Ukraine: AntiMicrobial-Resistant Infections

Below:  lung cavities, caused by XDR Tuberculosis

Unfortunately, various Antimicrobial-Resistant infections are widespread and rising in wartime Ukraine. This is just one facet of a worldwide challenge; WHO recently predicted that AMR infections could surpass cancer as the leading cause of death worldwide by 2050. 

Bacterial resistance is predominantly caused by the misuse or overuse of antibiotics. Broad-spectrum antibiotics have long been sold over-the-counter in many former USSR countries, including Ukraine. Patients commonly self-prescribe a round of antibiotics for inappropriate illnesses, such as viral colds. Further, patients may take only a partial course of antibiotics, or local doctors may prescribe prolonged low-dose courses of antibiotics, at below therapeutic dose levels. This stresses bacteria without killing them, and fosters development of AMR bacteria. One large 2020 study found that AMR was present in 25% of hospital infections in Ukraine. Microbes may be Antimicrobial-Resistant (AMR),  Multi-Drug Resistant (MDR) or Extensively-Drug-Resistant (XDR).

Antibiotic overuse is not unique to Ukraine. In the US, for example, the CDC estimates that 5 out of 6 Americans take a course of antibiotics each year, and 1 out of 3 of these treatments are unnecessary. The 2022 Global Antimicrobial Resistance and Use Surveillance System (GLASS) report highlights alarming resistance rates among prevalent bacterial pathogens. Median reported rates in 76 countries of 42% for third-generation cephalosporin-resistant E. coli and 35% for methicillin-resistant Staphylococcus aureus are a major concern. For urinary tract infections caused by E. coli, 1 in 5 cases exhibited reduced susceptibility to standard antibiotics like ampicillin, co-trimoxazole, and fluoroquinolones in 2020. This is making it harder to effectively treat common infections. Klebsiella pneumoniae, a common intestinal bacterium, also showed elevated resistance levels against critical antibiotics. Increased levels of resistance potentially lead to heightened utilization of last-resort drugs like carbapenems, for which resistance is in turn being observed across multiple regions. As the effectiveness of these last-resort drugs is compromised, the risks increase of infections that cannot be treated. Projections by the Organization for Economic Cooperation and Development (OECD) indicate an anticipated twofold surge in resistance to last-resort antibiotics by 2035, compared to 2005 levels, underscoring the urgent need for robust antimicrobial stewardship practices and enhanced surveillance coverage worldwide.

Wartime conditions facilitate the spread of AMR infections in multiple ways. Various strains of AMR bacteria may be acquired in the community, via contaminated food or physical contact with human or animal AMR carriers. Patients may harbor AMR bacteria asymptomatically in the digestive tract or in skin before injury, which is then carried into the wound during the injury event. Infection may also occur during injury, or post-injury, by bacteria in the environment, or from neighboring injured personnel. Bullets and shrapnel wounds allow contaminants deep into the body. Evacuation from the drone-infested frontlines may be impossible to do safely for multiple days. During this time, infection sets in. 

When patient transport and treatment finally occur, staffing and equipment shortages may prevent adequate infection control. For instance, ambulances or ad-hoc casevac vehicles may not have access to equipment needed to fully decon contaminated surfaces, or replace bloody stretchers, etc. If there is only time to address immediate life threats, multi-trauma patients may go through several stages of evacuation with uncovered open wounds. Nurses may be caring for 15-20 patients simultaneously, and lack time or supplies to ensure clean gloves, beds, and equipment are used for every patient contact. Hospitals are overcrowded; for example, patient loads at Dnipro’s Mechnikov Hospital have increased 10-fold during the war, according to Chief Surgeon Sergiy Kosulnikov. Kosulnikov estimates that 50% of his patients developed AMR before ever starting treatment. “Has he been in hospital before? Somewhere else?”, he ponders. The origins of individual AMR infections in the Ukraine war is a key question for public health experts. 

Multi-stage patient care means that patients pass through multiple facilities before discharge, with potential to acquire and spread different strains of AMR bacteria at each facility. Overcrowded facilities cannot afford to isolate AMR patients. Severely injured combat trauma patients are generally immediately started on broad-spectrum antibiotics, because care cannot be delayed several days pending results of drug-susceptibility cultures. While this is in patients’ best interests, it creates opportunities for bacteria to evolve resistance to advanced antibiotics. 

Anecdotal accounts and some science are beginning to emerge on rates of wartime AMR in Ukraine. At the Feofaniya Hospital in Kyiv, for example, more than 80% of recently admitted patients had infections caused by AMR microbes, according to the hospital’s deputy chief physician. “It’s eye-opening just how incredibly resistant some of the bacteria coming out of Ukraine are. I haven’t seen anything like it,” says Jason Bennett, director of the Multidrug-Resistant Organism Repository and Surveillance Network at the Walter Reed Army Institute of Research (WRAIR). A 2023 study by Ukrainian MOH and the US CDC tested 353 Ukrainian patients with hospital-acquired infections in late 2022. They found that 60% were fighting infection resistant to carbapenem antibiotics, which are considered the last resort in treating infections. A German report found a rapid rise in. AMR infections treated in Germany in late 2022, following the influx of refugees and wounded patients from Ukraine.  IN 2023, a Ukrainian burn patient was treated at the US military hospital in Germany. Cultures revealed the presence of six different XDR bacterial strains, which were resistant to nearly all known antibiotics. 

Ukraine is not the first war to foster AMR. Acinetobacter baumannii, or “Iraqibacter”, evolved during the Iraq war, and went on to cause 19% of European ventilator-associated pneumonia cases by 2009.

If the Ukraine war has a “signature bacteria”, it is probably Klebsiella pneumoniae. This organism is already responsible for 20% of AMR deaths worldwide. A unique feature of Klebsiella is the copious mucous it produces, which allows AMR Klebsiella colonies on the surface of the wound to act as a biofilm, shielding susceptible bacteria deeper in the wound. Cultures from Ukrainian casualties have contained hyper-virulent, pan-drug resistant strains of K. pneumoniae (i.e. only treatable with a sophisticated multi-drug cocktail).

AMR prevention: Local measures. Good infection control measures are crucial to preventing spread of AMR in hospitals and on ambulances. 

Gloves should be changed between patients

Provide handwashing facilities and encourage frequent use by providers and patients

All commonly touched ambulance surfaces should be cleaned with hospital-grade disinfectant after every transport. Patient treatment areas in-facility should be cleaned thoroughly between patients. Ensure the cleaning agent has enough contact time (see bottle, or ~1-2min on the surface before drying occurs). 

Fully decontaminate or replace all instruments and patient care equipment between patients (including trauma shears, BVMs, etc)

Keep a fresh, clean sheet or mylar foil blanket on stretchers and hospital beds

Irrigate away gross wound contamination with sterile fluids as early as possible in stable patients (but do not risk causing hypothermia to do so)

If time allows, cut away patient clothing to remove as many gross contamination sources as possible, before pt transfer from ambo stretcher onto a facility bed

Cover open wounds, when possible, with CLEAN dressings. Be careful not to cross-contaminate multi-packs of dressings and other materials.

Avoid unnecessary dressing changes during interfacility transports

Nationally, Ukraine is making efforts to reduce AMR spread. In 2022, Ukraine ceased over-the-counter sales of antibiotics. A prescription is now required. 

On an international level, the US CDC and ICAP are working to strengthen AMR surveillance, prevention, and treatment in three Ukrainian pilot hospitals and labs. These are large regional facilities in Vinnytsia, Ternopil, and Khmelnytskyi. The selected hospitals “are dealing with the equivalent of a mass casualty event on a weekly basis because there are so many people getting injured,” said ICAP’s regional AMR advisor. The project also supports the national reference lab at the Ukrainian Public Health Center. 

By Sept 2024, Ukraine had 100 labs carrying out surveillance for AMR bacteria, as compared to just 3 in 2017. Yet, no systematic data collection for wound infections yet exists in Ukraine. The University of Colorado School of Medicine was recently awarded a $5million US DOD grant to create such infrastructure. This project is called the ARROW (Antimicrobial Resistance Research to Improve Outcomes of Traumatic Wounds) study. 

BBC Newstory: Dangerous Drug-Resistant Bacteria are Spreading in Ukraine

WHO: AMR Could Surpass Cancer as the Leading Cause of Death by 2050

Science: War-torn Ukraine has become a breeding ground for lethal drug-resistant bacteria

TB and the Ukraine War

Not only does the current Russia-Ukraine pose unique risks of regional and global military escalation, it is also creating historic levels of population displacement and military mobilization of convicts, in one of the world's foremost multi-drug-resistant tuberculosis hotspots.

TB, or "consumption" is an ancient disease, closely associated with malnutrition and overcrowding. It is the disease that killed Chekhov, Chopin, Emily Bronte, Orwell, Kafka, Keats, Thoreau, and many others at the height of their creative years.

TB is caused by the bacteria 'Mycobacterium tuberculosis'. Mycobacteria have evolved a waxy coating which allows them to survive and reproduce inside macrophages, thus evading our immune system's first line of defense. Tuberculosis can remain latent within the body for many years, becoming active once the immune system is sufficiently weakened by factors such as malnutrition, diabetes, HIV, or smoking. A patient with latent TB has a 5-10% lifetime chance of developing active TB. Classic symptoms of active pulmonary TB include night sweats, weight loss, and a cough that produces blood-tinged sputum. Untreated, pulmonary TB eventually destroys the lungs in a "swiss cheese" pattern, and leads to patient death. TB bacteria may also disseminate throughout the body, creating a variety of symptoms, such as cutaneous nodules, engorged lymph nodes (scrofula), meningitis, and an array of internal organ problems. 

TB is the world's top infectious disease killer, and fully 1/4 of the world population currently carries latent tuberculosis. Infection rates vary locally, ranging from as low as 3% in some developed countries, to 90%+ in parts of Africa. Only patients with active TB can pass the bacteria on to others, and may infect 15 other individuals per year. Conflict and other social disruption events can have a major impact on spread. Firstly, conflict subjects individuals to physical hardships, such as poor nutrition, inadequate housing, and exposure to other infectious diseases. Second, conflicts displace populations, and lead to overcrowding, poor sanitation, and breakdown of healthcare systems. Studies suggest that war increases annual TB incidence up by up to 20%. The 2022 Russian invasion of Ukraine has resulted in the fastest mass refugee migration since WWII. In 2022, the world-wide number of displaced persons hit a new record of over 100 million souls.

Social disruptions do not have to be conflict-based to facilitate the spread of TB. Russia and other former USSR members have the developed world's highest TB rates, due to social disruptions that occurred during the decade after the fall of the USSR. The 1990's reversed a huge amount of Soviet progress on TB control, which had been achieved via xray detection, isolation, and treatment in sanitariums. Infection rates in Russia fell from 1910 levels of 400/100,000, down to a rate of 17.3/100,000 (in men) and 1.9/100,000 (in women) in 1990. But post-Soviet poverty and healthcare system collapse caused Russian TB rates to double between 1991-1998. During the same time period, incarceration rates tripled in most post-Soviet states. By the late 1990's, TB had become a raging epidemic within the overcrowded Russian prison system, with prisoner infection rates averaging 4,000/100.0000, and in some regions reaching 7,000/100.000.

Mycobacterium tuberculosis's ability to hide from the immune system means that treatment regimes, even for cases that are susceptible to first-line antibiotics, are lengthy. If, due to treatment costs, disruptions in health services, or poor patient education, a patient stops treatment early, evolutionary forces favor the growth of antiobiotic-resistant bacteria within that patient's body. This resistant bacteria can then be passed on to others, garnering new opportunities, with each unsuccessful treatment course, to become resistant to additional medications. The result is multi-drug-resistant TB, or "MDR-TB"- one of today's major public health challenges. Treatment regimes for MDR-TB last up to two years, may cause uncomfortable side effects, and have a significant failure rate. To reduce risk of MDR-TB, DOTS, or Directly Observed Treatment, has become the gold standard for TB treatment worldwide.

However, in post-Soviet states, corruption and economic woes interfered with successful TB programs. Physicians opposed DOTs, feeling that it threatened their already precarious livelihoods. TB medications were re-purposed and sold in markets by crooked pharmacists, or traded for other items by prisoners in treatment programs. Until fairly recently, antibiotics were widely available without prescription at pharmacies in both Russia and Ukraine. It was quite common to self-prescribe an inappropriate course of antibiotics, for example, for a viral cold infection. By 1998 20% of Russian prison cases were MDR-TB. As prisoners were released mid-treatment, this trend spread into the general population. Eastern Europe now accounts for the largest MDR-TB burden in the world. 

In recent years Russia, along with many former Soviet states, has resumed making progress on TB control. Between 2010-2020, Russian TB mortality halved, and general population infection rates fell to 45-50/100,000 (48% MDR-TB). WHO estimated 2021 TB incidence in Ukraine to be 71/100,000 (31% MDR-TB in new cases and 45% in relapse cases). In contrast, average 2021 TB incidence in the EU was 8.4/100,000 (33% MDR-TB). Thus, TB infection in refugee populations moving from Eastern to Western Europe is a major public health concern.

Despite progress within prisons, as well as amongst the general population, TB remains a major problem in Russian prisons. Russia has one the world's highest incarceration rates, with overcrowding and poor living conditions extremely common. A 2017 study estimated that 1 in 10 Russian prisoners have active TB, and that the majority of remaining prisoners have latent infections. A 2019 study found that Russia had the world's second-highest number of new active TB cases amongst prisoners (~13,000 cases, second only to 15,000 cases in Brazil). A 2-3 yr prison sentence leads almost inevitably to TB infection. 48% of Russian prison cases are multi-drug-resistant. Russia also has one of the highest rates in the world of "extensively drug-resistant TB", which is even more difficult to treat than MDR-TB. Russia's heavy reliance on convicts as soldiers, low health standards for enlistment, difficult frontline living conditions, unreliability of medication supplies, potential for injury or capture, and inter-mixing with and displacement of civilian populations all create a major risk for wartime transmission of TB, MDR-TB, and XDR-TB.

In the Ukraine war, post-Soviet health challenges are potentiated by the melange of convict soldiers, frontline conditions, and mass displacement of civilians. The result is a myriad of spread opportunities for the world's new diseases of disruption: MDR-TB, MDR wound infections, and potentially also novel respiratory viruses (think a new wartime COVID variant or a 1918-style influenza). 

Spread of MDR-TB is not the only concern. TB comes in a variety of strains. Interestingly, the prevalent strain in Russia is the "Beijing" type. The Beijing TB strain, first described in 1995, has unique proteins. These potentially make it more infectious and more resistant to treatments. A 2020 literature review of studies involving 7,000 patients found strong support for correlation between the Beijing strain and more unfavorable treatment outcomes. Despite global implementation of DOTS, TB incidence seems to be declining at only 1-2%/yr- far slower than math models predict. The reasons for this include prevalence of HIV coinfection, diabetes, malnutrition, drug resistance, crowding, and poor control infrastructure. Arguably, another reason is the spread of Bejing subtypes- which will also likely be further facilitated by the disruptions of the Ukraine war.     

There is hope on the horizon for TB control. A currently approved vaccine, the BCG TB vaccine, does not prevent TB, but it does serve to lessen risk of some severe forms of disseminated disease in children. Several vaccines designed to prevent pulmonary TB in all ages are currently under development. The most promising is M72. M72 was dropped by its original creator due to low profit potentials, but has recently been picked up by the Gates Foundation and has entered Phase III trials. M72 may be able to prevent pulmonary disease in 54% of infected adults. And for a disease that can take years to treat, and becomes active in 5-10% of patients, who go on to infect 15 other people per year, 54% prevention be a game-changing statistic.

WHO TB page
WHO TB Surveillance and Monitoring in Europe, 2023
The 2020 clinical update by the Global Tuberculosis Network
2020 Stanford-China study: Mycobacterium tuberculosis Beijing genotype strains and unfavourable treatment outcomes: a systematic review and meta-analysis
2017 literature review: Multidrug resistant tuberculosis in prisons located in former Soviet countries: A systematic review