Ball, A. McC: Antibacterial drugs today: I. Drugs 1—55 Barr, W. Clinical Pharmacology and Therapeutics — Brise, H. Acta Medica Scandinavica Suppl. Brumfitt, W. Journal of Antimicrobial Chemotherapy 1: — Chin, T. American Journal of Hospital Pharmacy — Edlund, A. PubMed Google Scholar. Gothoni, G. Acta Medica Scandinavica — Annals of Clinical Research 4: — Greenberger, N. Annals of Internal Medicine — American Journal of Clinical Nutrition — Gastroenterology — Harcourt, R. Epimerization of minocycline also results in the formation of 4-epiminocycline.
Minocycline reaches C max after 2—3 h post-oral dose and then has a prolonged serum half-life of 12—18 h. Interesting is in one study which reported the data where the serum half-life was increased after multiple doses.
There are no data on the effects of age, sex, changes in body mass, co-morbidity or infection on the pharmacokinetics of minocycline except for a small number of studies carried out in patients with renal impairment and end stage renal disease. Renal impairment and end stage renal disease have little effect on the serum concentrations and serum half-life or AUC of minocycline 34 , 50 , 53 , 55 in both single dose and short multi-dosing studies.
In animal models it is substantially unbound in plasma at concentrations ranging from 0. In the presence of liver homogenates it appears to be metabolically stable with no detectable loss of compound over 60 min.
As yet, there is only an intravenous formulation of tigecycline which is infused over a 1 h period. There are no data on absorption of tigecycline, but its oral bioavailability is reported to be limited. A light breakfast did not have a significant effect on iv tigecycline pharmacokinetics. The more recent presentation of a dose ranging study of The reasons for these differences are at present unclear; however, in the dose range used in man mg loading, then 50 mg 12 hourly, the volume of distribution is somewhere in the range 2.
The equivalent C max concentrations were 0. Further studies in adult humans who received mg iv tigecycline have indicated concentrations in lung tissue of 0.
There was significance between subject variability in measured drug concentrations. As may be expected, bile concentrations were high, ranging from 0. This is consistent with biliary excretion of tigecycline. Radiolabelled tigecycline has been administered to Sprague-Dawley rats as a single infusion to study the drug distribution.
AUC values were highest in the bone, bone marrow, salivary gland, thyroid, spleen and kidney. The high ratio in bone may be related to calcium binding.
An N-acetylaminominocycline metabolite is also formed to a less degree. This presumably means that, like some other tetracyclines, there is biliary excretion and perhaps also an enterohepatic circulation. The proposed dosing in man is a mg loading dose followed by 50 mg 12 hourly.
This will give a C max of 0. The C max of the mg dose is 0. The half-life of the mg dose is 22 h in the single dose study and 66 h in the multi-dose, equivalent values for the 50 mg dose are 18 and 38 h, indicating lengthening of the half-life with multiple doses.
There is rough linearity with dose in terms of AUC and C max values. Steady state is reached within 3 days. Using the single and multiple dose data from Phase 1 subject populations, pharmacokinetic models have been developed. However a two-compartment model provided the most unbiased estimates of AUC 0—12 and is therefore most appropriate to multi-dose studies in patients. The effects of age, gender, excretory organ failure and infection on the pharmacokinetics of tigecycline have been studied.
These data were compared with those from healthy volunteers. A single mg infusion over 1 h was administered. Pharmacokinetics of tigecycline mg infusion in healthy subjects, those with severe renal impairment and those with end stage renal disease. There are no published data as yet on the impact of liver impairment on the pharmacokinetics of tigecycline. A non-compartmental pharmacokinetic analysis was performed on 15 patients in the Phase 3 study in complicated skin and soft structure infections.
The patients' weights varied from 57 to kg; mean 80 kg. The C max was 0. These data are in very close agreement with data from treated patients with intra-abdominal sepsis and from healthy volunteers in Phase 1 and Phase 2 studies. Co-administration of digoxin plus tigecycline or warfarin plus tigecycline in healthy male volunteers had no impact on the pharmacokinetics of either agent. Pharmacodynamics is the relationship between measurements of antimicrobial exposure in body fluids with the antibacterial and toxicological effects of the drug.
The pattern of the antibacterial killing effect of doxycycline, minocycline and tigecycline has been studied using time—kill curve methods. Doxycycline produces a 0. Bacterial inoculum appears to have a modest effect on tigecycline MICs which are 1—2 dilutions higher with to fold increases in inoculum.
Persistent antibiotic effects have been studied with tetracyclines in vitro and in vivo ; however, the significance of persistent antibiotic effects such as the post-antibiotic effect PAE remains to be established.
Doxycycline has a PAE against S. Similar data to those of Bowker et al. Tigecycline produced a greater antibacterial effect against fluoroquinolone-resistant S. Van Ogtrop et al. The dose of tigecycline for a 24 h static effect was 0. Against K. These data with that from time—kill curves suggest that the drug exposures to clear different bacterial species with tigecycline may be different, with S.
More recently, based on likely drug exposures in man, tetracyclines have been classified as AUC driven agents. There are four studies relating tetracycline serum concentrations, pathogen MIC and species to clinical outcomes.
Table 7 shows the successes and failures by species and the MIC 90 s of representatives of those species performed by the authors. Successes and failures in man with iv doxycycline according to bacterial species and expected MIC In a different indication, Q fever endocarditis, 16 patients were studied over 1 year.
Coxiella burnetii MIC, doxycycline serum concentrations and serological response phase 1, C. Serum AUC values were not calculated and it was obviously difficult to generalize from this infection to others.
Drug bound in this fashion is pharmacologically inactive. Biotransformation of the tetracyclines seems to be limited in most domestic animals, and generally about one-third of a given dose is excreted unchanged. Rolitetracycline is metabolized to tetracycline.
Tetracyclines are excreted via the kidneys glomerular filtration and the GI tract biliary elimination and directly. Doxycycline appears to be eliminated through feces predominantly through intestinal cells, rather than bile.
A portion of doxycycline is also renally excreted in active form in some species. For minocycline, bile appears to be the major route of excretion. Tetracyclines are also eliminated in milk; concentrations peak 6 hr after a parenteral dose, and traces are still present up to 48 hr later. Tetracyclines also are excreted in saliva and tears. The plasma half-lives of tetracyclines are 6—12 hr and can be longer depending on age slower elimination in animals Elimination, Distribution, and Clearance of Tetracyclines Elimination, Distribution, and Clearance of Tetracyclines The tetracyclines are broad-spectrum antibiotics with similar antimicrobial features, but they differ somewhat from one another in terms of their spectra and pharmacokinetic disposition.
In large animals, daily injections of standard dosages usually are sufficient to maintain effective inhibitory concentrations. Tetracyclines usually are administered PO bid-tid every 12—24 hr for doxycycline and minocycline.
The tetracyclines are used to treat both systemic and local infections. However, resistance and their bacteriostatic nature suggest caution with empirical use for bacterial infections, particularly in dogs and cats. Specific conditions include infectious keratoconjunctivitis in cattle, chlamydiosis, heartwater, anaplasmosis, actinomycosis, actinobacillosis, nocardiosis especially minocycline , ehrlichiosis especially doxycycline , Wolbachia , eperythrozoonosis, and haemobartonellosis.
Minocycline and doxycycline are often effective to a somewhat lesser degree against resistant strains of Staphylococcus aureus. In addition to antimicrobial chemotherapy, the tetracyclines are used for other purposes. As additives in animal feeds, they serve as growth promoters.
Because of the affinity of tetracyclines for bones, teeth, and necrotic tissue, they can be used to delineate tumors by fluorescence. Demethylchlortetracycline has been used to inhibit the action of antidiuretic hormone in cases of excessive water retention.
A selection of general dosages for some tetracyclines is listed in Dosages of Tetracyclines Dosages of Tetracyclines The tetracyclines are broad-spectrum antibiotics with similar antimicrobial features, but they differ somewhat from one another in terms of their spectra and pharmacokinetic disposition.
The dose rate and frequency should be adjusted as needed for the individual animal. Because several diverse effects may result from administration of tetracyclines, caution should be exercised. Superinfection by nonsusceptible pathogens such as fungi, yeasts, and resistant bacteria is always a possibility when broad-spectrum antibiotics are used.
Severe and even fatal diarrhea can occur in horses receiving tetracyclines, especially if the animals are severely stressed or critically ill. High doses administered PO to ruminants seriously disrupt microfloral activity in the ruminoreticulum, eventually producing stasis. Elimination of the gut flora in monogastric animals reduces the synthesis and availability of the B vitamins and vitamin K from the large intestine.
With prolonged therapy, vitamin supplementation is a useful precaution. Tetracyclines chelate calcium in teeth and bones; they become incorporated into these structures, inhibit calcification eg, hypoplastic dental enamel , and cause yellowish then brownish discoloration. At extremely high concentrations, the healing processes in fractured bones is impaired. Rapid IV injection of a tetracycline can result in hypotension and sudden collapse.
This appears to be related to the ability of the tetracyclines to chelate ionized calcium, although a depressant effect by the propylene glycol carrier itself may also be involved. Glycylcyclines were derived from the chemical structure of tetracyclines.
After they started to be used in clinical practice, tetracycline group came into focus as a whole. First-generation tetracyclines feature low lipophilia and they are usually available in peroral form only, except rolitetracycline.
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