonococcal resistance to tetracycline than to azithromycin among GISP isolates, particularly in strains with elevated cefixime MICs.

Recommendations

For treatment of uncomplicated urogenital, anorectal, and pharyngeal gonorrhea, CDC recommends combination therapy with a single intramuscular dose of ceftriaxone 250 mg plus either a single dose of azithromycin 1 g orally or doxycycline 100 mg orally twice daily for 7 days (Box).

Clinicians who diagnose gonorrhea in a patient with persistent infection after treatment (treatment failure) with the recommended combination therapy regimen should culture relevant clinical specimens and perform antimicrobial susceptibility testing of N. gonorrhoeae isolates. Phenotypic antimicrobial susceptibility testing should be performed using disk diffusion, Etest (BioMérieux, Durham, NC), or agar dilution. Data currently are limited on the use of NAAT-based antimicrobial susceptibility testing for genetic mutations associated with resistance in N. gonorrhoeae. The laboratory should retain the isolate for possible further testing. The treating clinician should consult an infectious disease specialist, an STD/HIV Prevention Training Center (http://www.nnptc.orgExternal Web Site Icon), or CDC (telephone: 404-639-8659) for treatment advice, and report the case to CDC through the local or state health department within 24 hours of diagnosis. A test-of-cure should be conducted 1 week after re-treatment, and clinicians should ensure that the patient’s sex partners from the preceding 60 days are evaluated promptly with culture and treated as indicated.

When ceftriaxone cannot be used for treatment of urogenital or rectal gonorrhea, two alternative options are available: cefixime 400 mg orally plus either azithromycin 1 g orally or doxycycline 100 mg twice daily orally for 7 days if ceftriaxone is not readily available, or azithromycin 2 g orally in a single dose if ceftriaxone cannot be given because of severe allergy. If a patient with gonorrhea is treated with an alternative regimen, the patient should return 1 week after treatment for a test-of-cure at the infected anatomic site. The test-of-cure ideally should be performed with culture or with a NAAT for N. gonorrhoeae if culture is not readily available. If the NAAT is positive, every effort should be made to perform a confirmatory culture. All positive cultures for test-of-cure should undergo phenotypic antimicrobial susceptibility testing. Patients who experience treatment failure after treatment with alternative regimens should be treated with ceftriaxone 250 mg as a single intramuscular dose and azithromycin 2 g orally as a single dose and should receive infectious disease consultation. The case should be reported to CDC through the local or state health department.

For all patients with gonorrhea, every effort should be made to ensure that the patients’ sex partners from the preceding 60 days are evaluated and treated for N. gonorrhoeae with a recommended regimen. If a heterosexual partner of a patient cannot be linked to evaluation and treatment in a timely fashion, then expedited partner therapy should be considered, using oral combination antimicrobial therapy for gonorrhea (cefixime 400 mg and azithromycin 1 g) delivered to the partner by the patient, a disease investigation specialist, or through a collaborating pharmacy.

The capacity of laboratories in the United States to isolate N. gonorrhoeae by culture is declining rapidly because of the widespread use of NAATs for gonorrhea diagnosis, yet it is essential that culture capacity for N. gonorrhoeae be maintained to monitor antimicrobial resistance trends and determine susceptibility to guide treatment following treatment failure. To help control gonorrhea in the United States, health-care providers must maintain the ability to collect specimens for culture and be knowledgeable of laboratories to which they can send specimens for culture. Health-care systems and health departments must support access to culture, and laboratories must maintain culture capacity or develop partnerships with laboratories that can perform culture.

Treatment of patients with gonorrhea with the most effective therapy will limit the transmission of gonorrhea, prevent complications, and likely will slow emergence of resistance. However, resistance to cephalosporins, including ceftriaxone, is expected to emerge. Reinvestment in gonorrhea prevention and control is warranted. New treatment options for gonorrhea are urgently needed.

Reported by

Carlos del Rio, MD, Rollins School of Public Health, Emory Univ, Atlanta, Georgia. Geraldine Hall, PhD, Dept of Clinical Pathology, Cleveland Clinic, Cleveland, Ohio. King Holmes, MD, Olusegun Soge, PhD, Dept of Medicine, Univ of Washington. Edward W. Hook, MD, Div of Infectious Diseases, Univ of Alabama at Birmingham. Robert D. Kirkcaldy, MD, Kimberly A. Workowski, MD, Sarah Kidd, MD, Hillard S. Weinstock, MD, John R. Papp, PhD, David Trees, PhD, Thomas A. Peterman, MD, Gail Bolan, MD, Div of Sexually Transmitted Diseases Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, CDC.Corresponding contributor: Robert D. Kirkcaldy, rkirkcaldy@cdc.gov, 404-639-8659.

Acknowledgments

Collaborating state and local health departments. Baderinwa Offut, Emory Univ, Atlanta, Georgia. Laura Doyle, Cleveland Clinic, Ohio. Connie Lenderman, Paula Dixon, Univ of Alabama at Birmingham. Karen Winterscheid, Univ of Washington, Seattle. Tamara Baldwin, Elizabeth Delamater, Texas Dept of State Health Svcs. Alesia Harvey, Tremeka Sanders, Samera Bowers, Kevin Pettus, Div of STD Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, CDC.

References

  1. Fleming D, Wasserheit J. From epidemiological synergy to public health policy and practice: the contribution of other sexually transmitted diseases to sexual transmission of HIV infection. Sex Transm Infect 1999;75:3–17.
  2. CDC. Sexually transmitted diseases treatment guidelines, 2010. MMWR 2010;59(No. RR-12).
  3. CDC. Update to CDC’s sexually transmitted diseases treatment guidelines, 2006: fluoroquinolones no longer recommended for treatment of gonococcal infections. MMWR 2007;56:332–6.
  4. CDC. Cephalosporin susceptibility among Neisseria gonorrhoeae isolates—United States, 2000–2010. MMWR 2011;60:873–7.
  5. Unemo M, Golparian D, Syversen G, Vestrheim DF, Moi H. Two cases of verified clinical failures using internationally recommended first-line cefixime for gonorrhea treatment, Norway, 2010. Euro Surveill 2010;15(47):pii:19721.
  6. Ison C, Hussey J, Sankar K, Evans J, Alexander S. Gonorrhea treatment failures to cefixime and azithromycin in England, 2010. Euro Surveill 2011;16(14):pii:19833.
  7. Unemo M, Golparian D, Stary A, Eigentler A. First Neisseria gonorrhoeae strain with resistance to cefixime causing gonorrhea treatment failure in Austria, 2011. Euro Surveill 2011;16(43):pi:19998.
  8. Unemo M, Golparian D, Nicholas R, Ohnishi M, Gallay A, Sednaoui P. High-level cefixime- and ceftriaxone-resistant Neisseria gonorrhoeae in France: novel penA mosaic allele in a successful international clone causes treatment failure. Antimicrob Agents Chemother 2012;56:1273–80.
  9. National Committee for Clinical Laboratory Standards. Approved Standard M100-S20 performance standards for antimicrobial susceptibility testing; twentieth informational supplement. Wayne, PA: Clinical and Laboratory Standards Institute; 2010.
  10. Moran JS, Levine WC. Drugs of choice for the treatment of uncomplicated gonococcal infections. Clin Infect Dis 1995;20(Suppl 1):S47–65.
  11. Handsfield HH, McCormack WM, Hook EW 3rd, et al. A comparison of single-dose cefixime with ceftriaxone as treatment for uncomplicated gonorrhea. The Gonorrhea Treatment Study Group. New Engl J Med 1991;325:1337–41.

* U.S. Census regions. Northeast: Connecticut, Maine, Massachusetts, New Jersey, New Hampshire, New York, Pennsylvania, Rhode Island, and Vermont; Midwest: Illinois, Indiana, Iowa, Kansas, Michigan, Minnesota, Missouri, Nebraska, North Dakota, Ohio, South Dakota, and Wisconsin; South:Alabama, Arkansas, Delaware, District of Columbia, Florida, Georgia, Kentucky, Louisiana, Maryland, Mississippi, North Carolina, Oklahoma, South Carolina, Tennessee, Texas, Virginia, and West Virginia; West: Alaska, Arizona, California, Colorado, Hawaii, Idaho, Montana, New Mexico, Nevada, Oregon, Utah, Washington, and Wyoming.

TABLE. Percentage of urethral Neisseria gonorrhoeae isolates with elevated cefixime MICs (≥0.25 µg/mL), by U.S. Census region and gender of sex partner — Gonococcal Isolate Surveillance Project, United States, 2006–August 2011
Region 2006 2009 2010 2011*
% (95% CI) % (95% CI) % (95% CI) % (95% CI)
West† (total) 0.2 (0.1–0.4) 1.9 (1.4–2.6) 3.3 (2.6–4.0) 3.2 (2.3–4.2)
MSM 0.1 (0.0–0.6) 2.6 (1.7–3.8) 5.0 (3.8–6.5) 4.5 (3.1–6.3)
MSW 0.2 (0.0–0.6) 1.4 (0.7–2.3) 1.3 (0.7–2.2) 1.8 (0.9–3.1)
Midwest§ (total) 0.0 (0.0–0.3) 0.5 (0.2–1.0) 0.5 (0.2–1.1) 0.6 (0.2–1.5)
MSM 0.0 (0.0–2.8) 2.3 (0.6–5.7) 3.4 (1.1–7.7) 4.9 (1.4–12.2)
MSW 0.0 (0.0–0.3) 0.3 (0.1–0.7) 0.1 (0.0–0.6) 0.0 (0.0–0.6)
Northeast and South¶ (total) 0.1 (0.0–0.3) 0.0 (0.0–0.2) 0.1 (0.0–0.4) 0.3 (0.1–0.8)
MSM 0.6 (0.0–3.0) 0.3 (0.0–1.9) 0.9 (0.2–2.5) 1.5 (0.4–3.9)
MSW 0.0 (0.0–0.2) 0.0 (0.0–0.2) 0.0 (0.0–0.2) 0.1 (0.0–0.4)
Abbreviations: CI = confidence interval; MICs = minimum inhibitory concentrations; MSM = men who have sex with men; MSW = men who have sex exclusively with women.

* January–August 2011.

† Includes data from Albuquerque, New Mexico; Denver, Colorado; Honolulu, Hawaii; Las Vegas, Nevada; Los Angeles, California; Orange County, California; Phoenix, Arizona; Portland, Oregon; San Diego, California; San Francisco, California; and Seattle, Washington.

§ Includes data from Chicago, Illinois; Cincinnati, Ohio; Cleveland, Ohio; Detroit, Michigan; Kansas City, Missouri; and Minneapolis, Minnesota.

¶ Includes data from Atlanta, Georgia; Baltimore, Maryland; Birmingham, Alabama; Dallas, Texas; Greensboro, North Carolina; Miami, Florida; New Orleans, Louisiana; New York, New York; Oklahoma City, Oklahoma; Philadelphia, Pennsylvania; and Richmond, Virginia.

FIGURE. Percentage of urethral Neisseria gonorrhoeae isolates (n = 32,794) with elevated cefixime MICs (≥0.25 µg/mL) and ceftriaxone MICs (≥0.125 µg/mL) — Gonococcal Isolate Surveillance Project, United States, 2006–August 2011

The figure shows the percentage of Neisseria gonorrhoeae isolates (n = 32,794) with elevated cefixime MICs (≥0.25 μg/mL) and ceftriaxone MICs (≥0.125 μg/mL) in the United States during 2006-August 2011, according to the Gonococcal Isolate Surveillance Project. The percentage of isolates with elevated cefixime MICs (MICs ≥0.25 μg/mL) increased from 0.1% in 2006 to 1.5% during January-August 2011.

Abbreviation: MICs = minimum inhibitory concentrations.

* Cefixime susceptibility not tested during 2007–2008.

† January–August 2011.

Alternate Text: The figure above shows the percentage of Neisseria gonorrhoeae isolates (n = 32,794) with elevated cefixime MICs (≥0.25 μg/mL) and ceftriaxone MICs (≥0.125 μg/mL) in the United States during 2006-August 2011, according to the Gonococcal Isolate Surveillance Project. The percentage of isolates with elevated cefixime MICs (MICs ≥0.25 μg/mL) increased from 0.1% in 2006 to 1.5% during January-August 2011.

BOX. Updated recommended treatment regimens for gonococcal infections
Uncomplicated gonococcal infections of the cervix, urethra, and rectum

Recommended regimen

Ceftriaxone 250 mg in a single intramuscular dose

PLUS

Azithromycin 1 g orally in a single dose

or doxycycline 100 mg orally twice daily for 7 days*

 

Alternative regimens

If ceftriaxone is not available:

Cefixime 400 mg in a single oral dose

PLUS

Azithromycin 1 g orally in a single dose

or doxycycline 100 mg orally twice daily for 7 days*

PLUS

Test-of-cure in 1 week

 

If the patient has severe cephalosporin allergy:

Azithromycin 2 g in a single oral dose

PLUS

Test-of-cure in 1 week

 

Uncomplicated gonococcal infections of the pharynx

Recommended regimen

Ceftriaxone 250 mg in a single intramuscular dose

PLUS

Azithromycin 1 g orally in a single dose

or doxycycline 100 mg orally twice daily for 7 days*

 

* Because of the high prevalence of tetracycline resistance among Gonococcal Isolate Surveillance Project isolates, particularly those with elevated

 

NOTE: THIS IS FOR YOUR INFORMATION ONLY, BUT “NOT A MEDICAL ADVISE”.

 

source

http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6131a3.htm?s_cid=mm6131a3_w

 

 

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Reporter: Aviva Lev-Ari, PhD, RN
July 25, 2012
Insights into protein folding may lead to better flu vaccine
folding proteins

S.B. Qian
This image shows shows mRNA (purple) with ribosomes (beige) bearing nascent protein chains (pink) in different stages of folding.

A new method for looking at how proteins fold inside mammal cells could one day lead to better flu vaccines, among other practical applications, say Cornell researchers.

The method, described online in the Proceedings of the National Academy of Sciences July 16, allows researchers to take snapshots of the cell’s protein-making machinery — called ribosomes — in various stages of protein production. The scientists then pieced together the snapshots to reconstruct how proteins fold during their synthesis.

Proteins are made up of long chains of amino acids called polypeptides, and folding gives each protein its characteristic structure, which determines its function. Though researchers have used synthetic and purified proteins to study protein folding, this study looks at proteins from their inception, providing a truer picture for how partially synthesized polypeptides can fold in cells.

Proteins fold so quickly — in microseconds — that it has been a longtime mystery just how polypeptide chains fold to create the protein’s structure.

“The speed is very fast, so it’s very hard to capture certain steps, but our approach can look at protein folding at the same time as it is being synthesized by the ribosomes,” said Shu-Bing Qian, assistant professor of nutritional sciences and the corresponding author on the paper. Yan Han, a postdoctoral associate in Qian’s lab, is the paper’s first author.

In a nutshell, messenger RNA (mRNA) carries the coding information for proteins from the DNA to ribosomes, which translate those codes into chains of amino acids that make up proteins. Previously, other researchers had developed a technique to localize the exact position of the ribosomes on the mRNA. Qian and colleagues further advanced this technique to selectively enrich only a certain portion of the protein-making machinery, basically taking snapshots of different stages of the protein synthesis process.

“Like a magnifier, we enrich a small pool from the bigger ocean and then paint a picture from early to late stages of the process,” Qian said.

In the paper, the researchers also describe applying this technique to better understanding a protein called hemagglutinin (HA), located on the surface of the influenza A virus; HA’s structure (folding) allows it to infect the cell.

Flu vaccines are based on antibodies that recognize such proteins as HA. But viruses have high mutation rates to escape antibody detection. Often, flu vaccines lose their effectiveness because surface proteins on the virus mutate. HA, for example, has the highest mutation rate of the flu virus’ surface proteins.

The researchers proved that their technique can identify how the folding process changes when HA mutates.

“If people know the folding picture of how a mutation changes, it will be helpful for designing a better vaccine,” Qian said.

“Folding is a very fundamental issue in biology,” Qian added. “It’s been a long-term mystery how the cell achieves this folding successfully, with such speed and with such a great success rate.”

Co-authors include researchers at the National Institute of Allergy and Infectious Diseases.

The research was funded by the National Institute of Allergy and Infectious Diseases Division of Intramural Research, National Institutes of Health Grant, Ellison Medical Foundation Grant and U.S. Department of Defense Exploration-Hypothesis Development Award.

 http://www.news.cornell.edu/stories/July12/ProteinFoldingQian.html

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