Nicola M. Parry, BVSc, MRCVS, MSc, DipACVP ELS

Piperacillin-tazobactam is especially harmful to microbiota in the human gut, according to the results of a new 

 published online November 1, 2018, in the journal 

. Additionally, its use is associated with colonization of the gastrointestinal tract by lower relative quantities of some potentially protective bacterial organisms.

“Antibiotics are major contributors to dysbiosis in the gastrointestinal microbiota,” wrote Melinda M. Pettigrew, PhD, from Yale School of Public Health, New Haven, Connecticut, and colleagues. “However, data to guide clinicians in the selection of antibiotics that minimize microbiota disruption remain limited.”

According to the authors, many hospitalized patients experience the collapse of their gastrointestinal microbiota, which increases their risk of colonization and infection by antibiotic-resistant pathogens. Nevertheless, in contrast, most studies investigating the effect of antibiotics on the gut microbiota tend to focus on healthy individuals, they say.

In particular, Dr. Pettigrew and colleagues note that 

 readily colonizes hospitalized patients, and carbapenem-resistant 

 (CRPA) has been reported to cause infections in 28% of colonized patients in intensive care units (ICUs).  

As a consequence, “prevention of CRPA colonization-acquisition represents an important target for interventions to reduce infection and spread of CRPA in the hospital,” the authors stressed.

With this in mind, Dr. Pettigrew and colleagues conducted a study in 109 ICU patients. They collected peri-rectal swabs from patients at the time of admission to ICU, and at subsequent times thereafter, as part of an ongoing surveillance program to culture for vancomycin-resistant 

 (VRE). Swabs were also cultured for imipenem-resistant 

 to identify CRPA colonization-acquisition.  

The investigators also performed rRNA sequencing analysis on the swabs to examine the links between factors such as patient characteristics, medications, gastrointestinal microbiota, and CRPA colonization-acquisition.

In particular, the study showed that ICU patients have a gastrointestinal microbiota composed of large quantities of pathogenic bacterial species such as 

Additionally, patients with CRPA colonization-acquisition had more commonly received piperacillin-tazobactam than patients without colonization. And piperacillin-tazobactam use was associated with the presence of lower quantities of potentially protective bacterial species. These included 

, which tends to be more abundant in patients without multidrug-resistant infections, and 

Patients who had received piperacillin-tazobactam also had a greater risk of colonization by high levels of 

“Our data suggest that piperacillin-tazobactam contributes to microbiota disruption, and indicate that low relative abundances of specific taxa may be related to the risk of CRPA colonization-acquisition,” Dr. Pettigrew and colleagues wrote.

They stressed the need for further studies to determine which commensal organisms are causally related to colonization resistance. Increased understanding of these relationships will assist the development of microbiota disruption indices for monitoring patients at risk of CRPA colonization and infection, they concluded, as well as the development of strategies to minimize infection and spread of CRPA in the hospital.

Dr. Parry, a board-certified veterinary pathologist, graduated from the University of Liverpool in 1997. After 13 years in academia, she founded Midwest Veterinary Pathology, LLC, where she now works as a private consultant. Dr. Parry writes regularly for veterinary organizations and publications.

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Additionally, its use is associated with colonization of the gastrointestinal tract by lower relative quantities of some potentially protective bacterial organisms.

Piperacillin-Tazobactam Very Disruptive to Gut Flora

Salmonellosis continues to be a topical public health threat for Americans, as highlighted by 2 new studies featured in the 

the monthly peer-reviewed public health journal of the US Centers for Disease Control and Prevention (CDC).

Allison C. Brown, PhD, MPH, from the CDC, Atlanta, Georgia, and colleagues share data about a new strain of multidrug-resistant 

 that has recently emerged in the United States, linked with retail chicken meat. “This strain possesses clinically important resistance associated with higher hospitalization rates,” they stressed.

Cindy R. Friedman, MD, also from the CDC, explained why this finding is so concerning. “This multidrug-resistance eliminates many of the recommended treatment options for the management of severe 

infection, such as ampicillin, trimethoprim-sulfamethoxazole, ceftriaxone, and ciprofloxacin,” she told 

In contrast, however, Melanie Firestone, MPH, a PhD candidate from the University of Minnesota School of Public Health, Minneapolis, and colleagues report data from a different study, highlighting 1 approach that proved beneficial to reducing rates of foodborne 

“Our research looked at the public health impact of New York City's letter grade program,” she told 

®. “We found that there was a significant decline in 

 infections in New York City after the letter grade program was implemented.”

 infection is one of the most important causes of bacterial foodborne illness in the United States. This frequently involves 

 serotype Infantis), the incidence of which has risen by 60% in the past decade. Poultry and pigs represent the main animal reservoirs of this serovar.

self-limiting episodes of gastroenteritis, severe cases, especially in patients who have a high risk for invasive disease, require antibiotic therapy.

Extended-spectrum β-lactamases (ESBLs) are bacterial enzymes that confer resistance to clinically useful third-generation cephalosporins that are often used in these invasive cases. Of the ESBLs, the CTX-M family has become one of the most important families of these enzymes worldwide.

Infantis strain was isolated from retail chicken meat in 2014.

Dr. Brown and colleagues showed this isolate to have a unique DNA fingerprint, characterized as pattern 787.

The investigators also examined 34 isolates with this pattern that were collected from human surveillance and associated metadata during 2012 through 2015. They found that these clinical isolates were genetically related to the original isolate obtained from retail chicken in 2014.

In addition, 29 (85%) of the clinical isolates had resistance phenotypes consistent with ESBL-conferred resistance to ceftriaxone, ceftiofur, and ampicillin, and also contained the blaCTX-M-65 gene with multiple additional resistance genes on 1 plasmid.

The investigators had outcome data for 18 of the patients infected with CTX-M-65 Infantis, showing that 8 (44%) were hospitalized. This hospitalization rate was 50% higher than for patients infected with all 

They also found that 12 (63%) patients with CTX-M-65 Infantis infections had traveled internationally in the 7 days before they developed symptoms.

“All reported travel to South America, 10 to Peru, and 2 to Ecuador,” they wrote. In contrast, travel was less common among patients infected with all 

<.01) and with other common serotypes (8%, 

<.01). “This finding is consistent with those of other studies that found foreign travel to be a risk factor for CTX-M—type ESBLs,” the authors said.

Because more than one-third of CTX-M-65 Infantis-infected patients had no history of recent international travel, they were likely exposed via a domestic source. CTX-M genes have been linked with poultry, particularly broiler chickens, and reports have indicated that this strain was present in domestic food processing plants at the end of study period (2014—2015). However, because extensive sampling of poultry plants did not occur before 2014, it remains unknown how and when this new strain entered poultry stock in the United States.

Given the multidrug resistant profile of CTX-M-65 Infantis, the potential for the gene to be transmitted to other bacteria, high hospitalization rates among infected persons, and evidence of this strain in domestic poultry, Dr. Friedman told 

® that action is needed to prevent further dissemination in poultry flocks in the United States, and to decrease opportunities for it to spread to other food animals and to people.

“Enhanced surveillance and additional studies in humans and food animals may help pinpoint the sources of infection for implementation of prevention and control measures,” Dr Brown and colleagues conclude. “Meanwhile, travelers and health care providers should be aware of the risks and implications of infection with this strain, including the potential for antimicrobial treatment failure.”

And, for patients who require treatment, Dr. Friedman encourages healthcare providers to order a culture with antimicrobial susceptibility testing, because some common first-line antibiotics may not work.

“Since this study was reported, there have been further links between 

,” she added. “Therefore, consumers should remember to follow 

, such as washing hands before and after handling chicken and cooking chicken to an internal temperature of 165&#730;F.”

According to Ms. Firestone and colleagues, restaurants also play a key role in the epidemiology of foodborne 

 infections. This is becoming more evident as consumers continue to increasingly favor eating food prepared at restaurants, rather than at home. Indeed, “in 2015, 60% of foodborne illness outbreaks were associated with restaurants,” they wrote.

“Restaurants are frequent settings for transmission of 

 can take advantage of many transmission pathways in restaurants,” Ms. Firestone told 

 infections is a Healthy People 2020 objective, she noted that rates of 

 infection in the United States have not been declining in the past 20 years, despite efforts to improve food safety.

Since 2010, New York City has required restaurants to post letter grades in their windows that correspond to scores received from sanitary inspections by the Department of Health and Mental Hygiene.

“Letter grades for restaurant inspections promote transparency by triggering a feedback loop that leads to improved sanitary conditions,” Ms. Firestone said. “By improving sanitary conditions, an expected outcome is a reduction in risk of illness.”

And this is exactly what the results of this study showed.

“Compared to the rest of the state, we found that 

 infections declined an average of 5.3% per year in New York City after the letter grade program was implemented, compared to the period before implementation,” Ms. Firestone said. 

“This study demonstrates the usefulness of 

 surveillance data for evaluating the effectiveness of food safety policies and programs, and in identifying opportunities for prevention,” she noted.

Although the letter grading approach used in New York City provides a valuable case study of the beneficial impact of such programs for restaurant inspections, Ms. Firestone also emphasized the need for additional studies to better understand which factors contribute the most to declines in infections.

“As the use of culture-independent diagnostic tests increases,” she explained. “More cases of 

 infection will likely be reported, which will provide more data and possibly more ways to use these data to guide prevention efforts.”

In 2015, 60% of foodborne illness outbreaks were associated with restaurants.

Salmonella Studies: New Drug-Resistant Strain, Effective Control Measure

The follicular phase of the menstrual cycle may be the most vulnerable time for HIV-1 acquisition in women—not the luteal phase, as previously thought&mdash;according to the results of a new 

“Our study showed that levels of the chemokine CCL2 were higher in the follicular phase and represented an accurate marker of that phase when controlled for multiple factors,” Keith Fowke, PhD, from 

, Winnipeg, Canada, the study’s principal investigator, shared in an interview with 

HIV-1 infection is a public health issue that disproportionally affects women of reproductive age, wrote Genevieve Boily-Larouche, PhD, also from the University of 

, and colleagues. They note that genital immune parameters are key factors that drive the sexual transmission of HIV in women.

Dr. Fowke explained that inflammation in the female reproductive tract is a known risk factor for HIV because it brings HIV target cells (CD4+ T cells) into the area. It is also known that the immune system varies throughout the menstrual cycle, he added. However, how this variation affects HIV susceptibility is not known.

With this in mind, the investigators conducted a longitudinal study to measure markers of inflammation and HIV target cells from the blood and genital tract of 37 women during the follicular and luteal phases of the menstrual cycle.

They found significant differences in the cervical concentrations of certain factors between the 2 phases of the cycle. In particular, the follicular phase was characterized by increased CCL2 levels, decreased interleukin 1α and interleukin 1β concentrations, and a significant rise in the proportion of CD4+ T cells that expressed CD69.

“The genital concentration of CCL2 was the best marker to distinguish the follicular from the luteal phase in univariate and multivariate analyses, and remained independent of elevated genital inflammation and bacterial vaginosis,” the authors wrote.

According to Dr. Fowke, the role of CCL2 is to attract immune cells to the genital tract, and so, it makes sense that the follicular phase also showed higher levels of CD4+ T cells with the activation/tissue retention marker CD69 on them.

“Because activated CD4+ T cells are highly susceptible to HIV infection, this study suggests that the follicular phase of the menstrual cycle, and not the luteal phase as previously thought, may be the phase of the menstrual cycle where HIV risk is greatest,” he noted.

Understanding how the menstrual cycle affects HIV risk is important when designing HIV prevention strategies, Dr. Fowke said. As well as helping to map out the cause and effect of how chemokine fluctuations affect HIV target cells during the menstrual cycle, this study could also help future studies by narrowing down all of the potential immune parameters that can be measured, to just a few key factors that help define menstrual cycle stage and assess HIV risk—namely CCL2, and CD69 on CD4+ T cells.

“Tracking these key factors will help other researchers determine the impact of their intervention on HIV risk,” Dr. Fowke said.

However, he also emphasized the need for follow-up studies to test the findings of this current study in different cohorts. “Studies testing the susceptibility of cells taken from different phases of the menstrual cycle to HIV infection in vitro, will help determine if cells from one phase are more likely to be infected by HIV,” Dr. Fowke concluded.

The follicular phase of the menstrual cycle may be the most vulnerable time for HIV-1 acquisition in women&mdash;not the luteal phase, as previously thought.

HIV Risk Greatest During Follicular Phase of Menstrual Cycle

Oritavancin is a useful antimicrobial option to help clinicians manage methicillin-resistant 

 (MRSA) infections and other serious Gram-positive cocci (GPC) infections in patients with cancer, including in those at the end-of-life, according to the findings of two recent studies.

“Infection represents an important cause of increased morbidity and mortality in patients with cancer and early introduction of appropriate antimicrobial therapy is essential for patient survival, write Michael A. Pfaller, MD, from the University of Iowa, Iowa City, and colleagues, in their recent 

GPC are the most common pathogens isolated from cancer patients, they explain, and these especially include organisms such as MRSA and vancomycin-resistant enterococci (VRE). Approved for use in the United States in 2014, oritavancin belongs to the lipoglycopeptide class of antimicrobial agents and is effective against these and other GPC. The antimicrobial agent has a long half-life, and acts by interfering with the production of the bacterial cell wall and by disrupting the structural integrity of the bacterial cell membrane,

In their study, the researchers tested the antimicrobial activity of oritavancin against 1,357 isolates of GPC causing infections in cancer patients from 51 European and US medical centers. They also compared its activity with that of several other GPC agents, including daptomycin, vancomycin, teicoplanin, trimethoprim-sulfamethoxazole, and linezolid.

According to Dr. Pfaller and colleagues, more than half (54.6%) of the isolates were from bloodstream infections.

and 98.9% of streptococci, were susceptible to oritavancin at £0.12 mg/L and £0.25 mg/L, respectively. The activity of oritavancin against these isolates was comparable to that of daptomycin, linezolid, teicoplanin, and vancomycin, in particular. And, oritavancin, daptomycin, and linezolid showed activity against VRE, including VanA-type VRE.

Dr. Pfaller and colleagues stress that these findings provide useful information about the antimicrobial resistance profile of GPC isolates that affect patients with cancer and highlight the potential for oritavancin to treat serious GPC infections, including those associated with MRSA and VRE.

, Rupak Datta, MD, PhD, Yale School of Medicine, New Haven, Connecticut, added that such infections are also common among advanced cancer patients near the end of life. “The management of these infections may be complicated,” he said, “particularly when intravenous antimicrobials are indicated and there are stated goals of comfort. Intravenous antimicrobials may cause discomfort and delay transition to hospice care.”

However, being a long-acting lipoglycopeptide with broad Gram-positive coverage, oritavancin avoids both this discomfort and the risks associated with intravenous dosing, including phlebitis and skin and soft tissue infections. Its long half-life also makes it useful for treating infections in end-of-life patients who may be entering the care of hospice agencies that preclude intravenous antimicrobial therapies.

, Dr. Datta, and colleagues report three cases of patients with terminal cancer who had MRSA, 

 bacteremia who received the long-acting lipoglycopeptide oritavancin to facilitate discharge to hospice.

These patients included: a 64-year-old man with metastatic hepatocellular carcinoma and poorly controlled diabetes; a 72-year-old woman with recurrent non—small cell lung cancer; and a 69-year-old woman with metastatic stage IV non–small cell lung cancer.

“We show that long-acting lipoglycopeptides may have benefit in select patients with invasive infection in whom antimicrobial therapy is desired per patient and family discussions,” Dr. Datta concluded to 

Dr. Parry graduated from the University of Liverpool, England in 1997 and is a board-certified veterinary pathologist. After 13 years working in academia, she founded Midwest Veterinary Pathology, LLC where she now works as a private consultant. She is passionate about veterinary education and serves on the Indiana Veterinary Medical Association’s Continuing Education Committee. She regularly writes continuing education articles for veterinary organizations and journals and has also served on the American College of Veterinary Pathologists’ Examination Committee and Education Committee.

Oritavancin is a useful antimicrobial option to help clinicians manage MRSA infections and other serious GPC infections in patients with cancer, including in those at the end-of-life.

Oritavancin Useful for Managing Serious Infections in Cancer Patients

Shortening the rabies pre-exposure prophylaxis (PrEP) regimen is both effective and safe, a recent study 

“In healthy adults, ID [intradermal] administration of a double dose of 0.1 ml of HDCV [human diploid cell culture rabies vaccine] over two-visits (day 0 and day 7) was safe and not inferior to the single-dose three-visit schedule,” writes Patrick Soentjens, MD, PhD, from the Institute of Tropical Medicine, Antwerp, Belgium, and colleagues.

According to the authors, rabies is a neglected global challenge, with a case fatality rate approaching 100%.

As a consequence, PrEP is a key component of rabies prevention and is recommended by the World Health Organization (WHO) for anyone at high risk of exposure to the virus because of their occupation, travel, or residence in a rabies-endemic area with poor access to timely and adequate PEP.

The standard PrEP schedule is comprised of 3 vaccinations given over a 28-day period. However, because this regimen is not always practical, effective, and safe, alternate schedules have been designed.

In their study, Dr Soentjens and colleague investigated the safety and efficacy of using an ID vaccine, with 2 doses administered 7 days apart.

The researchers recruited healthy participants (aged 18 to 47 years), from the Belgian Armed Forces, randomly assigning 500 of them to receive either two 0.1-mL doses of the ID HDCV rabies vaccine on days 0 and 7 (2ID), or a single 0.1-mL dose of ID HDCV on days 0, 7, and 28 (3ID).

One to 3 years later, the researchers gave participants in both groups a single booster dose of HDCV, in order to examine the anamnestic response.

A total of 211 participants in the 2ID group and 200 in the 3ID group completed the primary vaccination regimens and received a booster vaccination.

All participants in both groups had a rabies antibody titer >0.5 IU/mL on day 7 after the booster injection. “[S]ubjects exposed to the double-dose two-visit ID schedule had a geometric mean titer of 37 IU/ml, versus 25 IU/ml for the single-dose three-visit schedule (p<0.001),” the authors added.

The most common adverse event was a local reaction at the injection site, but this was typically mild and transient, according to the authors. After the primary vaccination, this type of reaction occurred more frequently in the 3ID group (51.8% vs 43.4%, 

=.07). However, after the booster dose, it occurred more frequently in the 2ID group (38.8% vs 48.8%, 

“Data from the present study substantiates the safety and the immunogenicity of the 2ID regimen for rabies immunization in adult healthy travelers,” the authors conclude. “Shortened PrEP ID schedules, using simpler low-dose vaccine regimens, can be considered an illustration that less can be more,” they emphasize.

A recent study finds that shortening the rabies pre-exposure prophylaxis regimen is both effective and safe.

Shorter Pre-exposure Rabies Vaccination Schedule Effective 

In the wake of the Ebola epidemic in West Africa, the World Health Organization (WHO) put forth a worldwide coalition to develop an 

R&D [Research and Development] Blueprint for Action to Prevent Epidemics

. One focus of this blueprint involves creating R&D roadmaps for 

The Center for Infectious Disease Research and Policy (CIDRAP) at the University of Minnesota in Minneapolis is working with WHO and the Wellcome Trust to create these roadmaps and providing information about the process via a series of webinars which will allow a wide range of stakeholders from the private and public sectors, as well as from government and academia, to participate in developing measures to help prevent and control priority diseases.

 hosted by CIDRAP, the Center’s director, Michael T. Osterholm, PhD, MPH, shared information about the process involved in developing an R&D roadmap for the priority pathogen Nipah virus.

Nipah virus is an emerging infectious disease

 that is endemic in Southeast Asia. It is a zoonotic paramyxovirus, and predominantly spreads through contact with bats (in particular, fruit bats) or infected pigs. However, it can also be spread person-to-person. It causes severe disease in people, with 

 that have been reported to range from 40% to 100%.

first identified in 1998-1999 in Malaysia and Singapore

, in association with an outbreak of infectious respiratory and neurologic disease in farmed pigs. The pigs served as a source of infection among pig farmers and other people who were in close contact with the animals, resulting in encephalitis and respiratory illness in these individuals.

Although Nipah virus infection has not been identified in Malaysia or Singapore since 1999, outbreaks of Nipah encephalitis with high fatality rates have occurred on an almost annual basis in Bangladesh since 2001 (see 

The roadmap for Nipah prioritizes the development of “robust medical countermeasures to detect, prevent, and control outbreaks” of infection in countries affected by the virus, said Dr. Osterholm. These measures include diagnostics, therapeutics, and vaccines.

According to the US Centers for Disease Control and Prevention, although ribavirin has been shown to be effective against Nipah virus in vitro, “human investigations to date have been inconclusive and the clinical usefulness of ribavirin remains uncertain.” Therefore, 

Dr. Osterholm stressed during the webinar that “roadmaps are pivotal in understanding markets for innovative products and identifying ways to leverage R&D investments, through coordinating research activities across a multitude of different partners.”

 is currently on schedule. To date, a Nipah Roadmap Taskforce of 13 members have already participated in an expert review meeting and have continued to provide a review of the roadmap document. 

The final draft of the roadmap document is anticipated in June, after incorporating additional feedback from stakeholders. However, the document will continue to be revised with input from WHO and other key partners before its final publication in August or September.

In the wake of the Ebola epidemic in West Africa, the World Health Organization is working with the Center for Infectious Disease Research and Policy and the Wellcome Trust to create research & development roadmaps for priority diseases, such as Nipah virus.

Nicola M. Parry, BVSc, MRCVS, MSc, DipACVP ELS

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