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Infections with multidrug-resistant microorganisms after war injuries in victims from Ukraine��Maria Virginia Dos Santos�Resident – Infectious Diseases��ECCMID 2023 - Copenhagen

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Patient collective �03/2022 – Present day

14/47 mostly civilians treated at Charité with infections after war injuries

10 males, 4 females, among them 3 children
Median age 36 years (range: 14-64 years)

Spiegel 2022, BZ 2022

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Characteristics of infections

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Type of infection

8 Osteomyelitis

6 after open fracture

5 Implant-associated infections
4 Soft tissue infections
1 Septic arthritis

Anatomic region

10 Lower extremity
7 Upper extremity
2 Spine
1 Mandibula

Mechanism of injury

8 explosion (bomb, grenade, mine, vehicle)
5 gunshot

Multiple anatomic regions injured: 6

Different sites of infection: 2

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The challenge

Compromised bone/

soft tissue

Implant/

Foreign body

Infection

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1. Compromised bone and soft tissue

Multifragment fractures
Bone defects
Open fractures

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Extensive damage
VAC therapy
Plastic coverage

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2. Implants/foreign bodies

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Shrapnel

Plate Nail

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3. Infection

Microbiology

🡪Polymicrobial

🡪Multidrug-resistant organisms (MDRO)

Primary treatment

🡪low resource conditions/war zone

🡪high risk of contamination

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Diagnostic algorithm

(preoperative/intraoperative)

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Metsemakers WJ. Injury. 2018

3-5 tissue samples

Implants to sonication

FRI = fracture-related infections

The diagnostic steps are crucial especially since most patients are pretreated. Apart from clinical signs it‘s important to optimize the preoperative and intraoperative diagnostics, including tissue sampling from representative areas and sonication of existing implants. All patients were also screened colonization of multidrug-resistant pathogens as per our hygiene guideline, 11 were colonizd with MDRO.

(rectum, urine, oral/nasal/pharyngeal cavity and large-area skin samples)

which can also help to guide our empiric therapy depending on anatomic region and injuries.

The analysis of all swabs was performed in our laboratory based on the EUCAST criteria (European Committee on Antimicrobial Susceptibility Testing) for antibiotic resistance and using immunochromatography and polymerase chain reaction (PCR) for the determination of resistance genes.

The germ spectra of war injuries differed significantly from those of refugee cases. In patients who presented with mostly chronic wounds due to supply shortages, however, complex pathogens were also detected in the microbiological examinations. Colonisation of war wounds with multidrug-resistant gram-negative bacteria (MRGN), in particular 3- and 4-MRGN bacteria, was previously found to be more common in the treatment of patients from crisis regions such as Libya, Syria, Afghanistan, Iraq and Ukraine (9, 20, 21). In patients with war injuries and presentations due to supply shortages, we were also able to detect predominantly colonisations or infections with 3- and 4-MRGN rods and enterobacteria, with vancomycin-resistant enterococci (VRE) and with methicillin-resistant Staphylococcus aureus (MRSA). The increase in bacterial resistance has been observed especially in war zones over the last few years (7, 15, 20, 22)

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Expected microbiology in Germany

Staphylococci (coagulase-negative, S. aureus)

Streptococci/Enterococci

Gram-negative rods

Fungi

Polymicrobial 10-30%

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Microbiology - War injuries Ukraine�

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Gram-negative rods

(MDRO)

Staphylo-cocci

Streptococci

Enterococci

Fungi

Polymicrobial 100%

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Microbiology in our collective

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Gram-negative rods (n=25)

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Multidrugresistant K. pneumoniae

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Increase in NDM-1 and NDM-1/OXA-48-producing Klebsiella pneumoniae in Germany associated with the war in Ukraine, 2022

Sandfort et al., Eurosurveillance 2022

Our data correlates with the report from surveillance systems in Germany, showing an increase of NDM-1 and OXA-48 producing Klebsiella pneumoniae since the start of the war.

As a result, the European Centre for Disease Prevention and Control (ECDC) recommended in March 2022 to screen for carriage of multidrug-resistant organisms (MDRO) in patients transferred from hospitals in Ukraine or with a history of hospital admission in Ukraine and to implement multimodal infection prevention and control (IPC) measures.

Since March 2022, NDM-1-producing K. pneumoniae increased rapidly in Germany and in these cases, presence in Ukraine before diagnosis was frequently reported. Ukraine reported high AMR proportions in Gram-negative bacterial isolates previously (mostly bloodstream infections) to the Central Asian and European Surveillance of Antimicrobial Resistance (CAESAR) network, including K. pneumoniae with resistance to carbapenems in 64% and Acinetobacter spp. with resistance to carbapenems in 73% in 2021.

The combination of aztreonam with ceftazidime-avibactam may be considered for the treatment of severe infections caused by these K. pneumoniae strains. (in our cohort 4 of 7).

We‘ve used aztreonam avibactam in 2.

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Usual empiric therapy:

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Targeted therapy according to microbiology:

Colistin, Fosfomycin, Ceftazidime-avibactam (+/- Aztreonam), Ceftozolan-tazobactam, Cefiderocol

Ampicillin/Sulbactam +/- Vancomycin

Meropenem + Colistin + Vancomycin

Empiric therapy in victims from Ukraine:

This means we‘ve had to adjust from our previous empiric antibiotic treatment strategies and directly cover these MDRO, frequently using combinations and tailoring individually. And then deescalating according to microbiology, but we found it‘s also important to not deescalate so quickly as soon as we have one bacterial growth, because most infections, as mentioned, have multiple pathogens which may grow at different times.

After the experience with the initial cases, we deecided for an empiric therapy of Mero+Coli+Vanco.

Aztreonam alone not regulated, with ceftazidim for the avibactam part, Pfizer phase 3 studies. Off-label, studies not applicable to this population, all polymicrobial patients, interpretations different and pathogens may go undetected, we don‘t find all the pathogens. If we didn‘t treat broad, we have relapse with the one we didn‘t cover.

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Local antibiotics

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High local concentrations, minimal systemic effects

Resorbable carriers/Direct application

Non-resorbable carriers (PMMA Cement)

Photo courtesy of Dr. Cristina Ojeda

PRO/IMPLANT Foundation

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Short term follow-up

Infection outcome:

2 lost to FU
2 current treatment
2 new infections (different site, different pathogens)
No infection persistence

Functional outcome

3 amputations (all externally in Ukraine)

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August 2022

November 2022

Projectile exit wound

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Conclusion

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War injuries result in complex bone and soft-tissue infections with MDRO

Radical surgical débridement, efficient local and systemic antimicrobial therapy

Outlook

Antibiotic carriers for local delivery (resorbable)
adjunctive bacteriophage therapy

Social and emotional impact, rehabilitation process

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Multidisciplinary approach

The solution:

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ID/Microbiology

Surgery

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Thank you!

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virginia.dos-santos@charite.de

Special thanks to Andrej Trampuz, Nora Renz, Olga Pidgaiska and the CMSC team