In vitroactivity of apramycin against multidrug-, carbapenem- and aminoglycoside-resistant Enterobacteriaceae andAcinetobacter baumannii (2025)

Evaluation of apramycin activity against carbapenem-resistant and -susceptible strains of Enterobacteriaceae

Diagnostic microbiology and infectious disease, 2016

We evaluated activity of apramycin, a non-ototoxic/non-nephrotoxic aminocyclitol against 141 clinical Enterobacteriaceae isolates, 51% of which were non-susceptible to carbapenems (CRE). Among CRE, 70.8% were apramycin susceptible, which compared favorably to aminoglycosides in current clinical use. Our data suggest that apramycin deserves further investigation as a repurposed, anti-CRE therapeutic.

Apralogs: Apramycin 5-O-Glycosides and Ethers with Improved Antibacterial Activity and Ribosomal Selectivity and Reduced Susceptibility to the Aminoacyltransferase (3)-IV Resistance Determinant

Journal of the American Chemical Society, 2019

Apramycin is a structurally unique member of the 2-deoxystreptamine class of aminoglycoside antibiotics characterized by a mono-substituted 2-deoxystreptamine ring that carries an unusual bicyclic eight-carbon dialdose moiety. Because of its unusual structure apramycin is not susceptible to the most prevalent mechanisms of aminoglycoside resistance including the aminoglycoside-modifying enzymes and the ribosomal methyltransferases whose widespread presence severely compromises all aminoglycosides in current clinical practice. These attributes coupled with minimal ototoxocity in animal models combine to make apramycin an excellent starting point for the development of next-generation aminoglycoside antibiotics for the treatment

Resistance Patterns and Prevalence of the Aminoglycoside Modifying Enzymes in Clinical Isolates of Gram Negative Pathogens

In this nationwide study we investigated the occurrence of aminoglycoside resistance patterns and prevalence of the aminoglycoside modifying enzymes (AMEs), aac(6), ant(2) and aph , in clinical isolates of Acinetobacter species, E. coli, Klebsiella species and Pseudomonas species isolates from various clinical specimens. A total of 319 clinical specimens recovered from urine, blood, wound, catheter tips and sputum were collected and were processed for identification of bacterial isolates in these specimens. The selected bacterial isolates were examined for susceptibility to Potentox, cefepime, amikacin, tobramycin, meropenem, gentamicin, piperacillin plus tazobactam by disc diffusion method. AMEs were detected by polymerase chain reaction (PCR). A total of 255 Gram negative clinical isolates were recovered from clinical specimens that include 9.0 % of Acinetobacter species, 34.9% of Escherichia coli, 29.0% of Pseudomonas species and 27.0% of Klebsiella species. Among the 255 clinical isolates, 75.7% isolates were found to carry AMEs. The AMEs genes found were aac(6) (43.5 to 51.7%), ant(2) (17.4 to 20.2%) and aph(3) (5.6 to 10.1%) of the isolates. The most prevalent AMEs was aac(6). Our data displayed that Potentox was the most active antibacterial agent against AMEs followed by meropenem. Potentox exhibited more than 93% susceptibility to all 3 types of AMEs (aac, ant & aph) whereas meropenem response was almost 20% lesser with susceptibility ranging not more than 73.4%. Piperacillin plus tazobactam was found to be the least active with less than 20% susceptibility. The susceptibility of other antibacterial agents varied between 20% to <40% %. In conclusion 75.7 % isolates carried AMEs that included aac(6), ant(2) and aph(3) which are responsible for resistance. Among the tested drugs, traditionally used aminoglycoside showed the maximum resistance. Surprizingly, broad spectrum antibiotics like meropenem, cefepime and piperacillin tazobactam also exhibited resistance to aminoglycoside modifying enzyme producing strains. However, in this study, Potentox showed excellent in vitro antibacterial activity up to 95 % of all isolates. We suggest that that Potentox which has been introduced recently into clinical settings would allow clinicinas to overcome the aminoglycoside resistance acquired by some bacterial strains.

Role of aminoglycoside-modifying enzymes and 16S rRNA methylase (ArmA) in resistance of Acinetobacter baumannii clinical isolates against aminoglycosides

Revista da Sociedade Brasileira de Medicina Tropical

Introduction: This study aimed to determine the role of genes encoding aminoglycoside-modifying enzymes (AMEs) and 16S rRNA methylase (ArmA) in Acinetobacter baumannii clinical isolates. Methods: We collected 100 clinical isolates of A. baumannii and identified and confirmed them using microbiological tests and assessment of the OXA-51 gene. Antibiotic susceptibility testing was carried out using disk agar diffusion and micro-broth dilution methods. The presence of AME genes and ArmA was detected by PCR and multiplex PCR. Results: The most and least effective antibiotics in this study were netilmicin and ciprofloxacin with 68% and 100% resistance rates, respectively. According to the minimum inhibitory concentration test, 94% of the isolates were resistant to gentamicin, tobramycin, and streptomycin, while the highest susceptibility (20%) was observed against netilmicin. The proportion of strains harboring the aminoglycoside resistance genes was as follows: APH(3′)-VIa (aphA6) (77%), ANT(2")-Ia (aadB) (73%), ANT(3")-Ia (aadA1) (33%), AAC(6′)-Ib (aacA4) (33%), ArmA (22%), and AAC(3)-IIa (aacC2) (19%). Among the 22 gene profiles detected in this study, the most prevalent profiles included APH(3′)-VIa + ANT(2")-Ia (39 isolates, 100% of which were kanamycin-resistant), and AAC(3)-IIa + AAC(6′)-Ib + ANT(3")-Ia + APH(3′)-VIa + ANT(2")-Ia (14 isolates, all of which were resistant to gentamicin, kanamycin, and streptomycin). Conclusions: High minimum inhibitory concentration of aminoglycosides in isolates with the simultaneous presence of AME-and ArmA-encoding genes indicated the importance of these genes in resistance to aminoglycosides. However, control of their spread could be effective in the treatment of infections caused by A. baumannii.

In vivo efficacy of apramycin in murine infection models

Antimicrobial agents and chemotherapy, 2014

Apramycin is a unique aminoglycoside with a dissociation of antibacterial activity and ototoxicity. We assessed the antibacterial efficacy of apramycin in two murine models of infection, Mycobacterium tuberculosis aerosol infection and Staphylococcus aureus septicemia. In both infection models, the efficacy of apramycin was comparable to that of amikacin. These results suggest that apramycin has the potential to become a clinically useful agent against drug-resistant pathogens and support further development of this promising unique aminoglycoside.

Aminoglycoside Resistance Rates, Phenotypes, and Mechanisms of Gram-Negative Bacteria from Infected Patients in Upper Egypt

PLOS One, 2011

With the re-emergence of older antibiotics as valuable choices for treatment of serious infections, we studied the aminoglycoside resistance of Gram-negative bacteria isolated from patients with ear, urinary tract, skin, and gastrointestinal tract infections at Minia university hospital in Egypt. Escherichia coli (mainly from urinary tract and gastrointestinal tract infections) was the most prevalent isolate (28.57%), followed by Pseudomonas aeruginosa (25.7%) (mainly from ear discharge and skin infections). Isolates exhibited maximal resistance against streptomycin (83.4%), and minimal resistance against amikacin (17.7%) and intermediate degrees of resistance against neomycin, kanamycin, gentamicin, and tobramycin. Resistance to older aminoglycosides was higher than newer aminoglycoides. The most common aminoglycoside resistance phenotype was that of streptomycin resistance, present as a single phenotype or in combination, followed by kanamycinneomycin as determined by interpretative reading. The resistant Pseudomonas aeruginosa strains were capable of producing aminoglycoside-modifying enzymes and using efflux as mechanisms of resistance. Using checkerboard titration method, the most frequently-observed outcome in combinations of aminoglycosides with b-lactams or quinolones was synergism. The most effective combination was amikacin with ciprofloxacin (100% Synergism), whereas the least effective combination was gentamicin with amoxicillin (53.3% Synergistic, 26.7% additive, and 20% indifferent FIC indices). Whereas the studied combinations were additive and indifferent against few of the tested strains, antagonism was never observed. The high resistance rates to aminoglycosides exhibited by Gram-negative bacteria in this study could be attributed to the selective pressure of aminoglycoside usage which could be controlled by successful implementation of infection control measures.

Resistance pattern of different aminoglycosides against Gram positive and Gram negative clinical isolates of Karachi

Pakistan Journal of Pharmaceutical Sciences, 2002

Microbial resistance to majority of the available antimicrobial agent is a serious and global problem. Due to heavy and discriminate usage of antibiotics, high prevalence of drug-resistant bacteria in the indigenous fecal flora, poor standards of sanitation, lack of education and prevalence of malnutrition. This problem is at its extreme in developing countries like Pakistan. For this various Aminoglycosides were tested against different Gram positive and Gram negative isolates. The results showed that these isolates were resistant against most of these antibiotics with increase in MIC's. In Aminoglycoside group Tobramycin was the most effective agent against Staph. aureus and E. coli with MIC 90s of 1 ug/ml and 2 ug/ml, while against Klebsiella and P. aeruginosa its activity was moderate to low. Amikacin showed highest activity against P. aeruginosa, E. coli and Klebsiella species with MIC 90s of 4 ug/ml and 8 ug/ml. Kanamycin and Streptomycin were not active against the tested isolates.

Comprehensive study to investigate the role of various aminoglycoside resistance mechanisms in clinical isolates of Acinetobacter baumannii

Therapeutic resistance towards most of the current treatment regime by Acinetobacter baumannii has reduced the prescribing antibiotic pattern and option is being re-shifted towards more toxic agents including aminoglycosides. The present investigation aimed at to study various mechanisms towards aminoglycoside non-susceptibility in clinical isolates of A. baumannii. The bacteria were subjected to genetic basis assessment for the presence of aminoglycoside modifying enzymes (AME), 16S rRNA methylase encoding genes and relative expression of AdeABC and AbeM efflux pumps in relation to their susceptibility to five aminoglycosides. When isolates were subjected to typing by repetitive extragenic palindromic (REP) PCR, isolates could be separated into thirteen definite clones. The majority of isolates (94%) were positive for AME encoding genes. Possession of ant(2 0)-Ia correlated with non-susceptibility towards gentamicin, amikacin, kanamycin, tobramycin; while, presence of aph(3 0)-VIa attributed to resistance towards amikacin, kanamycin; possession of aac(3 0)-Ia allied with non-susceptibility to ami-kacin, tobramycin and presence of aac(3 0)IIa correlated with kanamycin non-susceptibility. Presence of armA was detected in 34.4%, 34.2%, 29.2%, 40.3%, and 64.2% of isolates showing non-susceptibility to gentamicin, amikacin, kanamycin, tobramycin and netilmicin, respectively. No isolates were found to carry rmtB or rmtC. Amikacin non-susceptibility in comparison to other aminoglycosides correlated with over production of adeB. Overall, the results represented a definitive correlation between presence of AME encoding genes as well as armA and resistance of A. baumannii towards aminoglycosides. On the other hand, the up-regulation of AdeABC and AbeM systems was found to have only the partial role in development of aminoglycoside resistance.

Effects of Apramycin, a Novel Aminoglycoside Antibiotic on Bacterial Protein Synthesis

European Journal of Biochemistry, 1979

1. The novel aminoglycoside antibiotic apramycin is shown to be a potent inhibitor of protein synthesis in bacteria both in vivo and in vitro. 2. In cell-free systems from Escherichia coli programmed with poly(U), apramycin induces translation errors, as assayed by incorporation of leucine, isoleucine and serine, although this effect occurs only to a limited extent. 3. Apramycin inhibits the translocation step of protein synthesis both in vivo, in protoplasts of Bacillus megaterium, and in vitro, in cell-free systems from E. coli. It is proposed that this is the primary inhibitory effect of the drug.

Analysis of neomycin, kanamycin, tobramycin and amikacin resistance mechanisms in gentamicin-resistant isolates of Enterobacteriaceae

Journal of Medical Microbiology, 1998

Twenty-four gentamicin-resistant isolates of Enterobacteriaceae, obtained from the clinical laboratories of three health centres in Nablus, Palestine, were tested for susceptibility to neomycin, kanamycin, tobramycin and amikacin. Resistance rates were 29.2% for neomycin, 58.3% for kanamycin, 45.8% for tobramycin and 8.3% for amikacin. Fourteen (58.3%) isolates were noted to be multiresistant, i.e., resistant to gentamicin and two or more other aminoglycosides; resistance to gentamicin, kanamycin and tobramycin was the most common pattern of multiple resistance. This pattern implies the involvement of adenyltransferase ANT(2")-I activity. Plasmid profiles and curing experiments suggested a plasmid localisation of gentamicin, neomycin, kanamycin and tobramycin resistance genes. However, a chromosomal location is proposed for plasmid-deficient strains. Cross-resistance in two isolates to all aminoglycosides tested suggested membrane impermeability to aminoglycosides as the mechanism of resistance.