Activity of Plazomicin Tested against Enterobacterales Isolates Collected from U.S. Hospitals in 2016-2017: Effect of Different Breakpoint Criteria on Susceptibility Rates among Aminoglycosides.

Plazomicin was active against 97.0% of 8,783 Enterobacterales isolates collected in the United States (2016 and 2017), and only 6 isolates carried 16S rRNA methyltransferases conferring resistance to virtually all aminoglycosides. Plazomicin (89.2% to 95.9% susceptible) displayed greater activity than amikacin (72.5% to 78.6%), gentamicin (30.4% to 45.9%), and tobramycin (7.8% to 22.4%) against carbapenem-resistant and extensively drug-resistant isolates. The discrepancies among the susceptibility rates for these agents was greater when applying breakpoints generated using the same stringent contemporary methods applied to determine plazomicin breakpoints.

Effects of the 1- N-(4-Amino-2 S-hydroxybutyryl) and 6'- N-(2-Hydroxyethyl) Substituents on Ribosomal Selectivity, Cochleotoxicity, and Antibacterial Activity in the Sisomicin Class of Aminoglycoside Antibiotics.

Syntheses of the 6'- N-(2-hydroxyethyl) and 1- N-(4-amino-2 S-hydroxybutyryl) derivatives of the 4,6-aminoglycoside sisomicin and that of the doubly modified 1- N-(4-amino-2 S-hydroxybutyryl)-6'- N-(2-hydroxyethyl) derivative known as plazomicin are reported together with their antibacterial and antiribosomal activities and selectivities. The 6'- N-(2-hydroxyethyl) modification results in a moderate increase in prokaryotic/eukaryotic ribosomal selectivity, whereas the 1- N-(4-amino-2 S-hydroxybutyryl) modification has the opposite effect. When combined in plazomicin, the effects of the two groups on ribosomal selectivity cancel each other out, leading to the prediction that plazomicin will exhibit ototoxicity comparable to those of the parent and the current clinical aminoglycoside antibiotics gentamicin and tobramycin, as borne out by ex vivo studies with mouse cochlear explants. The 6'- N-(2-hydroxyethyl) modification restores antibacterial activity in the presence of the AAC(6') aminoglycoside-modifying enzymes, while the 1- N-(4-amino-2 S-hydroxybutyryl) modification overcomes resistance to the AAC(2') class but is still affected to some extent by the AAC(3) class. Neither modification is able to circumvent the ArmA ribosomal methyltransferase-induced aminoglycoside resistance. The use of phenyltriazenyl protection for the secondary amino group of sisomicin facilitates the synthesis of each derivative and their characterization through the provision of sharp NMR spectra for all intermediates.

Can Plazomicin Alone or in Combination Be a Therapeutic Option against Carbapenem-Resistant Acinetobacter baumannii?

Nosocomial pathogens can be associated with a variety of infections, particularly in intensive care units (ICUs) and in immunocompromised patients. Usually these pathogens are resistant to multiple drugs and pose therapeutic challenges. Among these organisms, Acinetobacter baumannii is one of the most frequent being encountered in the clinical setting. Carbapenems are very useful to treat infections caused by these drug-resistant Gram-negative bacilli, but carbapenem resistance is increasing globally. Combination therapy is frequently given empirically for hospital-acquired infections in critically ill patients and is usually composed of an adequate beta-lactam and an aminoglycoside. The purpose of this study was to evaluate the in vitro activity of plazomicin against carbapenem-resistant Acinetobacter baumannii. Amikacin was used as a comparator. The activity of plazomicin in combination with several different antibiotics was tested by disk diffusion, the checkerboard method, and time-kill studies. Synergy was consistently observed with carbapenems (meropenem and/or imipenem) along with plazomicin or amikacin. When the aminoglycosides were combined with other classes of antibiotics, synergy was observed in some cases, depending on the strain and the antibiotic combination; importantly, there was no antagonism observed in any case. These findings indicate the potential utility of plazomicin in combination with other antibiotics (mainly carbapenems) for the treatment of A. baumannii infections, including those caused by carbapenem-resistant isolates.

[Antibiotics of the aminoglycoside group (gentamicin, sisomicin and amikacin) in the prevention and treatment of experimental plague]. / Antibiotiki gruppy aminoglikozidov (gentamitsin, sizomitsin, amikatsin) v profilaktike i lechenii éksperimental'noi chumnoi infektsii.

Activity of aminoglycosides such as gentamicin, sisomicin and amikacin against plague microbe strains of natural origin was studied in vitro. It was also studied in prophylaxis and treatment of experimental plague infection in albino mice. The MAC of gentamicin and sisomicin for 50 strains of the plague microbe was 0.2-1.6 micrograms/ml. For the majority of the strains it was 0.4 micrograms/ml. The amikacin MICs were 0.4-3.2 and 0.8 micrograms/ml, respectively. High efficacy of gentamicin, sisomicin and amikacin was shown in prophylaxis and treatment of experimental plague infection in albino mice. The optimal doses of the antibiotics were determined. Under definite conditions such as the use of short-term regimens and higher intervals, advantages of sisomicin over gentamicin and amikacin in prophylaxis of experimental plague infection were observed.

[Effectiveness of the new aminoglycoside sisomicin in surgery]. / Effektivnost' novogo aminoglikozida sizomitsina v khirurgii.

Antimicrobial activity of sisomicin against causative agents of wound infections was studied. It was shown that by its antimicrobial activity and the rate of bactericidal effect attainment sisomicin is superior to other aminoglycosides, such as gentamicin and tobramycin. Individual variability of the pharmacokinetics of sisomicin on its intravenous and intramuscular injection to patients with wound infections was observed. For prediction of the treatment efficacy it is suggested that the drug be used under the control of its blood levels in comparison to the MTC for the isolated causative agent.

[Methods of evaluating the efficacy of combinations of aminoglycosides with penicillins and their value for the possibility of predicting the therapeutic effect in patients]. / Metody otsenki éffektivnosti kombinatsii aminoglikozidov s penitsillinami i ikh znachenie dlia vozmozhnosti prognozirovaniia lechebnogo éffekta u bol'nogo.

The efficacy of the combinations of aminoglycosides and penicillin with respect to Pseudomonas, Klebsiella and Escherichia strains was estimated with the methods of two-fold serial dilutions of aminoglycosides and constant concentrations of penicillin and the "chess board" method. Correlation between the synergistic effect and sensitivity of the strains to separate components of the combinations was observed. For prediction of the combination efficacy these methods are not useful, since they are labour-intensive and their results are very variable. In this connection a simple informative test is recommended. With the use of this test it is possible to judge the chemotherapeutic efficacy of antibiotics and their combinations by the value of the serum antibacterial activity (titer) against the infection causative agent. The blood serum titer of at least 1:8 is accompanied by a pronounced effect. The test also indirectly provides information on the sensitivity of isolated pathogens and adequacy of the drug blood levels after administration of the chosen dose.

Assessment of the in vitro and in vivo activity of ciprofloxacin measured against current standards of therapy.

The bactericidal activity of ciprofloxacin in active human serum was investigated using serum-resistant Escherichia coli C14 and Pseudomonas aeruginosa 220 as test organisms. In 100% or 80% human serum the growth rate of E. coli C14 was lower than in broth. This also influenced the killing rate of ciprofloxacin. Ciprofloxacin was more active in serum than norfloxacin or ofloxacin and killed Pseudomonas aeruginosa 220 much more rapidly than azlocillin or tobramycin. Rapid killing was also observed in vivo in the blood of intraperitoneally infected mice, ciprofloxacin being superior to norfloxacin, ofloxacin and sisomicin. In mouse protection studies with E. coli Neumann as infecting organism, the dose-effect ratio showed that, despite extremely low blood concentrations, ciprofloxacin had a full therapeutic effect at a dose of 2.5 mg/kg p.o. or less than or equal to 0.5 mg/kg s.c., whereas cefotaxime, despite similar low MIC values in vitro, had to be administered at a dose of 20 mg/kg s.c. in order to achieve 100% survival. These data indicate that ciprofloxacin is effective at low concentrations both in vitro and in vivo.

Activity of netilmicin compared with those of gentamicin and tobramycin against enterobacteria and Pseudomonas aeruginosa.

The inhibitory activity of netilmicin against 500 isolates of gram-negative bacteria was compared with those of gentamicin and tobramycin. Netilmicin was considerably less active than tobramycin and slightly less inhibitory than gentamicin for Pseudomonas aeruginosa but was at least as active against Escherichia coli and Klebsiella pneumoniae as were the other two antibiotics. A few Klebsiella and Serratia isolates resistant to gentamicin and tobramycin were inhibited by netilmicin. All three antibiotics were strongly bactericidal for E. coli, K. pneumoniae and P. aeruginosa but had less lethal activity against the otherwise susceptible Serratia isolates tested. Some necessary precautions in reading minimal inhibitory concentrations on agar media are stressed, and some possible advantages of a 4-h bactericidal test, using a constant antibiotic concentration, are defined.

Antimicrobial activity in vitro of netilmicin and comparison with sisomicin, gentamicin, and tobramycin.

The antimicrobial activity of netilmicin, a new semisynthetic aminoglycosidic aminocyclitol, was determined against 123 recent gram-negative clinical isolates susceptible to gentamicin and 60 isolates resistant to either sisomicin, gentamicin, or tobramycin. The minimal inhibitory concentrations and minimal bactericidal concentrations of netilmicin, sisomicin, gentamicin, and tobramycin against Pseudomonas, Escherichia coli, Klebsiella, Enterobacter, Proteus mirabilis, and indole-positive Proteus were, in general, quite similar. Gentamicin was the most active against Serratia. A total of 54, 67, and 88% of gentamicin-resistant Pseudomonas, Serratia, and Klebsiella, respectively, were susceptible to netilmicin. Strains of indole-positive Proteus, Acinetobacter, Providencia, and E. coli resistant to gentamicin were likely to be resistant also to netilmicin.

Comparative evaluation of five aminoglycosides for treatment.

Gentamicin, tobramycin, sisomicin, amikacin and kanamycin are compared for therapeutic use by correlating the in vitro minimal inhibitory concentration with the in vivo concentration of the antibiotic attainable in the serum at half the time intervall between two administrations of the drugs. Using this method of evaluation, E. coli, Enterobacter and sensitive strains of the Klebsiella and Pseudomonas species can be treated in principle equally well with gentamicin, tobramycin and sisomicin, and to a large degree also with amikacin. Gentamicin, sisomicin and amikacin are useful against Serratia infections; but in each case, a higher dosage is needed. Within the family of aminoglycosides, sisomicin has a noteworthy activity against Enterobacter and Proteus species, while tobramycin is most outstanding against pseudomonas strains. Amikacin is especially useful against infections involving Klebsiella, Providencia and Pseudomonas strains with resistance to nearly all antibiotics including the other aminoglycosides.