Search

Staphylococcus aureus bone infections remain a therapeutic challenge, leading to long and expensive hospitalizations. Systemic antibiotic treatments are inconsistently effective, due to insufficient penetration into the infectious site. In an osteomyelitis model, the single local administration of nanoparticle-encapsulated daptomycin allows sterilization of the infectious sites after 4 and 14 days of treatment, while daily systemic daptomycin treatment for 4 days was not effective. These results demonstrate the great potential of this local antibiotic treatment.

Impeding, as well as reducing, the burden of antimicrobial resistance in Gram-negative pathogens is an urgent public health endeavor. Our current antibiotic armamentarium is dwindling, while major resistance determinants (e.g., extended-spectrum β-lactamases [ESBLs]) continue to evolve and disseminate around the world. One approach to attack this problem is to develop novel therapies that will protect our current agents. AAI101 is a novel penicillanic acid sulfone β-lactamase inhibitor similar in structure to tazobactam, with one important difference. AAI101 possesses a strategically placed methyl group that gives the inhibitor a net neutral charge, enhancing bacterial cell penetration. AAI101 paired with cefepime, also a zwitterion, is in phase III of clinical development for the treatment of serious Gram-negative infections. Here, AAI101 was found to restore the activity of cefepime against class A ESBLs (e.g., CTX-M-15) and demonstrated increased potency compared to that of piperacillin-tazobactam when tested against an established isogenic panel. The enzymological properties of AAI101 further revealed that AAI101 possessed a unique mechanism of β-lactamase inhibition compared to that of tazobactam. Additionally, upon reaction with AAI101, CTX-M-15 was modified to an inactive state. Notably, the in vivo efficacy of cefepime-AAI101 was demonstrated using a mouse septicemia model, indicating the ability of AAI101 to bolster significantly the therapeutic efficacy of cefepime in vivo The combination of AAI101 with cefepime represents a potential carbapenem-sparing treatment regimen for infections suspected to be caused by Enterobacteriaceae expressing ESBLs., (Copyright © 2019 American Society for Microbiology.)

We assessed the in vitro and in vivo efficacy of the novel parenteral broad-spectrum cephalosporin ceftaroline against Enterococcus faecalis in time-kill experiments and in a rabbit endocarditis model with simulated human dosing. Ceftaroline was more active than either vancomycin or linezolid against vancomycin-sensitive and -resistant isolates of E. faecalis.

Pregnant rabbits were treated with ciprofloxacin alone or with gentamicin in a model of Escherichia coli chorioamnionitis, and the results were compared with those for untreated rabbits. The survival rate increased and the bacteremia decreased significantly in treated fetuses in comparison to controls (P = 0.003). Nevertheless, rapid selection of resistant mutants is a major limit to ciprofloxacin applications.

Using the rabbit endocarditis model, we compared the activity of a new broad-spectrum cephalosporin, ceftaroline, with those of linezolid and vancomycin against methicillin-resistant Staphylococcus aureus. After a 4-day treatment, ceftaroline exhibited superior bactericidal in vivo activity against resistant S. aureus strains and appeared to be the most effective drug against a heterogeneous glycopeptide-intermediate S. aureus strain.

We investigated the efficacies of moxifloxacin, cloxacillin, and vancomycin in a rabbit model of Staphylococcus aureus arthritis. No significant difference between therapeutic regimens was observed after a 7-day treatment. Oral moxifloxacin could be a suitable alternative to standard parenteral therapy for S. aureus arthritis.

Linezolid in combination with ertapenem showed in vitro synergy against methicillin-resistant Staphylococcus aureus strains. We confirmed this interaction in vivo by using a rabbit endocarditis experimental model and simulation of the human pharmacokinetics in animals for both antibiotics. Linezolid plus ertapenem exhibited highly synergistic activity in vivo after 4 days of treatment.

The in vivo efficacy of vancomycin and teicoplanin against five Staphylococcus aureus strains with different susceptibilities to them and methicillin was studied. Rabbits were allocated at random to groups for endocarditis induction with one of these five strains and then treated for 2 days with vancomycin or teicoplanin. Each treated group was compared with a control group infected with the same strain. Vancomycin and teicoplanin showed similar activities. Low MICs did not predict better in vivo results.

Incubation in CO(2) resulted in higher (> or =3 doubling dilution) MICs of telithromycin than those found in ambient air for 31.2% of 346 Streptococcus pneumoniae ermB-positive strains. An increased telithromycin MIC in CO(2) was not correlated with loss of its activity in the murine sepsis/peritonitis model.

Indifference or moderate antagonism of linezolid combined with other antibiotics in vitro and in vivo have mainly been reported in the literature. We have assessed the in vitro activities of linezolid, alone or in combination with imipenem, against methicillin-resistant Staphylococcus aureus (MRSA) strains using the dynamic checkerboard and time-kill curve methods. Linezolid and low concentrations of imipenem had a synergistic effect, leading us to evaluate the in vivo antibacterial activity of the combination using the rabbit endocarditis experimental model. Two MRSA strains were used for in vivo experiments: one was a heterogeneous glycopeptide-intermediate clinical S. aureus strain isolated from blood cultures, and the other was the S. aureus COL reference strain. Animals infected with one of two MRSA strains were randomly assigned to one of the following treatments: no treatment (controls), linezolid (simulating a dose in humans of 10 mg/kg of body weight every 12 h), a constant intravenous infusion of imipenem (which allowed the steady-state concentration of about 1/32 the MIC of imipenem for each strain to be reached in serum), or the combination of both treatments. Linezolid and imipenem as monotherapies exhibited no bactericidal activity against either strain. The combination of linezolid plus imipenem showed in vivo bactericidal activity that corresponded to a decrease of at least 4.5 log CFU/g of vegetation compared to the counts for the controls. In conclusion, the combination exhibited synergistic and bactericidal activities against two MRSA strains after 5 days of treatment. The combination of linezolid plus imipenem appears to be promising for the treatment of severe MRSA infections and merits further investigations to explore the mechanism underlying the synergy between the two drugs.

Significant differences between animal and human pharmacokinetics may be responsible for the conflicting results of experimental studies. This study determined the impact of human pharmacokinetic simulation (HPS) on gentamicin activity in an Enterococcus faecalis endocarditis model. The decrease in bacterial counts was greater with HPS than with a dose-equivalent regimen without HPS.

Linezolid is the first drug issued from the oxazolidinones, a novel class of antimicrobial agents with potent activity against gram-positive pathogens. A rabbit endocarditis model was used to compare the in vivo activities of different linezolid regimens mimicking intermittent dosing of 10 mg/kg of body weight every 12 h for 5 days or continuous (constant-rate) infusion of a daily dose of 20 mg/kg (for 5 days) or 40 mg/kg (for 3 and 5 days) and the activities of intermittent dosing and continuous infusion of vancomycin (for 5 days). The in vivo activities of these regimens were tested against three strains of methicillin-resistant Staphylococcus aureus. A human-like pharmacokinetic simulation was used for linezolid in order to improve the extrapolation of the results to human therapy. All linezolid regimens significantly reduced the numbers of S. aureus cells in aortic valve vegetations compared to the numbers in the control groups. Linezolid intermittent dosing had an in vivo bacteriostatic effect. Switching from intermittent dosing to continuous infusion (at the same dose) led to in vivo bactericidal activity, with a decrease of at least 3 log(10) CFU/g of vegetation compared to the counts for the controls. After 5 days of treatment, continuous infusion of linezolid (corresponding to a daily dose of 40 mg/kg in humans) seemed to be at least as effective as vancomycin against the three strains. No resistant variant was isolated from the vegetations during any of the treatments. These data suggest that continuous infusion of linezolid could be an appropriate alternative to the use of glycopeptides for the treatment of severe methicillin-resistant S. aureus infections.

The combination of quinupristin-dalfopristin (Q-D) and gentamicin was tested against two strains of gentamicin- and dalfopristin-susceptible methicillin-resistant Staphylococcus aureus (MRSA). One strain was susceptible to macrolides, lincosamides, and streptogramin B type antibiotics (MLS(B)), and the other was constitutively resistant to these antibiotics by virtue of the ermA gene. The checkerboard method and time-kill curves showed that the combination of Q-D and gentamicin was indifferent. A rabbit endocarditis model simulated the pharmacokinetics achieved in humans receiving intravenous injections of Q-D (7.5 mg/kg of body weight three times a day) and gentamicin (3 mg/kg once daily). For the MLS(B)-susceptible strain, a 4-day regimen reduced mean bacterial titers (MBT) in vegetations from 8.5 +/- 0.8 log CFU/g (control group) to 4.1 +/- 2.6 (gentamicin), 3.0 +/- 0.9 (Q-D), and 2.6 +/- 0.5 log CFU/g (Q-D plus gentamicin). For the strain constitutively resistant to MLS(B), a 4-day regimen reduced MBT in vegetations from 8.7 +/- 0.9 log CFU/g (control group) to 5.0 +/- 2.2 (gentamicin), 5.2 +/- 2.2 (Q-D), and 5.1 +/- 2.4 log CFU/g (Q-D plus gentamicin). The differences between control and treatment groups were significant for both strains (P < 0.0001), although there was no significant difference between treatment groups. No resistant variant was isolated from vegetations, and no significant difference in MBT in vegetations of treatment groups after 1-day regimens was observed. This experimental study found no additive benefit in combining Q-D and gentamicin against dalfopristin- and gentamicin-susceptible MRSA.