Multidrug-resistant Corynebacterium diphtheriae in people with travel history from West Africa to France, March to September 2023.

We describe 10 unlinked cases of Corynebacterium diphtheriae infection (nine cutaneous, one respiratory) in France in 2023 in persons travelling from Guinea, Mali, Senegal, Niger or Nigeria and Central African Republic. Four isolates were toxigenic. Seven genomically unrelated isolates were multidrug-resistant, including a toxigenic respiratory isolate with high-level resistance to macrolides and beta-lactams. The high rates of resistance, including against first-line agents, call for further microbiological investigations to guide clinical management and public health response in ongoing West African outbreaks.

Several confirmed and probable zoonotic cases of toxigenic Corynebacterium ulcerans, Queensland, Australia.

Background: Toxigenic Corynebacterium ulcerans is an emerging zoonosis globally, causing both cutaneous and respiratory diphtheria-like illness. In Queensland, human infection with toxigenic C. ulcerans is rare, with only three cases reported before October 2015. This case series describes five subsequent cases of toxigenic C. ulcerans in Queensland with links to companion animals. Methods: All data were collected as part of routine public health response, and strains were whole genome sequenced for further characterisation. Household contacts were screened, treated with appropriate antibiotics, and received a diphtheria toxoid-containing vaccine if more than five years had elapsed since their last dose. Findings: No epidemiological or genomic links could be established between any of the five patients, including between the two cases notified from the same locality within eight days of each other. The C. ulcerans strains from Cases Two, Four and Five were closely related to the strains isolated from their respective pets by whole genome sequencing. Domestic dogs were identified as the most likely mode of transmission for Cases One and Three; however, this was unable to be laboratory confirmed, since Case One's dog was treated with antibiotics before it could be tested, and Case Three's dog was euthanised and cremated prior to case notification. Interpretation: These are the first reported Australian cases of this emerging zoonosis with links to companion animals. These cases demonstrate the likely transmission route between companion animals and humans, with no evidence of human-to-human transmission. The existing requirement in the Queensland Health Public Health Management Guidelines, of restrictions on cases and some contacts while awaiting swab results, is currently under review.

Immunogenicity of tetanus, diphtheria and acellular pertussis vaccination among pregnant women living with and without HIV.

OBJECTIVE: Vaccination during pregnancy with tetanus-diphtheria-acellular pertussis (Tdap) vaccine is recommended to protect the young infants against pertussis. There is a paucity of data on immune responses to Tdap in pregnant women with HIV (PWWH), and its impact on the protection of their infants has not been described. METHODS: In an open label phase IV clinical trial in South Africa, we evaluated the immunogenicity and safety of Tdap in PWWH compared with HIV-uninfected women. Antigen-specific immunoglobulin G (IgG) to pertussis toxoid, filamentous haemagglutinin, pertactin, fimbriae, diphtheria and tetanus were measured by electrochemiluminescence-based multiplex assay. RESULTS: Overall, 91 PWWH and 136 HIV-uninfected pregnant women were enrolled. All PWWH were on antiretroviral treatment and 94.5% had HIV viral loads <40 copies per millilitre. Antibody levels prevaccination were lower among PWWH compared with HIV-uninfected women for all antigens. At 1 month postvaccination PWWH compared with HIV-uninfected women had lower fold-increase and antibody concentrations for all epitopes. Also, a lower proportion of PWWH achieved ≥4-fold increase from pre to postvaccination for pertussis toxoid and pertactin, or diphtheria IgG levels ≥0.1 IU/ml and ≥1 IU/ml postvaccination. Adverse events postvaccination were similar in PWWH and HIV-uninfected. CONCLUSION: Tdap vaccination was safe and immunogenic. PWHW had, however, attenuated humoral immune responses, which could affect the effectiveness of protecting their infants against pertussis compared with those born to women without HIV.ClinicalTrials.gov identifier: NCT05264662.

Future perspectives of emerging novel drug targets and immunotherapies to control drug addiction.

Substance Use Disorder (SUD) is one of the major mental illnesses that is terrifically intensifying worldwide. It is becoming overwhelming due to limited options for treatment. The complexity of addiction disorders is the main impediment to understanding the pathophysiology of the illness. Hence, unveiling the complexity of the brain through basic research, identification of novel signaling pathways, the discovery of new drug targets, and advancement in cutting-edge technologies will help control this disorder. Additionally, there is a great hope of controlling the SUDs through immunotherapeutic measures like therapeutic antibodies and vaccines. Vaccines have played a cardinal role in eliminating many diseases like polio, measles, and smallpox. Further, vaccines have controlled many diseases like cholera, dengue, diphtheria, Haemophilus influenza type b (Hib), human papillomavirus, influenza, Japanese encephalitis, etc. Recently, COVID-19 was controlled in many countries by vaccination. Currently, continuous effort is done to develop vaccines against nicotine, cocaine, morphine, methamphetamine, and heroin. Antibody therapy against SUDs is another important area where serious attention is required. Antibodies have contributed substantially against many serious diseases like diphtheria, rabies, Crohn's disease, asthma, rheumatoid arthritis, and bladder cancer. Antibody therapy is gaining immense momentum due to its success rate in cancer treatment. Furthermore, enormous advancement has been made in antibody therapy due to the generation of high-efficiency humanized antibodies with a long half-life. The advantage of antibody therapy is its instant outcome. This article's main highlight is discussing the drug targets of SUDs and their associated mechanisms. Importantly, we have also discussed the scope of prophylactic measures to eliminate drug dependence.

A case of fulminant respiratory diphtheria in a 24-year-old Afghan refugee in Austria in May 2022: a case report.

PURPOSE: Raising awareness of respiratory diphtheria and for the importance of early antitoxin administration. METHODS: Report of a case of fulminant, imported respiratory diphtheria in an otherwise healthy 24-year-old Afghan refugee in Austria in May 2022. RESULT: This was the first case of respiratory diphtheria in Austria since 1993. Diphtheria antitoxin was administered at an already progressed disease stage. This delay contributed to a fulminant disease course with multiorgan failure and death. CONCLUSION: In high-income countries with low case numbers, awareness of respiratory diphtheria and for the importance of early antitoxin administration must be raised.

Case Report: Bloodstream Infection with Toxigenic Corynebacterium diphtheriae and Gram-Negative Sepsis in a Child with Burns.

Corynebacterium (C.) diphtheriae is the agent for a contagious infection, diphtheria. It may manifest as pharyngitis with pseudomembrane formation and cervical lymphadenopathy, cutaneous infection, or as an asymptomatic carrier. Corynebacterium (C.) diphtheriae is not an invasive organism and it remains in the superficial layers of skin lesions and respiratory mucosa. Systemic complications, such as bacteremia, are rare. We report a case of toxigenic C. diphtheriae detected from blood culture of a 1-year-old male patient with burns, who succumbed to the infection after 8 days of stay in the hospital. Patient did not have specific clinical features suggestive of diphtheria. Initial identification of C. diphtheriae was done based on culture, Albert stain findings, biochemical tests and subsequently toxigenicity testing was done by polymerase chain reaction. Although diphtheria vaccination in infancy is universally recommended since the creation of the Expanded Program on Immunization in the 1970s, there have been reports of toxigenic strains of C. diphtheriae in a considerable number of cases. Rapid and accurate identification of C. diphtheriae infection is crucial to prevent mortality. Continued surveillance for diphtheria is needed to reduce transmission and mortality rates.

Non-toxigenic Corynebacterium diphtheriae in hallux ulceration.

INTRODUCTION: Toxigenic Corynebacterium diphtheriae causes classical diphtheria. Skin infections by toxigenic or non-toxigenic Corynebacterium diphtheriae are prevalent in the tropics but are rarely reported. CASE PRESENTATION: We report the identification of a non-toxigenic Corynebacterium diphtheriae (biovar Gravis) isolate in a 52-year-old Cambodian male. The patient presented purulent and non-healing ulcerations on the right hallux. The wound has healed after 7 days of antibiotic therapy with a favourable outcome. CONCLUSIONS: This case represents, to our knowledge, the first report of Corynebacterium diphtheriae in Cambodia in the last 10 years, and highlights the lack of diagnosis and notifications of diphtheria. It is important to raise awareness among clinicians and to set up diphtheria surveillance in Cambodia.

Novel Clinical Monitoring Approaches for Reemergence of Diphtheria Myocarditis, Vietnam.

Diphtheria is a life-threatening, vaccine-preventable disease caused by toxigenic Corynebacterium bacterial species that continues to cause substantial disease and death worldwide, particularly in vulnerable populations. Further outbreaks of vaccine-preventable diseases are forecast because of health service disruptions caused by the coronavirus disease pandemic. Diphtheria causes a spectrum of clinical disease, ranging from cutaneous forms to severe respiratory infections with systemic complications, including cardiac and neurologic. In this synopsis, we describe a case of oropharyngeal diphtheria in a 7-year-old boy in Vietnam who experienced severe myocarditis complications. We also review the cardiac complications of diphtheria and discuss how noninvasive bedside imaging technologies to monitor myocardial function and hemodynamic parameters can help improve the management of this neglected infectious disease.

Adult-onset nasopharyngeal diphtheria: an uncommon but rapidly progressive and potentially fatal infection.

Nasopharyngeal diphtheria is an acute infectious upper respiratory tract disease caused by toxigenic strains of Corynebacterium diphtheriae. We report a case of a young adult who presented to us with a short history of fever, sore throat, hoarseness of voice and neck swelling. He claimed to have received all his childhood vaccinations and had no known medical illnesses. During laryngoscopy, a white slough (or membrane) was seen at the base of his tongue. The epiglottis was also bulky and the arytenoids were swollen bilaterally. The membrane was sent to the microbiology laboratory for culture. A diagnosis of nasopharyngeal diphtheria was made clinically and the patient was treated with an antitoxin together with erythromycin, while awaiting the culture result. Nevertheless, the patient's condition deteriorated swiftly and although the laboratory eventually confirmed an infection by toxin-producing C. diphtheriae, the patient had already succumbed to the infection.

Production of IgY polyclonal antibody against diphtheria toxin and evaluation of its neutralization effect by Vero cell assay.

BACKGROUND: Diphtheria is a bacterial disease which is caused by Corynebacterium diphtheriae. The symptoms are due to the diphtheria toxin produced by the bacteria. Antibiotic therapy and the use of diphtheria antitoxin is a recommended strategy to control diphtheria. Although mammalian antibodies are used to treat patients, IgY antibody has advantages over mammalian ones, including cost-effectiveness and production through non-invasive means. Moreover, in contrast to mammalian antibodies, IgY does not bind to the rheumatoid factor and does not activate the complement system. The objective of this study was to evaluate the in vitro neutralizing effect of IgY against diphtheria toxin. RESULTS: Anti-DT IgY was produced by immunization of the laying white leghorn chickens. Indirect enzyme-linked immunosorbent assay revealed successful immunization of the animals, and the IgY was purified with a purity of 93% via polyethylene glycol precipitation method. The neutralizing activity of the purified IgY was evaluated by Vero cell viability assay. This assay confirmed that 1.95 µg (8.6 µg/ml of culture medium) of anti-DT IgY would neutralize 10 fold of cytotoxic dose 99% of DT, which was 0.3 ng (1.33 ng/ml of culture medium). CONCLUSION: This anti-DT IgY may be applicable for diphtheria treatment and quality controls in vaccine production.

Diphtheria Antitoxin Administration, Outcomes, and Safety: Response to a Diphtheria Outbreak in Cox's Bazar, Bangladesh.

BACKGROUND: Diphtheria has re-emerged over the past several years. There is a paucity of data on the administration and safety of diphtheria antitoxin (DAT), the standard treatment for diphtheria. The 2017-2018 outbreak among Rohingya refugees in Bangladesh was the largest in decades. We determined the outcomes of DAT-treated patients and describe the occurrence and risk factors associated with adverse reactions to DAT. METHODS: We conducted a retrospective study at the Médecins Sans Frontières Rubber Garden Diphtheria Treatment Center from December 2017-September 2018. Diphtheria was diagnosed based on the World Health Organization clinical case criteria. High-acuity patients were eligible for DAT. Safety precautions were meticulously maintained. We calculated the presence of adverse events by age, duration of illness, and DAT dosage using bivariate comparisons. RESULTS: We treated 709 patients with DAT; 98% (n = 696) recovered and were discharged. One-fourth (n = 170) had at least 1 adverse reaction. Common reactions included cough (n = 115, 16%), rash (n = 66, 9%), and itching (n = 37, 5%). Three percent (n = 18) had severe hypersensitivity reactions. Five patients died during their DAT infusion or soon afterwards, but no deaths were attributed to DAT. CONCLUSIONS: Outcomes for DAT-treated patients were excellent; mortality was <1%. Adverse reactions occurred in one-quarter of all patients, but most reactions were mild and resolved quickly. DAT can be safely administered in a setting with basic critical care, provided there is continuous patient monitoring during the infusion, staff training on management of adverse effects, and attention to safety precautions.

Fatal Respiratory Diphtheria Caused by ß-Lactam-Resistant Corynebacterium diphtheriae.

BACKGROUND: Diphtheria is a potentially fatal respiratory disease caused by toxigenic Corynebacterium diphtheriae. Although resistance to erythromycin has been recognized, ß-lactam resistance in toxigenic diphtheria has not been described. Here, we report a case of fatal respiratory diphtheria caused by toxigenic C. diphtheriae resistant to penicillin and all other ß-lactam antibiotics, and describe a novel mechanism of inducible carbapenem resistance associated with the acquisition of a mobile resistance element. METHODS: Long-read whole-genome sequencing was performed using Pacific Biosciences Single Molecule Real-Time sequencing to determine the genome sequence of C. diphtheriae BQ11 and the mechanism of ß-lactam resistance. To investigate the phenotypic inducibility of meropenem resistance, short-read sequencing was performed using an Illumina NextSeq500 sequencer on the strain both with and without exposure to meropenem. RESULTS: BQ11 demonstrated high-level resistance to penicillin (benzylpenicillin minimum inhibitory concentration [MIC] ≥ 256 µg/ml), ß-lactam/ß-lactamase inhibitors and cephalosporins (amoxicillin/clavulanic acid MIC ≥ 256 µg/mL; ceftriaxone MIC ≥ 8 µg/L). Genomic analysis of BQ11 identified acquisition of a novel transposon carrying the penicillin-binding protein (PBP) Pbp2c, responsible for resistance to penicillin and cephalosporins. When strain BQ11 was exposed to meropenem, selective pressure drove amplification of the transposon in a tandem array and led to a corresponding change from a low-level to a high-level meropenem-resistant phenotype. CONCLUSIONS: We have identified a novel mechanism of inducible antibiotic resistance whereby isolates that appear to be carbapenem susceptible on initial testing can develop in vivo resistance to carbapenems with repeated exposure. This phenomenon could have significant implications for the treatment of C. diphtheriae infection, and may lead to clinical failure.

Respiratory Illness Caused by Corynebacterium diphtheriae and C. ulcerans, and Use of Diphtheria Antitoxin in the United States, 1996-2018.

BACKGROUND: Respiratory diphtheria is a toxin-mediated disease caused by Corynebacterium diphtheriae. Diphtheria-like illness, clinically indistinguishable from diphtheria, is caused by Corynebacterium ulcerans, a zoonotic bacterium that can also produce diphtheria toxin. In the United States, respiratory diphtheria is nationally notifiable: specimens from suspected cases are submitted to the Centers for Disease Control and Prevention (CDC) for species and toxin confirmation, and diphtheria antitoxin (DAT) is obtained from CDC for treatment. We summarize the epidemiology of respiratory diphtheria and diphtheria-like illness and describe DAT use during 1996-2018 in the United States. METHODS: We described respiratory diphtheria cases reported to the National Notifiable Diseases Surveillance System (NNDSS) and C. ulcerans-related diphtheria-like illness identified through specimen submissions to CDC during 1996-2018. We reviewed DAT requests from 1997 to 2018. RESULTS: From 1996 to 2018, 14 respiratory diphtheria cases were reported to NNDSS. Among these 14 cases, 1 was toxigenic and 3 were nontoxigenic C. diphtheriae by culture and Elek, 6 were culture-negative but polymerase chain reaction (PCR)-positive for diphtheria toxin gene, 1 was culture-positive without further testing, and the remaining 3 were either not tested or tested negative. Five cases of respiratory diphtheria-like illness caused by toxigenic C. ulcerans were identified. DAT was requested by healthcare providers for 151 suspected diphtheria cases between 1997 and 2018, with an average of 11 requests per year from 1997 to 2007, and 3 per year from 2008 to 2018. CONCLUSIONS: Respiratory diphtheria remains rare in the United States, and requests for DAT have declined. Incidental identification of C. ulcerans-related diphtheria-like illness suggests surveillance of this condition might be warranted.

Two cases of imported respiratory diphtheria in Edinburgh, Scotland, October 2019.

We report two cases of respiratory toxigenic Corynebacterium diphtheriae infection in fully vaccinated UK born adults following travel to Tunisia in October 2019. Both patients were successfully treated with antibiotics and neither received diphtheria antitoxin. Contact tracing was performed following a risk assessment but no additional cases were identified. This report highlights the importance of maintaining a high index of suspicion for re-emerging infections in patients with a history of travel to high-risk areas outside Europe.

Diphtheria in the current era of universal vaccination.

Diphtheria is a vaccination preventable infectious disease with local and systemic complications predominantly affecting upper respiratory tract in younger (<5-year age) children. Its virulence is due to its ability to produce toxin which can cause fatal complications such as myocarditis and permanent damage in form of peripheral neuropathy. Diagnosis of diphtheria is primarily clinical supported by demonstration of toxin producing bacteria by culture. Early diagnosis and management with diphtheria anti-toxin can prevent mortality and morbidity. Here we present a case of 16-year-old boy managed with azithromycin, amoxycillin-clavulanic acid and diphtheria anti-toxin with complete recovery.This case brings out the importance of recognising the re-emergence of diphtheria in older age groups. Lacunae in the universal immunisation process, rumours on vaccination effects and poor living conditions for refugee population are likely reasons in Asia and Europe. Universal immunisation, early diagnosis, prophylaxis and adequate supportive care are measures to prevent it.

Using the North Dakota IIS to Assess the Response of Health Care Providers to the ACIP Recommendation for Tdap Vaccination During Pregnancy.

OBJECTIVES: To evaluate the response of North Dakota health care providers to follow the recommendation set forth by the Advisory Committee on Immunization Practices (ACIP) to administer a dose of tetanus, diphtheria, and acellular pertussis (Tdap) vaccine to women during each pregnancy using the North Dakota Immunization Information System (NDIIS). METHODS: Data from the NDIIS for North Dakota infants born during calendar years 2013-2018 were extracted. Mother's name was taken from the newborn records and matched to NDIIS female client records to identify the population of mothers of newborns who would have been recommended to receive Tdap during their pregnancy. Doses of Tdap vaccine administered after October 1, 2012, were extracted from the NDIIS, and the dose records were matched back to the mother's record. The time from baby's birthdate back to the doses of Tdap vaccine administered to the mother was measured to find any doses that would have been administered during pregnancy. RESULTS: The percentage of women receiving Tdap vaccine during pregnancy increased from 31.5% in 2013 to 60.6% in 2018. Of those women who received Tdap during pregnancy, 94% received the vaccine during the ACIP-recommended interval of 27 to 36 weeks' gestation, using the assumption that all babies were born at 40 weeks' gestation. CONCLUSIONS: North Dakota health care providers have responded positively to the recommendation of the ACIP to administer a dose of Tdap vaccine to women during each pregnancy and have increased their administration of the vaccine to their patients.

First-line antibiotic susceptibility pattern of toxigenic Corynebacterium diphtheriae in Indonesia.

BACKGROUND: Diphtheria has been reported as an outbreak in some regions in Indonesia, most especially in East Java Province. Resistance to penicillin, erythromycin, and other antibiotics, single or multiple, has been reported in several studies. This study aims to evaluate the first-line antibiotic susceptibility pattern of toxigenic Corynebacterium diphtheriae isolates. METHODS: This descriptive observational study was performed from August to November 2018. C. diphtheriae isolates were collected from diphtheria patients and carriers in East Java from 2012 to 2017 and kept at the Balai Besar Laboratorium Kesehatan Daerah Surabaya or the Public Health Laboratory of Surabaya. Sample selection was done by random cluster sampling. The sensitivity test by E-test®of the five antibiotics (penicillin, oxacillin, erythromycin, azithromycin, and clarithromycin) was done to determine the minimum inhibitory concentration (MIC). The Clinical and Laboratory Standards Institute M45A (2015) Corynebacterium spp. for penicillin and erythromycin was used as standard. RESULTS: From 114 targeted isolates, 108 were viable and toxigenic. The E-test was performed on the viable isolates. The majority of the hosts were male (58.3%), with median (range) age of 6.5 (1-14) years. Half of the samples were from the 1 to 5-year-old age group. The isolates were acquired much more from patients (78.7%) than carriers (21.3%) and from pharyngeal swab (74.1%). Most of these isolates were from Madura Island (47.2%) and the northern and eastern parts of the province (horseshoe area). Mitis isolates were the major variant (76.9%). The susceptibility pattern of C. diphtheriae to erythromycin was better than that to penicillin. The E-test result for penicillin was 68.52% susceptible, 31.48% intermediate, and 0% resistant (MIC range, < 0.016 to 2 µg/L) and for erythromycin (MIC range, < 0.016 to > 256 µg/L) was 85.2% susceptible, 12% intermediate, and 2.8% resistant The MIC range for oxacillin was 1 to 96 µg/L, while for both azithromycin and clarithromycin were <  0.016 to > 256 µg/L. CONCLUSION: The susceptibility rate of C. diphtheriae to erythromycin is higher than that to penicillin. The regular update of antibiotic selection to the national guidelines is recommended. The MIC reference standard to azithromycin and clarithromycin is also needed.