a Microbiology Department, Bichat-Claude Bernard University Hospital, 46 Rue Henri-Huchard, 75877 Paris Cedex 18; b Argenteuil Hospital, France
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Abstract |
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Introduction |
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There are significant differences between countries in terms of the acceptability of suppositories by patients, but, in some populations, rectal drug delivery could represent a convenient, alternative route of antibiotic administration when other routes are not available. This might occur in several situations : (i) when administration by the oral route results in intolerance, nausea, vomiting or gastric pain; (ii) when patients are uncooperative or have decreased consciousness; (iii) when access to the intravenous route is difficult, e.g. in children or in patients in intensive care units needing multiple drugs and continuous fluid infusions but with few veins undamaged; (iv) in ambulatory patients, when repeated, painful intramuscular administration of drugs is not well accepted. 1,2
This review deals with the available data on the pharmacokinetics and clinical efficacy of the suppository forms of antibiotics, as well as with the advantages and drawbacks of rectal antibiotic administration. Data collected from studies of rectal administration of preparations other than suppositories are also reported.
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Anatomical and physiological features |
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Since many experimental studies of rectal drug administration are performed in animals, it is necessary to note the differences in structure between human and animal rectums. In most animal species, histological analysis reveals more goblet cells in the rectal mucosa than in the colon; in rats and rabbits there are many lymph nodes in the lamina propria and submucosa. 5 The mucosa is also thrown into several longitudinal folds containing large veins: this structure seems favourable to local absorption of drugs. A rapid colorectal cell turnover has also been described, potentially stimulated by chemicals such as ethanol or isoenergetic carbohydrates6 but such response has not always been discussed in studies of antibiotic administration in rats or rabbits. 7,8,9
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Drug absorption in the rectum |
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Pharmaceutics of suppository form of antibiotics: experimental studies |
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Pharmacokinetics of antibiotics administered by the rectal route in humans |
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Ampicillin and bacampicillin are the only penicillins that have been administered to humans in the suppository form or in the form of rectal microenemas. 21,22,23 Maximal plasma concentrations achieved in children after ampicillin administration by suppositories were 5.9 mg/L (range 4.87.0 mg/L) and 8.5 mg/L (range 6.011.0 mg/L) after 125 mg and 250 mg doses, respectively. These figures are well above the MIC values for most respiratory pathogens; in this particular study the authors 23 indicated a clinical effect of rectally administered ampicillin similar to that of orally administered amoxycillin. A comparison of bacampicillin bioavailability after oral or microenema administration (microenema) of 400 mg in 12 volunteers showed a much smaller degree of rectal absorption than that by the oral route: as seen in Table II the peak (6 S.D.) plasma concentration was 1.16 6 0.33 mg/L and 4.77 6 0.98 mg/L after rectal and oral administration respectively. 22
Two studies of rectal administration of cefoxitin in humans used different suppository forms containing adjuvants such as sodium salicylate or a nonionic surface-active agent, Brij 35, 24 or rectal infusion with the addition of sodium octanoate or sodium salicylate. 25 The bioavailability of cefoxitin was significantly increased in the presence of adjuvants; both octanoate and salicylate similarly increased cefoxitin absorption following rectal infusion in the same study.25
Erythromycin
Owing to frequent gastrointestinal side effects after oral administration of erythromycin, suppositories have been used often, particularly in childhood infections. The chemical details of the adjuvants contained in erythromycin suppositories were not provided in most of the available studies; the trade names of the preparations were Proterytrin (Proter SpA, Milan, Italy) 26 and Neo-Bismocetina (Le Petit). 27 Maximal serum concentrations achieved after rectal administration varied from 0.44 6 0.11 to 0.78 6 0.07 mg/L (250 mg dose) and were 0.35 6 0.03 mg/L after a 150 mg dose administered to children. 28 Proterytrin and Neo-Bismocetina formulations did not show any significant difference in bioavailability the highest serum levels were 0.53 6 0.04 and 0.49 6 0.10 mg/L, respectively. 27 One study examined the concentrations of erythromycin achieved in sputum after rectal administration of 500 mg erythromycin base and Proterytrin: mean concentrations were 0.23 6 0.03 mg/L 4 h after the administration, a ratio of 34.9% of simultaneous serum concentrations. 26
In one study 29 the relationship between age and the rectal bioavailability of erythromycin was established in three groups of children and the pharmacokinetic parameters were compared with those after intravenous administration: the data are shown in Table II. The bioavailability of erythromycin administered rectally increased from 28% in neonates to 36% in infants and up to 54% in children older than 1 year; this may be explained by a delayed absorption in neonates and by age-dependent systemic parameters.
In one study, the azalide, azithromycin, was administered (500 mg) to six volunteers by the rectal route, and the Cmax and AUC (mg/mL) obtained were compared with those obtained after iv administration. 30 The rectal route resulted in an extremely low Cmax (0.11 mg/L) and AUC (0.31 mg·h/L); the corresponding values for the iv route were 3.99 mg/L and 10.00 mg·h/L, respectively. The bioavailability achieved following administration by the rectal route was estimated as only 3.2%.
Imidazoles
Serum pharmacokinetics of different dosages of metronidazole have been compared after tablet
and suppository administration. The results are summarized in Table II;
they show that that the suppositories provided significant absorption, with AUC0- values not significantly lower than those achieved with tablets. The
bioavailability of drug following administration by suppositories was 90% of that seen following
administration by tablets.31 The bioavailability of
tinidazole
was compared with that of metronidazole and there was no significant difference between
parameters established for both drugs administered in the suppository form at a dosage of 1 g.
The serum pharmacokinetics for the two drugs were somewhat different after iv administration
(500 mg infusion over 20 min) with a larger AUC0-
for tinidazole
(175.8 ± 12.7 mg·h/mL) than for metronidazole (106.9 ± 10.7
mg·h/mL). The longer half-life and larger volume of distribution for tinidazole
supported either smaller doses or less frequent administration of tinidazole.32
Other antibiotics
The rectal administration of 960 mg of co-trimoxazole at 8 h intervals has resulted in serum concentrations comparable to those achieved after repeated oral administration of equivalent doses at 12 h intervals. 32 A more recent study investigated suppositories containing 480 mg co-trimoxazole with Witepsol H-15, with and without 10% Tween 60. 33 The bioavailability of the combination was assessed on the basis of urinary excretion. Suppositories of Witepsol H-15 incorporated with Tween 60 showed the highest absorption of trimethoprim and sulphamethoxazole and the authors recommended this formulation as a suppository base. The rectal absorption of lincomycin, 35 chloramphenicol 20 or tetracyclines 36 was investigated in early studies but the technical and analytical procedures used may not have been reliable enough to give accurate results. One recent study evaluated the pharmacokinetics of fluconazole given as 25 mg and 200 mg suppositories to volunteers and compared the results with those obtained after oral administration of the same doses as capsules or suspension. As seen in Table II, the pharmacokinetic parameters were very similar for both oral and rectal routes of drug administration. 37
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Discussion |
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Human studies are limited due to ethical constraints. For a small number of antibiotics it has been shown that the rectal route is as effective as the oral route of administration with similar pharmacokinetics after each route. 38 However, there is reluctance in some societies to adopt the rectal route of administration. In addition, there are significant side effects in some circumstances: prolonged rectal use of some drugs has been found to induce rectal ulceration, rectal bleeding and pain. 2,3 Even the suppository base or the enhancer may damage the rectal mucosa and cause local inflammation.2, 3,16 Further research into safer absorption-promoting agents may be necessary in order to `rehabilitate' the rectal route of antibiotic administration which may then offer a very useful alternative route in intensive-care-unit patients and in children.
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Notes |
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References |
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Received 9 December 1996; returned 5 March 1997; revised 6 July 1998; accepted 4 September 1998