An experimental Ebola vaccine proved to be highly protective against the disease in a phase III trial involving close to 12,000 people living in a coastal region of West Africa, conducted in early 2015 while new cases of the deadly virus were still occurring. Among the roughly 6,000 residents of Guinea receiving the vaccine, no Ebola cases were recorded in the 10 days or more following vaccination, while 23 Ebola cases were recorded during the same period in unvaccinated study controls. The trial, led by the World Health Organization in conjunction with other local and international groups, examined the efficacy or the rVSV-ZEBOV vaccine. Developed in the early 2ooos, the vaccine is now manufactured by Merck, Sharpe & Dohme, which was able to fast-track its use in humans through special FDA and European Medicines Agency programs.
Starting in March 2014, West Africa experienced the largest outbreak of Ebola in history, with 15,261 laboratory-confirmed cases reported as of mid-April of this year and 11,325 confirmed Ebola deaths, according to the CDC. The rVSV-ZEBOV candidate Ebola vaccine had previously been shown to be protective in challenge in primates and select phase 1 and 2 trials in humans. But the newly reported trial is the first large phase III study of this vaccine to report findings, said Ana Maria Henao-Restrepo, MD, of the World Health Organization in Geneva, Switzerland, and colleagues in The Lancet, published Dec. 22.
Thomas Geisbert, PhD, of the University of Texas Medical Branch at Galveston, co-developed the vaccine along with Heinz Feldmann, MD, PhD. Geisbert said that concerns that the Ebola virus could be used as a biological weapon following 9/11 led U.S. lawmakers and other governments to invest in Ebola research. The rVSV-ZEBOV vaccine was an early, promising candidate Ebola vaccine, Geisbert said. But regulations requiring preclinical studies conducted under good laboratory practices criteria, specifically the FDA's Animal Rule, kept it from being used in previous, more isolated, Ebola outbreaks, he added. "We knew this vaccine protected monkeys in the early 2000s, but it just sat there because there was no way to push it past the finish line," he said. Geisbert called the international initiative leading to the phase III trial of rVSV-ZEBOV "unprecedented.
The trial was conducted in the coastal region of Basse-Guinee, in Guinea, and the researchers used a "ring vaccination" approach previously used with smallpox vaccines to identify candidates for vaccination. During the trial, when a new Ebola case was diagnosed in the region, the research team attempted to identify all people who had been in contact with the case within the three weeks prior to diagnosis, and in some cases the clusters included contacts of contacts. A total of 117 clusters or "rings" were identified, with an average of about 80 people in each. Initially, only adults over 18 years of age in each cluster were randomized to vaccination, either immediately or after a three-week delay. Once interim trial results suggested the vaccine was effective, children older than age 6 were included in the vaccination arm and the three-week vaccination delay was halted. Not only did the vaccine appear highly effective, there was also evidence of protection through "herd immunity" among unvaccinated contacts. Safety was assessed through 30-minute observation following vaccination and repeated home visits for up to three months. Approximately half of those vaccinated reported mild symptoms immediately following immunization, including headache, fatigue, and muscle pain. One febrile reaction and one case of anaphylaxis were judged to be related to vaccination, but both resolved without long term effects. Estimated vaccine efficacy was 100% (95% CI 79.3%-100.0%, P=0.0033).
"The evidence from all 117 clusters showed that no cases of Ebola virus disease occurred 10 days or more after randomization among all immediately vaccinated contacts and contacts of contacts versus 23 cases (11 clusters affected) among all eligible contacts and contacts of contacts in delayed plus all eligible contacts and contacts of contacts never vaccinated in immediate clusters," the researchers wrote. "While these compelling results come too late for those who lost their lives during West Africa's Ebola epidemic, they show that when the next Ebola outbreak hits, we will not be defenceless," principal investigator Marie-Paule Kieny, PhD, of WHO, said in a written press statement.
n an editorial published with the study, Geisbert wrote that while the phase III results show the single-injection vaccine to be highly effective, questions remain about its long-term efficacy. "Another question is in regard to improvements in safety: clearly, the VSV-based Ebola virus vaccines appear to be the lead candidates for use in human beings, but can they be further attenuated to reduce the number of adverse events noted in phase I trials without reducing efficacy?" Geisbert wrote. "Results of preclinical studies in non-human primates suggest that this attenuation might be possible."
Six people in Colorado recently became infected with a "nightmare" superbug that until now, has mostly been limited to people in hospitals, according to a new report. The new cases suggest the superbug may have spread outside of health care facilities. The superbug is known as carbapenem-resistant Enterobacteriaceae, or CRE, a family of bacteria that are difficult to treat because they are resistant to powerful antibiotics. So far, nearly all cases of CRE infections have been seen in people who stay health care facilities, or who have been treated with certain medical procedures or devices, according to the Centers for Disease Control and Prevention (CDC). But the six people in the new report had not stayed in a health care facility for at least a year before they contracted the infection. They had not recently undergone surgery or dialysis, either, and hadn't received any invasive devices, such as having a catheter or feeding tube inserted — all of which can be risk factors for CRE infections, the report said. Thus, the six cases appear to be "community-associated" CRE infections, meaning the patients may have picked up these bacteria from somewhere in their everyday lives, outside of a health care setting.
CRE infections outside of a health care setting are "unusual for these bacteria," said study researcher Sarah Janelle, a health care-associated infections epidemiologist at the Colorado Department of Public Health and Environment. These six cases suggest that "these bacteria might be moving from health care to community settings," Janelle said. "Further surveillance of CRE is needed to determine whether this pattern continues in Colorado and to determine if this trend is occurring in other parts of the United States," Janelle said. CRE have been dubbed "nightmare" bacteria because they are resistant to nearly all antibiotics, and they can be highly lethal, killing up to 50 percent of infected patients, according to the CDC.
n the new report, the six patients ranged in age from 20 to 85, with an average age of 61. All of the patients had been diagnosed with urinary tract infections. (CRE can also cause pneumonia and blood infections.) The cases were identified from 2014 to 2016, and all of the patients survived. All of the patients were infected with a type of CRE that produces an enzyme called New Delhi metallo-beta-lactamase. The enzyme makes the bacteria resistant to certain antibiotics, including the powerful carbapenem class of antibiotics. This type of CRE is not very common in the United States, but some people have become infected when they received health care abroad. Of the six patients in the new report, two had traveled internationally shortly before their diagnoses, one to an unknown country in Africa and one to the Bahamas, the report said. Two of the patients had underlying medical conditions, another risk factor for CRE, but three patients had no such conditions. One patient was pregnant at the time she tested positive for CRE. Being pregnant is known to suppress the body's immune system, which can increase the risk of infection.In addition, one patient who had an underlying medical condition reported having provided care for a family member at several different health care facilities before testing positive for CRE, the report said.
Another risk factor for CRE infection is taking antibiotics. Studies have shown that when a person's normal gut bacteria community is disturbed (which happens when antibiotics are used), it puts that individual at risk for becoming sick with "bad" bacteria, including CRE. In addition, use of antibiotics increases the likelihood that bacteria will develop resistance to the drugs, either through a mutation or by acquiring genes from other bacteria. "Any time antibiotics are used, this puts biological pressure on bacteria that promotes the development of resistance," Janelle said. Of the six patients, two had taken antibiotics within the month before they tested positive for CRE and one had taken antibiotics 10 months prior to testing positive. he findings point to the importance of prescribing antibiotics appropriately, Janelle said. Studies have shown that doctors sometimes prescribe antibiotics when the medicines aren't needed (such as when patients have a viral infection that can't be treated with antibiotics)."Proper use of antibiotics can slow the development of resistance in bacteria and can preserve this life-saving resource," Janelle said.The six cases do not appear to be connected, and the source of these CRE infections remains unknown, the report said.
The microcephaly epidemic, which started in Brazil in 2015, was most likely a result of congenital Zika virus infection, according to Brazilian researchers writing in the Lancet Infectious Diseases. The authors recruited 32 cases and 62 controls across eight hospitals in Brazil and found an infant with microcephaly had a substantially increased risk of Zika virus versus controls (13 cases versus 0 controls). Even when brain imaging was normal, infants with microcephaly were still significantly likely to have congenital Zika virus infection based on blood or cerebral spinal fluid samples (four of 16 cases versus 0 controls), but the risk of Zika infection was nonsignificant with blood samples alone (six of 16 cases versus 0 controls). The authors concluded that epidemics of microcephaly could follow in other places where Zika becomes endemic. Because Zika virus is a congenital infections, they recommend amending the TORCH infections (currently comprised of toxoplasmosis, others, such as syphilis, varicella-zoster, parvovirus B1, rubella, cytomegalovirus and herpes) as TORCHZ, to include Zika as a congenital infection a woman risks contracting during pregnancy.
Over a third of a small group of infants with microcephaly in Brazil also had vision-threatening "ocular abnormalities" after birth, and almost 80% of their mothers exhibited signs of Zika virus infection during pregnancy, according to a report in JAMA Ophthamology. Out of 29 infants, 10 had severe ocular abnormalities. Overall, 17 ocular abnormalities were present. Seven out of 10 patients with ocular lesions had them in both eyes. The most common of these were focal pigment mottling and chorioretinal atrophy, which can lead to impaired vision (found in 11 of 17 eyes). Optic nerve abnormalities were also present in eight eyes and one patient apiece had bilateral iris coloboma and lens subluxation. The findings add to the clinical management of infants with microcephaly, who have a high risk of ocular lesions and should undergo regular ophthalmic examinations, according to the authors.
Next Stop, Europe?
If Zika virus spread to Europe and caused a corresponding increase in microcephaly, would European countries be aware? The answers were mostly mixed, according to a questionnaire and observational study published in BMJ. Investigators surveyed the European Surveillance of Congenital Anomalies (EUROCAT) registries, and found out less than half were using the EUROCAT definition of microcephaly, specifically three standard deviations below the mean in head circumference. Instead, 20% used two standard deviations below the mean. However, due to the low incidence of microcephaly in Europe (1.53 per 10,000 births), the authors estimated prevalence would need to increase overall by 35% across Europe, or 300% in one country, to detect a statistically significant difference on microcephaly. The authors concluded that smaller increases in microcephaly due to Zika virus would not be detected in Europe, and that all European countries need to adopt a standard definition of the birth defect to enable better tracking
Clindamycin is an antibiotic in the lincosamide class, active against gram positive bacteria and anaerobes. It binds to the large subunit (50S) of the bacterial ribosome and inhibits new peptide-peptide bond formation. It is bacteriostatic in most cases, though can be bactericidal at high concentrations for certain species.Because of its ability to inhibit translation, clindamycin at sub-inhibitory concentrations can reduce production of bacterial toxins in cases of streptococcal or staphylococcal toxic shock syndrome or in necrotizing infections. By contrast, beta-lactams can actually induce production of alpha toxin in S. aureus. Clindamycin can therefore work synergistically with bacterial cell-wall inhibiting agents such as penicillins, cephalosporins, and vancomycin for toxin-synthesizing gram positive species.Clindamycin cannot penetrate Gram-negative organisms, so it is not active against them and does not affect Gram-negative endotoxin production.
The primary role for clindamycin is in skin and soft tissue infections. It is FDA-approved for use in SSTIs due to streptococcus or MSSA, toxic shock syndrome, impetigo, S. aureusosteomyelitis, pyomyositis, and amnionitis. It is also used off-label for anthrax, babesiosis, animal bite wounds (along with a cephalosporin), malaria treatment, MRSA infections,Pneumocystis pneumonia, septic arthritis, and MRSA SSTIs. For necrotizing SSTI, clindamycin can be given along with cefotaxime for polymicrobial infections, though vancomycin and pipercillin-tazobactam are recommended as first line, empiric treatment. If the necrotizing infection is known to be due to Clostridium perfringens or group A streptococcus, then clindamycin and penicillin IV are sufficient.Clindamycin can also be used for other indications in patients who have severe penicillin allergies. These include treatment of group A streptococcal pharyngitis, pelvic inflammatory disease, and necrotizing skin infections. Topical clindamycin can be used for acne and intra-vaginally for treatment of bacterial vaginosis.
Clindamycin has been available since 1968 after it was synthesized as a derivative of lincomycin, which is a natural product made by Streptomyces lincolnensis, an actinobacterium.
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A 2015 NEJM article found no difference in treatment efficacy or in complication rates between clindamycin and trimethoprim-sulfamethoxazole for treatment of uncomplicated cellulitis and abscess. Using an intention-to-treat analysis, cure rates were 80.3% in the clindamycin group, and 77.7% in the TMP-SMX group (P=0.52). The study included both children and adults with a total of 524 patients, of whom 53.4% had cellulitis, 30.5% had an abscess, and 15.6% had a mixed infection. 41.4% of the cultures grew S. aureus, of which 77% were methicillin-resistant. However, the latest IDSA SSTI guidelines for treatment of mild abscesses recommend incision and drainage only, with no antibiotics.
Common adverse reactions include nausea, vomiting, diarrhea, and abdominal pain. Anaphylactoid reactions and DRESS syndrome (drug reaction with eosinophilia and systemic symptoms) can also occur.
Clindamycin carries a black box warning for the risk of pseudomembranous colitis from C. difficile associated diarrhea (CDAD), which can be fatal. CDAD can occur during treatment with clindamycin, but has also been reported over 2 months after clindamycin use. It is important to take a good antibiotic history in the evaluation of patients with diarrhea to assess for CDAD risk. Because of the high risk of CDAD, other antibiotics should be considered before using clindamycin.
Dosing & Adjustments
Clindamycin is given IV at 600-900 mg Q8hr for severe infections. For mild infections, it can be given at 300-400 mg PO QID or 450 mg TID. Clindamycin has about 90% oral bioavailability, making it an attractive option for patients who do not have an IV, have limited IV access sites, and those who can be discharged on oral medications.
Clindamycin is pregnancy class B, and is considered safe in breastfeeding women, as it is minimally excreted in the breast milk. Tell patients to take an 8-oz. glass of water with each clindamycin dose. That helps prevent esophagitis, which is a common adverse reaction if the pill is taken with only a small sip of water.
A single dose of 600mg IV clindamycin costs from $3-$15. An oral clindamycin course of 300mg QID for 10 days costs around $150. The 1% topical clindamycin costs $50-$80 for a 30-g tube, while vaginal 2% clindamycin costs over $100 for a 40-g tube.
A new antibacterial drug and an anti-influenza medication got the nod from the FDA.
The agency approved the combination of ceftolozane, a cephalosporin
antibacterial drug, and tazobactam, a beta-lactamase inhibitor, which
will be sold as Zerbaxa and used to treat complicated intra-abdominal
infections and complicated urinary tract infections.
And it also approved peramivir (Rapivab), an
anti-influenza drug delivered by intravenous injection and intended for
patients unable to take medication orally or by inhalation.
The approval of ceftolozane/tazobactam is an important milestone, according to the Infectious Diseases Society of America (IDSA), which has been pushing for the development of 10 new systemic antibacterial drugs by 2020.
That campaign - dubbed the 10 x '20 Initiative - began in 2010, so this approval comes at the halfway mark, the society noted in a statement.
It's also the fifth new drug since the campaign was launched and the
first to address "certain serious and resistant Gram-negative bacteria,"
the IDSA statement said.
Zerbaxa's OK comes in a busy year for antibiotic development. The FDA this year has already approved dalbavancin (Dalvance), tedizolid (Sivextro), and oritavancin (Orbactiv).
The other new antibacterial is ceftaroline fosamil (Teflaro), approved late in 2010.
"The FDA approval of several new antibacterial drugs this year
demonstrates the agency's commitment to increasing the availability of
treatment options for patients and physicians," according to Edward Cox,
MD, of the agency's Center for Drug Evaluation and Research.
"We must continue to help foster the development of new antibacterial
drugs and encourage prudent use of existing treatments to conserve
their utility," Cox said in a statement.
On the other hand, the fight is not over, the IDSA said.
"Even this important approval doesn't address all of our antibiotic
needs," the society statement said. "Patients still face
life-threatening infections for which additional new antibiotics are
Ceftolozane/tazobactam got approval as a qualified
infectious disease product under the Generating Antibiotic Incentives
Now (GAIN) title of the FDA Safety and Innovation Act as "an
antibacterial or antifungal human drug intended to treat a serious or
life-threatening infection," the agency said in a statement.
September 18, President Obama announced
a new Executive Order and National
Strategy for Combating Antibiotic-Resistant Bacteria (National
Strategy) to carry out recommendations given by the President’s
Council of Advisors on Science and Technology (PCAST). CDDEP Director Ramanan
Laxminarayan was one of 15 key advisors on the concurrently-released PCAST
US Centers for Disease Control and Prevention (CDC) now has resources available
online related to these announcements, including a webpage on the National Strategy, in addition to the
publicly-available White House materials. A summary of all of these, with links
to each page, is below. A table of contents for where to find information on
specific topics is also available below.
Three Things to Know:
A remote-controlled vibrating capsule can relieve chronic constipation, researchers found.Anesthesia providers - not robots or RNs - should be pushing medications in gastroenterology centers, says Kim Riviello, DNP, MBA/HCM, CRNA. Fewer than half of those who should be screened for celiac disease are being evaluated for it, data showed. How do you decide what to do with a patient with complicated Crohn's disease - drugs, endoscopy, surgery, or all three? M. Bridget Duffy, MD, says that doctors can no longer afford to ignore social media. "We have to understand how patients are wanting to connect with us."
Two hundred and eighty-eight cases of measles
were reported to the Centers for Disease Control and Prevention (CDC)
in the United States between Jan. 1 and May 23, 2014. This is the
largest number of measles cases in the United States reported in the
first five months of a year since 1994. Nearly all of the measles cases
this year have been associated with international travel by
"The current increase in measles cases is being driven by unvaccinated
people, primarily U.S. residents, who got measles in other countries,
brought the virus back to the United States and spread to others in
communities where many people are not vaccinated," said Dr. Anne
Schuchat, assistant surgeon general and director of CDC's National
Center for Immunizations and Respiratory Diseases. "Many of the
clusters in the U.S. began following travel to the Philippines where a
large outbreak has been occurring since October 2013."
In all of the outbreaks, the report noted, one or more of those precautions was omitted. The
largest outbreak - in a New Jersey ophthalmologic practice that had
one main clinic and four satellites - involved 245 people. Some 55%
of the cases were directly associated with the facility.Limited
testing of eye swabs suggested the causative agent was human adenovirus
serotype 8. Environmental testing, however, was negative.Starting
in November 2008, 37 people in Florida developed epidemic
keratoconjunctivitis, 62% of them after visiting one of two
ophthalmologic clinics, both part of the same practice. One of the 37 was the practice's only staff physician, who worked despite being symptomatic, the agency report said. The
Illinois outbreak, in March 2009, involved a relative handful of
patients, but 12 of the 18 were babies in a neonatal intensive care
unit. The unit was later closed to new admissions for 23 days, the
agency report said.
All of the affected infants had been tested by an ophthalmologic team
for retinopathy of prematurity, employing reusable scleral depressors
and ocular specula that were soaked in isopropyl alcohol between uses.
The agency report noted that isopropyl alcohol is not a reliable
disinfectant for ophthalmic instruments and, in fact, 70% isopropyl
alcohol has previously been linked with outbreaks of human adenovirus. Investigation
showed that two family members of patients, two ICU staff, and two of
the ophthalmologic team also had epidemic keratoconjunctivitis,
including an ophthalmology resident who had worked while symptomatic. An ophthalmic equipment cart, disinfected and stored during the investigation, was found to be positive for human adenovirus 19. The
Minnesota outbreak, in the summer and fall of 2008, involved 70 cases,
including eight healthcare staff members from three ophthalmology and
optometry outpatient clinics.
Testing linked the outbreak to human adenovirus 8, and investigation
showed breaches of infection control, including poor hand hygiene and
lack of disinfection of medical equipment shared between patients. Two
smaller outbreaks in New Jersey involved a total of 41 people -- 17
in one case, including a staff optometrist, and 24 in the other. They
were linked to human adenovirus serotypes 3 and 8, respectively.
Thomas Geisbert, PhD, of the University of Texas Medical Branch at Galveston, co-developed the vaccine along with Heinz Feldmann, MD, PhD. Geisbert told MedPage Today that concerns that the Ebola virus could be used as a biological weapon following 9/11 led U.S. lawmakers and other governments to invest in Ebola research.
The rVSV-ZEBOV vaccine was an early, promising candidate Ebola vaccine, Geisbert said. But regulations requiring preclinical studies conducted under good laboratory practices criteria, specifically the FDA's Animal Rule, kept it from being used in previous, more isolated, Ebola outbreaks, he added.
"We knew this vaccine protected monkeys in the early 2000s, but it just sat there because there was no way to push it past the finish line," he said.
Geisbert called the international initiative leading to the phase III trial of rVSV-ZEBOV "unprecedented."
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