Advertisements
Feeds:
Posts
Comments

Posts Tagged ‘CDC’


New England Compounding Center (NECC): Tracking the Sources of Fungal Infections

Reporter: Alan F. Kaul, R.Ph., Pharm.D,, M.S., M.B.A, FCCP

The cause of the outbreak or fungal infections caused by contaminated steroids prepared by NECC has now been confirmed and treatment guidelines for those patients affected are in place.  Unfortunately, the toll in human lives and suffering cannot be rectified.  Clearly, compounding pharmacies are licensed by each state to produce products to meet individual patient needs. They are not legally licensed to manufacture drugs for mass distribution as is a pharmaceutical manufacturer that is licensed and inspected by the FDA.

The question of how to preclude further human disasters such as this is not yet resolved.  Painting all compounding pharmacies as unreliable as some have suggested does an enormous discredit to those pharmacists operating safe and reliable facilities where sterility testing meets or exceeds recommended standards. Political grandstanding also does a disservice towards working towards a viable answer. Should the Pharmacy Compounding Accreditation Board (PCAB), an organization that inspects and certifies that its members meet or exceed USP Chapter 797 standards be given deemed status like The Joint Commission or other similar accrediting organizations to accredit compounding pharmacies? Should state Boards Of Registrations in Pharmacy of Public Health Departments be funded for additional staff to monitor and inspect sterile compounding pharmacies? If so, will the additional expense be paid by the state, the compounding pharmacies, or the patients requiring the specially prepared drugs? Ultimately, the taxpayers will be required to pay for the requisite safeguards.  While the answer is still unresolved, careful though should be given to all possible options including a combination of them in moving forward.  The status quo is not an acceptable solution to meet the needs of providing safe and effective drugs to the public.

Investigations have now confirmed that NECC is the pharmacy linked to the deadly outbreak of fungal infections caused by Exserohilum rostratum, Aspergillus fumigatus, and Cladosporium species. An estimated 14,000 patients in 23 states received steroidal injections between May 21 to September 26, 2012 from lots of drugs prepared by NECC on May 21, June 29, and August 10, 2012. These three suspected lots of drugs prepared from steroids contained 17,676 doses were shipped to 75 locations. Three hundred forty-four infections including meningitis and those of the joints and 25 deaths have been attributed to the contaminated drugs.  As of October 22, 2012, there were 54 patients with CDC confirmed fungal meningitis. Of those, 52 were due to Exserohilum rostratum and one each due to Aspergillus fumigatus, and Cladosporium species.

Several hospitals including Saint Joseph Mercy Ann Arbor Hospital (Ypsilanti, MI), a Baltimore-area emergency room, Saint Thomas Hospital (Nashville, TN) independently noted patients presenting with symptoms including headaches, sensation to light, and neck stiffness, vertigo, double-vision, and loss of muscle co-ordination. In some patients, spinal taps were suggestive of meningitis and treatment was begun. However, infectious disease specialists were unable to identify the pathogen causing the infections. In late summer, across the United States, the same pattern appeared; patients with life-threating infections and an unknown cause. In North Carolina, a 77 year-old generally healthy female patient received the third of thee epidural injections for back pain. In September, she began experiencing terrible headaches. After multiple trips for medical care and being misdiagnosed with migraines and undergoing a brain scan, a family member insisted that she be hospitalized until they could diagnose her illness. A spinal tap was performed and spinal fluid was cultured. Meningitis of an unknown cause was diagnosed.

In Tennessee a man in his 50’s who initially responded to treatment for meningitis and went home returned to Vanderbilt University Medical when his infection reappeared. The patient presented visibly ill and had unintelligible speech. Dr. April Petit an infectious disease specialist ordered the laboratory to test for unusual microbes and also fungi.  The later generally is found in immunocompromised patients. The laboratory reported that the cerebrospinal fluid culture grew Aspergillus.  After again reviewing the patient’s medical history, Dr. Petit noted that the patient had received an epidural steroid injection at the Saint Thomas Outpatient Neurosurgery Center several weeks prior to the onset of his symptoms.  She contacted the Tennessee Department of Health on September 18.

The TN Department of Health contacted Saint Thomas infection prevention staff and learned that another patient who had received an epidural steroid injection at the same facility followed a similar clinical path. Saint Thomas closed its Outpatient Neurosurgery Department on September 20 and TN notified the CDC.  State health officials in TN conducted an inspection of the Saint Thomas Outpatient neurosurgery Department to try to determine the etiology of the infection. Some considerations included improper infection control procedures, contaminated equipment, and contaminated drug.

Within a few days, several more cases of rare fungal meningitis was identified that developed between July 30 and September 18 and the TN Department of Health notified the MA Department of Public Health. The patients shared four commonalties, one being that they ad received an injection of methylprednisolone acetate manufactured by NECC.  On September 25, MA state regulators requested NECC provide a list of all medical centers that had received shipments of the suspect steroid.  They learned that the three suspect lots of drugs totaling 17,676 doses had been shipped to 75 centers.

As the CDC conducted its investigation of sites that had received the drug, they learned that other cases outside of TN had occurred including North Carolina and Michigan.  The CDC issued a health advisory.  Because of the rarity of fungal meningitis, few researchers and clinicians were accustomed to dealing with it. CDC convened an expert advisory panel to develop recommended treatment guidelines.  In addition to the initial discovery of Aspergillus fumigatus, thesubsequent cases were discovered to be caused principally by the black mold, Exserohilum rostratum.  Experts concurred that while cases caused by the former fungus were rare, cases caused by the later were even rarer and treatment options were not well identified. Many effected patients were elderly and had other co-morbidities further complicating distinguishing symptoms and making the choice of pharmacotherapy with drugs often associated with serious side effects even more difficult.

Multidisciplinary teams quickly developed expertise at Saint Joseph Mercy Ann Arbor where 66 patients were being treated.  The team included the Chief Medical Officer, pharmacists, emergency room physicians, infectious disease specialists convened for daily discussions and updates.  Drug regimens for each patient were finely tuned and a special clinic was opened to assist patients in managing their disease.

As the saga continued, more patients in multiple states were identified and treated. Unfortunately, the epidemic had already taken its grim toll.

http://www.cdc.gov/hai/outbreaks/currentsituation/

http://www.fda.gov/Drugs/DrugSafety/FungalMeningitis/default.htm

The United States Food and Drug Administration (FDA) continues to reiterate that there should be follow-up with patients who meet the following three conditions:

  1. The medication used was an injectable product purchased from or produced by NECC, including an ophthalmic drug that is an injectable used in conjunction the eye surgery, or a cardioplegic solution,
  2. The medication was shipped by NECC on or after May 21, 2012, and
  3. The medication was administered on or after May 21, 2012.

On October 22, 2012, the FDA made available a list of customers (no product information available) of NECC from May 21, 2012 sorted by state which can be found at:

http://www.fda.gov/downloads/Drugs/DrugSafety/FungalMeningitis/UCM325467.pdf

On October 23, 2012, the Centers for Disease Control and Prevention (CDC) issued a an Official Health Advisory Issuance of Guidance on Management of Asymptomatic Patients Who Received Epidural or Paraspinal Injections with Contaminated Steroid Products. CDC continues to recommend against treating using antifungal prophylaxis for treating exposed asymptomatic patients without a diagnostic testing indication meningitis. They indicate that the greatest risk of developing an infection is within the first six weeks 942 days) after injection. As an increased benefit from prophylaxis has not been demonstrated from currently available data, additional monitoring of these patients should be considered.

http://emergency.cdc.gov/HAN/han00330.asp

http://bostonglobe.com/lifestyle/health-wellness/2012/10/27/doctors-piece-together-rare-cases-fungal-meningitis-uncover-outbreak/55SIHvy58Pf8lCB0yFvpHJ/story.html

Outbreak baffled doctors until they saw common cause

By  Carolyn Y. Johnson   |   G L O B E S T AF F        O C T O B E R  2 8 ,  2 0 1 2

JEFF KOWALSKY FOR THE BOSTON GLOBE

Rhonda Hall, who had a steroid injection, talked with Anurag Malani, infectious disease specialist at a

Michigan hospital.

It was Labor Day weekend when the first patients began to trickle into an Ypsilanti, Mich., hospital complaining of headaches, sensitivity to light, and neck stiffness. Laboratory tests of the patients’ spinal fluid strongly suggested meningitis and physicians started treatment.

But in a cluster of offices on the third floor, four of Saint Joseph Mercy Ann Arbor Hospital’s infectious disease specialists wrestled with a puzzle: Why couldn’t the laboratory identify the microbe causing the infection?

 Later that week and some 500 miles away, a 51­ year­ old woman developed a powerful headache radiating into her face and headed to a Baltimore ­area emergency room. She was discharged after a normal brain scan, but returned the next day with distressing symptoms: double vision, nausea, vertigo, and a loss of muscle coordination. As her condition worsened, a spinal tap provided no clues to the underlying cause.

And then in mid­ September, Dr. Robert Latham at Saint Thomas Hospital in Nashville, Tenn., found himself perplexed by the case of a woman who returned to the hospital after a treatment for meningitis stopped working. Lab tests showed signs of a raging infection, but similarly, he could not identify the culprit.

At hospitals scattered across the country, it was the horror story of the waning days of summer. Teams of physicians faced the same medical mystery — patients with life­ threatening infections with an unknown cause. There were subtle hints that they were dealing with a highly unusual illness, and astute clinicians and state and federal health officials worked to connect the dots. Ultimately, they would discover that these seemingly isolated cases were the leading edge of an outbreak of a fungal meningitis so rare that many doctors will never see a case in their lifetimes.

 The cases would quickly be linked to three batches of an injected steroid produced by a Framingham compounding pharmacy, but by that time 14,000 people in 23 states had received the injections for back and joint pain. More than 300 have fallen ill, and 25 have died.

Still immersed in treating the illness, most doctors have not had time to reflect on it. But Latham compared the initial confusion, frustration, and growing alarm to the early 1980s, before HIV had been identified as the cause of AIDS. The impact of a tainted drug could never be compared to that global epidemic, but at Saint Thomas, where 38 patients have now been treated, the medical team had the same feeling of being overwhelmed by an unknown that was bigger than anyone imagined.

 “When the HIV patients first started presenting, we were all scratching our heads, saying, ‘What in the devil is this?’ ” Latham said. “Those of us here at Saint Thomas are having an experience similar to San Francisco General in the early 1980s, when young men were walking in” with pneumonia and cancer.

This time, the patients walking in were mostly middle­age and elderly, with signs of meningitis.

The struggle for answers

Elwina Shaw of Denton, N.C., received the third of a set of epidural injections for back pain at the end of August. A vibrant 77­year­old, Shaw was generally healthy, said her daughter, Dawn Frank, aside from a little bit of knee pain and the back trouble. She wanted back surgery, but she had been steered instead toward the shots to see whether they would help.

Shaw was working in her garden one day in September when she got a terrible headache, Frank recalled. Shaw went to the doctor, and at first was told she was having migraines. But they didn’t go away. She went to the hospital for a brain scan, but it still wasn’t clear what was wrong. She was sent home, Frank said, and was told it might be a virus.

Finally, on September 25, Frank brought her mother back to the hospital, determined that doctors would not send her away until they could figure out what was wrong. Near midnight, she remembers, they did a lumbar puncture, drawing out a sample of spinal fluid.

Frank prayed it would not be bad. Shaw’s 80 ­year ­old husband, Rex, needed her. A talented seamstress, eloquent writer, and a woman of great faith, she filled their home and lives with grace and love. She never drew attention to herself, and had always embraced being a homemaker and mother.

 The test results were clear: meningitis of unknown cause. Unbeknownst to her physicians and her family, Elwina Shaw had joined the constellation of cases that were challenging doctors and wrenching families in other states.

In Michigan, patients who responded initially to treatment for meningitis returned to the hospital, worse. In Maryland, the 51­year­old woman’s spinal fluid was tested for bacterial infection and viruses ranging from West Nile to herpes as medical teams tried to treat her, according to a report published in the  Annals of Internal Medicine . Within a week and a half of being admitted to the hospital, she was brain dead. In Tennessee, doctors were struggling to figure out how to help the woman who had seemed to recover, then relapsed.

Dr. Varsha Moudgal, an infectious disease specialist at Saint Joseph Mercy Ann Arbor in Michigan, said physicians there had been mulling over several unusual aspects of their handful of cases. Some patients seemed almost too well, Moudgal said, explaining that meningitis patients with the kind of sky­high counts of immune cells and extremely low glucose levels doctors measured would typically have more symptoms, such as altered mental abilities.

“They came in and didn’t appear to be as ill as their cerebrospinal fluid picture suggested,” Moudgal said. “They were talking to us. They were sitting up.”

Others had severe symptoms but their lab tests suggested their infections were not that bad.

The doctors turned to specialists in microbiology and pathology, asking them to rack their brains for better diagnostic methods. Physicians scoured the medical literature to see whether past cases could teach them how to treat their growing cluster of patients. Dr. Anurag Malani said he heard rumbles of a case at another hospital that echoed theirs.

“We knew something was wrong, but it was hard to put a finger on it,” Malani said. “In hindsight, I think a lot of other places were feeling the same frustration.”

Meanwhile, in Tennessee, Dr. April Pettit, an infectious disease specialist at Vanderbilt University Medical Center, had been struggling with the same disturbing pattern: A man in his 50s with what appeared to be meningitis. He initially responded to treatment, went home, and then returned, the infection careening out of control.

 When he came back, she reported in the  New England Journal of Medicine this month, he was visibly ill and his speech unintelligible. Searching for answers, she told the laboratory to test for unusual microbes, such as fungi, even though such infections are quite rare, usually occurring in people with suppressed immune systems.

“On morning rounds, Dr. Pettit gets a call from the microbiology laboratory,” said Dr. William Schaffner, an infectious disease specialist at Vanderbilt who is familiar with the case. “She steps out to get the call, and she receives the information the cerebrospinal fluid has grown a fungus: aspergillus. She is dumbfounded.”

A common denominator

Pettit reviewed her patient’s history, to see whether there was anything unusual, anything that could explain why an otherwise healthy, middle­aged man with no immune system problems could have gotten such a rare type of meningitis. Several weeks earlier, she learned, he had received an epidural steroid injection at Saint Thomas Outpatient Neurosurgery Center. It was the only thing that stood out. She contacted the Tennessee Department of Health.

Dr. Marion Kainer of the health department immediately got in touch with the infection prevention staff at Saint Thomas. She told them of the man in his 50s, whose disease had followed much the same trajectory as their patient — and who had also received an injection. Latham knew his patient had also gotten an epidural injection at the hospital’s neurosurgery clinic, but previously he had no reason to connect it to her symptoms.

“The fact we had two people with strange presentations, related to the epidural injection, I hope would have been a bellwether for us,” Latham said. But that day, they got an even clearer message that something larger was going on: Another person had been admitted with similar symptoms. That person had also had an injection at the same place.

Saint Thomas closed its Outpatient Neurosurgery Center on Thursday, Sept. 20, and Tennessee notified the Centers for Disease Control and Prevention in Atlanta. Latham accompanied state health officials on an inspection of the facility to see whether there were any clues as to where the infection had come from: Did the clinic have the proper infection ­control policies and procedures? Was there a chance equipment had been contaminated? Could it have been a contaminated drug?

 By that Sunday, other probable cases had been identified in Tennessee, and the next day the Tennessee Department of Health contacted their counterparts in Massachusetts. Late in the evening, the Tennessee officials told the Bay State regulators of six rare fungal meningitis cases that had developed between July 30 and Sept. 18 in their state. The patients had at least four things in common: one being that they had received an injection of methylprednisolone acetate made by New England Compounding Center.

A day later, state regulators asked the owners of the Framingham compounding pharmacy to compile a list of all the medical centers that had been shipped medication from three batches of the steroid that federal officials had flagged as suspicious. The lots, prepared on May 21, June 29, and Aug. 10, the officials learned, had been shipped to 75 locations — and they contained 17,676 doses.

The next day, Sept. 26, the company voluntarily recalled the products, but there was still no firm connection between the drugs and the outbreak.

Then, physicians at the High Point Regional Health System in North Carolina, where Elwina Shaw was being treated, received a call from the CDC. The High Point Surgery Center was among the places that received doses of the drug. The agency official asked whether there were any patients with symptoms similar to the Tennessee cases, according to hospital spokeswoman Tracie Blackmon. High Point did have such a patient, the hospital confirmed.

The CDC later said in a health advisory that it was that first case outside of Tennessee that was “possibly indicating contamination of a widely distributed medication.” Frank said her family was told her mother’s case helped point the finger at the contaminated drug. “The steroid was the common denominator,” Frank said.

The doctors in Michigan began to hear news reports of what was going on in Tennessee. They began to realize the common thread was the epidural injections their patients had received at a nearby clinic.

Treating an outbreak

Pinpointing the source of the infection was only the first step. Public health officials now realized that many more people were likely to be hospitalized in the coming weeks, but they had little idea how to treat them. Fungal meningitis occurs infrequently, and the circle of researchers who study such infections is small.

 The CDC convened a panel of experts to develop advice for physicians on what symptoms to watch for, how to best treat it, and when to start antifungal medications. Complicating matters was the fact that while the initial case in Tennessee involved a fungus called Aspergillus fumigatus, the subsequent cases were mainly caused by a black mold called Exserohilum rostratum.

Cases of meningitis caused by aspergillus were rare, say specialists in fungal diseases, but cases caused by black mold were even more so, making the outbreak almost entirely untrodden medical ground. The large number of elderly victims was another challenge, because many had chronic conditions that could make it difficult to distinguish symptoms or that make them unable to tolerate the harsh drugs.

Expertise rapidly developed at the centers that were hardest hit. At Saint Joseph Mercy Ann Arbor, where 66 patients had been treated as of Friday, there was a daily 9 a.m. “huddle” of health care providers, followed by a call that drew together people from across the hospital, from the chief medical officer to pharmacists to emergency room doctors to the infectious disease specialists.

Drug regimens were fine­tuned to diminish side effects, and a special clinic was set up to help patients manage the disease.

Patients will have to take the antifungal drugs for a minimum of three months — and possibly as long as a year.

More staff were brought in to help manage the flood of people who came to be tested for meningitis. On their busiest day, 66 spinal taps were drawn; during the last month, a couple hundred have been performed, Malani said.

Three patients have died, but two fell ill before the meningitis cases were connected to a fungus.

By the time Rhonda Hall showed up at the hospital a week and a half ago, systems and procedures were in place and the pace had slowed. The 49­year­old bus driver from Brighton, Mich., was in an accident a year ago that still causes her pain. She had recently had surgery on her left ankle and got a steroid injection in her hip.

Soon after, Hall found herself clutching the side of her mattress just to get out of bed, and she realized that it wasn’t just an after­effect of the surgery. Something was wrong with her hip.

After hearing about the contaminated injections on the news, she called and learned she had gotten one of the bad shots. She was diagnosed with a bone infection.

“I was very scared in the beginning,” Hall said last week, just before going into surgery to flush out the infected joint. “Now it’s to the point . . . I want it over with so I can start healing and feeling better.”

The lessons learned by physicians came too late for Elwina Shaw. During her time in the North Carolina hospital, Shaw had two strokes, her daughter said, but she was able to write her name in cursive and walk afterward. Her family was hopeful.

But her condition worsened, and she died Friday, Oct. 19. On that day, the CDC reported that 271 people were infected, 21 deceased.

Carolyn Y. Johnson can be reached at  cjohnson@globe.com. Follow her on Twitter

@carolynyjohnson.

© 2012 THE NEW YORK TIMES COMPANY

Advertisements

Read Full Post »


Reporter: Aviva Lev-Ari, PhD, RN

 

Meningitis outbreak: 13,000 got shots of recalled steroid but how many at risk unclear

(Kristin M. Hall/ Associated Press ) – A vial of injectable steroids from the New England Compounding Center is displayed in the Tennessee Department of Health in Nashville, Tenn., on Monday, Oct. 8, 2012. The CDC has said an outbreak of fungal meningitis may have been caused by steroids from the Massachusetts specialty pharmacy.

By Associated Press, Published: October 8

NEW YORK — As many as 13,000 people received steroid shots suspected in a national meningitis outbreak, health officials said Monday. But it’s not clear how many are in danger.Officials don’t how many of the shots may have been contaminated with meningitis-causing fungus. And the figure includes not only those who got them in the back for pain — who are most at risk — but also those who got the shots in other places, like knees and shoulders.

There was no breakdown on the number of back injections, said Curtis Allen, a spokesman for the Centers for Disease Control and Prevention. Those injected in joints are not believed to be at risk for meningitis, he said.The number of people sickened in the outbreak reached 105 on Monday. Deaths rose to eight, with another fatality in Tennessee, the CDC said. Tennessee has the most cases, followed by Michigan, Virginia, Indiana, Florida, Maryland, Minnesota, North Carolina and Ohio.

Investigators suspect a steroid medication made by a specialty pharmacy may be to blame. About 17,700 single-dose vials of the steroid were sent to 23 states. Inspectors found at least one sealed vial contaminated with fungus, and tests were being done on other vials.

The first known case of the rarely seen fungal meningitis was diagnosed last month in Tennessee. The steroid maker, New England Compounding Center of Framingham, Mass., recalled the drug, and over the weekend recalled everything else it makes.

“While there is no indication at this time of any contamination in other NECC products, this recall is being taken as a precautionary measure,” the company said in a statement.

Meningitis is an inflammation of the lining of the brain and spinal cord, and a back injection would put any contaminant in more direct contact with that lining.

Symptoms on meningitis include severe headache, nausea, dizziness and fever. The CDC said many of the cases have been mild and some people had strokes. Symptoms have been appearing between one and four weeks after patients got the shots.

A Michigan man whose wife’s death was linked to the outbreak said Monday that he, too, was treated with steroids from one of the recalled batches.

“Not only have I lost my wife, but I’m watching the clock to see if anything develops,” George Cary said, as friends and family gathered for his wife’s wake in Howell, 60 miles northwest of Detroit.

His wife, Lilian, 67, had been ill since late August, but meningitis wasn’t detected until Sept. 22, her husband said. She died Sept. 30.

Michigan officials have not released the names of two people who have died in the outbreak in that state, but did say one was a 67-year-old woman.

Fungal meningitis is not contagious like the more common forms. The two types of fungus linked so far to the outbreak are all around, but very rarely causes illness. Fungal meningitis is treated with high-dose antifungal medications, usually given intravenously in a hospital.

The steroid is known as preservative-free methylprednisolone acetate, which the compounding pharmacy creates by combining a powder with a liquid.

Doctors should contact any patient who got doses from any of the recalled lots, and should look back at their records as far back as mid-May, CDC officials say.

___

AP writer Ed White in Detroit contributed to this report.

___

Online:

CDC information: http://www.cdc.gov/HAI/outbreaks/meningitis.html

Copyright 2012 The Associated Press. All rights reserved. This material may not be published, broadcast, rewritten or redistributed.

http://www.washingtonpost.com/national/health-science/cdc-cases-of-a-rare-fungal-meningitis-rise-to-105-outbreak-tied-to-steroid-shots/2012/10/08/15f2468a-116e-11e2-9a39-1f5a7f6fe945_story.html

Read Full Post »


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

 

 

Read Full Post »