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FDA approves Recarbrio for cUTI, cIAI treatment in adults
The Recarbrio is a three-drug combo injection containing imipenem/cilastatin, an antibiotic previously approved by the FDA, and relebactam, a beta-lactamase inhibitor.
The efficacy of Recarbrio was supported by data on the efficacy of imipenem/cilastatin in the treatment of cUTI and cIAI and by in vitro studies and animal models of infection with treatment by relebactam. The safety was assessed in a pair of clinical studies, one that assessed cUTI patients and another that assessed cIAI patients.
The most common adverse events reported were nausea, diarrhea, headache, fever, and increased liver enzymes. Treatment with Recarbrio is not recommended in patients taking ganciclovir, valproic acid, or divalproex sodium because there is an increased risk of seizures, according to the FDA.
“The FDA remains focused on facilitating the development of safe and effective new antibacterial drugs to give patients more options to fight serious infections. It is important that the use of Recarbrio be reserved for situations when there are limited or no alternative antibacterial drugs for treating a patient’s infection,” Ed Cox, MD, MPH, director for the Office of Antimicrobial Products in FDA’s Center for Drug Evaluation and Research, said in the press release.
Find the full press release on the FDA website.
The Recarbrio is a three-drug combo injection containing imipenem/cilastatin, an antibiotic previously approved by the FDA, and relebactam, a beta-lactamase inhibitor.
The efficacy of Recarbrio was supported by data on the efficacy of imipenem/cilastatin in the treatment of cUTI and cIAI and by in vitro studies and animal models of infection with treatment by relebactam. The safety was assessed in a pair of clinical studies, one that assessed cUTI patients and another that assessed cIAI patients.
The most common adverse events reported were nausea, diarrhea, headache, fever, and increased liver enzymes. Treatment with Recarbrio is not recommended in patients taking ganciclovir, valproic acid, or divalproex sodium because there is an increased risk of seizures, according to the FDA.
“The FDA remains focused on facilitating the development of safe and effective new antibacterial drugs to give patients more options to fight serious infections. It is important that the use of Recarbrio be reserved for situations when there are limited or no alternative antibacterial drugs for treating a patient’s infection,” Ed Cox, MD, MPH, director for the Office of Antimicrobial Products in FDA’s Center for Drug Evaluation and Research, said in the press release.
Find the full press release on the FDA website.
The Recarbrio is a three-drug combo injection containing imipenem/cilastatin, an antibiotic previously approved by the FDA, and relebactam, a beta-lactamase inhibitor.
The efficacy of Recarbrio was supported by data on the efficacy of imipenem/cilastatin in the treatment of cUTI and cIAI and by in vitro studies and animal models of infection with treatment by relebactam. The safety was assessed in a pair of clinical studies, one that assessed cUTI patients and another that assessed cIAI patients.
The most common adverse events reported were nausea, diarrhea, headache, fever, and increased liver enzymes. Treatment with Recarbrio is not recommended in patients taking ganciclovir, valproic acid, or divalproex sodium because there is an increased risk of seizures, according to the FDA.
“The FDA remains focused on facilitating the development of safe and effective new antibacterial drugs to give patients more options to fight serious infections. It is important that the use of Recarbrio be reserved for situations when there are limited or no alternative antibacterial drugs for treating a patient’s infection,” Ed Cox, MD, MPH, director for the Office of Antimicrobial Products in FDA’s Center for Drug Evaluation and Research, said in the press release.
Find the full press release on the FDA website.
Study finds increase in dermatologic prescriptions for postsurgical antibiotics
WASHINGTON – , according to an analysis presented at the annual meeting of the American Academy of Dermatology.
John Barbieri, MD, a dermatologist and postdoctoral research fellow at the University of Pennsylvania, Philadelphia, who presented the results, and colleagues examined data about antibiotic use in dermatology between 2008 and 2016. Overall, antibiotic use decreased during this period, primarily for chronic conditions such as acne and rosacea. On the other hand, antibiotic use associated with surgical visits increased by approximately 70%.
Using data from 2008 to 2016 in the Optum Clinformatics DataMart deidentified commercial claims database, the researchers performed a repeated cross-sectional analysis of oral antibiotic prescriptions associated with encounters for surgical procedures performed by dermatologists. They found that oral antibiotic prescriptions increased from 2.9% to 4.4% of visits for benign excisions, from 4.2% to 6.3% of visits for malignant excisions, and from 9.9% to 13.8% of visits for Mohs procedures during this time period. Oral antibiotic prescribing was more common for procedures that entailed a flap or graft and among patients with diabetes, female patients, and younger patients.
The investigators observed greater than twofold variation in antibiotic-prescribing rates across geographic census divisions. “If higher-prescribing divisions were to develop antibiotic prescribing rates similar to [those of] lower-prescribing divisions, antibiotic use could be decreased by over 50%,” Dr. Barbieri said. Before prescribing antibiotic prophylaxis, dermatologists should consider which patients benefit most from it, he added.
The investigators also examined the duration of antibiotic courses. The median course duration of postoperative antibiotics was 7 days. Randomized, controlled trials that collectively included more than 600 patients have failed to demonstrate a benefit of long postoperative courses of antibiotics, compared with perioperative antibiotics alone, said Dr. Barbieri. “While it may be hard to have true perioperative antibiotics available in a dermatology surgical clinic, there likely are opportunities to reduce these postoperative courses to a day or 3 days from this mean of 7 days that we observed in the study.” Reducing these courses would decrease the risk of antibiotic-associated complications such as nausea, diarrhea, and skin rashes, he added.
SOURCE: AAD 2019, Abstract 11356.
WASHINGTON – , according to an analysis presented at the annual meeting of the American Academy of Dermatology.
John Barbieri, MD, a dermatologist and postdoctoral research fellow at the University of Pennsylvania, Philadelphia, who presented the results, and colleagues examined data about antibiotic use in dermatology between 2008 and 2016. Overall, antibiotic use decreased during this period, primarily for chronic conditions such as acne and rosacea. On the other hand, antibiotic use associated with surgical visits increased by approximately 70%.
Using data from 2008 to 2016 in the Optum Clinformatics DataMart deidentified commercial claims database, the researchers performed a repeated cross-sectional analysis of oral antibiotic prescriptions associated with encounters for surgical procedures performed by dermatologists. They found that oral antibiotic prescriptions increased from 2.9% to 4.4% of visits for benign excisions, from 4.2% to 6.3% of visits for malignant excisions, and from 9.9% to 13.8% of visits for Mohs procedures during this time period. Oral antibiotic prescribing was more common for procedures that entailed a flap or graft and among patients with diabetes, female patients, and younger patients.
The investigators observed greater than twofold variation in antibiotic-prescribing rates across geographic census divisions. “If higher-prescribing divisions were to develop antibiotic prescribing rates similar to [those of] lower-prescribing divisions, antibiotic use could be decreased by over 50%,” Dr. Barbieri said. Before prescribing antibiotic prophylaxis, dermatologists should consider which patients benefit most from it, he added.
The investigators also examined the duration of antibiotic courses. The median course duration of postoperative antibiotics was 7 days. Randomized, controlled trials that collectively included more than 600 patients have failed to demonstrate a benefit of long postoperative courses of antibiotics, compared with perioperative antibiotics alone, said Dr. Barbieri. “While it may be hard to have true perioperative antibiotics available in a dermatology surgical clinic, there likely are opportunities to reduce these postoperative courses to a day or 3 days from this mean of 7 days that we observed in the study.” Reducing these courses would decrease the risk of antibiotic-associated complications such as nausea, diarrhea, and skin rashes, he added.
SOURCE: AAD 2019, Abstract 11356.
WASHINGTON – , according to an analysis presented at the annual meeting of the American Academy of Dermatology.
John Barbieri, MD, a dermatologist and postdoctoral research fellow at the University of Pennsylvania, Philadelphia, who presented the results, and colleagues examined data about antibiotic use in dermatology between 2008 and 2016. Overall, antibiotic use decreased during this period, primarily for chronic conditions such as acne and rosacea. On the other hand, antibiotic use associated with surgical visits increased by approximately 70%.
Using data from 2008 to 2016 in the Optum Clinformatics DataMart deidentified commercial claims database, the researchers performed a repeated cross-sectional analysis of oral antibiotic prescriptions associated with encounters for surgical procedures performed by dermatologists. They found that oral antibiotic prescriptions increased from 2.9% to 4.4% of visits for benign excisions, from 4.2% to 6.3% of visits for malignant excisions, and from 9.9% to 13.8% of visits for Mohs procedures during this time period. Oral antibiotic prescribing was more common for procedures that entailed a flap or graft and among patients with diabetes, female patients, and younger patients.
The investigators observed greater than twofold variation in antibiotic-prescribing rates across geographic census divisions. “If higher-prescribing divisions were to develop antibiotic prescribing rates similar to [those of] lower-prescribing divisions, antibiotic use could be decreased by over 50%,” Dr. Barbieri said. Before prescribing antibiotic prophylaxis, dermatologists should consider which patients benefit most from it, he added.
The investigators also examined the duration of antibiotic courses. The median course duration of postoperative antibiotics was 7 days. Randomized, controlled trials that collectively included more than 600 patients have failed to demonstrate a benefit of long postoperative courses of antibiotics, compared with perioperative antibiotics alone, said Dr. Barbieri. “While it may be hard to have true perioperative antibiotics available in a dermatology surgical clinic, there likely are opportunities to reduce these postoperative courses to a day or 3 days from this mean of 7 days that we observed in the study.” Reducing these courses would decrease the risk of antibiotic-associated complications such as nausea, diarrhea, and skin rashes, he added.
SOURCE: AAD 2019, Abstract 11356.
REPORTING FROM AAD 2019
Candida auris: Dangerous and here to stay
Critical care units and long-term care facilities are on alert for cases of Candida auris, a novel fungal infection that is both dangerous to vulnerable patients and difficult to eradicate. The increased profile of C. auris is not a welcome development but is no surprise to critical care physicians.
This pathogen was first identified in 2009 and has since been found in increasing numbers of patients all over the world. As expected, cases of C. auris are on the rise in the United States.
The Centers for Disease Control and Prevention stated “Candida auris is an emerging fungus that presents a serious global health threat.” This is an opportunistic pathogen that hits critically ill patients and those with compromised immunity.
On March 29, 2019, CDC reported that confirmed clinical cases of C. auris in the United States have more than doubled over the past year, from 257 cases in 2018 to 587 cases with an additional 1,056 colonized patients identified as of February 2019. “Most C. auris cases in the United States have been detected in the New York City area, New Jersey, and the Chicago area. Strains of C. auris in the United States have been linked to other parts of the world. U.S. C. auris cases are a result of inadvertent introduction into the United States from a patient who recently received health care in a country where C. auris has been reported or a result of local spread after such an introduction.”
Case reports have found a mortality rate of up to 50% in patients with C. auris candidemia. The total number of cases is still small, but the trajectory is clear. The hunt is on in labs all over the world for optimal treatments and processes to handle outbreaks.
Jeniel Nett, MD, an infectious disease specialist, and a team of investigators at the University of Wisconsin, Madison, have focused their research on the characteristics of C. auris and its progression in patients and in medical facilities.
According to Dr. Nett, it’s not clear why this emerging threat has cropped up in multiple locations globally. “Candida auris was first recognized in 2009, in Japan, and relatively quickly we saw emergence of this species in relatively distant locations,” she said, adding that independent clades in these locations ruled out transmission as the source of the multiple outbreaks. Antifungal resistance is an epidemiologic area of concern and increased antifungal use may be a contributor, she said.
Once established, the organism is persistent: “It is found on mattresses, on bedsheets, IV poles, and a lot of reusable equipment,” said Dr. Nett in an interview. “It appears to persist in the environment for weeks – maybe longer.” In addition, “it seems to behave differently than a lot of the Candida species that we see; it readily colonizes the skin” to a much greater extent than does other Candida species, she said. “This allows it to be transmitted readily person to person, particularly in the hospitalized setting.” However, it can also colonize both the urinary and respiratory tracts, she said.
Which patients are susceptible to C. auris candidemia? “Many of these patients have undergone multiple procedures; they may have undergone mechanical ventilation as well as different surgical procedures,” said Dr. Nett. Affected patients often have received many rounds of antibiotic and antifungal treatment as well, she said, and may have an underlying illness like diabetes or malignancy.
Studies of C. auris outbreaks have begun to appear in the literature and give clinicians some perspective on the progression of an outbreak and potential strategies for containment. A prospective cohort study of a large outbreak of C. auris was conducted by Alba Ruiz-Gaitán, MD, and her colleagues at La Fe University and Polytechnic Hospital, Valencia, Spain (Expert Rev Anti Infect Ther. 2019 Apr;17[4]:295-305). The researchers followed 114 patients who were colonized with C. auris or had C. auris candidemia. The patients were compared with 114 case-matched controls within the hospital’s adult surgical and medical intensive care units over an 11-month period during the hospital’s protracted outbreak.
The investigators found a crude mortality rate of 58.5% at 30 days for patients with C. auris candidemia. All isolates in the study were completely resistant to fluconazole and had reduced susceptibility to voriconazole.
In critical care units at Hospital La Fe, investigators found C. auris on 25% of blood pressure cuffs, 10% of patient tables and keyboards, and 8% of infusion pumps.
Among the patients at Hospital La Fe, multivariable analysis revealed that those most likely to develop C. auris colonization or candidemia were individuals with polytrauma, cardiovascular disease, and cancer.
Patients receiving parenteral nutrition (odds ratio, 3.49), mechanical ventilation (OR, 2.43), and especially those having indwelling central venous catheters (OR, 13.48) were more likely to be colonized or have candidemia as well, according to Dr. Ruiz-Gaitán and her coauthors.
Once identified, how should C. auris be treated? “The majority of strains – upward of 90% – are resistant to fluconazole,” said Dr. Nett. “Moreover, 30%-50% of them are resistant to another antifungal, often amphotericin B. The isolates that we see in the United States are most often susceptible to an echinocandin, and echinocandins remain the choice for treatment of Candida auris pending susceptibility tests.”
However, in Valencia, “The susceptibility to echinocandins presented interesting features. These antifungals were not fungicidal against C. auris,” wrote Dr. Ruiz-Gaitán and her colleagues. They found that for caspofungin, “most isolates presented a clear paradoxical growth after 24 hours of incubation.” Additionally, fungal growth was inhibited at lower caspofungin concentrations, but rebounded at higher levels. Similar patterns were seen for anidulafungin and micafungin, they said.
These findings meant that Hospital La Fe patients received initial treatment with echinocandins, with the addition of liposomal amphotericin B or isavuconazole if candidemia persisted or clinical response was not seen, wrote the investigators.
Patient presentation is similar to other forms of candidiasis, said Dr. Nett. “Patients often have fever, chills, leukocytosis, and this persists despite antibacterial therapy… If Candida auris is suspected, the first course of action would be to place the patient in isolation, and laboratory staff should be alerted regarding the diagnosis.”
Most large clinical laboratories, she said, can now detect C. auris. Matrix-assisted laser desorption/ionization–time of flight is the identification technique of choice, provided that the databases are updated.
Smaller laboratories that use phenotypic tests may misidentify C. auris as another Candida species, or even as Saccharomyces cerevisiae – common beer yeast. Facilities without matrix-assisted laser desorption/ionization can find guidance for interpretation of phenotypic testing on the CDC website as well, said Dr. Nett.
After experiencing what they believe to be the largest C. auris outbreak at a single European hospital, Dr. Ruiz-Gaitán and her colleagues offered best-practice tips for treatment of patients with C. auris candidemia. These include removing mechanical devices as early as is safely practical; performing ophthalmologic examinations for endophthalmitis, a known C. auris complication; obtaining blood cultures every other day to track antimicrobial therapy to the point of sterilization; and searching for metastatic foci if blood cultures remain positive.
All instances of C. auris laboratory identification should be reported to the CDC at [email protected], and to local and state health agencies. The CDC recommends strict isolation and cleaning protocols, similar to those used for the spore-forming Clostridium difficile.
Dr. Nett reported funding support from the National Institutes of Health, the Burroughs Wellcome Fund, and the Doris Duke Charitable Foundation. She reported no conflicts of interest. Dr. Ruiz-Gaitán and her collaborators reported funding from Instituto de Salud Carlos III, Spain, and the Spanish Ministry of Science and University. They reported no conflicts of interest.
Critical care units and long-term care facilities are on alert for cases of Candida auris, a novel fungal infection that is both dangerous to vulnerable patients and difficult to eradicate. The increased profile of C. auris is not a welcome development but is no surprise to critical care physicians.
This pathogen was first identified in 2009 and has since been found in increasing numbers of patients all over the world. As expected, cases of C. auris are on the rise in the United States.
The Centers for Disease Control and Prevention stated “Candida auris is an emerging fungus that presents a serious global health threat.” This is an opportunistic pathogen that hits critically ill patients and those with compromised immunity.
On March 29, 2019, CDC reported that confirmed clinical cases of C. auris in the United States have more than doubled over the past year, from 257 cases in 2018 to 587 cases with an additional 1,056 colonized patients identified as of February 2019. “Most C. auris cases in the United States have been detected in the New York City area, New Jersey, and the Chicago area. Strains of C. auris in the United States have been linked to other parts of the world. U.S. C. auris cases are a result of inadvertent introduction into the United States from a patient who recently received health care in a country where C. auris has been reported or a result of local spread after such an introduction.”
Case reports have found a mortality rate of up to 50% in patients with C. auris candidemia. The total number of cases is still small, but the trajectory is clear. The hunt is on in labs all over the world for optimal treatments and processes to handle outbreaks.
Jeniel Nett, MD, an infectious disease specialist, and a team of investigators at the University of Wisconsin, Madison, have focused their research on the characteristics of C. auris and its progression in patients and in medical facilities.
According to Dr. Nett, it’s not clear why this emerging threat has cropped up in multiple locations globally. “Candida auris was first recognized in 2009, in Japan, and relatively quickly we saw emergence of this species in relatively distant locations,” she said, adding that independent clades in these locations ruled out transmission as the source of the multiple outbreaks. Antifungal resistance is an epidemiologic area of concern and increased antifungal use may be a contributor, she said.
Once established, the organism is persistent: “It is found on mattresses, on bedsheets, IV poles, and a lot of reusable equipment,” said Dr. Nett in an interview. “It appears to persist in the environment for weeks – maybe longer.” In addition, “it seems to behave differently than a lot of the Candida species that we see; it readily colonizes the skin” to a much greater extent than does other Candida species, she said. “This allows it to be transmitted readily person to person, particularly in the hospitalized setting.” However, it can also colonize both the urinary and respiratory tracts, she said.
Which patients are susceptible to C. auris candidemia? “Many of these patients have undergone multiple procedures; they may have undergone mechanical ventilation as well as different surgical procedures,” said Dr. Nett. Affected patients often have received many rounds of antibiotic and antifungal treatment as well, she said, and may have an underlying illness like diabetes or malignancy.
Studies of C. auris outbreaks have begun to appear in the literature and give clinicians some perspective on the progression of an outbreak and potential strategies for containment. A prospective cohort study of a large outbreak of C. auris was conducted by Alba Ruiz-Gaitán, MD, and her colleagues at La Fe University and Polytechnic Hospital, Valencia, Spain (Expert Rev Anti Infect Ther. 2019 Apr;17[4]:295-305). The researchers followed 114 patients who were colonized with C. auris or had C. auris candidemia. The patients were compared with 114 case-matched controls within the hospital’s adult surgical and medical intensive care units over an 11-month period during the hospital’s protracted outbreak.
The investigators found a crude mortality rate of 58.5% at 30 days for patients with C. auris candidemia. All isolates in the study were completely resistant to fluconazole and had reduced susceptibility to voriconazole.
In critical care units at Hospital La Fe, investigators found C. auris on 25% of blood pressure cuffs, 10% of patient tables and keyboards, and 8% of infusion pumps.
Among the patients at Hospital La Fe, multivariable analysis revealed that those most likely to develop C. auris colonization or candidemia were individuals with polytrauma, cardiovascular disease, and cancer.
Patients receiving parenteral nutrition (odds ratio, 3.49), mechanical ventilation (OR, 2.43), and especially those having indwelling central venous catheters (OR, 13.48) were more likely to be colonized or have candidemia as well, according to Dr. Ruiz-Gaitán and her coauthors.
Once identified, how should C. auris be treated? “The majority of strains – upward of 90% – are resistant to fluconazole,” said Dr. Nett. “Moreover, 30%-50% of them are resistant to another antifungal, often amphotericin B. The isolates that we see in the United States are most often susceptible to an echinocandin, and echinocandins remain the choice for treatment of Candida auris pending susceptibility tests.”
However, in Valencia, “The susceptibility to echinocandins presented interesting features. These antifungals were not fungicidal against C. auris,” wrote Dr. Ruiz-Gaitán and her colleagues. They found that for caspofungin, “most isolates presented a clear paradoxical growth after 24 hours of incubation.” Additionally, fungal growth was inhibited at lower caspofungin concentrations, but rebounded at higher levels. Similar patterns were seen for anidulafungin and micafungin, they said.
These findings meant that Hospital La Fe patients received initial treatment with echinocandins, with the addition of liposomal amphotericin B or isavuconazole if candidemia persisted or clinical response was not seen, wrote the investigators.
Patient presentation is similar to other forms of candidiasis, said Dr. Nett. “Patients often have fever, chills, leukocytosis, and this persists despite antibacterial therapy… If Candida auris is suspected, the first course of action would be to place the patient in isolation, and laboratory staff should be alerted regarding the diagnosis.”
Most large clinical laboratories, she said, can now detect C. auris. Matrix-assisted laser desorption/ionization–time of flight is the identification technique of choice, provided that the databases are updated.
Smaller laboratories that use phenotypic tests may misidentify C. auris as another Candida species, or even as Saccharomyces cerevisiae – common beer yeast. Facilities without matrix-assisted laser desorption/ionization can find guidance for interpretation of phenotypic testing on the CDC website as well, said Dr. Nett.
After experiencing what they believe to be the largest C. auris outbreak at a single European hospital, Dr. Ruiz-Gaitán and her colleagues offered best-practice tips for treatment of patients with C. auris candidemia. These include removing mechanical devices as early as is safely practical; performing ophthalmologic examinations for endophthalmitis, a known C. auris complication; obtaining blood cultures every other day to track antimicrobial therapy to the point of sterilization; and searching for metastatic foci if blood cultures remain positive.
All instances of C. auris laboratory identification should be reported to the CDC at [email protected], and to local and state health agencies. The CDC recommends strict isolation and cleaning protocols, similar to those used for the spore-forming Clostridium difficile.
Dr. Nett reported funding support from the National Institutes of Health, the Burroughs Wellcome Fund, and the Doris Duke Charitable Foundation. She reported no conflicts of interest. Dr. Ruiz-Gaitán and her collaborators reported funding from Instituto de Salud Carlos III, Spain, and the Spanish Ministry of Science and University. They reported no conflicts of interest.
Critical care units and long-term care facilities are on alert for cases of Candida auris, a novel fungal infection that is both dangerous to vulnerable patients and difficult to eradicate. The increased profile of C. auris is not a welcome development but is no surprise to critical care physicians.
This pathogen was first identified in 2009 and has since been found in increasing numbers of patients all over the world. As expected, cases of C. auris are on the rise in the United States.
The Centers for Disease Control and Prevention stated “Candida auris is an emerging fungus that presents a serious global health threat.” This is an opportunistic pathogen that hits critically ill patients and those with compromised immunity.
On March 29, 2019, CDC reported that confirmed clinical cases of C. auris in the United States have more than doubled over the past year, from 257 cases in 2018 to 587 cases with an additional 1,056 colonized patients identified as of February 2019. “Most C. auris cases in the United States have been detected in the New York City area, New Jersey, and the Chicago area. Strains of C. auris in the United States have been linked to other parts of the world. U.S. C. auris cases are a result of inadvertent introduction into the United States from a patient who recently received health care in a country where C. auris has been reported or a result of local spread after such an introduction.”
Case reports have found a mortality rate of up to 50% in patients with C. auris candidemia. The total number of cases is still small, but the trajectory is clear. The hunt is on in labs all over the world for optimal treatments and processes to handle outbreaks.
Jeniel Nett, MD, an infectious disease specialist, and a team of investigators at the University of Wisconsin, Madison, have focused their research on the characteristics of C. auris and its progression in patients and in medical facilities.
According to Dr. Nett, it’s not clear why this emerging threat has cropped up in multiple locations globally. “Candida auris was first recognized in 2009, in Japan, and relatively quickly we saw emergence of this species in relatively distant locations,” she said, adding that independent clades in these locations ruled out transmission as the source of the multiple outbreaks. Antifungal resistance is an epidemiologic area of concern and increased antifungal use may be a contributor, she said.
Once established, the organism is persistent: “It is found on mattresses, on bedsheets, IV poles, and a lot of reusable equipment,” said Dr. Nett in an interview. “It appears to persist in the environment for weeks – maybe longer.” In addition, “it seems to behave differently than a lot of the Candida species that we see; it readily colonizes the skin” to a much greater extent than does other Candida species, she said. “This allows it to be transmitted readily person to person, particularly in the hospitalized setting.” However, it can also colonize both the urinary and respiratory tracts, she said.
Which patients are susceptible to C. auris candidemia? “Many of these patients have undergone multiple procedures; they may have undergone mechanical ventilation as well as different surgical procedures,” said Dr. Nett. Affected patients often have received many rounds of antibiotic and antifungal treatment as well, she said, and may have an underlying illness like diabetes or malignancy.
Studies of C. auris outbreaks have begun to appear in the literature and give clinicians some perspective on the progression of an outbreak and potential strategies for containment. A prospective cohort study of a large outbreak of C. auris was conducted by Alba Ruiz-Gaitán, MD, and her colleagues at La Fe University and Polytechnic Hospital, Valencia, Spain (Expert Rev Anti Infect Ther. 2019 Apr;17[4]:295-305). The researchers followed 114 patients who were colonized with C. auris or had C. auris candidemia. The patients were compared with 114 case-matched controls within the hospital’s adult surgical and medical intensive care units over an 11-month period during the hospital’s protracted outbreak.
The investigators found a crude mortality rate of 58.5% at 30 days for patients with C. auris candidemia. All isolates in the study were completely resistant to fluconazole and had reduced susceptibility to voriconazole.
In critical care units at Hospital La Fe, investigators found C. auris on 25% of blood pressure cuffs, 10% of patient tables and keyboards, and 8% of infusion pumps.
Among the patients at Hospital La Fe, multivariable analysis revealed that those most likely to develop C. auris colonization or candidemia were individuals with polytrauma, cardiovascular disease, and cancer.
Patients receiving parenteral nutrition (odds ratio, 3.49), mechanical ventilation (OR, 2.43), and especially those having indwelling central venous catheters (OR, 13.48) were more likely to be colonized or have candidemia as well, according to Dr. Ruiz-Gaitán and her coauthors.
Once identified, how should C. auris be treated? “The majority of strains – upward of 90% – are resistant to fluconazole,” said Dr. Nett. “Moreover, 30%-50% of them are resistant to another antifungal, often amphotericin B. The isolates that we see in the United States are most often susceptible to an echinocandin, and echinocandins remain the choice for treatment of Candida auris pending susceptibility tests.”
However, in Valencia, “The susceptibility to echinocandins presented interesting features. These antifungals were not fungicidal against C. auris,” wrote Dr. Ruiz-Gaitán and her colleagues. They found that for caspofungin, “most isolates presented a clear paradoxical growth after 24 hours of incubation.” Additionally, fungal growth was inhibited at lower caspofungin concentrations, but rebounded at higher levels. Similar patterns were seen for anidulafungin and micafungin, they said.
These findings meant that Hospital La Fe patients received initial treatment with echinocandins, with the addition of liposomal amphotericin B or isavuconazole if candidemia persisted or clinical response was not seen, wrote the investigators.
Patient presentation is similar to other forms of candidiasis, said Dr. Nett. “Patients often have fever, chills, leukocytosis, and this persists despite antibacterial therapy… If Candida auris is suspected, the first course of action would be to place the patient in isolation, and laboratory staff should be alerted regarding the diagnosis.”
Most large clinical laboratories, she said, can now detect C. auris. Matrix-assisted laser desorption/ionization–time of flight is the identification technique of choice, provided that the databases are updated.
Smaller laboratories that use phenotypic tests may misidentify C. auris as another Candida species, or even as Saccharomyces cerevisiae – common beer yeast. Facilities without matrix-assisted laser desorption/ionization can find guidance for interpretation of phenotypic testing on the CDC website as well, said Dr. Nett.
After experiencing what they believe to be the largest C. auris outbreak at a single European hospital, Dr. Ruiz-Gaitán and her colleagues offered best-practice tips for treatment of patients with C. auris candidemia. These include removing mechanical devices as early as is safely practical; performing ophthalmologic examinations for endophthalmitis, a known C. auris complication; obtaining blood cultures every other day to track antimicrobial therapy to the point of sterilization; and searching for metastatic foci if blood cultures remain positive.
All instances of C. auris laboratory identification should be reported to the CDC at [email protected], and to local and state health agencies. The CDC recommends strict isolation and cleaning protocols, similar to those used for the spore-forming Clostridium difficile.
Dr. Nett reported funding support from the National Institutes of Health, the Burroughs Wellcome Fund, and the Doris Duke Charitable Foundation. She reported no conflicts of interest. Dr. Ruiz-Gaitán and her collaborators reported funding from Instituto de Salud Carlos III, Spain, and the Spanish Ministry of Science and University. They reported no conflicts of interest.
Anti-infective update addresses SSSI choices
ORLANDO – What’s new in infectious disease therapeutics for dermatologists? He ran through an array of updates at the Orlando Dermatology Aesthetic and Clinical Conference.
While naturally occurring smallpox was globally eradicated in 1980, small research stores are held in the United States and Russia, and effective antivirals are part of a strategy to combat bioweapons. Tecovirimat (TPOXX) is an antiviral that inhibits a major envelope protein that poxviruses need to produce extracellular virus. Approved by the Food and Drug Administration in mid-2018, it is currently the only antiviral for treating variola virus infection approved in the United States, noted Dr. Finch of the University of Connecticut, Farmington. He added that 2 million doses are currently held in the U.S. Strategic National Stockpile.
Another anti-infective agent that won’t be used by those practicing in the United States, but which promises to alleviate a significant source of suffering in the developing world, is moxidectin. The anthelmintic had previously been approved for veterinary uses, but in June 2018, the FDA approved moxidectin to treat onchocerciasis, also known as river blindness. The drug defeats the parasitic worm by binding to glutamate-gated chloride ion channels; it is licensed by the nonprofit Medicines Development for Global Health.
Another antiparasitic drug, benznidazole, was approved to treat children aged 2-12 years with Chagas disease in 2017, Dr. Finch said.
Also in 2017, a topical quinolone, ozenoxacin (Xepi) was approved to treat impetigo in adults and children aged at least 2 months. Formulated as a 1% cream, ozenoxacin is applied twice daily for 5 days. In clinical trials, ozenoxacin was shown to be noninferior to retapamulin, he said.
A new topical choice is important as mupirocin resistance climbs, Dr. Finch added. A recent Greek study showed that 20% (437) of 2,137 staph infections studied were mupirocin resistant. Of the 20%, all but one were skin and skin structure infections (SSSIs), with 88% of these being impetigo.
In the United States, mupirocin resistance has been seen in one in three outpatients in a Florida study and in 31% of patients in a New York City sample. Other studies have shown mupirocin resistance in Staphylococcus aureus isolates with resistance in the 10%-15% range among children with SSSIs, Dr. Finch said.
Two other new antibiotics to fight SSSIs can each be administered orally or intravenously. One, omadacycline (Nuzyra), is a novel tetracycline that maintains efficacy against bacteria that express tetracycline resistance through efflux and ribosomal protection. Approved in late 2018 for acute bacterial SSSIs, omadacycline treats not just methicillin-sensitive and methicillin-resistant S. aureus, but also Streptococcus species and gram-negative rods such as Enterobacter and Klebsiella pneumoniae, Dr. Finch noted.
Another new fluorinated quinolone, approved in 2017, delafloxacin (Baxdela) has broad spectrum activity against gram-negative and gram-positive bacteria.
Dr. Finch reported that he has no relevant conflicts of interest.
ORLANDO – What’s new in infectious disease therapeutics for dermatologists? He ran through an array of updates at the Orlando Dermatology Aesthetic and Clinical Conference.
While naturally occurring smallpox was globally eradicated in 1980, small research stores are held in the United States and Russia, and effective antivirals are part of a strategy to combat bioweapons. Tecovirimat (TPOXX) is an antiviral that inhibits a major envelope protein that poxviruses need to produce extracellular virus. Approved by the Food and Drug Administration in mid-2018, it is currently the only antiviral for treating variola virus infection approved in the United States, noted Dr. Finch of the University of Connecticut, Farmington. He added that 2 million doses are currently held in the U.S. Strategic National Stockpile.
Another anti-infective agent that won’t be used by those practicing in the United States, but which promises to alleviate a significant source of suffering in the developing world, is moxidectin. The anthelmintic had previously been approved for veterinary uses, but in June 2018, the FDA approved moxidectin to treat onchocerciasis, also known as river blindness. The drug defeats the parasitic worm by binding to glutamate-gated chloride ion channels; it is licensed by the nonprofit Medicines Development for Global Health.
Another antiparasitic drug, benznidazole, was approved to treat children aged 2-12 years with Chagas disease in 2017, Dr. Finch said.
Also in 2017, a topical quinolone, ozenoxacin (Xepi) was approved to treat impetigo in adults and children aged at least 2 months. Formulated as a 1% cream, ozenoxacin is applied twice daily for 5 days. In clinical trials, ozenoxacin was shown to be noninferior to retapamulin, he said.
A new topical choice is important as mupirocin resistance climbs, Dr. Finch added. A recent Greek study showed that 20% (437) of 2,137 staph infections studied were mupirocin resistant. Of the 20%, all but one were skin and skin structure infections (SSSIs), with 88% of these being impetigo.
In the United States, mupirocin resistance has been seen in one in three outpatients in a Florida study and in 31% of patients in a New York City sample. Other studies have shown mupirocin resistance in Staphylococcus aureus isolates with resistance in the 10%-15% range among children with SSSIs, Dr. Finch said.
Two other new antibiotics to fight SSSIs can each be administered orally or intravenously. One, omadacycline (Nuzyra), is a novel tetracycline that maintains efficacy against bacteria that express tetracycline resistance through efflux and ribosomal protection. Approved in late 2018 for acute bacterial SSSIs, omadacycline treats not just methicillin-sensitive and methicillin-resistant S. aureus, but also Streptococcus species and gram-negative rods such as Enterobacter and Klebsiella pneumoniae, Dr. Finch noted.
Another new fluorinated quinolone, approved in 2017, delafloxacin (Baxdela) has broad spectrum activity against gram-negative and gram-positive bacteria.
Dr. Finch reported that he has no relevant conflicts of interest.
ORLANDO – What’s new in infectious disease therapeutics for dermatologists? He ran through an array of updates at the Orlando Dermatology Aesthetic and Clinical Conference.
While naturally occurring smallpox was globally eradicated in 1980, small research stores are held in the United States and Russia, and effective antivirals are part of a strategy to combat bioweapons. Tecovirimat (TPOXX) is an antiviral that inhibits a major envelope protein that poxviruses need to produce extracellular virus. Approved by the Food and Drug Administration in mid-2018, it is currently the only antiviral for treating variola virus infection approved in the United States, noted Dr. Finch of the University of Connecticut, Farmington. He added that 2 million doses are currently held in the U.S. Strategic National Stockpile.
Another anti-infective agent that won’t be used by those practicing in the United States, but which promises to alleviate a significant source of suffering in the developing world, is moxidectin. The anthelmintic had previously been approved for veterinary uses, but in June 2018, the FDA approved moxidectin to treat onchocerciasis, also known as river blindness. The drug defeats the parasitic worm by binding to glutamate-gated chloride ion channels; it is licensed by the nonprofit Medicines Development for Global Health.
Another antiparasitic drug, benznidazole, was approved to treat children aged 2-12 years with Chagas disease in 2017, Dr. Finch said.
Also in 2017, a topical quinolone, ozenoxacin (Xepi) was approved to treat impetigo in adults and children aged at least 2 months. Formulated as a 1% cream, ozenoxacin is applied twice daily for 5 days. In clinical trials, ozenoxacin was shown to be noninferior to retapamulin, he said.
A new topical choice is important as mupirocin resistance climbs, Dr. Finch added. A recent Greek study showed that 20% (437) of 2,137 staph infections studied were mupirocin resistant. Of the 20%, all but one were skin and skin structure infections (SSSIs), with 88% of these being impetigo.
In the United States, mupirocin resistance has been seen in one in three outpatients in a Florida study and in 31% of patients in a New York City sample. Other studies have shown mupirocin resistance in Staphylococcus aureus isolates with resistance in the 10%-15% range among children with SSSIs, Dr. Finch said.
Two other new antibiotics to fight SSSIs can each be administered orally or intravenously. One, omadacycline (Nuzyra), is a novel tetracycline that maintains efficacy against bacteria that express tetracycline resistance through efflux and ribosomal protection. Approved in late 2018 for acute bacterial SSSIs, omadacycline treats not just methicillin-sensitive and methicillin-resistant S. aureus, but also Streptococcus species and gram-negative rods such as Enterobacter and Klebsiella pneumoniae, Dr. Finch noted.
Another new fluorinated quinolone, approved in 2017, delafloxacin (Baxdela) has broad spectrum activity against gram-negative and gram-positive bacteria.
Dr. Finch reported that he has no relevant conflicts of interest.
EXPERT ANALYSIS FROM ODAC 2019
More than 23% of antibiotic fills deemed unnecessary
More than 23% of all antibiotic prescriptions filled in 2016 were medically unnecessary, and another 36% were questionable, according to an analysis of prescribing data for 19.2 million children and nonelderly adults.
Based on the diagnosis codes for 15.5 million prescriptions filled that year, at least 3.6 million (23.2%) were “inappropriate” – prescribed for conditions for which an antibiotic is almost never recommended, such as acute upper respiratory conditions – and 5.5 million (35.5%) were “potentially inappropriate” – conditions such as acute sinusitis or otitis media, for which an antibiotic is only sometimes recommended, Kao-Ping Chua, MD, PhD, of the University of Michigan, Ann Arbor, and his associates reported in the BMJ.
Only 12.8% of filled prescriptions for the 39 oral antibiotics assessed were classified as “appropriate” under the investigators’ scheme, which assigned an antibiotic appropriateness level to all 91,738 diagnostic codes in the 2016 ICD-10-CM. Finally, 28.5% of antibiotic fills were not associated with a recent diagnosis code, suggesting that they involved phone consultations that did not result in claims or visits that were paid out of pocket and did not make it into the Truven MarketScan Commercial Claims and Encounters database used in the study, the investigators said.
The three highest levels of inappropriate fills were 70.7% in office-based settings, 6.2% in urgent care centers, and 4.7% in emergency departments.
“The unacceptable scale of inappropriate antibiotic prescribing in the United States ... underscores the need to learn more about prescriptions that aren’t justified by a diagnosis – or are written after no diagnosis at all,” coinvestigator Jeffrey Linder, MD, of Northwestern University, Chicago, said in a written statement.
Prescriptions for children, who represented almost a quarter of all antibiotic fills, were less likely to be inappropriate than those for adults aged 18-64 years. Proportions for children were 17.1% inappropriate, 48.7% potentially inappropriate, and 17.0% appropriate, compared with 25.2%, 31.4%, and 11.4%, respectively, for adults, Dr. Chua and his associates said.
“This study shows how data and analytics can help us identify and understand important challenges facing the American health care system,” said Gopal Khanna, director of the Agency for Healthcare Research and Quality, which funded the study. “We now need to use these data to spur change in the prescribing of these very common medications.”
SOURCE: Chua K-P et al. BMJ. 2019;364:k5092. doi: 10.1136/bmj.k5092.
More than 23% of all antibiotic prescriptions filled in 2016 were medically unnecessary, and another 36% were questionable, according to an analysis of prescribing data for 19.2 million children and nonelderly adults.
Based on the diagnosis codes for 15.5 million prescriptions filled that year, at least 3.6 million (23.2%) were “inappropriate” – prescribed for conditions for which an antibiotic is almost never recommended, such as acute upper respiratory conditions – and 5.5 million (35.5%) were “potentially inappropriate” – conditions such as acute sinusitis or otitis media, for which an antibiotic is only sometimes recommended, Kao-Ping Chua, MD, PhD, of the University of Michigan, Ann Arbor, and his associates reported in the BMJ.
Only 12.8% of filled prescriptions for the 39 oral antibiotics assessed were classified as “appropriate” under the investigators’ scheme, which assigned an antibiotic appropriateness level to all 91,738 diagnostic codes in the 2016 ICD-10-CM. Finally, 28.5% of antibiotic fills were not associated with a recent diagnosis code, suggesting that they involved phone consultations that did not result in claims or visits that were paid out of pocket and did not make it into the Truven MarketScan Commercial Claims and Encounters database used in the study, the investigators said.
The three highest levels of inappropriate fills were 70.7% in office-based settings, 6.2% in urgent care centers, and 4.7% in emergency departments.
“The unacceptable scale of inappropriate antibiotic prescribing in the United States ... underscores the need to learn more about prescriptions that aren’t justified by a diagnosis – or are written after no diagnosis at all,” coinvestigator Jeffrey Linder, MD, of Northwestern University, Chicago, said in a written statement.
Prescriptions for children, who represented almost a quarter of all antibiotic fills, were less likely to be inappropriate than those for adults aged 18-64 years. Proportions for children were 17.1% inappropriate, 48.7% potentially inappropriate, and 17.0% appropriate, compared with 25.2%, 31.4%, and 11.4%, respectively, for adults, Dr. Chua and his associates said.
“This study shows how data and analytics can help us identify and understand important challenges facing the American health care system,” said Gopal Khanna, director of the Agency for Healthcare Research and Quality, which funded the study. “We now need to use these data to spur change in the prescribing of these very common medications.”
SOURCE: Chua K-P et al. BMJ. 2019;364:k5092. doi: 10.1136/bmj.k5092.
More than 23% of all antibiotic prescriptions filled in 2016 were medically unnecessary, and another 36% were questionable, according to an analysis of prescribing data for 19.2 million children and nonelderly adults.
Based on the diagnosis codes for 15.5 million prescriptions filled that year, at least 3.6 million (23.2%) were “inappropriate” – prescribed for conditions for which an antibiotic is almost never recommended, such as acute upper respiratory conditions – and 5.5 million (35.5%) were “potentially inappropriate” – conditions such as acute sinusitis or otitis media, for which an antibiotic is only sometimes recommended, Kao-Ping Chua, MD, PhD, of the University of Michigan, Ann Arbor, and his associates reported in the BMJ.
Only 12.8% of filled prescriptions for the 39 oral antibiotics assessed were classified as “appropriate” under the investigators’ scheme, which assigned an antibiotic appropriateness level to all 91,738 diagnostic codes in the 2016 ICD-10-CM. Finally, 28.5% of antibiotic fills were not associated with a recent diagnosis code, suggesting that they involved phone consultations that did not result in claims or visits that were paid out of pocket and did not make it into the Truven MarketScan Commercial Claims and Encounters database used in the study, the investigators said.
The three highest levels of inappropriate fills were 70.7% in office-based settings, 6.2% in urgent care centers, and 4.7% in emergency departments.
“The unacceptable scale of inappropriate antibiotic prescribing in the United States ... underscores the need to learn more about prescriptions that aren’t justified by a diagnosis – or are written after no diagnosis at all,” coinvestigator Jeffrey Linder, MD, of Northwestern University, Chicago, said in a written statement.
Prescriptions for children, who represented almost a quarter of all antibiotic fills, were less likely to be inappropriate than those for adults aged 18-64 years. Proportions for children were 17.1% inappropriate, 48.7% potentially inappropriate, and 17.0% appropriate, compared with 25.2%, 31.4%, and 11.4%, respectively, for adults, Dr. Chua and his associates said.
“This study shows how data and analytics can help us identify and understand important challenges facing the American health care system,” said Gopal Khanna, director of the Agency for Healthcare Research and Quality, which funded the study. “We now need to use these data to spur change in the prescribing of these very common medications.”
SOURCE: Chua K-P et al. BMJ. 2019;364:k5092. doi: 10.1136/bmj.k5092.
FROM THE BMJ
How to assess an Antimicrobial Stewardship Program
A study compares the merits of DOT and DOTA
The currently recommended method for hospital antimicrobial stewardship programs (ASPs) to measure antibiotic use is Days of Therapy/1,000 patient-days, but there are a few disadvantages of using the DOT, said Maryrose Laguio-Vila, MD, coauthor of a recent study on stewardship.
“For accurate measurement, it requires information technology (IT) support to assist an ASP in generating reports of antibiotic prescriptions and administrations to patients, often from an electronic medical record (EMR). In hospitals where there is no EMR, DOT is probably not easily done and would have to be manually extracted (a herculean task),” she said. “Second, DOT tends to be an aggregate measurement of antibiotics used at an institution or hospital location; if an ASP does a specific intervention targeting a group of antibiotics or infectious indication, changes in the hospital-wide DOT or drug-class DOT may not accurately reflect the exact impact of an ASP’s intervention.”
The paper offers an alternative/supplemental method for ASPs to quantify their impact on antibiotic use without using an EMR or needing IT support: Days of Therapy Avoided. “DOTA can be tracked prospectively (or retrospectively) with each intervention an ASP makes, and calculates an exact amount of antibiotic use avoided,” Dr. Laguio-Vila said. “If the ASP also tracks the types of antibiotic recommendations made according to infectious indication, comparison of DOTA between indications – such as pneumonia versus UTI [urinary tract infection] – can lead to ideas of which type of indication needs clinical guidelines development, or order set revision, or which type of infection the ASP should target to reduce high-risk antibiotics.”
Also, she added, because most ASPs have several types of interventions at once (such as education on pneumonia guidelines, as well as penicillin-allergy assessment), aggregate assessments of institutional antibiotic use like the DOT cannot quantify how much impact a specific intervention has accomplished. DOTA may offer a fairer assessment of the direct changes in antibiotic use resulting from specific ASP activities, because tracking DOTA is extracted from each specific patient intervention.
“Now that the Joint Commission has a requirement that all hospitals seeking JC accreditation have some form of an ASP in place and measure antibiotic use in some way at their institution, there may be numerous hospitals facing the same challenges with calculating a DOT. DOTA would meet these requirements, but in a ‘low tech’ way,” Dr. Laguio-Vila said. “For hospitalists with interests in being the antibiotic steward or champion for their institution, DOTA is an option for measuring antibiotic use.”
Reference
Datta S et al. Days of therapy avoided: A novel method for measuring the impact of an antimicrobial stewardship program to stop antibiotics. J Hosp Med. 2018 Feb 8. doi: 10.12788/jhm.2927.
A study compares the merits of DOT and DOTA
A study compares the merits of DOT and DOTA
The currently recommended method for hospital antimicrobial stewardship programs (ASPs) to measure antibiotic use is Days of Therapy/1,000 patient-days, but there are a few disadvantages of using the DOT, said Maryrose Laguio-Vila, MD, coauthor of a recent study on stewardship.
“For accurate measurement, it requires information technology (IT) support to assist an ASP in generating reports of antibiotic prescriptions and administrations to patients, often from an electronic medical record (EMR). In hospitals where there is no EMR, DOT is probably not easily done and would have to be manually extracted (a herculean task),” she said. “Second, DOT tends to be an aggregate measurement of antibiotics used at an institution or hospital location; if an ASP does a specific intervention targeting a group of antibiotics or infectious indication, changes in the hospital-wide DOT or drug-class DOT may not accurately reflect the exact impact of an ASP’s intervention.”
The paper offers an alternative/supplemental method for ASPs to quantify their impact on antibiotic use without using an EMR or needing IT support: Days of Therapy Avoided. “DOTA can be tracked prospectively (or retrospectively) with each intervention an ASP makes, and calculates an exact amount of antibiotic use avoided,” Dr. Laguio-Vila said. “If the ASP also tracks the types of antibiotic recommendations made according to infectious indication, comparison of DOTA between indications – such as pneumonia versus UTI [urinary tract infection] – can lead to ideas of which type of indication needs clinical guidelines development, or order set revision, or which type of infection the ASP should target to reduce high-risk antibiotics.”
Also, she added, because most ASPs have several types of interventions at once (such as education on pneumonia guidelines, as well as penicillin-allergy assessment), aggregate assessments of institutional antibiotic use like the DOT cannot quantify how much impact a specific intervention has accomplished. DOTA may offer a fairer assessment of the direct changes in antibiotic use resulting from specific ASP activities, because tracking DOTA is extracted from each specific patient intervention.
“Now that the Joint Commission has a requirement that all hospitals seeking JC accreditation have some form of an ASP in place and measure antibiotic use in some way at their institution, there may be numerous hospitals facing the same challenges with calculating a DOT. DOTA would meet these requirements, but in a ‘low tech’ way,” Dr. Laguio-Vila said. “For hospitalists with interests in being the antibiotic steward or champion for their institution, DOTA is an option for measuring antibiotic use.”
Reference
Datta S et al. Days of therapy avoided: A novel method for measuring the impact of an antimicrobial stewardship program to stop antibiotics. J Hosp Med. 2018 Feb 8. doi: 10.12788/jhm.2927.
The currently recommended method for hospital antimicrobial stewardship programs (ASPs) to measure antibiotic use is Days of Therapy/1,000 patient-days, but there are a few disadvantages of using the DOT, said Maryrose Laguio-Vila, MD, coauthor of a recent study on stewardship.
“For accurate measurement, it requires information technology (IT) support to assist an ASP in generating reports of antibiotic prescriptions and administrations to patients, often from an electronic medical record (EMR). In hospitals where there is no EMR, DOT is probably not easily done and would have to be manually extracted (a herculean task),” she said. “Second, DOT tends to be an aggregate measurement of antibiotics used at an institution or hospital location; if an ASP does a specific intervention targeting a group of antibiotics or infectious indication, changes in the hospital-wide DOT or drug-class DOT may not accurately reflect the exact impact of an ASP’s intervention.”
The paper offers an alternative/supplemental method for ASPs to quantify their impact on antibiotic use without using an EMR or needing IT support: Days of Therapy Avoided. “DOTA can be tracked prospectively (or retrospectively) with each intervention an ASP makes, and calculates an exact amount of antibiotic use avoided,” Dr. Laguio-Vila said. “If the ASP also tracks the types of antibiotic recommendations made according to infectious indication, comparison of DOTA between indications – such as pneumonia versus UTI [urinary tract infection] – can lead to ideas of which type of indication needs clinical guidelines development, or order set revision, or which type of infection the ASP should target to reduce high-risk antibiotics.”
Also, she added, because most ASPs have several types of interventions at once (such as education on pneumonia guidelines, as well as penicillin-allergy assessment), aggregate assessments of institutional antibiotic use like the DOT cannot quantify how much impact a specific intervention has accomplished. DOTA may offer a fairer assessment of the direct changes in antibiotic use resulting from specific ASP activities, because tracking DOTA is extracted from each specific patient intervention.
“Now that the Joint Commission has a requirement that all hospitals seeking JC accreditation have some form of an ASP in place and measure antibiotic use in some way at their institution, there may be numerous hospitals facing the same challenges with calculating a DOT. DOTA would meet these requirements, but in a ‘low tech’ way,” Dr. Laguio-Vila said. “For hospitalists with interests in being the antibiotic steward or champion for their institution, DOTA is an option for measuring antibiotic use.”
Reference
Datta S et al. Days of therapy avoided: A novel method for measuring the impact of an antimicrobial stewardship program to stop antibiotics. J Hosp Med. 2018 Feb 8. doi: 10.12788/jhm.2927.
Designing a better EHR
Hospitals can create a more effective system
It’s well known that overuse is an enormous problem in medicine, and when it comes to antibiotics, the problem is even more striking.
“Half of all inpatient antibiotic use is inappropriate,” says Valerie Vaughn, MD, MSc, a hospitalist at the University of Michigan, Ann Arbor, and coauthor of a BMJ editorial about EHRs and antibiotic overuse.
“This has led to an increase in antibiotic-related adverse events (~20% of all hospitalized patients on antibiotics), Clostridium difficile infections (half a million infections and 29,000 deaths in U.S. annually), and resistant bacteria (which now account for nearly 12% of all bacterial infections, costing $2.2 billion annually).”
EHRs can be a tool to combat that trend – if they are well designed. Clinicians are influenced by the design of their electronic health record, Dr. Vaughn said. “Rather than leave its influence to chance, we should capitalize on what is known about design to promote appropriate testing and treatment through the EHR.” Hospitalists – integral to quality improvement – can have a role in making these changes.
“These improvements will be the most effective if behavioral economics and nudging are considered while designing,” Dr. Vaughn said. “For example, when creating order sets, list recommended options first and when possible make them the default,” she said. “This little change will greatly improve appropriate use.”
For every hour physicians spend on direct patient care, they spend another two with the EHR, Dr. Vaughn wrote. “Given this degree of attention, it is not surprising that the EHR influences physician behavior, especially the overuse of low-value medical care. … Displaying brand-name instead of generic options leads to more expensive prescribing. Allowing labs to be ordered recurrently increases unnecessary phlebotomy. Even individually listing inappropriate antibiotics (rather than grouping them) can make them more noticeable, resulting in more broad-spectrum use.”
“All hospitalists – and humans – are affected by knee-jerk responses. One of the most common in medicine is the urge to treat a positive culture or any positive test. Recognize this urge and resist!” she said. “Antibiotics may be the correct response, but clinicians should first think about whether treatment is necessary based on that patient’s symptoms and comorbidities. Resist the knee-jerk urge to give antibiotics for every positive culture.”
Reference
Vaughn VM et al. Thoughtless design of the electronic health record drives overuse, but purposeful design can nudge improved patient care. BMJ Qual Saf. 24 Mar 2018. doi: 10.1136/bmjqs-2017-007578.
Hospitals can create a more effective system
Hospitals can create a more effective system
It’s well known that overuse is an enormous problem in medicine, and when it comes to antibiotics, the problem is even more striking.
“Half of all inpatient antibiotic use is inappropriate,” says Valerie Vaughn, MD, MSc, a hospitalist at the University of Michigan, Ann Arbor, and coauthor of a BMJ editorial about EHRs and antibiotic overuse.
“This has led to an increase in antibiotic-related adverse events (~20% of all hospitalized patients on antibiotics), Clostridium difficile infections (half a million infections and 29,000 deaths in U.S. annually), and resistant bacteria (which now account for nearly 12% of all bacterial infections, costing $2.2 billion annually).”
EHRs can be a tool to combat that trend – if they are well designed. Clinicians are influenced by the design of their electronic health record, Dr. Vaughn said. “Rather than leave its influence to chance, we should capitalize on what is known about design to promote appropriate testing and treatment through the EHR.” Hospitalists – integral to quality improvement – can have a role in making these changes.
“These improvements will be the most effective if behavioral economics and nudging are considered while designing,” Dr. Vaughn said. “For example, when creating order sets, list recommended options first and when possible make them the default,” she said. “This little change will greatly improve appropriate use.”
For every hour physicians spend on direct patient care, they spend another two with the EHR, Dr. Vaughn wrote. “Given this degree of attention, it is not surprising that the EHR influences physician behavior, especially the overuse of low-value medical care. … Displaying brand-name instead of generic options leads to more expensive prescribing. Allowing labs to be ordered recurrently increases unnecessary phlebotomy. Even individually listing inappropriate antibiotics (rather than grouping them) can make them more noticeable, resulting in more broad-spectrum use.”
“All hospitalists – and humans – are affected by knee-jerk responses. One of the most common in medicine is the urge to treat a positive culture or any positive test. Recognize this urge and resist!” she said. “Antibiotics may be the correct response, but clinicians should first think about whether treatment is necessary based on that patient’s symptoms and comorbidities. Resist the knee-jerk urge to give antibiotics for every positive culture.”
Reference
Vaughn VM et al. Thoughtless design of the electronic health record drives overuse, but purposeful design can nudge improved patient care. BMJ Qual Saf. 24 Mar 2018. doi: 10.1136/bmjqs-2017-007578.
It’s well known that overuse is an enormous problem in medicine, and when it comes to antibiotics, the problem is even more striking.
“Half of all inpatient antibiotic use is inappropriate,” says Valerie Vaughn, MD, MSc, a hospitalist at the University of Michigan, Ann Arbor, and coauthor of a BMJ editorial about EHRs and antibiotic overuse.
“This has led to an increase in antibiotic-related adverse events (~20% of all hospitalized patients on antibiotics), Clostridium difficile infections (half a million infections and 29,000 deaths in U.S. annually), and resistant bacteria (which now account for nearly 12% of all bacterial infections, costing $2.2 billion annually).”
EHRs can be a tool to combat that trend – if they are well designed. Clinicians are influenced by the design of their electronic health record, Dr. Vaughn said. “Rather than leave its influence to chance, we should capitalize on what is known about design to promote appropriate testing and treatment through the EHR.” Hospitalists – integral to quality improvement – can have a role in making these changes.
“These improvements will be the most effective if behavioral economics and nudging are considered while designing,” Dr. Vaughn said. “For example, when creating order sets, list recommended options first and when possible make them the default,” she said. “This little change will greatly improve appropriate use.”
For every hour physicians spend on direct patient care, they spend another two with the EHR, Dr. Vaughn wrote. “Given this degree of attention, it is not surprising that the EHR influences physician behavior, especially the overuse of low-value medical care. … Displaying brand-name instead of generic options leads to more expensive prescribing. Allowing labs to be ordered recurrently increases unnecessary phlebotomy. Even individually listing inappropriate antibiotics (rather than grouping them) can make them more noticeable, resulting in more broad-spectrum use.”
“All hospitalists – and humans – are affected by knee-jerk responses. One of the most common in medicine is the urge to treat a positive culture or any positive test. Recognize this urge and resist!” she said. “Antibiotics may be the correct response, but clinicians should first think about whether treatment is necessary based on that patient’s symptoms and comorbidities. Resist the knee-jerk urge to give antibiotics for every positive culture.”
Reference
Vaughn VM et al. Thoughtless design of the electronic health record drives overuse, but purposeful design can nudge improved patient care. BMJ Qual Saf. 24 Mar 2018. doi: 10.1136/bmjqs-2017-007578.
Be judicious with empiric antibiotics for febrile neutropenia
SAN FRANCISCO – Empiric antibiotic therapy for febrile neutropenia, a common and life-threatening complication of chemotherapy, hasn’t really changed much in 20 years, according to Alison Freifeld, MD, director of the section of oncology infectious diseases at the University of Nebraska, Omaha.
Antibiotic resistance has become a major problem over that time. Multidrug-resistant, gram-negative blood stream infections are not uncommon, particularly with extended-spectrum, beta-lactamase–producing Escherichia coli and Klebsiella pneumoniae. Carbapenemase-producing Enterobacteriaceae are also on the rise, among others.
“Our standard empiric antibiotics” – ceftazidime, cefepime, piperacillin/tazobactam, and carbapenems – “are generally not active against these organisms, putting us in a major dilemma about what to do” with patients who have them, Dr. Freifeld said.
“Our goal at the moment is to unpack this ship, take some of these loads of antibiotics off, and figure out how we can more effectively bridge the gap between risk factors and outcomes, with fewer and more stringently applied targeted antibiotics,” she said at ID Week, an annual scientific meeting on infectious diseases.
Dr. Freifeld shared her advice at the meeting on what to do as that plays out. The main driver is to protect the remaining potency of current antibiotics without sacrificing patient care while also keeping new options in reserve for the sickest patients, so “we do not overuse these precious commodities.”
For one thing, it’s okay to shorten treatment – traditionally around 2 weeks, until the absolute neutrophil count (ANC) tops 500 cells/mcg – once the fever abates and cultures turn negative, even if the ANC remains low.
A recent trial put the approach to the test. A total of 78 patients had their antibiotics stopped after they had been free of fever for 72 hours, with normal vital signs and no other signs of infection; 79 in the control group had usual care, continuing treatment until their ANC recovered.
Early withdrawal shortened treatment by about 3 days and there were no statistically significant differences in mortality, with one death in the short-arm group and three in the long-arm group. Over half of the patients in the short-arm group were neutropenic when antibiotics were discontinued.
Serious adverse events, meanwhile, were far less common in the short-arm group (18 vs. 38). The take-home lesson is that “interventions to shorten duration of empiric antibiotics are safe and effective and important to implement now,” Dr. Freifeld said (Lancet Haematol. 2017 Dec;4(12):e573-83).
Also, “use escalation and deescalation approaches,” she said. The basic idea is to begin with monotherapy – cefepime or piperacillin/tazobactam – in uncomplicated cases, bumped up as necessary, and, in complicated cases, to start with broad, multidrug regimens, deescalated as culture reports and other information comes in (Haematologica. 2013 Dec;98(12):1826-35).
Finally, fluoroquinolone prophylaxis, “once considered the wonder of the world,” Dr. Freifeld said, needs to be limited to the highest-risk patients, particularly those with neutropenia expected to last a week or more. It does seem to lower the rates of fever and bloodstream infections, but recent investigations have shown no mortality benefit, and fluoroquinolone prophylaxis makes patients more likely to be colonized by multidrug-resistant bacteria. Many centers have opted against it, even in higher-risk patients (J Infect. 2018 Jan;76(1):20-37).
Dr. Freifeld serves on a data adjudication committee for Merck, and reported research support from the company.
SAN FRANCISCO – Empiric antibiotic therapy for febrile neutropenia, a common and life-threatening complication of chemotherapy, hasn’t really changed much in 20 years, according to Alison Freifeld, MD, director of the section of oncology infectious diseases at the University of Nebraska, Omaha.
Antibiotic resistance has become a major problem over that time. Multidrug-resistant, gram-negative blood stream infections are not uncommon, particularly with extended-spectrum, beta-lactamase–producing Escherichia coli and Klebsiella pneumoniae. Carbapenemase-producing Enterobacteriaceae are also on the rise, among others.
“Our standard empiric antibiotics” – ceftazidime, cefepime, piperacillin/tazobactam, and carbapenems – “are generally not active against these organisms, putting us in a major dilemma about what to do” with patients who have them, Dr. Freifeld said.
“Our goal at the moment is to unpack this ship, take some of these loads of antibiotics off, and figure out how we can more effectively bridge the gap between risk factors and outcomes, with fewer and more stringently applied targeted antibiotics,” she said at ID Week, an annual scientific meeting on infectious diseases.
Dr. Freifeld shared her advice at the meeting on what to do as that plays out. The main driver is to protect the remaining potency of current antibiotics without sacrificing patient care while also keeping new options in reserve for the sickest patients, so “we do not overuse these precious commodities.”
For one thing, it’s okay to shorten treatment – traditionally around 2 weeks, until the absolute neutrophil count (ANC) tops 500 cells/mcg – once the fever abates and cultures turn negative, even if the ANC remains low.
A recent trial put the approach to the test. A total of 78 patients had their antibiotics stopped after they had been free of fever for 72 hours, with normal vital signs and no other signs of infection; 79 in the control group had usual care, continuing treatment until their ANC recovered.
Early withdrawal shortened treatment by about 3 days and there were no statistically significant differences in mortality, with one death in the short-arm group and three in the long-arm group. Over half of the patients in the short-arm group were neutropenic when antibiotics were discontinued.
Serious adverse events, meanwhile, were far less common in the short-arm group (18 vs. 38). The take-home lesson is that “interventions to shorten duration of empiric antibiotics are safe and effective and important to implement now,” Dr. Freifeld said (Lancet Haematol. 2017 Dec;4(12):e573-83).
Also, “use escalation and deescalation approaches,” she said. The basic idea is to begin with monotherapy – cefepime or piperacillin/tazobactam – in uncomplicated cases, bumped up as necessary, and, in complicated cases, to start with broad, multidrug regimens, deescalated as culture reports and other information comes in (Haematologica. 2013 Dec;98(12):1826-35).
Finally, fluoroquinolone prophylaxis, “once considered the wonder of the world,” Dr. Freifeld said, needs to be limited to the highest-risk patients, particularly those with neutropenia expected to last a week or more. It does seem to lower the rates of fever and bloodstream infections, but recent investigations have shown no mortality benefit, and fluoroquinolone prophylaxis makes patients more likely to be colonized by multidrug-resistant bacteria. Many centers have opted against it, even in higher-risk patients (J Infect. 2018 Jan;76(1):20-37).
Dr. Freifeld serves on a data adjudication committee for Merck, and reported research support from the company.
SAN FRANCISCO – Empiric antibiotic therapy for febrile neutropenia, a common and life-threatening complication of chemotherapy, hasn’t really changed much in 20 years, according to Alison Freifeld, MD, director of the section of oncology infectious diseases at the University of Nebraska, Omaha.
Antibiotic resistance has become a major problem over that time. Multidrug-resistant, gram-negative blood stream infections are not uncommon, particularly with extended-spectrum, beta-lactamase–producing Escherichia coli and Klebsiella pneumoniae. Carbapenemase-producing Enterobacteriaceae are also on the rise, among others.
“Our standard empiric antibiotics” – ceftazidime, cefepime, piperacillin/tazobactam, and carbapenems – “are generally not active against these organisms, putting us in a major dilemma about what to do” with patients who have them, Dr. Freifeld said.
“Our goal at the moment is to unpack this ship, take some of these loads of antibiotics off, and figure out how we can more effectively bridge the gap between risk factors and outcomes, with fewer and more stringently applied targeted antibiotics,” she said at ID Week, an annual scientific meeting on infectious diseases.
Dr. Freifeld shared her advice at the meeting on what to do as that plays out. The main driver is to protect the remaining potency of current antibiotics without sacrificing patient care while also keeping new options in reserve for the sickest patients, so “we do not overuse these precious commodities.”
For one thing, it’s okay to shorten treatment – traditionally around 2 weeks, until the absolute neutrophil count (ANC) tops 500 cells/mcg – once the fever abates and cultures turn negative, even if the ANC remains low.
A recent trial put the approach to the test. A total of 78 patients had their antibiotics stopped after they had been free of fever for 72 hours, with normal vital signs and no other signs of infection; 79 in the control group had usual care, continuing treatment until their ANC recovered.
Early withdrawal shortened treatment by about 3 days and there were no statistically significant differences in mortality, with one death in the short-arm group and three in the long-arm group. Over half of the patients in the short-arm group were neutropenic when antibiotics were discontinued.
Serious adverse events, meanwhile, were far less common in the short-arm group (18 vs. 38). The take-home lesson is that “interventions to shorten duration of empiric antibiotics are safe and effective and important to implement now,” Dr. Freifeld said (Lancet Haematol. 2017 Dec;4(12):e573-83).
Also, “use escalation and deescalation approaches,” she said. The basic idea is to begin with monotherapy – cefepime or piperacillin/tazobactam – in uncomplicated cases, bumped up as necessary, and, in complicated cases, to start with broad, multidrug regimens, deescalated as culture reports and other information comes in (Haematologica. 2013 Dec;98(12):1826-35).
Finally, fluoroquinolone prophylaxis, “once considered the wonder of the world,” Dr. Freifeld said, needs to be limited to the highest-risk patients, particularly those with neutropenia expected to last a week or more. It does seem to lower the rates of fever and bloodstream infections, but recent investigations have shown no mortality benefit, and fluoroquinolone prophylaxis makes patients more likely to be colonized by multidrug-resistant bacteria. Many centers have opted against it, even in higher-risk patients (J Infect. 2018 Jan;76(1):20-37).
Dr. Freifeld serves on a data adjudication committee for Merck, and reported research support from the company.
EXPERT ANALYSIS FROM IDWEEK 2018
Single-dose zoliflodacin successfully treats uncomplicated urogenital gonorrhea
A new antibiotic successfully treated uncomplicated urogenital and rectal gonococcal infections, but was not as effective as ceftriaxone in treating pharyngeal infections, according to the results of a randomized, phase 2 study.
About 96% of patients with infection at urogenital sites had microbiologic cure with zoliflodacin, a novel antimicrobial agent that inhibits DNA biosynthesis. The cure rate was 100% for rectal infections, but was just 50%-82% for pharyngeal infections, though few participants in this study had infection at either of those sites.
The study investigators, led by Stephanie N. Taylor, MD, professor of medicine and microbiology at Louisiana State University, New Orleans, wrote that the need for new antimicrobial agents has been underscored by reports of multidrug-resistant Neisseria gonorrhoeae and the possibility of untreatable gonorrhea.
“This phase 2 trial creates equipoise for larger, more definitive studies of zoliflodacin,” Dr. Taylor and her coauthors wrote in the New England Journal of Medicine.
At this point, N. gonorrhoeae has developed resistance to every recommended antibiotic class, including cephalosporins and macrolides, they added.
Zoliflodacin (ETX0914) is an antimicrobial that has received fast-track designation from the Food and Drug Administration specifically for development as an oral treatment for gonococcal infections, the authors noted.
“The mechanism of action of zoliflodacin differs from currently available therapies in that it inhibits microbial biosynthesis by arresting the cleaved covalent gyrase complex and the formation of fused circular DNA required for biosynthesis,” they wrote.
Dr. Taylor and her colleagues studied single 2- and 3-gram doses of zoliflodacin in comparison with 500 mg of intramuscular ceftriaxone in 181 patients with uncomplicated urogenital gonorrhea enrolled in the open-label, randomized, phase 2 study between November 2014 and December 2015.
A total of 141 patients included in the microbiologic intention-to-treat analysis had confirmed positive urethral or cervical cultures. Cures were seen in 55 of 57 infections treated with 2 grams (96%) and 54 of 56 treated with 3 grams (96%) of zoliflodacin, and in 28 of 28 infections (100%) treated with ceftriaxone.
Of 15 confirmed rectal infections, 100% were cured, including 12 treated with zoliflodacin at 2 or 3 grams and 3 treated with ceftriaxone. Of 23 confirmed pharyngeal infections, cures were seen in 4 of 8 (50%) treated with 2 grams of zoliflodacin and 9 of 11 (82%) treated with 3 grams, compared with 4 of 4 cured (100%) with ceftriaxone.
That suggests zoliflodacin was not as effective as ceftriaxone in treating pharyngeal gonorrhea, which is generally considered more difficult to treat than infections at other sites, according to Dr. Taylor and her coauthors.
“Currently, this limitation has not curtailed recommendations for the use of drugs such as spectinomycin or fluoroquinolones for the treatment of gonorrhea,” they wrote.
The study was funded by the National Institutes of Health and Entasis Therapeutics. Dr. Taylor reported grants from the NIH during the study, and other disclosures related to a variety of pharma companies. Her coauthors reported disclosures related to AstraZeneca (parent company of Entasis, which is developing zoliflodacin) and other pharmaceutical companies.
SOURCE: Taylor SN et al. N Engl J Med. 2018 Nov 7; 379:1835-45.
This study represents a “step forward” in identifying new antimicrobial treatment options for patients with gonorrhea, according to Susan Blank, MD, and Demetre C. Daskalakis, MD.
“Given the challenges in clinical follow-up in this patient population, the single-dose regimen is promising,” Dr. Blank and Dr. Daskalakis wrote in a editorial.
While zoliflodacin has the potential to be an effective treatment for gonorrhea, its activity needs to be better defined, particularly in key anatomical sites of infection such as the pharynx, where limited activity was observed.
Progression of resistance of Neisseria gonorrhoeae is an “ever-present concern” given the history of the organism, the authors wrote.
“We are facing the real danger of multidrug-resistant, nearly untreatable gonorrhea,” they wrote. “To avoid untreatable cases of this high-incidence infection, we need to advance diagnostic technology and develop treatments with different mechanisms of action.”
Dr. Blank and Dr. Daskalakis are with the division of disease control in the New York City Department of Health and Mental Hygiene. Their editorial appears in the New England Journal of Medicine . Both reported having no conflicts of interest.
This study represents a “step forward” in identifying new antimicrobial treatment options for patients with gonorrhea, according to Susan Blank, MD, and Demetre C. Daskalakis, MD.
“Given the challenges in clinical follow-up in this patient population, the single-dose regimen is promising,” Dr. Blank and Dr. Daskalakis wrote in a editorial.
While zoliflodacin has the potential to be an effective treatment for gonorrhea, its activity needs to be better defined, particularly in key anatomical sites of infection such as the pharynx, where limited activity was observed.
Progression of resistance of Neisseria gonorrhoeae is an “ever-present concern” given the history of the organism, the authors wrote.
“We are facing the real danger of multidrug-resistant, nearly untreatable gonorrhea,” they wrote. “To avoid untreatable cases of this high-incidence infection, we need to advance diagnostic technology and develop treatments with different mechanisms of action.”
Dr. Blank and Dr. Daskalakis are with the division of disease control in the New York City Department of Health and Mental Hygiene. Their editorial appears in the New England Journal of Medicine . Both reported having no conflicts of interest.
This study represents a “step forward” in identifying new antimicrobial treatment options for patients with gonorrhea, according to Susan Blank, MD, and Demetre C. Daskalakis, MD.
“Given the challenges in clinical follow-up in this patient population, the single-dose regimen is promising,” Dr. Blank and Dr. Daskalakis wrote in a editorial.
While zoliflodacin has the potential to be an effective treatment for gonorrhea, its activity needs to be better defined, particularly in key anatomical sites of infection such as the pharynx, where limited activity was observed.
Progression of resistance of Neisseria gonorrhoeae is an “ever-present concern” given the history of the organism, the authors wrote.
“We are facing the real danger of multidrug-resistant, nearly untreatable gonorrhea,” they wrote. “To avoid untreatable cases of this high-incidence infection, we need to advance diagnostic technology and develop treatments with different mechanisms of action.”
Dr. Blank and Dr. Daskalakis are with the division of disease control in the New York City Department of Health and Mental Hygiene. Their editorial appears in the New England Journal of Medicine . Both reported having no conflicts of interest.
A new antibiotic successfully treated uncomplicated urogenital and rectal gonococcal infections, but was not as effective as ceftriaxone in treating pharyngeal infections, according to the results of a randomized, phase 2 study.
About 96% of patients with infection at urogenital sites had microbiologic cure with zoliflodacin, a novel antimicrobial agent that inhibits DNA biosynthesis. The cure rate was 100% for rectal infections, but was just 50%-82% for pharyngeal infections, though few participants in this study had infection at either of those sites.
The study investigators, led by Stephanie N. Taylor, MD, professor of medicine and microbiology at Louisiana State University, New Orleans, wrote that the need for new antimicrobial agents has been underscored by reports of multidrug-resistant Neisseria gonorrhoeae and the possibility of untreatable gonorrhea.
“This phase 2 trial creates equipoise for larger, more definitive studies of zoliflodacin,” Dr. Taylor and her coauthors wrote in the New England Journal of Medicine.
At this point, N. gonorrhoeae has developed resistance to every recommended antibiotic class, including cephalosporins and macrolides, they added.
Zoliflodacin (ETX0914) is an antimicrobial that has received fast-track designation from the Food and Drug Administration specifically for development as an oral treatment for gonococcal infections, the authors noted.
“The mechanism of action of zoliflodacin differs from currently available therapies in that it inhibits microbial biosynthesis by arresting the cleaved covalent gyrase complex and the formation of fused circular DNA required for biosynthesis,” they wrote.
Dr. Taylor and her colleagues studied single 2- and 3-gram doses of zoliflodacin in comparison with 500 mg of intramuscular ceftriaxone in 181 patients with uncomplicated urogenital gonorrhea enrolled in the open-label, randomized, phase 2 study between November 2014 and December 2015.
A total of 141 patients included in the microbiologic intention-to-treat analysis had confirmed positive urethral or cervical cultures. Cures were seen in 55 of 57 infections treated with 2 grams (96%) and 54 of 56 treated with 3 grams (96%) of zoliflodacin, and in 28 of 28 infections (100%) treated with ceftriaxone.
Of 15 confirmed rectal infections, 100% were cured, including 12 treated with zoliflodacin at 2 or 3 grams and 3 treated with ceftriaxone. Of 23 confirmed pharyngeal infections, cures were seen in 4 of 8 (50%) treated with 2 grams of zoliflodacin and 9 of 11 (82%) treated with 3 grams, compared with 4 of 4 cured (100%) with ceftriaxone.
That suggests zoliflodacin was not as effective as ceftriaxone in treating pharyngeal gonorrhea, which is generally considered more difficult to treat than infections at other sites, according to Dr. Taylor and her coauthors.
“Currently, this limitation has not curtailed recommendations for the use of drugs such as spectinomycin or fluoroquinolones for the treatment of gonorrhea,” they wrote.
The study was funded by the National Institutes of Health and Entasis Therapeutics. Dr. Taylor reported grants from the NIH during the study, and other disclosures related to a variety of pharma companies. Her coauthors reported disclosures related to AstraZeneca (parent company of Entasis, which is developing zoliflodacin) and other pharmaceutical companies.
SOURCE: Taylor SN et al. N Engl J Med. 2018 Nov 7; 379:1835-45.
A new antibiotic successfully treated uncomplicated urogenital and rectal gonococcal infections, but was not as effective as ceftriaxone in treating pharyngeal infections, according to the results of a randomized, phase 2 study.
About 96% of patients with infection at urogenital sites had microbiologic cure with zoliflodacin, a novel antimicrobial agent that inhibits DNA biosynthesis. The cure rate was 100% for rectal infections, but was just 50%-82% for pharyngeal infections, though few participants in this study had infection at either of those sites.
The study investigators, led by Stephanie N. Taylor, MD, professor of medicine and microbiology at Louisiana State University, New Orleans, wrote that the need for new antimicrobial agents has been underscored by reports of multidrug-resistant Neisseria gonorrhoeae and the possibility of untreatable gonorrhea.
“This phase 2 trial creates equipoise for larger, more definitive studies of zoliflodacin,” Dr. Taylor and her coauthors wrote in the New England Journal of Medicine.
At this point, N. gonorrhoeae has developed resistance to every recommended antibiotic class, including cephalosporins and macrolides, they added.
Zoliflodacin (ETX0914) is an antimicrobial that has received fast-track designation from the Food and Drug Administration specifically for development as an oral treatment for gonococcal infections, the authors noted.
“The mechanism of action of zoliflodacin differs from currently available therapies in that it inhibits microbial biosynthesis by arresting the cleaved covalent gyrase complex and the formation of fused circular DNA required for biosynthesis,” they wrote.
Dr. Taylor and her colleagues studied single 2- and 3-gram doses of zoliflodacin in comparison with 500 mg of intramuscular ceftriaxone in 181 patients with uncomplicated urogenital gonorrhea enrolled in the open-label, randomized, phase 2 study between November 2014 and December 2015.
A total of 141 patients included in the microbiologic intention-to-treat analysis had confirmed positive urethral or cervical cultures. Cures were seen in 55 of 57 infections treated with 2 grams (96%) and 54 of 56 treated with 3 grams (96%) of zoliflodacin, and in 28 of 28 infections (100%) treated with ceftriaxone.
Of 15 confirmed rectal infections, 100% were cured, including 12 treated with zoliflodacin at 2 or 3 grams and 3 treated with ceftriaxone. Of 23 confirmed pharyngeal infections, cures were seen in 4 of 8 (50%) treated with 2 grams of zoliflodacin and 9 of 11 (82%) treated with 3 grams, compared with 4 of 4 cured (100%) with ceftriaxone.
That suggests zoliflodacin was not as effective as ceftriaxone in treating pharyngeal gonorrhea, which is generally considered more difficult to treat than infections at other sites, according to Dr. Taylor and her coauthors.
“Currently, this limitation has not curtailed recommendations for the use of drugs such as spectinomycin or fluoroquinolones for the treatment of gonorrhea,” they wrote.
The study was funded by the National Institutes of Health and Entasis Therapeutics. Dr. Taylor reported grants from the NIH during the study, and other disclosures related to a variety of pharma companies. Her coauthors reported disclosures related to AstraZeneca (parent company of Entasis, which is developing zoliflodacin) and other pharmaceutical companies.
SOURCE: Taylor SN et al. N Engl J Med. 2018 Nov 7; 379:1835-45.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point:
Major finding: Cure rates of 96% and 100% were reported for urethral/cervical and rectal infections, respectively, and ranged from 50% to 82% in pharyngeal infections.
Study details: A randomized, open-label, phase 2 study including 181 patients with uncomplicated urogenital gonorrhea who received zoliflodacin or ceftriaxone.
Disclosures: The study authors reported disclosures related to AstraZeneca (parent company of Entasis Therapeutics, which is developing zoliflodacin) and other pharmaceutical companies.
Source: Taylor SN et al. N Engl J Med. 2018 Nov 7; 379:1835-45.
H. pylori antibiotic resistance reaches ‘alarming levels’
Over the past decade, Helicobacter pylori strains have reached “alarming levels” of antimicrobial resistance worldwide, investigators reported in the November issue of Gastroenterology.
In a large meta-analysis spanning 2007-2017, H. pylori isolates showed a 15% or higher pooled prevalence of primary and secondary resistance to clarithromycin, metronidazole, and levofloxacin in almost all World Health Organization (WHO) regions. “Local surveillance networks are required to select appropriate eradication regimens for each region,” concluded Alessia Savoldi, MD, of the University of Tübingen (Germany) and her associates.
Typically, the threshold of antimicrobial resistance for choosing empiric regimens is 15%, Dr. Savoldi and her associates noted. Their systematic review and meta-analysis included 178 studies comprising 66,142 isolates from 65 countries. They defined H. pylori infection as a positive histology, serology, stool antigen, urea breath test, or rapid urease test. They excluded studies of fewer than 50 isolates, studies that only reported resistance as a percentage with no denominator, studies that failed to specify time frames or clustered data over more than 3 years, and data reported in guidelines, conference presentations, or letters without formal publication.
The prevalence of primary clarithromycin resistance exceeded 15% in the WHO European Region (18%; 95% confidence interval, 16%-20%), the Eastern Mediterranean Region (33%), and the Western Pacific Region (34%) and reached 10% in the Americas and the South East Asia region. Furthermore, primary resistance to metronidazole exceeded 15% in all WHO regions, ranging from 56% in the Eastern Mediterranean Region to 23% in the Americas. Resistance to levofloxacin was at least 15% in all WHO regions except the European region (11%).
In most regions, H. pylori also accrued substantially more antimicrobial resistance over time, the investigators said. Clarithromycin resistance rose from 13% during 2006 through 2008 to 21% during 2012 through 2016 (P less than .001). Levofloxacin resistance in the Western Pacific region increased from 12% to 31% during the same two time periods (P less than .001). Several other WHO regions showed less significant trends toward increasing resistance. Multidrug resistance also rose. Resistance to both clarithromycin and metronidazole increased markedly in all WHO areas with available data, reaching 14% in the Eastern Mediterranean and Western Pacific regions and 23% in the European region.
Secondary analyses linked resistance with dramatic increases in the odds of treatment failure. For example, clarithromycin resistance conferred a sevenfold increase in the odds of treatment failure for regimens containing clarithromycin (odds ratio, 7.0; 95% CI, 5.2 to 9.3; P less than .001). Corresponding ORs were 8.2 for levofloxacin resistance, 2.5 for metronidazole resistance, and 9.4 for dual clarithromycin-metronidazole resistance.
The investigators acknowledged several limitations. Of publications in this meta-analysis, 85% represented single-center studies with limited sample sizes, they wrote. Studies often excluded demographic and endoscopic details. Furthermore, only three studies provided prevalence data for the WHO Africa Region and these only provided overall estimates without stratifying by resistance type.
The German Center for Infection Research, Clinical Research Unit, and the WHO Priority List Pathogens project helped fund the work. One coinvestigator disclosed ties to RedHill Biopharma, BioGaia, and Takeda related to novel H. pylori therapies.
SOURCE: Savoldi A et al. Gastroenterology. 2018 Nov. doi: 10.1053/j.gastro.2018.07.007.
The first-line treatment of individuals with Helicobacter pylori infection using clarithromycin-based triple therapies or, if penicillin allergic, bismuth-based quadruple therapies is generally effective. However, reports of declining therapeutic efficacy have led to published guidelines to recommend confirmation of H. pylori eradication after completing a course of antibiotics. It is believed that increasing antibiotic use in agriculture and medicine around the globe have contributed to the increasing H. pylori antibiotic resistance and declining efficacy of standard H. pylori regimens.
Indeed, most H. pylori guidelines recommend antibiotic sensitivity testing after failing two courses of treatment; however, performing such testing successfully may require sending fresh gastric biopsy samples to an in-house H. pylori culture lab within 1 hour, which is generally not available to most clinicians. Clearly, the gap in knowledge of local antibiotic resistance could be addressed by having a readily accessible culture facility and the testing should be reimbursed by health insurance.
Single-center experiences with antibiotic sensitivity–guided salvage therapy in the United States, however, registered a lower efficacy rate of approximately 50%, which indicates that other host factors (such as gastric acidity pH less than 5.5 or body mass index greater than 30 kg/m2) may affect the minimum inhibitory concentration (MIC) of the antibiotics against H. pylori.
In order to better study the effects of these host factors relative to the effect of antibiotic resistance on therapeutic efficacy, it is critical that we practice precision medicine by determining the antibiotic sensitivity of the H. pylori strain prior to initiating the antibiotic treatment. It may be possible to achieve more than 90% therapeutic efficacy given known antibiotic sensitivities of the bacteria and optimized host factors to lower the MIC. In addition, with the increasing awareness of the importance of gut microbiota in health and disease, clinicians should strive to narrow the antibiotic coverage that will be possible if antibiotic sensitivity is known (for example, use high-dose amoxicillin and proton-pump inhibitor dual therapy).
John Y. Kao, MD, AGAF, is the current chair of the AGA Institute Council Esophageal, Gastric and Duodenal Disorders Section, a physician investigator in the University of Michigan Center for Gastrointestinal Research, and an associate professor in the department of medicine in the division of gastroenterology & hepatology and an associate program director of the GI Fellowship Program at Michigan Medicine at the University of Michigan, Ann Arbor. He has no conflicts.
The first-line treatment of individuals with Helicobacter pylori infection using clarithromycin-based triple therapies or, if penicillin allergic, bismuth-based quadruple therapies is generally effective. However, reports of declining therapeutic efficacy have led to published guidelines to recommend confirmation of H. pylori eradication after completing a course of antibiotics. It is believed that increasing antibiotic use in agriculture and medicine around the globe have contributed to the increasing H. pylori antibiotic resistance and declining efficacy of standard H. pylori regimens.
Indeed, most H. pylori guidelines recommend antibiotic sensitivity testing after failing two courses of treatment; however, performing such testing successfully may require sending fresh gastric biopsy samples to an in-house H. pylori culture lab within 1 hour, which is generally not available to most clinicians. Clearly, the gap in knowledge of local antibiotic resistance could be addressed by having a readily accessible culture facility and the testing should be reimbursed by health insurance.
Single-center experiences with antibiotic sensitivity–guided salvage therapy in the United States, however, registered a lower efficacy rate of approximately 50%, which indicates that other host factors (such as gastric acidity pH less than 5.5 or body mass index greater than 30 kg/m2) may affect the minimum inhibitory concentration (MIC) of the antibiotics against H. pylori.
In order to better study the effects of these host factors relative to the effect of antibiotic resistance on therapeutic efficacy, it is critical that we practice precision medicine by determining the antibiotic sensitivity of the H. pylori strain prior to initiating the antibiotic treatment. It may be possible to achieve more than 90% therapeutic efficacy given known antibiotic sensitivities of the bacteria and optimized host factors to lower the MIC. In addition, with the increasing awareness of the importance of gut microbiota in health and disease, clinicians should strive to narrow the antibiotic coverage that will be possible if antibiotic sensitivity is known (for example, use high-dose amoxicillin and proton-pump inhibitor dual therapy).
John Y. Kao, MD, AGAF, is the current chair of the AGA Institute Council Esophageal, Gastric and Duodenal Disorders Section, a physician investigator in the University of Michigan Center for Gastrointestinal Research, and an associate professor in the department of medicine in the division of gastroenterology & hepatology and an associate program director of the GI Fellowship Program at Michigan Medicine at the University of Michigan, Ann Arbor. He has no conflicts.
The first-line treatment of individuals with Helicobacter pylori infection using clarithromycin-based triple therapies or, if penicillin allergic, bismuth-based quadruple therapies is generally effective. However, reports of declining therapeutic efficacy have led to published guidelines to recommend confirmation of H. pylori eradication after completing a course of antibiotics. It is believed that increasing antibiotic use in agriculture and medicine around the globe have contributed to the increasing H. pylori antibiotic resistance and declining efficacy of standard H. pylori regimens.
Indeed, most H. pylori guidelines recommend antibiotic sensitivity testing after failing two courses of treatment; however, performing such testing successfully may require sending fresh gastric biopsy samples to an in-house H. pylori culture lab within 1 hour, which is generally not available to most clinicians. Clearly, the gap in knowledge of local antibiotic resistance could be addressed by having a readily accessible culture facility and the testing should be reimbursed by health insurance.
Single-center experiences with antibiotic sensitivity–guided salvage therapy in the United States, however, registered a lower efficacy rate of approximately 50%, which indicates that other host factors (such as gastric acidity pH less than 5.5 or body mass index greater than 30 kg/m2) may affect the minimum inhibitory concentration (MIC) of the antibiotics against H. pylori.
In order to better study the effects of these host factors relative to the effect of antibiotic resistance on therapeutic efficacy, it is critical that we practice precision medicine by determining the antibiotic sensitivity of the H. pylori strain prior to initiating the antibiotic treatment. It may be possible to achieve more than 90% therapeutic efficacy given known antibiotic sensitivities of the bacteria and optimized host factors to lower the MIC. In addition, with the increasing awareness of the importance of gut microbiota in health and disease, clinicians should strive to narrow the antibiotic coverage that will be possible if antibiotic sensitivity is known (for example, use high-dose amoxicillin and proton-pump inhibitor dual therapy).
John Y. Kao, MD, AGAF, is the current chair of the AGA Institute Council Esophageal, Gastric and Duodenal Disorders Section, a physician investigator in the University of Michigan Center for Gastrointestinal Research, and an associate professor in the department of medicine in the division of gastroenterology & hepatology and an associate program director of the GI Fellowship Program at Michigan Medicine at the University of Michigan, Ann Arbor. He has no conflicts.
Over the past decade, Helicobacter pylori strains have reached “alarming levels” of antimicrobial resistance worldwide, investigators reported in the November issue of Gastroenterology.
In a large meta-analysis spanning 2007-2017, H. pylori isolates showed a 15% or higher pooled prevalence of primary and secondary resistance to clarithromycin, metronidazole, and levofloxacin in almost all World Health Organization (WHO) regions. “Local surveillance networks are required to select appropriate eradication regimens for each region,” concluded Alessia Savoldi, MD, of the University of Tübingen (Germany) and her associates.
Typically, the threshold of antimicrobial resistance for choosing empiric regimens is 15%, Dr. Savoldi and her associates noted. Their systematic review and meta-analysis included 178 studies comprising 66,142 isolates from 65 countries. They defined H. pylori infection as a positive histology, serology, stool antigen, urea breath test, or rapid urease test. They excluded studies of fewer than 50 isolates, studies that only reported resistance as a percentage with no denominator, studies that failed to specify time frames or clustered data over more than 3 years, and data reported in guidelines, conference presentations, or letters without formal publication.
The prevalence of primary clarithromycin resistance exceeded 15% in the WHO European Region (18%; 95% confidence interval, 16%-20%), the Eastern Mediterranean Region (33%), and the Western Pacific Region (34%) and reached 10% in the Americas and the South East Asia region. Furthermore, primary resistance to metronidazole exceeded 15% in all WHO regions, ranging from 56% in the Eastern Mediterranean Region to 23% in the Americas. Resistance to levofloxacin was at least 15% in all WHO regions except the European region (11%).
In most regions, H. pylori also accrued substantially more antimicrobial resistance over time, the investigators said. Clarithromycin resistance rose from 13% during 2006 through 2008 to 21% during 2012 through 2016 (P less than .001). Levofloxacin resistance in the Western Pacific region increased from 12% to 31% during the same two time periods (P less than .001). Several other WHO regions showed less significant trends toward increasing resistance. Multidrug resistance also rose. Resistance to both clarithromycin and metronidazole increased markedly in all WHO areas with available data, reaching 14% in the Eastern Mediterranean and Western Pacific regions and 23% in the European region.
Secondary analyses linked resistance with dramatic increases in the odds of treatment failure. For example, clarithromycin resistance conferred a sevenfold increase in the odds of treatment failure for regimens containing clarithromycin (odds ratio, 7.0; 95% CI, 5.2 to 9.3; P less than .001). Corresponding ORs were 8.2 for levofloxacin resistance, 2.5 for metronidazole resistance, and 9.4 for dual clarithromycin-metronidazole resistance.
The investigators acknowledged several limitations. Of publications in this meta-analysis, 85% represented single-center studies with limited sample sizes, they wrote. Studies often excluded demographic and endoscopic details. Furthermore, only three studies provided prevalence data for the WHO Africa Region and these only provided overall estimates without stratifying by resistance type.
The German Center for Infection Research, Clinical Research Unit, and the WHO Priority List Pathogens project helped fund the work. One coinvestigator disclosed ties to RedHill Biopharma, BioGaia, and Takeda related to novel H. pylori therapies.
SOURCE: Savoldi A et al. Gastroenterology. 2018 Nov. doi: 10.1053/j.gastro.2018.07.007.
Over the past decade, Helicobacter pylori strains have reached “alarming levels” of antimicrobial resistance worldwide, investigators reported in the November issue of Gastroenterology.
In a large meta-analysis spanning 2007-2017, H. pylori isolates showed a 15% or higher pooled prevalence of primary and secondary resistance to clarithromycin, metronidazole, and levofloxacin in almost all World Health Organization (WHO) regions. “Local surveillance networks are required to select appropriate eradication regimens for each region,” concluded Alessia Savoldi, MD, of the University of Tübingen (Germany) and her associates.
Typically, the threshold of antimicrobial resistance for choosing empiric regimens is 15%, Dr. Savoldi and her associates noted. Their systematic review and meta-analysis included 178 studies comprising 66,142 isolates from 65 countries. They defined H. pylori infection as a positive histology, serology, stool antigen, urea breath test, or rapid urease test. They excluded studies of fewer than 50 isolates, studies that only reported resistance as a percentage with no denominator, studies that failed to specify time frames or clustered data over more than 3 years, and data reported in guidelines, conference presentations, or letters without formal publication.
The prevalence of primary clarithromycin resistance exceeded 15% in the WHO European Region (18%; 95% confidence interval, 16%-20%), the Eastern Mediterranean Region (33%), and the Western Pacific Region (34%) and reached 10% in the Americas and the South East Asia region. Furthermore, primary resistance to metronidazole exceeded 15% in all WHO regions, ranging from 56% in the Eastern Mediterranean Region to 23% in the Americas. Resistance to levofloxacin was at least 15% in all WHO regions except the European region (11%).
In most regions, H. pylori also accrued substantially more antimicrobial resistance over time, the investigators said. Clarithromycin resistance rose from 13% during 2006 through 2008 to 21% during 2012 through 2016 (P less than .001). Levofloxacin resistance in the Western Pacific region increased from 12% to 31% during the same two time periods (P less than .001). Several other WHO regions showed less significant trends toward increasing resistance. Multidrug resistance also rose. Resistance to both clarithromycin and metronidazole increased markedly in all WHO areas with available data, reaching 14% in the Eastern Mediterranean and Western Pacific regions and 23% in the European region.
Secondary analyses linked resistance with dramatic increases in the odds of treatment failure. For example, clarithromycin resistance conferred a sevenfold increase in the odds of treatment failure for regimens containing clarithromycin (odds ratio, 7.0; 95% CI, 5.2 to 9.3; P less than .001). Corresponding ORs were 8.2 for levofloxacin resistance, 2.5 for metronidazole resistance, and 9.4 for dual clarithromycin-metronidazole resistance.
The investigators acknowledged several limitations. Of publications in this meta-analysis, 85% represented single-center studies with limited sample sizes, they wrote. Studies often excluded demographic and endoscopic details. Furthermore, only three studies provided prevalence data for the WHO Africa Region and these only provided overall estimates without stratifying by resistance type.
The German Center for Infection Research, Clinical Research Unit, and the WHO Priority List Pathogens project helped fund the work. One coinvestigator disclosed ties to RedHill Biopharma, BioGaia, and Takeda related to novel H. pylori therapies.
SOURCE: Savoldi A et al. Gastroenterology. 2018 Nov. doi: 10.1053/j.gastro.2018.07.007.
FROM GASTROENTEROLOGY
Key clinical point: Helicobacter pylori now shows significant levels of antibiotic resistance worldwide, complicating choices of empiric therapy.
Major finding: Primary and secondary resistance to clarithromycin, metronidazole, and levofloxacin was 15% or more in all WHO regions except for primary clarithromycin resistance in the Americas (10%) and South East Asia (10%) and primary levofloxacin resistance in Europe (11%).
Study details: Meta-analysis of 178 studies comprising 66,142 isolates from 65 countries.
Disclosures: The German Center for Infection Research, Clinical Research Unit, and the WHO Priority List Pathogens project helped fund the work. One coinvestigator disclosed ties to RedHill Biopharma, BioGaia, and Takeda related to novel H. pylori therapies.
Source: Savoldi A et al. Gastroenterology. 2018 Nov. doi: 10.1053/j.gastro.2018.07.007