​ESBL+ bacteria tend to fall in one of three classes which are: TEM (Temorina Escherichia coli mutant), SHV (Sulfhydryl variant), and CTX-M (Cefotaximase-Munich) types, with ESBL+ K. pneumoniae strains being predominantly in the SHV-1 group, while most ESBL+ E. coli strains falling in the TEM group [2,11].

ESBL+ K. pneumoniae in particular is a resilient bacterium that has been noted to cause uncomplicated, complicated and recurrent UTIs. In uncomplicated cases of tract infections, symptoms are typically presented in women who are not pregnant, and the symptoms are localized to the lower urinary tract and are either of a dysuria or frequency or urgency nature [4,12].

Complicated cases of UTI caused by ESBL+ K. pneumoniae include complicated pyelonephritis, with 42.8% of cases in North America and Europe being linked to ESBL+ K. pneumoniae [4]. It persists in complicated pyelonephritis because continued antibiotic treatment with antibiotics such as ciprofloxacin in its mild stages, eventually makes the pathogen resistant to carbapenem through its synthesis of carbapenemase This in turn, makes it resistant to almost every beta lactam-based antibiotic available [4,12].

Azadirachta indica (Neem): The benefit of the Neem plant on UTI and other infections

Neem trees have attracted world prominence as holy trees with unique medicinal properties that include immunomodulatory effects, anticancerous effects, hepatoprotective effects amongst others as shown in figure 2. 

Literature by Yadav [10] has cited links between compounds like azadirachtin to the leaf’s anticancerous properties, with compounds such as Nimbolide being shown to suppress tumor growth by inhibiting cell viability through the induction of programmed cell death (apoptosis). The hepatoprotection of neem leaves was demonstrated through rats, whereby anti-tubercular drug-induced damage was reduced by minimizing alteration of bilirubin, alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase in vitro serums. In Yadav’s [10], study, antimicrobial, antiviral and antibacterial properties had not yet fully been explored, to explain which compounds were responsible for these effects.

Treatment of ESBL-Positive E. coli and K. pneumoniae using Azadirachta indica (Neem)

The antifungal and antibacterial properties of neem leaves seem to be linked to their antioxidant and anti-inflammatory effects, which in turn, affect bacterial cell processes and inhibit cell growth [10,14].

A study by Mistry [15] revealed that neem extract was active against S. mutans, E. faecalis, and S. aureus. The leaves’ extract was also found to be effective for inhibiting the growth of P. aeruginosa, S. aureus, and Bacillus pumilus, and the effect was compatible with that of antibiotics [16]. A similar study conducted by Parashar, Sutar, and Sanap [17] showed that the optimal effect on E. coli, S. aureus, P. aeruginosa and Bacillus subtilis can be achieved by combining the neem extract with lantana (Lantana Camara) extract made from the plants’ leaves.

Research shows that neem is active against both gram-positive and gram-negative bacteria. A study by Rathod [18] examined the effects of ethanol and aqueous extracts of neem leaves and bark on B. subtilis, S. aureus, K. pneumoniae, and E. coli. It has been found that neem bark was the most effective against the listed bacteria. However, the use of the low concentrations was found to be ineffective as bacteria were resistant to them. Thus, Rathod [18] proved the potential usefulness of neem for primary health care, as it can become an effective alternative to antibiotics. Francine [19] also discussed the importance of extract concentration. The researchers found that the higher the concentration of the extract is, the greater the inhibition zone. In addition, they proved the superiority of fresh leaves and bark over dried parts. Ethanol extracts, in turn, were found to be more effective than aqueous [19].

Along similar lines, Mamman [20] argued that concentration matters when it comes to achieving a significant antibacterial effect. The scholars conducted a study exploring the effects of neem on E. coli, Salmonella spp, and S. aureus. Results have demonstrated that a minimum concentration of 43.75 mg/ml inhibited the growth of E. coli for both the aqueous and methanolic extracts. However, a higher concentration (87.50 mg/ml) was needed to kill the bacteria altogether. To kill E. coli using a methanolic extract, the researchers had to increase the time of exposure and extract concentration (250 mg/ml) [20]. Banna, Parveen, and Iqbal [21], in turn, found that at the concentration of 12.5 mg/mL, ethanolic extract of neem leaves has an inhibitory effect on K. pneumoniae. In this way, both Mamman [20] and Banna [21] vividly demonstrated the importance of measuring the right dosages, concentration, and type of extract to achieve the optimal results.

Recommendations and Future plans:

While neem leaves have shown tremendous therapeutic and medicinal potential, the unfortunate part is research on the effects of neem on antibiotic-resistant bacteria is scarce. Nayim [21] who explored the effects of plants on gram-negative resistant bacteria, including E. coli and K. pneumoniae, conducted one of the studies on the topic.

Interestingly, it has been found that bark extract of neem improved the antibacterial activities of such antibiotics like tetracycline, chloramphenicol, kanamycin, streptomycin, and others. In this way, one may suggest that the combination of commonly used antibiotics with neem extracts can be effective for treating infections caused by multidrug-resistant bacteria. Given the knowledge gap, more research is needed to explore whether neem could be used against ESBL-producing E. coli and K. pneumoniae.

Secondly, based on the case studies explored in this study, age and gender appear to be factors that play a part in the persistence of ESBL+ bacteria in causing UTIs. This needs to be explored more, particularly in relation to how optimal dosages can be achieved in antibiotic treatments for different age and gender demographics, as this will also become a guideline on how to accurately produce neem extracts with the right concentration needed to treat bacterial infections.

Thirdly, research should focus on the mechanisms by which neem antimicrobial/ antibacterial/ antifungal potential works in disrupting bacterial and/or microbial cell growth. Because of knowledge gaps in how these properties are achieved, it then becomes difficult to understand what optimum dosages can be used and what other factors can influence or retard the medicinal properties of neem leaves.

The bean tree has upheld its medicinal prominence for decades, particularly in populations that the tree is indigenous. Indians have used the leaves' extract to heal wounds, eliminate effects of bacterial and fungal infections as well as reduce toxicity in the body. The focus of this particular study was to assess how neem leaf extracts affect ESBL+ bacteria that cause bacteria and while, results gathered from other studies reflected a positive outcome, the knowledge gaps on mechanisms and reactivity to antibiotic-resistant bacteria makes it difficult to fully endorse the use of neem leaf extract as a stand-alone alternative to antibiotic treatment of UTIs. The need for more research that focuses on the influence of factors such as age and gender and how they relate to the resistance of ESBL+ bacteria is apparent. Furthermore, the need for exploring how these factors play a part in determining treatment alternatives is key. However, from this study alone, there is enough evidence to expect an eye-opening outcome from the suggested future investigations. But until then, neem leaf extract must continue to be considered as a viable treatment option for bacterial infections.