By Mary Hearty

A study done by the Kenya Medical Research Institute (KEMRI) researchers has found that majority of the bacteria responsible for severe infections, are becoming highly resistant to Carbapenem, one of the last- resort antibiotics that are widely used in Kenya.

To make it worse, these bacteria have been found to be resistant to other newer drugs that were recently approved by the Food and Drug Administration (FDA), but are not yet available in the market as well.

These other newer drugs include: Eravacycline, Cefiderocol, Cefepime/Sulbactam, Relebactam and Vaborbactam.

Anne Amulele, Doctoral Researcher in Antimicrobial Resistance at the KEMRI Wellcome-Trust Research Organization, who presented on this study during the 12th KEMRI Annual Scientific and Health conference (KASH) held virtually and physically stated that this finding was identified from clinical isolates from the Kilifi County hospital surveillance in Kenya.

Notably, she stated that the specific objectives of the study were to understand Carbapenem resistance in coastal Kenya and the types of patients developing these infections.

It also sought to look for resistance to other drugs, especially newly developed drugs that are coming to the market and approved by the FDA as well as to determine the resistant mechanisms and severity traits of these organisms.

Further was aimed at evaluating the effects of resistance on the biological fitness of these organisms.

“We started from 2005 up to 2020, where we retrieved these isolates and confirmed their identity using matrix-assisted laser desorption ionization (MALDI) and Carbapenem resistance using the minimum inhibitor concentration (MIC),” she said.

These clinical isolates which were found to be resistant to Carbapenem and other newer drugs were identified from blood infections, followed by urinary tract infections, and skin and soft tissue infections among patients admitted at the Kilifi County Hospital.

They include: Enterobacteriaceae, A. baumannii, and P. aeruginosa and other Acinetobacter like Klebsiella pneumonia, and E. coli.

Dr Amulele mentioned that majority of the bacteria that were non-susceptible to Carbapenem were Acinetobacter species, and majority of the isolates were from those species as well.

The Centre for Disease Control (CDC) defines non-susceptible as an isolate that is either resistant or not completely resistant to one or more antibiotics.

Regarding the newer antibiotics, she noted that from their observations of Klebsiella pneumonae and E coli is already high resistance being detected against these new antibiotics.

Similarly, within A. baumannii, they found some few resistances to Eravacycline and Cefiderocol, and resistance to Relebactam and Vaborbactam, the new Beta-lactamase inhibitors.

They also tested antimicrobial susceptibility of these bacteria to the commonly known antibiotics such as ampicillin, cefoxitin,cefotaxime, ceftazidime, ceftriazone, imipenem, meropenem, ertapenem, gentamicin, amikacin, ciprofloxacin, chloramphenicol, co-trimoxazolle, and collistin, and detected a bit of resistance as well.

About 61% of the overall characteristics of these patients who were admitted and had carbapenem resistant bacteria were male; whereas half of those who had an infection that is resistant to carbapenem were children under the age of five years.

Moreover, majority of these infections were hospital-acquired and they mainly occurred in younger children considering their high numbers in the study.

Although, the researcher noted that there is a strong focus on surveillance for young children in Kilifi County hospital than adults.

The presenting symptoms at the hospital were: lower respiratory tract infection as the main one, followed by sepsis, then malaria.

“We also found out that majority of these infections were healthy- associated, and about 65% of them were identified from samples collected more than 48 hours of admission. Whereas, the overall length of stay was about two weeks, and 33% of the patients died in the hospital,” she said.

The researchers also tried to look for the phenotypic and genotypic detection of carbapenemases in these bacteria and identified carbapenemase activity in almost all the strains except a few.

For instance, Dr Amulele noted, what was striking in pseudomonas, only one pathogen showed many carbapenemase activities, and majority of those detected were Beta-lactamase, which also explains why high resistance was observed in Vaborbactam, Relebactam within A. baumannii.

With regards to PCR detection of the types of carbapenemases that were in these particular isolates, she explained that majority of the isolates had majorly Beta-lactamase. “In E. coli, it was the main gene identified in the clinical strain, while A. baumannii and Acinetobacter species, it was either found alone or in combination.”

For the ones that were tested with PCR, the researchers did not detect any of the genes as well as enzymes like Klebsiella pneumonia carbapenemase (KPC).

In vivo fitness, they subjected K. pneumoniae and E. coli in a normal and stressful environment- the normal environment was standard LB media, where growth caps was done, while the stressful environment was putting them in 5% salty environment.

Results showed that carbapenem susceptible bacteria were able to perform better than the resistant bacteria in normal environment. For K. pneumoniae, the susceptible bacteria grew better than the resistant bacteria in both normal and stressful environment.

For E. coli, the researchers observed that in a stressful environment, the resistant bacteria performed better than the susceptible bacteria with minimal differences.

The study also tried to look for the ability of these bacteria to complement activity to normal human serum; and we found it was not always consistent, and the particular patient who had carbapenem susceptible E. coli on admission, and went on to be infected with a resistant E. coli during his admission stage.

We found that the carbapenem susceptible E. coli was able to resist the action of the complement activity while the resistant ones were inhibited by the complement activity. For K. pneumoniae, we found that the resistant bacteria were able to perform better than the susceptible bacteria.

Majority of the isolates were multi-drug resistant. We not only found carbapenemase genes but also other Beta-lactamase genes as well as resistance to aminoglycosides genes and other bacteria.

The study which focused on understanding how important antimicrobial stewardship (AMS) is in controlling antimicrobial resistance (AMR), found that while carbapenem resistant bacteria were fit, this was not always the case.

Meaning even though AMS might have an impact in some of the strains, it cannot be relied on alone to control carbapenem resistance.

“AMS is known to be more effective if acquiring a resistance affects the ability of bacteria to grow and thrive. As bacteria acquire carbapenem resistance, it will have a negative impact on its growth, meaning that AMS will be helpful in controlling carbapenem resistance,” Dr. Amulele said.

“But other measures such as newer drugs are needed to enhance the use of carbapenem, as well as proper sanitation and hygiene, and public health measures to help control AMR.”

With limited treatment options for patients infected with these highly resistant bacteria, the World Health Organization lists Carbapenem resistance as a critical priority that need to be addressed.

Unfortunately, there has been no new antibiotic drugs discovered in the past two decades, and the current new drugs coming into the market, are modifications which are within the current classes.

So far, AMR is considered as one of the top ten public health threats globally as it is estimated to cause about 10 million deaths annually, with economic loss in terms of trillions, with most of these losses occurring in low- and middle – income countries.

In addition, a recent study by the Lancet estimated that in 2019, about 1.2 million deaths were directly attributed to bacterial pathogens when they studied about 88 drug combinations; and majority of these deaths occurred in low- and middle- income countries especially in sub Saharan Africa.

Apart from newer drugs, antimicrobial stewardship, improving sanitation and hygiene as well as public health measures, other interventions such scaling up research and development could help simplify the complexity of this AMR menace.