Synergistic activity of astromicin and .BETA.-lactam antibiotics against Pseudomonas aeruginosa in vitro and in vivo.

ABSTRACT The increasing prevalence of antibiotic resistance has created an urgent need for alternative drugs with new mechanisms of action. Antimicrobial peptides (AMPs) are promising candidates that could address the spread of multidrug-resistant bacteria, either alone or in combination with conventional antibiotics. We studied the antimicrobial efficacy and bactericidal mechanism of cecropin A2, a 36-residue α-helical cationic peptide derived from Aedes aegypti cecropin A, focusing on the common pathogen Pseudomonas aeruginosa. The peptide showed little hemolytic activity and toxicity toward mammalian cells, and the MICs against most clinical P. aeruginosa isolates were 32 to 64 μg/ml, and its MICs versus other Gram-negative bacteria were 2 to 32 μg/ml. Importantly, cecropin A2 demonstrated synergistic activity against P. aeruginosa when combined with tetracycline, reducing the MICs of both agents by 8-fold. The combination was also effective in vivo in the P. aeruginosa/Galleria mellonella model (P < 0.001). We found that cecropin A2 bound to P. aeruginosa lipopolysaccharides, permeabilized the membrane, and interacted with the bacterial genomic DNA, thus facilitating the translocation of tetracycline into the cytoplasm. In summary, the combination of cecropin A2 and tetracycline demonstrated synergistic antibacterial activity against P. aeruginosa in vitro and in vivo, offering an alternative approach for the treatment of P. aeruginosa infections.

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Kinetics of active efflux via choroid plexus of beta-lactam antibiotics from the CSF into the circulation

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1994.266.2.r392 ◽

1994 ◽

Vol 266 (2) ◽

pp. R392-R399 ◽

Cited By ~ 2

Author(s):

M. Ogawa ◽

H. Suzuki ◽

Y. Sawada ◽

M. Hanano ◽

Y. Sugiyama

Keyword(s):

Choroid Plexus ◽

Maximum Velocity ◽

Organic Anions ◽

Dependent Manner ◽

Beta Lactam ◽

Active Efflux ◽

Beta Lactam Antibiotics ◽

Elimination Clearance

To examine the role of the choroid plexus in eliminating organic anions from the cerebrospinal fluid (CSF), a kinetic study was performed both in in vivo and in vitro experiments using [3H]benzylpenicillin (PCG) as a model compound. In vivo, after intracerebroventricular administration, [3H]PCG was eliminated from the CSF much more rapidly than [14C]mannitol. Analysis of the elimination clearance from the CSF revealed that 12 and 24% of the disappearance of [3H]PCG can be accounted for by convective loss at a rate equivalent to CSF turnover, and by diffusional loss across the ependymal surface into the brain extracellular space, respectively. Approximately two-thirds of [3H]PCG elimination was due to a saturable process [Michaelis constant (Km) = 43.0 +/- 17.8 microM, maximum velocity (Vmax) = 619 +/- 286 pmol.min-1 x rat-1]. These kinetic parameters obtained in vivo were comparable to those determined previously in vitro, i.e., [3H]PCG was accumulated by the isolated rat choroid plexus via an active transport mechanism (Km = 58 microM, Vmax = 504 pmol.min-1 x rat-1; H. Suzuki, Y. Sawada, Y. Sugiyama, T. Iga, and H. Hanano, J. Pharmacol. Exp. Ther. 242: 660-665, 1987). Furthermore, other organic anions (probenecid, ampicillin, cefodizime, cefotaxime, and ceftriaxone) reduced the transport of [3H]PCG in a dose-dependent manner both in vivo and in vitro. A good correlation was observed between the log inhibition constant (Ki) values obtained for these ligands in vivo and in vitro (r = 0.94, P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

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In vitro and in vivo antibacterial effects of combinations of beta-lactam antibiotics.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.19.4.634 ◽

1981 ◽

Vol 19 (4) ◽

pp. 634-638 ◽

Cited By ~ 34

Author(s):

N A Kuck ◽

R T Testa ◽

M Forbes

Keyword(s):

Beta Lactam ◽

Antibacterial Effects ◽

Beta Lactam Antibiotics

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Antibiotic Treatment of Experimental Pneumonic Plague in Mice

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.42.3.675 ◽

1998 ◽

Vol 42 (3) ◽

pp. 675-681 ◽

Cited By ~ 55

Author(s):

William R. Byrne ◽

Susan L. Welkos ◽

M. Louise Pitt ◽

Kelly J. Davis ◽

Ralf P. Brueckner ◽

...

Keyword(s):

Mouse Model ◽

Antibiotic Treatment ◽

Survival Rates ◽

Blood Cultures ◽

High Dose ◽

Beta Lactam ◽

Pneumonic Plague ◽

Beta Lactam Antibiotics

ABSTRACT A mouse model was developed to evaluate the efficacy of antibiotic treatment of pneumonic plague; streptomycin was compared to antibiotics with which there is little or no clinical experience. Infection was induced by inhalation of aerosolized Yersinia pestisorganisms. Antibiotics were administered by intraperitoneal injection every 6 hours for 5 days, at doses that produced levels of drug in serum comparable to those observed in humans treated for other serious infections. These studies compared in vitro to in vivo activity and evaluated the efficacy of antibiotics started at different times after exposure. Early treatment (started 24 h after challenge, when 0 of 10 mice tested had positive blood cultures) with netilmicin, ciprofloxacin, ofloxacin, ceftriaxone, ceftazidime, aztreonam, ampicillin, and rifampin (but not cefazolin, cefotetan, or ceftizoxime) demonstrated efficacy comparable to streptomycin. Late treatment (started 42 h after exposure, when five of five mice tested had positive blood cultures) with netilmicin, ciprofloxacin, ofloxacin, and a high dose (20 mg/kg of body weight every 6 h) of gentamicin produced survival rates comparable to that with streptomycin, while all of the beta-lactam antibiotics (cefazolin, cefotetan, ceftriaxone, ceftazidime, aztreonam, and ampicillin) and rifampin were significantly inferior to streptomycin. In fact, all groups of mice treated late with beta-lactam antibiotics experienced accelerated mortality rates compared to normal-saline-treated control mice. These studies indicate that netilmicin, gentamicin, ciprofloxacin, and ofloxacin may be alternatives for the treatment of pneumonic plague in humans. However, the beta-lactam antibiotics are not recommended, based upon poor efficacy in this mouse model of pneumonic plague, particularly when pneumonic plague may be associated with bacteremia.

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