Ken reports on medical innovations and advances in practice and edits presentations for news and professional education publications. He previously taught and mentored pharmacy and medical students, and provided and managed pharmacy care and drug information services. He regularly contributes to Contagion Live, HCP Live, Neurology Live, and Pain Medicine News.

Kenneth Bender, PharmD, MA

The hazards that monkeypox poses to maternal and fetal health prompted experts from several countries to recently propose a clinical management 

 (decision tree) on isolating and testing after exposure and treating the infection during pregnancy.

Pradi Dashraath, MBBS, Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, National University Hospital, Singapore, and colleagues in Singapore, the US, France, French Guiana and Switzerland warn of the risk of severe congenital infection, miscarriage, and maternal morbidity and mortality.

Although the west African clade of monkeypox virus implicated in the current outbreak is associated with milder disease in general than the central African clade, Dashraath and colleagues note that its effects in pregnancy are not yet known. They warn that the experience with monkeypox in the Congo—including miscarriages and stillbirths, as well as the virus DNA confirmed in fetal tissue, umbilical cord and placenta, consistent with vertical transmission—warrants precautions against exposure, isolation and testing if exposed, and prompt treatment if infected.

"Clinicians must maintain a high index of suspicion for monkeypox virus in any pregnant woman presenting with lymphadenopathy and vesiculopustular rash, including rash localized to the genital or perianal region, even if there are no apparent epidemiological links," Dashraath and colleagues advise.

Dashraath and colleagues recommend PCR testing for monkeypox for all pregnant individuals with suspected exposure to monkeypox whether or not they are symptomatic. The medical management decisions then flow from test results, with positive tests in asymptomatic individuals necessitating isolation at home for 21 days, self-monitoring for such symptoms as fever and rash, and considering an orthopox vaccine. The algorithm also recommends ultrasound fetal surveillance, and possible amniocentesis if there are signs of hydrops or hepatomegaly.

A vaccine, the algorithm notes, is optimally used within 4 days of exposure, but can be effective if administered within 14 days in the absence of symptoms. Dashraath and colleagues suggest that a third-generation smallpox vaccine, MVA-BN (Modified Vaccinia Ankara-Bavarian Nordic), recently approved in the US, Canada and the EU, could be safer for the fetus as it contains non-replicating virus and has not demonstrated adverse pregnancy outcomes.

For individuals with apparent symptoms but a negative test for monkeypox, other causes for the symptoms should be determined, and the same period of isolation with self-monitoring should be undertaken. Dashraath and colleagues suggest ruling out varicella, herpes simplex and syphilis, as possible sources of similar symptoms. Repeat testing for monkeypox is recommended if symptoms persist without other causes identified.

For pregnant individuals who are symptomatic and test positive for monkeypox, hospitalization may be clinically indicated, with the algorithm referring to the WHO clinical severity score based on number of skin lesions. Maternal surveillance should include monitoring temperature, heart rate, and blood pressure multiple times a day—along with supportive care and pain management.

For these infected individuals, Dashraath and colleagues indicate that in addition to infection-specific treatment with tecovirimat, vaccinia immune globulin and an othopox vaccine, antibiotics may be necessary to prevent bacterial superinfection. They warn that cidofovir should be considered only in critically ill patients, as it is a known teratogen. Fetal assessments will be necessary, and administration of corticosteriods should be considered for fetal lung maturation, depending on gestational age, according to the algorithm.

Dasbraath and colleagues do not favor cesarean section over vaginal delivery except if genital lesions are present. They do call for PCR testing of the newborn, particularly from suspicious mucocutaneous lesions. They also recommend assessment of monkeypox viral load from umbilical cord and placenta; noting that monkeypox virus is likely to be shed in the amniotic fluid only after approximately 18-21 weeks gestation, when fetal kidneys begin producing sufficient urine.

"Finally, we encourage the reporting of all cases of monkeypox virus in pregnancy to WHO and an international registry for emerging pathogens," Dashraath and colleagues conclude.

Articles

Algorithm offers guidance on clinically managing pregnant individuals exposed to monkeypox and on treating the virus during pregnancy. 

Treatment Algorithm Addresses Monkeypox in Pregnancy

The most common of carbapenem resistant enterobacterales (CRE) infections in Saudi Arabia is attributed to 

 carrying the beta-lactamase (bla) gene blaOXA-48, in a large prospective cohort 

 which the investigators hope will inform future studies into prevention and treatment.

"Knowledge regarding the molecular epidemiology of CRE in Gulf countries and in the Middle East in general is limited," observed lead author Basem Alraddadi, MD, King Faisal Specialist Hospital and Research Center, Jeddah, Saudi Arabia and colleagues.

 of CRE treatment considerations in this era of evolving enzymology, Maxwell Lasko, PharmD, and David Nicolau, PharmD, Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT, affirm that OXA carbapenemases are endemic to the Middle East, as well as Europe and Northern Africa. They note that the 

 carbapenemase (KPC) is the most prominent in North America and Israel, and the metallo-β-lactamase (MBL) in India, Italy and Greece.

Although a region's most prevalent carbapenemase may not be the source of an individual's treatment-resistant infection (which may not only arise from another carbapenemase, but also from non-carbapenemase mechanisms) data on prevalence could help in the choice of initial, empiric therapy. Lasko and Nicolau point out, for example, that the OXA-48 found in the Middle East is a serine-based carbapenemase which will hydrolyze carbapenems but will not counter ceftazidime and cefepime activity.

Alraddadi and colleagues note that most other studies that have identified OXA-48 the most prevalent carbapenemase in the Middle East were retrospective and based on smaller sample sizes than in the current study. In this prospective study, the investigators identified 189 patients 14 years of age or older (median 62.8 years) over a 28-month period from August 2018 through November 2020, from eight hospital systems in Saudi Arabia.

Patients had a positive CRE culture with 

 and a clinically established infection. The interpretation of the minimum inhibitory concentration (MIC) for carbapenems was based on CLSI guidelines; with resistance to ertapenem defined at MIC ≥2μg/ml and to imipenem at ≥4μg/ml. Phenotype of CRE isolates were differentiated for the bla genes KPC, NDM, VIM and OXA-48. The primary outcome in the study was 30-day all-cause mortality; with secondary measures including length of hospital stay, relapse within 30 days and acute kidney injury.

Alraddadi and colleagues reported that the most common CRE infections were nosocomial pneumonia (23.8%) and complicated urinary tract infection (23.8%); and 77 patients (40.7%) had CRE bacteremia. A clinical cure was attained in 100 patients (52.9%); 57 (30.2%) died within 30 days and 23 (12.2%) relapsed. Multivariable analysis revealed CRE bacteremia as an independent predictor of 30 day all-cause mortality.

In their review, Lasko and Nicolau describe the CRE as among the group of organisms that are the most difficult treat. "It is no surprise that the CDC considers them to be one of the top three most urgent threats, with resistance spreading rapidly in the USA and throughout the world," they wrote.

Alraddadi and colleagues indicate that their study helps to define the burden of CRE infection in the region, as well as the phenotypic epidemiology, and the therapeutic approaches being applied. "This information will inform local and global preventive and therapeutic interventoin protocols for CRE infection," they conclude.

Carbapenem-resistant enterobacterales in Saudi Arabia were genotyped and the course of illness characterized to help inform treatment and prevention.

Carbapenem-Resistant Enterobacterales Characterized in Region of Middle East

There are now more than 1000 confirmed cases of monkeypox in 29 countries that are not endemic for the virus, including 45 in the US across 15 states and Washington DC.The spread can be contained with such measures as appropriate testing, tracing, and targeted use of the vaccines that are currently available, according to updates offered by both the World Health Organization (WHO) and US Centers for Disease Control and Prevention (CDC) at their separate press conferences held, respectively, on 

In his introductory remarks, WHO Director General Tedros Adhanom Ghebreyesus, PhD, indicated that the sudden and unexpected emergence of monkeypox in nonendemic regions suggests that there could have been undetected transmission for some time.

He noted the WHO is particularly concerned about the risk to vulnerable groups, including children and pregnant women, and lamented that robust preventative efforts had not been conducted earlier.

“This virus has been circulating and killing in Africa for decades. It’s an unfortunate reflection of the world we live in that the international community is only now paying attention to monkeypox because it has appeared in high-income countries,” Ghebreyesus said. “The communities that live with the threat of this virus every day deserve the same concern, the same care, and the same access to tools to protect themselves.”

In her opening statement, CDC Director Rochelle Walensky MD, MPH, described how the disease manifests, and noted that the CDC is working to increase public awareness as well as to advise clinicians and public health departments.Although the disease has been known and studied for years, gaps remain.

“We do not yet know whether the virus may be spread through contact with semen or vaginal fluids, or the potential for transmission among people who are infected with monkey box but have no, or mild symptoms,” Walensky observed.

“What we do know is that those diagnosed with monkey pox in this current outbreak described close, sustained physical contact with other people who were infected with the virus.This is consistent with what we've seen in prior outbreaks and what we know from decades of studying this virus and clinically related viruses,” Walensky said.

Questions posed at the WHO conference were related to vaccine availability, modes of transmission, and the underlying factors driving the increase in cases. To the first, Sylvie Briand, MD, MPH, PhD, WHO Director for Global Infectious Hazard Preparedness, responded that while the stockpile of vaccines against smallpox should be effective against monkeypox, the potency of stored vaccines has not been checked regularly.

“So, this is what we are currently doing,” Briand said, “checking also the potency of vaccines that are available in different places in the world.”

Regarding the current emergence, Rosamund Lewis, MDCM, MSc, WHO Technical Lead on Monkeypox, conceded that, despite studies on monkeypox dating back 50 years, “there's a great deal that we don't know at this time yet, especially including in the new circumstances.”

Lewis posited that there may initially have been increased zoonotic transfer resulting from climate change, deforestation, increased population, and demographic pressures. She suggested that the current spread outside endemic regions by the one of the two clades of monkeypox which causes less severe disease may be a factor in the rate of spread.

“When there is less severe disease, then people don't need to stay home. It's easier to move out and about if you're not feeling all that ill,” Lewis commented.

On the modes of transmission, Lewis reiterated that the primary driver in the nonendemic setting is direct contact, which can include sexual contact. “As we've said before, there’s a lot we still don't know about this new outbreak. However, this classic mode of transmission is well-described in the past as having been due to personal physical contact.”

The first question posed at the CDC briefing, on why the amount of stockpiled vaccine was disclosed in this briefing when it had not been previously made public, was answered by Dawn O'Connell, HHS Assistant Secretary for Preparedness and Response.

“So, we don't traditionally share what we have in the strategic national stockpile for national security,” O'Connell replied.

“We thought it would help in this case to give just a little more granularity: that the number of vaccines is not something the American public needs to worry about, that we do have more than enough...and, frankly, if our adversaries hear that, I think that would be a deterrent for them to know too,” O'Connell added.

To a question about whether and how the US is working with partners such as the WHO on multinational approaches, Raj Panjabi, MD, senior director of the White House Office for Global Health Security and Biodefense, remarked that it is well recognized that there is no "domestic only" approach to a multinational outbreak.

“In the context of this outbreak, we do have a dual goal of both responding effectively to the outbreak here and also assisting countries more to respond to the outbreak,” Panjabi said.

At the following week's WHO media briefing, on Tuesday, 

, Ghebreyesus announced he would be convening its Emergency Committee, under the International Health Regulations, to determine whether monkeypox should be designated a “public health emergency of international concern”—the designation that was applied in early 2020 to COVID-19.

At separate press conferences, the CDC and WHO indicate that containing monkeypox will depend on testing, tracing, and currently available vaccines.


CDC, WHO Answer Questions From the Press on Monkeypox

 from the scientific advisory group for the origins of novel pathogens (SAGO) to the World Health Organization (WHO) did not identify the source of SARS-CoV-2, but rather was presented June 9 to the Member State Information Session on COVID-19 in Geneva, Switzerland as preliminary, and a work in progress.

WHO Director-General Tedros Adhanom Ghebreyesus, PhD, remarked at the 

 that the SAGO was established in October 2021 to create a global framework for studying the origins of emerging and re-emerging pathogens. He acknowledged that 2 1/2 years after identifying the first cases, the origin of the novel coronavirus remains unknown.

"The longer it takes, the harder it becomes. We need to speed up, and act with a sense of urgency," Ghebreyesus said. "All hypotheses must remain on the table until we have evidence that enables us to rule certain hypotheses in or out."

A briefing on the report was provided by SAGO Chair, Marietjie Venter, PhD, Department of Medical Virology, University of Pretoria, South Africa, and by Michael Ryan, MD, MPH, executive director, WHO Health Emergencies Program, and Maria Van Kerkhove, PhD, WHO technical lead, COVID-19. Ryan and Van Kerkhove had led a panel to identify 27 members of SAGO, from over 800 applicants.

In this first report, SAGO emphasizes that it was not formed to find the origins of SARS-CoV-2, but rather to advise on the studies that will be necessary to achieve that. The report acknowledges, "so far neither the virus progenitors nor the natural/intermediate hosts or spill-over event to humans have been identified."

The report lays out the complexity of a global framework of research which could advance understanding of the emergence of SARS-CoV-2 in humans, and indicates that working groups have been tasked to address each, including: reassessment of the initial human and anthropology studies, investigations of animal/human interface, environmental and ecological studies, genomics and phylogenetics and assessments of biosafety and biosecurity. It also suggests, however, that it is unclear whether these studies will be accomplished and/or the results disclosed.

"It is important to note that at the time of writing (version 1 submitted to WHO April 13, 2022 and version 2 on May 15) there are outstanding results from the recommended studies from the 2021 Joint Report, that the SAGO feels need to be conducted. It is also important to note, the SAGO was not provided any information related to studies conducted evaluating the laboratory hypotheses as a possible introduction into the human population," the investigators wrote in the report.

The likelihood of obtaining evidence to confirm or rule out the possible introduction of SARS-CoV-2 through a laboratory incident notwithstanding, the SAGO report calls on staff in the laboratories who were tasked with managing and implementing biosafety and biosecurity to conduct/disclose the necessary investigations. Their call-out applies to laboratories in the proximity of the original COVID-19 outbreak working with SARS-like viruses in Wuhan, China as well as those located worldwide where early COVID-19 cases have been retrospectively detected before 2020.

Ghebreyesus emphasized the importance of the SAGO undertaking, while also revealing his frustration with the obstacles to its progress.

"Understanding the origins of the virus is very important scientifically, to prevent future epidemics and pandemics, but morally, we also owe it to all those who have suffered and died, and their families," he said.

"This makes it all the more urgent that this scientific work be kept separate from politics," Ghebreyesus indicated. "The way to prevent politicization is for countries to share data and samples, with transparency and without interference from any government. The only way this scientific work can progress successfully is with full collaboration from all countries, including China, where the first cases of SARS-CoV-2 were reported."

The first report from WHO Scientific Advisory Group for the Origins of Novel Pathogens (SAGO) concedes SARS-CoV-2 source remains a mystery.

WHO Report: Origin of COVID-19 Remains to be Determined


Reports of a "rebound" in COVID-19 symptoms and retesting positive for SARS-CoV-2 after testing negative with Paxlovid (nirmatrelvir/ritonavir, NM/R) treatment have marred the experience of the "test and treat" initiative. While the intervention continues to protect at-risk individuals with mild symptoms from severe illness, these reports prompted a health 

 from the Centers for Disease Control and Prevention (CDC).

The CDC advisory characterizes the apparent rebound as typically short-lived (median 3 days), occurring 2 to 8 days after putative response to treatment, and not requiring additional anti-COVID-19 treatment. The recurrence of symptoms and positive testing does, however, warrant resuming a period of isolation consistent with CDC 

. The advisory emphasizes that Paxlovid treatment, under Emergency Use 

 by the FDA, continues to be recommended for early-stage, mild to moderate COVID-19 among persons at high risk for progression to severe disease.

The evidence cited in the advisory points to rebound rather than to reinfection, or an additional infecting pathogen, or to development of resistance to Paxlovid. The frequency of the occurrence is unclear, as the advisory notes that there was a "small" number of participants in the Paxlovid clinical trial (an FDA 

 indicates a range of 1-2%) who became symptomatic and tested positive after initial resolution; but that this was observed in both the active drug and placebo groups.

 cited in the advisory, however, Michael Charness, MD, chief of staff, VA Boston Healthcare System, Boston, MA and colleagues indicate that while their series comprised a convenience sample, "it is noteworthy that 5 of 8 cases occurred within two families, suggesting that relapse following NM/R treatment is not rare."

Anecdotal, first person reports don't clarify how likely the rebound is to occur, but they are intriguing. In her reporting for 

, Rachel Gutman reached out to Robert Wachter, MD, chair of the Department of Medicine, University of California, San Francisco, who provided her with the number of his social media contacts who had reported experiencing the rebound after Paxlovid treatment. Several hours after their interview, he re-contacted Gutman to add his wife to the list, as she had just relapsed after recovering.

) coverage of the phenomenon, health policy reporter Fran Kritz offered a first-person testimonial from their own science correspondent, Joe Palca, who she characterized as a "rebounder." To these, this reporter for 

 can add his own experience with recurrence of minor symptoms and positive SARS-CoV-2 test, 3 days after being symptom-free and testing negative at the completion of a 5-day course of Paxlovid.

The possibility that a rebound of COVID-19 might be less likely with an extension of treatment is being considered by the manufacturer, according to Kit Longley, Pfizer Global Media Relations.

"There may be some patient populations who may benefit from longer durations of treatment, and we are considering additional studies to evaluate this in some populations," Longley told 

There has been one trial comparing a 5- and 10-day course of Paxlovid, but this was for a cohort of 

 contacts rather than symptomatic persons at risk for severe illness. Although it did not yield statistically significant results to ascertain the potential for prophylactic use, it did indicate that the 10-day regimen was well tolerated.

"These findings may help inform future study designs, including those evaluating the potential of a longer treatment duration in some patient populations," Longley commented.

Davey Smith, MD, MAS, head, Division of Infectious Diseases and Global Public Health, Department of Medicine, University of California San Diego, whose group helped to 

 both the development of drug resistance and an absence of neutralizing antibody for the apparent rebound, agreed with the notion of investigating a different regimen.

"Definitely need more trials," Smith remarked to 

. "May need to figure out which patient characteristics predispose to this phenomenon."

Smith also considered what mechanism might underlie the rebound, having ruled out the emergence of drug resistance. "I think there are many possibilities, including cells harboring live virus in various tissues, upper or lower respiratory tract," he posited.

Kalpana Gupta, MD, a co-author and colleague of Charness at VA Boston Healthcare, also suggested a possible mechanism for the rebound, in discussing their case series report with 

"We do know that the magnitude of the immune response is a function of the magnitude and duration of the immune stimulus," Gupta said. "Conceivably, reductions in viral load after early treatment with antivirals dampen or delay the immune response, and the terminatoin of antiviral treatment allows viral replication to resume until the immune response catches up and clears residual virus."

Rebound in COVID-19 symptoms, retesting positive for SARS-CoV-2, and recurring infectivity after Paxlovid treatment mars "test and treat."

COVID-19 Rebound After Paxlovid Tests the "Test and Treat" Plan for Pandemic

A novel vaccine against COVID-19, ZF2001 (Zifivax), from the China-based developer, Zhifei, that builds its protein subunit platform with a receptor-binding domain (RBD)-dimer demonstrated safety and efficacy in a phase 3 trial reported in the 

The double-blind, placebo-controlled trial evaluated a 3-dose regimen of the adjuvanted vaccine administered at 30-day intervals to over 28,000 adult participants at 31 centers in 4 countries. Over 25,000 received all 3 doses, and were followed for approximately 6 months after the final dose.

Lead author Lianpan Dai, PhD, CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China, and colleagues reported an overall efficacy of 75.7% in preventing COVID-19; with 87.6% (95% CI, 70.6 to 95.7) efficacy against severe to critical illness and 86.5% (CI 38.9 to 98.5%) against mortality.

The trial was conducted between December 12, 2020 and December 15, 2021 in regions where the delta variant was initially prevalent, but with alpha and kappa variants also encountered. The investigators reported that efficacy against alpha was 92.7% in short-term follow-up and 88.3% in long-term; 81.4% and 76.1%, respectively against delta; and 84.8% and 75.2%, respectively for the kappa variant.There were comparable adverse events reported in active and placebo groups, with most (98.5%) of grade 1 or 2, and there were no vaccine-related deaths (determined within 7 days of final dose)..

"The high cross-protection conferred by ZF2001 against different SARS-CoV-2 variants is encouraging," Dai and colleagues commented.


A separate multinational phase 3 trial in same issue of the 

 demonstrated efficacy and safety of another adjuvanted vaccine with a novel platform, CoVLP+AS03, Covifenz, from Medicago, which employs a plant-based coronavirus-like particle (CoVLP), previously reported 

. Those simultaneously published reports also coincide with the currently anticipated FDA approval of the protein-based vaccine from Novavax, which delivers copies of the coronavirus spike protein grown in insect cells.

These developments prompt the question posed in the title of an 

, "Does the World Still Need New COVID-19 Vaccines?"

Hanna Nohynek, MD, PhD, Finnish Institute for Health and Welfare, Helsinki, Finland, and Annelies Wilder-Smith, MD, PhD, Institute of Preventive and Social Medicine, University of Bern, Switzerland, answer in the affirmative, while acknowledging more than 300 vaccine candidates comprising at least 5 different technology platforms currently in development.

"Many reasons dictate a need for the development of a range of COVID-19 vaccines available for use across the world with the aim of bringing the pandemic under control," Nohynek and Wilder-Smith assert.

They point out that efficacy and safety are not the sole outcomes that are assessed in a country's decision to procure and provide a particular vaccine product. Ease of schedules, effectiveness in routine programs, frequency of needed boosters, costs, cold-chain logistic requirements, manufacturing scalability are among other factors that are considered.

Dai and colleagues point to several other RBD-based COVID-19 vaccines under development, with some having been approved and some in late stage clinical trials. Noting that inactivated virion and full length spike are the 2 other major antigen targets in currently approved vaccines, they indicate that their trial results with this RBD-based product "add a piece to the puzzle in understanding one of the major viral targets used in COVID-19 vaccines."

Nohynek and Wilder-Smith's view suggests that multiple pieces will have to be placed to complete that puzzle. "The next generation of COVID-19 vaccines will need to have broader epitope coverage to provide cross-immunity against SARS-CoV-2 variants, confer a longer duration of protection, and be easy to update in a timely manner for protection against new variants," they opine.

"With more vaccine platforms available, we can possibly improve decision making regarding the selection of a vaccine, since different vaccine platforms may be more suitable for certain age groups, certain subpopulations—eg, those with underlying immune-compromising or other medical conditions—and pregnant women," say Nohyynek and Wilder-Smith.

New vaccine for COVID-19 employing receptor-binding domain-dimer-based platform achieves 87.6% efficacy against severe to critical illness.

Kenneth Bender, PharmD, MA

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