Aminoglycosides discovered 80 years ago are still the drug of choice for combating a range of infections, including those caused by multiple drug-resistant (MDR) strains of bacteria. These bactericidal antibiotics are nephrotoxic and ototoxic and often not permitted for therapeutic use in animals and birds. This study analyzed the comparative in vitro antimicrobial activity of amikacin and gentamicin on 517 isolates of potentially pathogenic bacteria isolated from environment and food samples (53), reference strains (11) and from clinical samples (453) of defined ailments in animals (299), humans (85), and birds (69). Gentamicin inhibited 77.37%, and amikacin inhibited 73.11% of the isolates. Of 378 strains of bacteria susceptible to amikacin 13.76% were resistant to gentamicin, and of the 400 strains susceptible to gentamicin 18.50% were resistant to amikacin. A significant (p 0.05). A wide variation in susceptibility of bacterial strains of different species causing various types of infections in animals and birds under different husbandry practices suggests that antimicrobial susceptibility should be conducted before the use of amikacin or gentamicin in therapeutics.

• Aminoglycosides

• Carbapenem resistance

• ESBL

• Proteus

• Staphylococcus

• Streptococcus

Singh BR, Agri H, Karthikeyan R, Jayakumar V (2023) Comparative Antimicrobial Activity of Amikacin and Gentamicin on Clinically Important Bacteria. J Pharmacol Clin Toxicol 11(3):1180.

Streptomycin   was   the    first    aminoglycoside    isolated in 1943 from Streptomyces griseus followed by neomycin (from Streptomyces fradiae). Though neomycin had better antimicrobial action against aerobic G-ve bacteria than streptomycin, due to its high toxicity its systemic use was formidable. Gentamicin, isolated in 1966 from Micromonospora purpura,   brought   a   breakthrough   in   the   treatment    of G-ve bacterial infections and then came semisynthetic aminoglycosides amikacin, isepamicin, dibekacin, arbekacin and tobramycin [1,2]. Aminoglycosides are strong bactericidal antibiotics and their bactericidal action cannot be fully explained through their commonly understood action through inhibition of protein synthesis via irreversible binding to the 30s ribosome. Their bactericidal activity is mainly attributable to their action on bacterial cell membranes [3]. Aminoglycocides being potent antibiotic molecules disrupt the outer cell membrane causing leakage of intracellular contents and eventually bacterial cell death [4].

Aminoglycosides are often recommended for the treatment of life-threatening infections by G-ve bacteria including complicated skin, bone or soft tissue infections, urinary tract infection (UTI), septicaemia, peritonitis and other severe intra- abdominal infections, severe pelvic inflammatory disease, endocarditis, mycobacterium infection, neonatal sepsis, and eye and ear infections [1]. In earlier clinical studies gentamicin has been reported to be a little superior to amikacin, in the treatment of enteric infection, bacteraemia, urinary tract infections, pneumonia and serious soft tissue infections yielding favourable outcomes in 78% and 77% cases, respectively [5]. Evidence suggests that there is no appreciable difference in their nephrotoxic and ototoxic effects [5, 6]. In a early small study on 30 human UTI patients, gentamicin and amicacin had no appreciable difference in the therapeutic outcome [7]. Another study on 1000 bacterial isolates reported better antimicrobial action of gentamicin than amikacin against enterobacteria, Haemophilus influenzae and Staphylococcus aureus while amikacin was more active against Klebsiella and Providencia species isolates [8].

In animals, use of aminoglycosides is not recommended unless required for life-saving purposes and systemic use of amikacin and other aminoglycoside antibiotics in animals is mainly avoided due to their nephrotoxicity and ototoxicity [9]. However, in cats, gentamicin appeared to cause more histological renal tissue change than amikacin [10]. In an experimental study in guinea pigs on severity of the cochlear damage, it was the maximum due to gentamicin followed by amikacin, streptomycin, and netilmicin, but the difference in ototoxicity was statistically insignificant between different aminoglycosides [11]. In another study on rabbits, of the four aminoglycosides (tobramycin, sisomicin, amikacin and gentamicin) in the therapy of experimental E. coli meningitis sisomycin had marginally better bactericidal action than the other three aminoglycosides [12]. Despite all these observations and indications, aminoglycosides are extensively used in veterinary medicine in treatment of for treatment of bacteraemia, gastrointestinal tract infections, and respiratory and urinary tract infections in many animal species [13]. However, the use of aminoglycosides in animals is not recommended [14] without antimicrobial susceptibility testing (AST) but is almost impracticable in most of developing and poor countries where AST is sparsely available for humans. Though systemic use is rare in food animals, in horses and other companion animals aminoglycosides (amikacin and gentamicin) are commonly used to treat septicaemia, respiratory tract infection, peritonitis, metritis, osteomyelitis, leptospirosis, nocardiosis, meningitis, wound infections, joint infections, endometritis, and UTIs caused by ESBL E. coli [14]. Although aminoglycosides have no synergy with β-lactam antibiotics [15], they are rarely used alone and mostly prescribed in combination with β-lactam antibiotics [14]. Aminoglycosides as topical use preparation of gentamicin, neomycin and framycetin are often used as drug of choice for the treatment of eye, ear and skin infections in animals and humans [14,16]. Though amikacin and gentamicin belong to the same class of aminoglycosides, it has been suggested earlier that there is no cross-resistance for the two drugs [17]. However, resistance to streptomycin was much higher than resistance to gentamicin in most of the common pathogens affecting animals in the EU. About 2% of the Enterococcus spp., Salmonella enterica, and E. coli isolates from animal cases in the EU are reported resistant to gentamicin and the resistance levels were higher in isolates from conventional broilers [14]. Enterococcus faecium and E. faecalis isolates were rarely resistant to gentamicin [16]. With the rampant use of aminoglycosides in humans and animals, there is an imminent risk of the emergence of zoonotic pathogens either due to clonal selection of resistant Mycobacterium tuberculosis, Enterobacteriaceae members and Enterococcus spp., or through horizontal transfer of resistance (R) factors at high frequency among members of Enterobacteriaceae, E. faecium and E. faecalis [14].

To determine the susceptibility of bacteria to aminoglycosides measurement of minimum inhibitory concentration is the method of choice but in most of the clinical laboratories disk diffusion assays are the method of choice and breakpoints for amikacin applicable to E. coli and P. aeruginosa isolates from dogs, foals, adult horses, Staphylococcus spp. isolates from dogs, S. aureus isolates from foals and adult horses, Streptococcus spp. isolates from dogs, Streptococcus equi subsp. zooepidemicus and subsp. equi isolates from foals and adult horses are available for long but results may be misleading [18]. In vitro tests may indicate the susceptibility of E. faecalis, E. faecium, E. gallinarum,E. casseliflavus to aminoglycosides but are rarely of therapeutic utility, and as per CLSI guidelines they should not be reported as susceptible to aminoglycosides [18]. Gentamicin and other aminoglycosides’ resistance has more commonly been reported from many countries in E. coli, and Staphylococcus species especially methicillin-resistant (MRS) isolates from human clinical cases than those isolated from dairy and other domestic animals [14]. Therefore, in the present analytical study, we attempted to understand gentamicin and amikacin susceptibility patterns among bacterial isolates from clinical samples of humans, animals, and birds causing infection and from their environment.

Microbial strains in the study

For the study antimicrobial susceptibility tests data of 517 isolates with known sources and with defined ailments and tested for amikacin, gentamicin, carbapenem susceptibility as per CLSI criteria [18], and extended-spectrum β-lactamase (ESBL) production was retrieved from the Division of Epidemiology Data resources for the last four years (2019-2022). The repository data on bacterial isolates included only those strains which were isolated and identified (Table 1)

Table 1: Resistance to amicacin (Ak), gentamicin (G), carbapenems (Imipenem, meropenem, Ertapenem, IME) and extended spectrum β-lactam antibiotics (cefalosporins) in bacteria isolated from different clinical and environmental samples

through conventional methods and confirmed either through specific polymerase reaction, gene sequencing MALDI TOF-MS or both.

Detection of extended-spectrum β-lactamase (ESBL) production by Gram-negative bacterial strains

For this purpose E-test was performed using E-strips (Biomeriux India Ltd.) carrying two gradients of ceftazidine and cefotaxime with and without clavulanic acid on Mueller Hinton agar plates as per the recommendations of the E-strip producer [19,20].

Carbapenems, gentamicin (30 µg) and amikacin (30 µg) susceptibility assay

The disk diffusion assay tests were performed and interpreted as per CLSI [18] guidelines. The disks of imipenem (10 µg), meropenem (10 µg) and ertapenem (5 µg) were used for determining susceptibility to carbapenems, bacteria resistant to any of the three carbapenems was considered carbapenem- resistant (CR). All antimicrobial disks and media used in the study were procured from Difco-BBL (USA).

Statistical analysis

Data of all 517 strains included in the study along with their source of isolation, association with specified ailment, and susceptibility to amikacin, gentamicin, carbapenems and ESBL production ability was line-entered in an Excel sheet and analyzed using Chi-square statistics to understand the significance of the different associations. For analysis, only those sets were compared where strain numbers or cases were ≥ 6. To determine the relationship among susceptibility to different antibiotics Pearson correlation was done in MS Excel 2007.

The in-vitro susceptibility study on 517 isolates of bacteria of different origins and associated with different types of infections revealed that gentamicin inhibited more number of bacterial isolates (77.37%) than amikacin (73.11%). Both the antibiotics failed to inhibit 65 (12.57%) of the isolates. However, of the 378 strains of bacteria susceptible to amikacin 52 (13.76%) were resistant to gentamicin, and of the 400 strains susceptible to gentamicin 74 (18.50%) were resistant to amikacin. Correlation analysis of zones of bacterial growth inhibition produced by amikacin and gentamicin revealed a strong (p, <0.001) correlation (r, 0.45) in their antimicrobial activity. Paired t-test analysis of the zone of inhibition by amikacin and gentamicin revealed acceptance of the null hypothesis that there is no significant difference between the susceptibility of microbes to gentamicin and amikacin. A significant relationship (p <0.001) between carbapenem resistance and amikacin (r, 0.264) and gentamicin (r, 0.31) resistance was evident.

Susceptibility to gentamicin and amikacin varied among different bacteria (Table 1) viz., Alcaligenes spp. (15.38%, 23.08%), Enterococcus spp. (37.50%, 37.50%), Escherichia spp.(27.13%, 24.03%), Klebsiella spp. (1.58%, 21.05%), Pantoea agglomerans (24.14%, 31.03%), Proteus spp. (28.57%, 78.57%), Pseudomonas spp. (15.38%,   26.92%),   Salmonella   enterica ssp. enterica serovars (16.67%, 16.67%), Staphylococcus spp. (18.81%, 24.75%), and Streptococcus spp. (34.69%, 44.90%), respectively were resistant to gentamicin and amikacin. About 13.33% and 46.67% of E. coli isolates from poultry birds were resistant to gentamicin and amikacin, respectively but none of the E. coli isolated from infections in pigs was resistant to gentamicin or amikacin.

Though there was no significant difference in susceptibility to amikacin and gentamicin for bacterial strains of different species and causing different ailments, it was evident that where G+ve bacteria were the cause of infection, and isolates from bacterial infections of cattle and pigs significantly (p, <0.025) more number of isolates were susceptible to gentamicin than to amikacin. However, on bacterial isolates from clinical samples from sick lions, amikacin was the better (p, <0.001) antibiotic than gentamicin. Of the 22 isolates of bacteria from infections in lions (A. calcoacetus-baumanii complex 1, Enterobacter cloacae 1, Enterococcus casseliflavus 2, E. coli 16, P. agglomerans 1, P. vulgaris 1), 10 (A. calcoaceticus-baumanii 1, E. coli 8, P. vulgaris ) were resistant to gentamicin and none of the isolates was amikacin-resistant. Of the 19 strains of Klebsiella species, six were resistant to gentamicin and only four to amikacin. Similarly of the 129 isolates of E. coli 35 and 31 were resistant to gentamicin and amikacin, respectively.

Higher proportions of   carbapenem-resistant   bacteria were (p, <0.001) resistant to gentamicin and amikacin but no significant association (p, 0.98) was apparent with respect to their ESBL production ability. Though for most of the bacteria, ESBL production and susceptibility to gentamicin or amikacin were not significantly (p, >0.05) associated, ESBL E. coli were significantly (p, 0.004) more often susceptible to gentamicin (but not to amikacin) than non-ESBL E. coli. Oxidase-positive bacteria were significantly more susceptible to amikacin (p, 0.04) and gentamicin (p, 0.01), than oxidase-negative bacteria. However, no such difference was evident with respect to ESBL production and CR. The bacterial isolates from environmental samples were more often (p, 0.04) producers of ESBL than those isolated from clinical sample.

Bacterial isolates from clinical infections in lions were significantly more susceptible to amikacin than those infected buffaloes, cattle, dogs, deer, pigs, birds, mithuns and swamp buffaloes. On the other hand, significantly (p, <0.05) more of the bacterial isolates causing infections in mithuns and swamp buffaloes were amikacin-resistant than those infecting other animals. Among all, isolates of Bacillus spp. and Bordetella avium were the most susceptible to amikacin and Proteus spp. strains were often resistant to amikacin. Significantly (p, <0.05) higher proportion of the isolates from genital tract infections (not abortions) were resistant to amikacin than isolates associated with other infections (Table 2).

Table 2: Comparative susceptibility of different types of bacteria from various sources to amikacin and other antimicrobials

More often (p, <0.05) bacteria causing genital tract, urinary tract and eye infections were more resistant to gentamicin than those associated with other infections. Among all, B. avium isolates were the most susceptible to gentamicin (similar to amikacin) and Enterococcus species strains were the most often gentamicin-resistant ones (Table 2).

Carbapenem resistance was more common among bacterial isolates causing gastrointestinal tract ailments followed by those associated with UTIs. Among all, isolates belonging to Acinetobacter, Alcaligenes, Enterococcus, Proteus, Pseudomonas and Streptococcus species were often resistant to one or more carbapenem antibiotics than B. avium, Bacillus, Citrobacter, Escherichia, Klebsiella, Lysinibacillus sphaericus, Pantoea agglomerans, Salmonella, and Staphylococcus species strains (Table 2)

Bacteria isolated from clinical cases in deer and mithuns were more often ESBL producers than those associated with infections in other animals. Bacterial isolates from abortion and mastitis were among the most common pathogens having ESBL production ability. More number of bacterial isolates belonging to Aeromonas, Alcaligenes, Citrobacter and Klebsiella species produced ESBL and only a few of the Acinetobacter spp.,Bordetella avium, and Salmonella enterica ssp. enterica strains produced ESBL (Table 2).

Amikacin and gentamicin are two commonly used antibiotics in animals, especially in companion animals in India [21]. The detection of gentamicin and amikacin resistance in 23.97% and 22.60% of the isolates from companion animals (dogs, horses), was comparable to gentamicin and amikacin resistance in bacteria causing infections in human beings, 25.8% and 28.24%, respectively. Though   more   elaborate   studies   are   required, it may be speculated that some kind of clonal selection may exist in many of the bacteria isolated from animals or humans in the present study that were of zoonotic potential [14]. The occurrence of gentamicin and amikacin resistance in 17.48% and 27.18% of the isolates from dairy (cattle, buffaloes and goats), and 13.95% and 27.18% of the isolates from poultry birds, respectively was a bit lower than in bacterial isolates from companion animals and humans but was much lower than those bacteria isolated from semi-domestic swamp buffaloes and mithuns where 65% and 70% of the bacteria isolated were resistant to gentamicin and amikacin, respectively. However, the resistance to aminoglycosides detected in bacterial isolates in India seems to be much higher than that reported in most of the other countries [14,16], but the data compared seems to be much older from other countries and some recent observations made globally needs to be analysed. But this explanation is contradicted by the facts that earlier studies on humans [1,5], reported the effectiveness of amikacin and gentamicin was 77-78% and is quite comparable to the resistance pattern observed in the present study (71.76 to 74.2%). Therefore, more systematic studies on a comparable number of isolates from humans and different animals are required. The high level of amikacin (70%), and gentamicin (65%), resistance in bacteria isolated from semi-domestic animals is of high concern as these animals may spread AMR pathogens in the environment of a larger geographical area. The AMR traits might be persisting in the semi-domestic animals due to some clonality or something else, needs more elaborate molecular studies on AMR in bacterial isolates from semi-domestic animals, interestingly, despite the high occurrence of aminoglycoside resistance none of the isolates from semi-domestic animals had either carbapenem resistance or produced ESBL. However, the observation of a significantly high occurrence of amikacin and gentamicin resistance in strains of semi-domestic mithuns (Bos frontalis) and swamp buffaloes (Bubalus bubalis kerebau) and also in wild animals and birds than in isolates of cattle and pig origin could not be substantiated with available literature but aminoglycoside resistance has rampantly been reported in bacteria causing lethal infections in zoo and wild animals and birds [22, 23].

The observations revealed that 25.11% and 26.84% of isolates belonging to members of Enterobacteriaceae were resistant to gentamicin and amikacin and observations corroborate earlier studies on a large number of bacteria [8], indicating better but insignificantly different activity of gentamicin than amikacin.

However, in contrast to other members of Enterobacteriacea Klebsiella species isolates were more susceptible to amikacin (78.95%) than to gentamicin (68.42%) similar to earlier observations [8].

The study indicated that gentamicin was significantly (p, 0.003) more effective on ESBL E. coli than on non-ESBL E. coli and a similar trend but statistically insignificant was observed for amikacin, >25% non-ESBL E. coli and 15% of ESBL E. coli were resistant, indicating the utility of aminoglycosides to treat infections caused by ESBL E. coli. The observations are in line of observations in many of the EU nations [14].

Of the 24 isolates of enterococci, nine each were resistant to amikacin and gentamicin and seven to carbapenems too. Carbapenem resistance in enterococci is commonly reported despite being susceptible to penicillin and penicillin derivatives due to the presence of variant or overproduced penicillin- binding proteins [24], and carbapenem-resistant enterococci have commonly been reported causing infections in animals and inhabiting their environment [25,26]. Though enterococci are often reported as resistant to aminoglycosides [27], some studies reported susceptibility of E. faecium and E. faecalis isolates to gentamicin [16]. Enterococci isolates were significantly more often resistant to aminoglycosides than isolates of other bacteria and this may be attributed to intrinsic and acquired resistance in enterococci [24]. A total of 29.17% of the enterococci were carbapenem-resistant. The observations are in concurrence with earlier reports [24,28]. In the study, seven strains were resistant to both gentamicin and amikacin but two strains each were resistant to only one of the two antibiotics. A similar variation in susceptibility to different aminoglycosides in strains of enterococci has commonly been reported [24].

Among all the bacteria tested, Proteus strains were the most resistant to amikacin (78.57%), which may be due to fast acquisition of transmissible amikacin resistance by Proteus species [29,30]. Though amikacin was suggested to be one of the best antibiotics for treating infections caused by MDR strains of Proteus species strains in 20th centry [31], it seems to be useless now. In the present study, gentamicin was significantly more effective on Proteus strains inhibiting 71.43% of the isolates than amikacin (21.43%) and observations further confirm the therapeutic utility of gentamicin for infections by Proteus species strains [32].

Bacteria causing eye infections and genital tract infections were more often resistant to gentamicin as well as amikacin than bacteria causing, abscess, wound, ear, and respiratory tract infections, and septicaemia; this may be of serious concern as at one time amikacin was considered as gold standard treatment for the treatment of genital tract infections [33], and still now aminoglycoside preparations are often recommended for treatment of ophthalmic and genital tract infection in humans [34,35]. Besides, bacteria causing gastrointestinal infections in animals and birds were more resistant to amikacin than those isolated from cases of ear infections and septicaemia is also of concern as bacteria present in excreta may contaminate environment and water bodies [26].

This analytical study concludes that amikacin and gentamicin resistance is common among bacteria causing infections in animals too despite the fact that therapeutic use of aminoglycosides is restricted in animals and birds. Further, the preferred use of aminoglycosides in the treatment of eye infections and genital tract infections appears to be erroneous as bacteria isolated from eye and genital tract infections were not only more resistant to amikacin but also to gentamicin than bacteria causing other infections. The major limitation of the study is non-equitable numbers of the isolates of different bacteria and of different sources compared for efficacy of the amikacin and gentamicin. Another limitation is, the study analysed in-vitro susceptibility data while it is known fact that in-vivo or therapeutic outcome sometimes may not match with in-vitro observations. The study recommends that looking at the wide variation in the susceptibility of bacterial strains of different species causing various types of infections in animals and birds under different husbandry practices antimicrobial susceptibility should be conducted before the use of amikacin or gentamicin in therapeutics.

The research work was supported by grants received from CAAST-ACLH (No. NAHEP/CAAST/2018-19) of ICAR-World Bank-funded National Agricultural Higher Education Project (NAHEP).

The authors are thankful to the Division of Epidemiology, ICAR-ICAR-Indian Veterinary Research Institute, Izatnagar for permitting full access to the investigation data. Authors, H. Agri, R. Karthikeyan and V. Jayakumar thanks to the Director and Joint Director (Academic) of ICAR-Indian Veterinary Research Institute, Izatnagar for permitting to be participants in the study.

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