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

1994 ◽  
Vol 266 (2) ◽  
pp. R392-R399 ◽  
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)

scholarly journals The renal mitochondrial toxicity of beta-lactam antibiotics: in vitro effects of cephaloglycin and imipenem.

1990 ◽  
Vol 1 (5) ◽  
pp. 815-821
Author(s):  
B M Tune ◽  
C Y Hsu
Keyword(s):  
Protective Action ◽  
Substrate Uptake ◽  
Dependent Manner ◽  
Mitochondrial Toxicity ◽  
Beta Lactam ◽  
Beta Lactams ◽  
Beta Lactam Antibiotics ◽  
In Vitro Exposure

The nephrotoxic beta-lactam antibiotics cephaloridine, cephaloglycin, and imipenem produce irreversible injury to renal mitochondrial anionic substrate uptake and respiration after 1 to 2 h of in vivo exposure. Toxicity during in vitro exposure is nearly identical but is immediate in onset and is reversed by the mitochondria being washed or the substrate concentrations being increased. A model of injury that accounts for these findings proposes that the beta-lactams fit carriers for mitochondrial substrate uptake, causing inhibition that is initially reversible and becomes irreversible as the antibiotics acylate the transporters. These studies were designed to create an environment of prolonged in vitro exposure, first, to determine whether toxicity becomes irreversible with time and, second, to study the molecular properties of toxicity. Respiration with and the uptake of succinate and ADP were measured in rabbit renal cortical mitochondria exposed for 2 to 6 h to 300 to 3,000 micrograms of cephalexin (nontoxic) or cephaloglycin or imipenem (nephrotoxic) per mL and then washed to remove the antibiotic. In vitro cephalexin reduced respiration only slightly and was therefore not studied further. Cephaloglycin and imipenem irreversibly reduced both respiration and succinate uptake. ADP uptake was unaffected by cephaloglycin and was slightly reduced by imipenem. Finally, cilastatin, which prevents the tubular necrosis produced by imipenem in vivo, reduced its mitochondrial toxicity in vitro. It is concluded that the pattern of in vitro injury of the nephrotoxic beta-lactams to mitochondrial substrate uptake and respiration evolves in a time-dependent and concentration-dependent manner, consistent with the proposed model of acylation and inactivation of substrate transporters, and that the protective action of cilastatin against imipenem occurs at least partly at a subcellular level.

Morphologic changes produced by amdinocillin alone and in combination with beta-lactam antibiotics: In vitro and in vivo

1983 ◽  
Vol 75 (2) ◽  
pp. 30-41 ◽  
Author(s):  
Michael J. Kramer ◽  
Yolanda R. Mauriz ◽  
Maria D. Timmes ◽  
Tamara L. Robertson ◽  
Roy Cleeland
Keyword(s):  
Beta Lactam ◽  
Beta Lactam Antibiotics ◽  
Morphologic Changes

scholarly journals Antibiotic Treatment of Experimental Pneumonic Plague in Mice

1998 ◽  
Vol 42 (3) ◽  
pp. 675-681 ◽  
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.

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

1984 ◽  
Vol 37 (12) ◽  
pp. 1681-1686 ◽  
Author(s):  
KOZO KITAURA ◽  
KAZUYUKI MINEURA ◽  
NOBUHIRO NAKAMIZO ◽  
KHOYA SHIBA ◽  
MASAHISA OHMORI ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Synergistic Activity ◽  
Beta Lactam ◽  
Beta Lactam Antibiotics
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