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J ournal of Antimicrobial Chemotherapy (1999) 43, 177185

Introduction
Antibiotics are usually administered either orally or by a
parenteral route, the latter being used for drugs that are
poorly or not bioavailable by the oral route or when clinical
situations require rapid or higher antibiotic concentrations
to be achieved in the body. The rectal route of antibiotic
administration is seldom mentioned in experimental and
clinical pharmacokinetic studies and the characteristics
of administration of antibiotics by suppository is poorly
documented.
There are signicant 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 con-
sciousness; (iii) when access to the intravenous route is
difcult, e.g. in children or in patients in intensive care units
needing multiple drugs and continuous uid 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 pharma-
cokinetics and clinical efcacy 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.
Anatomical and physiological features
I n humans the rectum comprises the last 1219 cm of the
large intestine and the rectal epithelium is formed by a
single layer of columnar or cuboidal cells and goblet cells;
its surface area is about 200400 cm
2
. The absorbing
surface area of the rectum is considerably smaller than that
of the small intestine, as the former lacks villi and micro-
villi.
2,3
However, the epithelia in the rectum and the upper
intestinal tract are histologically similar, giving them
comparable abilities to absorb drugs.
1
The rectal mucosa is
richly vascularized: this important blood supply comprises
the inferior and middle veins, which are directly connected
to the systemic circulation, and the superior rectal vein,
which is connected to the portal system. This ensures that
drugs in suppository form which are absorbed in the upper
rectum will not by-pass the hepatic rst-pass elimination,
4
responsible for the metabolism and rapid clearance of
many orally administered drugs, such as the macrolides.
177
Review
The suppository form of antibiotic administration: pharmacokinetics
and clinical application
E. Bergogne-Brzin
a
* and A. Bryskier
b
a
Microbiology Department, Bichat-Claude Bernard University Hospital, 46 Rue Henri-Huchard,
75877 Paris Cedex 18;
b
Argenteuil Hospital, France
The rectal route of antibiotic administration might be used effectively when other routes of
administration are inadequate or unsuitable. With the use of various adjuvants, the rectal route
can provide satisfactory pharmacokinetics and acceptable local tolerance. Experiments in
animals have demonstrated the inuence of the pharmaceutical formulation of suppositories
on the rectal absorption and systemic distribution of -lactams and aminoglycosides. In
healthy volunteers and in children under treatment, similar adjuvantsmainly glyceride
mixtures or non-ionic surface agentshave increased the rectal absorption of aminopeni-
cillins, cephalosporins and macrolides. Other antibiotics, including metronidazole and co-
trimoxazole, have been investigated in respect of their potential rectal administration.
*Tel: 33-1-40-25-85-27; Fax: 33-1-42-28-99-51
1999 The British Society for Antimicrobial Chemotherapy
J AC
E. Bergogne-Brzin and A. Bryskier
Since many experimental studies of rectal drug admini-
stration are performed in animals, it is necessary to note the
differences in structure between human and animal rec-
tums. I n 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 struc-
ture 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
carbohydrates
6
but such response has not always been
discussed in studies of antibiotic administration in rats or
rabbits.
79
Drug absorption in the rectum
The mechanisms of rectal absorption of drugs are not sig-
nicantly different from those in the upper part of the gas-
trointestinal tract. The rectal absorption of sulphonamides
with perfusion techniques has been studied in rats;
7
these
authors and some others
2,3
have concluded that, after rectal
administration, passive transport is the main mechanism of
absorption, that the absorption is mainly dependent on the
molecular weight, liposolubility and degree of ionization of
molecules, and that basic drugs are absorbed faster in the
presence of anions like sodium lauryl sulphate. Hence, rec-
tal absorption of drugs is governed largely by the general
principles of transfer of antibiotics.
10
Depending on their
chemical structure, drugs may cross the rectal wall either by
absorption across the epithelial cell (transcellular) or via
the tight junctions interconnecting the mucosal cells (para-
cellular).
2
Several local host factors may inuence absorp-
tion in the rectum: the mucous layer, the variable volume of
rectal uid, the basal cell membrane, the tight junctions and
the intracellular compartments may each constitute local
barriers to drug absorption, depending on histological fac-
tors and on the molecular structure of the administered
drug. The pharmaceutical formulation, therefore, may play
a major role in the rectal absorption and consequently in
the systemic distribution and pharmacokinetics of anti-
biotics administered via suppository.
Pharmaceutics of suppository form of
antibiotics: experimental studies
Various pharmaceutical formulations are available or are
under investigation for rectal delivery of antibiotics; these
include suppositories, rectal capsules and enemas (solu-
tions and suspensions). Many adjuvants have been pro-
posed and experiments in animals have been carried out
with various preparations.
9,1113
Some agents may increase
the absorption of the administered drug by improving
mucosal permeability of poorly absorbed antibiotics, such
as aminoglycosides or parenteral cephalosporins (Table I ).
The promoting effect of sodium salts of saturated straight-
chain fatty acids on the rectal absorption of ampicillin and
of ceftizoxime has been conrmed in mice, rats, rabbits and
dogs with bioavailability rates higher in mice and rabbits
(76100%) than in dogs (28.9% and 42% for ampicillin and
ceftizoxime, respectively
14
). The fatty acid used in the latter
study and in others
9
was sodium caprate, a carboxylic acid
sodium salt, which improved the rectal absorption of
poorly absorbed drugs such as -lactams. Several other
fatty acid salts, e.g. sodium capronate, sodium caprylate
and sodium palmitate, also improved the absorption of
ampicillin but the best absorption-promoting effect was
exhibited by sodium caprate, with satisfactory bioavailabil-
ities of 71.3% and 64.2% for ampicillin and piperacillin,
respectively. I n the same study, the bioavailabilities of
cephalosporins generally ranged between 60.6% (cefo-
tiam) and 92.4% (cefazolin), with lower bioavailabilities
for cefpiramide (26.2%) and cefoperazone (27.5%). I t
seems likely that the absorption-promoting effect on -
lactams is stronger for antibiotics of smaller molecular
size.
9
As summarized in Table I , various other absorption-
promoters have been used in experiments in animals. For
example, Witepsol H-15, a saturated triglyceride, has been
used in suppositories of bacampicillin and compared with
the same formulation of ampicillin.
15
For the rectal admin-
istration of latamoxef in rats,
16
the release rates from
suppositories containing Witepsol H-15 only, or with the
addition of Tween 80 (1%), with or without diclofenac
sodium, a non-steroidal antiinammatory drug, were com-
pared. I t was shown that the latter additions signicantly
increased the rectal absorption of latamoxef, with bio-
availability as high as 72%.
Various other commercially available preparations (e.g.
glyceride mixture MGK), mainly composed of glyceryl-l-
monooctanoate, glyceryl-1,3-dioctanoate and several other
glycerides, have been assayed as absorption promoters
(Table I ).
17
Rectal infusion (over 30 min) produced more
favourable parameters than bolus administration for cefa-
zolin. Cefoxitin administered in a rectal solution including
a glyceride mixture, 3-amino-1-hydroxy-propylidene-1,1-
diphosphonate disodium salt (APD), provided a high rate
of absorption, with 85% bioavailability, thanks to the
enhancing effects of calcium-binding agents.
18
Several
other studies in animals of the suppository route of admin-
istration of aminoglycosides have used similar prepara-
tions, with triglycerides (Witepsol H-15 or H-42) for
gentamicin
11
or with medium-chain glycerides (Capmul)
for gentamicin and tobramycin rectal administration,
19
resulting in enhanced absorption of aminoglycosides which
are otherwise poorly absorbed.
Pharmacokinetics of antibiotics administered by
the rectal route in humans
A limited number of studies have been carried out in
178
Rectal route of antibiotic administration
humans to determine pharmacokinetic parameters and
bioavailability of antibiotics administered by the rectal
route. The data collected from experiments in volunteers
(generally adults) or in patients (children) receiving anti-
biotics are summarized in Table I I . Only three main classes
of antibiotic have been studied recently in respect of their
rectal absorption and distribution; these are the -lactams,
macrolides (erythromycin only) and imidazoles (tinidazole
and metronidazole). Other antibiotics have been adminis-
tered rectally but the data published for chloramphenicol
or tetracyclines, for instance, are very old (19691972) and
the usage of these drugs is, currently, very restricted.
20
-Lactams
Ampicillin and bacampicillin are the only penicillins that
have been administered to humans in the suppository form
or in the form of rectal microenemas.
2123
Maximal plasma
concentrations achieved in children after ampicillin admin-
istration 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 gures are well above
the MI C 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 I I the peak ( S.D.) plasma concen-
tration was 1.16 0.33 mg/L and 4.77 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 adju-
vants 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 bioavail -
ability of cefoxitin was signicantly increased in the pres-
ence 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 chem-
ical details of the adjuvants contained in erythromycin sup-
positories were not provided in most of the available
studies; the trade names of the preparations were Protery-
trin (Proter SpA, Milan, I taly)
26
and Neo-Bismocetina (Le
Petit).
27
Maximal serum concentrations achieved after
rectal administration varied from 0.44 0.11 to 0.78 0.07
mg/L (250 mg dose) and were 0.35 0.03 mg/L after a 150
mg dose administered to children.
28
Proterytrin and Neo-
Bismocetina formulations did not show any signicant
difference in bioavailability the highest serum levels were
0.53 0.04 and 0.49 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
0.03 mg/L 4 h after the administration, a ratio of 34.9% of
simultaneous serum concentrations.
26
I n one study
29
the relationship between age and the rec-
tal bioavailability of erythromycin was established in three
groups of children and the pharmacokinetic parameters
were compared with those after intravenous administra-
tion: the data are shown in Table I I . 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.
I n one study, the azalide, azithromycin, was adminis-
tered (500 mg) to six volunteers by the rectal route, and the
C
max
and AUC (mg/mL) obtained were compared with
those obtained after iv administration.
30
The rectal route
resulted in an extremely low C
max
(0.11 mg/L) and AUC
(0.31 mgh/L); the corresponding values for the iv route
were 3.99 mg/L and 10.00 mgh/L, respectively. The bio-
availability achieved following administration by the rectal
route was estimated as only 3.2%.
I midazoles
Serum pharmacokinetics of different dosages of metron-
idazole have been compared after tablet and suppository
administration. The results are summarized in Table I I ;
they show that that the suppositories provided signicant
absorption, with AUC
0
values not signicantly 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 bio-
availability of tinidazole was compared with that of
metronidazole and there was no signicant difference
between parameters established for both drugs adminis-
tered in the suppository form at a dosage of 1 g. The serum
pharmacokinetics for the two drugs were somewhat differ-
ent after iv administration (500 mg infusion over 20 min)
with a larger AUC
0
for tinidazole (175.8 12.7 mgh/mL)
than for metronidazole (106.9 10.7 mgh/mL). The longer
half-life and larger volume of distribution for tinidazole
supported either smaller doses or less frequent administra-
tion 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 adminis-
tration 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%
179
E. Bergogne-Brzin and A. Bryskier
180
Rectal route of antibiotic administration
181
E. Bergogne-Brzin and A. Bryskier
182
Rectal route of antibiotic administration
183
E. Bergogne-Brzin and A. Bryskier
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 sulphamethoxa-
zole 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 uconazole 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 I I , the pharmacokinetic
parameters were very similar for both oral and rectal routes
of drug administration.
37
Discussion
Although the rectal route of antibiotic administration is
less commonly used today, and then only in some countries,
it can be regarded as an important alternative way of drug
delivery in several clinical situations in which other routes
of administration are impracticable. The development of
new formulations of suppositories has resulted in improved
absorption and bioavailability of -lactams and aminogly-
cosides. The enhancing effect of Witepsol H15 (saturated
triglycerides), Tween 60, Tween 80 or various saturated
straight-chain fatty acids on the rectal absorption of anti-
biotics has been proven in animal experiments. However,
extrapolation of data obtained in experimental studies in
animals to the human situation remains questionable,
owing to differences in the doses administered and to sig-
nicant differences in intestinal structure, histology and
physiology between rodents and humans.
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 administra-
tion with similar pharmacokinetics after each route.
38
How-
ever, there is reluctance in some societies to adopt the
rectal route of administration. I n addition, there are signif-
icant side effects in some circumstances: prolonged rectal
use of some drugs has been found to induce rectal ulcera-
tion, rectal bleeding and pain.
2,3
Even the suppository base
or the enhancer may damage the rectal mucosa and cause
local inammation.
2,3,16
Further research into safer absorp-
tion-promoting agents may be necessary in order to reha-
bilitate 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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Received 9 December 1996; returned 5 March 1997; revised 6 July
1998; accepted 4 September 1998
185