PHARMACOKINETIC-PHARMACODYNAMIC RELATIONSHIPS Clin Pharmacokinet 1999 May; 36 (5): 353-373

0312-5963/99/0005-0353/$10.50/0

© Adis International Limited. All rights reserved.

Pharmacokinetics and
Pharmacodynamics of the
Nitroimidazole Antimicrobials
Kenneth C. Lamp,1,2 Collin D. Freeman,2,3 Neil E. Klutman2,4 and Melinda K. Lacy2,4
1 University of Missouri-Kansas City School of Pharmacy, Kansas City, Missouri, USA
2 Kansas City Anti-Infective Research Group, Kansas City, Missouri, USA
3 Bayer Pharmaceuticals, Department of Scientific Affairs, West Haven, Connecticut, USA
4 University of Kansas Medical Center, School of Pharmacy, Kansas City, Kansas, USA

Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353
1. Analytical Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 354
2. Mechanisms of Action and Resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355
3. Pharmacokinetics of Metronidazole . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355
3.1 Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355
3.2 Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 358
3.3 Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 360
3.4 Elimination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 360
4. Special Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361
4.1 Renal Dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361
4.2 Haemodialysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361
4.3 Continuous Ambulatory Peritoneal Dialysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 362
4.4 Liver Dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 362
4.5 Infants and Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 363
4.6 Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 363
4.7 Enteric Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 363
4.8 Critically Ill Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 364
5. Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 364
5.1 Bactericidal Effect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 364
5.2 Post-Antibiotic Effect and Concentration-Dependent Killing . . . . . . . . . . . . . . . . . . . 364
5.3 Serum Bactericidal Titres . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 364
6. Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 365
7. Other Nitroimidazoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 365
7.1 Tinidazole . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 365
7.2 Ornidazole . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 367
7.3 Secnidazole . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 369
8. Therapeutic Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 370

Abstract Metronidazole, the prototype nitroimidazole antimicrobial, was originally in-

troduced to treat Trichomonas vaginalis, but is now used for the treatment of
anaerobic and protozoal infections. The nitroimidazoles are bactericidal through
354 Lamp et al.

toxic metabolites which cause DNA strand breakage. Resistance, both clinical
and microbiological, has been described only rarely.
Metronidazole given orally is absorbed almost completely, with bioavailability
>90% for tablets; absorption is unaffected by infection. Rectal and intravaginal
absorption are 67 to 82%, and 20 to 56%, of the dose, respectively.
Metronidazole is distributed widely and has low protein binding (<20%). The
volume of distribution at steady state in adults is 0.51 to 1.1 L/kg. Metronidazole
reaches 60 to 100% of plasma concentrations in most tissues studied, including the
central nervous system, but does not reach high concentrations in placental tissue.
Metronidazole is extensively metabolised by the liver to 5 metabolites. The
hydroxy metabolite has biological activity of 30 to 65% and a longer elimination
half-life than the parent compound. The majority of metronidazole and its meta-
bolites are excreted in urine and faeces, with less than 12% excreted unchanged
in urine.
The pharmacokinetics of metronidazole are unaffected by acute or chronic
renal failure, haemodialysis, continuous ambulatory peritoneal dialysis, age,
pregnancy or enteric disease. Renal dysfunction reduces the elimination of met-
ronidazole metabolites; however, no toxicity has been documented and dosage
alterations are unnecessary. Liver disease leads to a decreased clearance of metro-
nidazole and dosage reduction is recommended.
Recent pharmacodynamic studies of metronidazole have demonstrated activ-
ity for 12 to 24 hours after administration of metronidazole 1g. The post-antibiotic
effect of metronidazole extends beyond 3 hours after the concentration falls below
the minimum inhibitory concentration (MIC). The concentration-dependent
bactericidal activity, prolonged half-life and sustained activity in plasma support
the clinical evaluation of higher doses of metronidazole given less frequently.
Metronidazole-containing regimens for Helicobacter pylori in combination
with proton pump inhibitors demonstrate higher success rates than antimicrobial
regimens alone. The pharmacokinetics of metronidazole in gastric fluid appear
contradictory to these results, since omeprazole reduces peak drug concentration
and area under the concentration-time curve for metronidazole and its hydroxy
metabolite; however, concentrations remain above the MIC.
Other members of this class include tinidazole, ornidazole and secnidazole.
They are also well absorbed and distributed after oral administration. Their only
distinguishing features are prolonged half-lives compared with metronidazole.
The choice of nitroimidazole may be influenced by the longer administration
intervals possible with other members of this class; however, metronidazole re-
mains the predominant antimicrobial for anaerobic and protozoal infections.

Metronidazole [1-(2-hydroxyethyl)-2-methyl-5- 1. Analytical Methods

nitroimidazole] is the prototype for the nitro-
imidazole class of antimicrobials. Originally intro-
duced over 25 years ago for the treatment of patients
with Trichomonas vaginalis, it has since been eval-
uated in the treatment of diverse anaerobic and gastro-
intestinal tract infections. This article reviews the
pharmacokinetics and pharmacodynamics of metro-
nidazole and related antimicrobials.
Early detection methods for measuring metroni-
dazole relied on bioassay or gas-liquid chromatog-
raphy. These methods were time consuming and
did not allow for the determination of metabolite
concentrations. Bioassay methodology was initially
developed with T. vaginalis as the indicator organ-
ism, but were quickly replaced with methods employ-

© Adis International Limited. All rights reserved. Clin Pharmacokinet 1999 May; 36 (5)
Nitroimidazole Antimicrobials
ing Clostridium species. These latter bioassays
were more accurate but were still only able to mea-
sure total bioactivity of the specimen.[1] The chem-
ical determination of the nitro group was also em-
ployed and even proposed as an aid in determining
compliance; however, this method suffered from
measuring all nitro-containing compounds and
was not accurate for evaluating the pharmacokinet-
ics of metronidazole and its metabolites.[2]
When bioassay is compared directly with high
performance liquid chromatography (HPLC), the
detected concentrations are variable. Higher values
may be detected because of the measurement of the
active metabolites and lower values have also been
seen when concentrations are above the linear
range of the bioassay.[3,4] Pharmacokinetic param-
eters calculated from bioassay results tend to give
higher elimination half-lives. HPLC has many advan-
tages over bioassay and other methods, including
ease of use, accuracy and sensitivity. The mobile
phase consists of methanol/acetonitrile/5 mmol/L
potassium dihydrogen phosphate in varying ratios.
Detection is usually accomplished at 320nm. Sam-
ple preparation was improved with the use of per-
chloric acid precipitation, although more compli-
cated extractions have also been employed.[3]
HPLC methods are able to quantify metronidazole
and its 2 major hydroxy and acetic acid metabo-
lites. The measurement of concentrations of the
acetic acid metabolite may be hampered by degra-
dation of the standards, which should be prepared
new each day.[4] HPLC is widely employed as the
method of choice for determining metronidazole
and metabolite concentrations.
2. Mechanisms of Action and
Resistance
Metronidazole and the nitroimidazoles are thought
to produce their bactericidal activity through 4
phases:[5]
(i) entry into the bacterial cell
(ii) nitro group reduction
(iii) action of the cytotoxic byproducts
(iv) production of inactive end products.
© Adis International Limited. All rights reserved.
355
Bactericidal activity appears to be dependent on
the formation of a redox intermediate metabolite
in the bacterium. This toxic metabolite may inter-
act primarily with DNA, RNA or intracellular
proteins; however, its main effect is DNA strand
breakage, inhibited repair and ultimately disrupted
transcription and cell death.[6] Additional mecha-
nisms may be present in polymicrobial infections.
The addition of facultative anaerobes such as Esch-
erichia coli to cultures of Bacteroides fragilis re-
sults in faster bactericidal activity of metronida-
zole. The mechanism may be the formation by E. coli
of a bactericidal intermediate metabolite.[7]
Both clinical and microbiological resistance
have been demonstrated with metronidazole; how-
ever, these are rare events. Therapeutic failures for
T. vaginalis vaginal infections may occur when or-
ganisms unaffected by metronidazole, such as
E. coli, Enterococcus faecalis, Proteus or Klebsi-
ella, are able to absorb metronidazole and decrease
concentrations in vaginal fluid below those that are
effective. In these situations, T. vaginalis when tested
retains full susceptibility to metronidazole.[6] Iso-
lates of B. fragilis have developed metronidazole
resistance in both in vivo and in vitro. The mecha-
nism involves decreased uptake and metabolism of
metronidazole. Resistant strains with moderate
levels of resistance [minimum inhibitory concen-
tration (MIC) 25 mg/L] may still be capable of re-
sponding to moderate doses of metronidazole.
Strains with higher levels of resistance (MIC 100
mg/L) would be unlikely to respond to typical
doses.[8]
3. Pharmacokinetics of Metronidazole
The following is a summary of the many studies
of the pharmacokinetics of metronidazole (table I).
3.1 Absorption
The absorption of metronidazole has been stud-
ied in a variety of dosage forms, for example oral
tablets, vaginal and rectal suppositories, and as a
topical gel.
Clin Pharmacokinet 1999 May; 36 (5)
356 Lamp et al.

Table I. Pharmacokinetics of metronidazole in adults

n Dose Schedule F Cmax Vss AUC t1⁄2β CL Reference
(mg) (%) (mg/L) (L/kg) (mg/L • h) (h) (L/h)a
10 250 PO S 6.95 ± 3.1 47.4 ± 16.7 10 ± 6.1 9
5 250 PO S 6.23 ± 1.1 8.2 ± 0.36 10
7 400 PO S 99 6.90 ± 0.9 0.96 ± 0.083 80 ± 6.73 8.4 ± 0.4 11
10 400 PO S 94 92 ± 32 8.3 ± 3.0 12
13 400 PO S 8.5 ± 2.3 82 ± 17 8.6 ± 1.2 13
5 400 PO S 100 ± 5 8.9 ± 1.3 0.65 ± 0.05 107 ± 10.3 7.3 ± 0.7 3.9 ± 0.44 14
8 500 PO S 99 100 ± 16 8.0 ± 1.6 15
10 500 PO S 13.8 ± 5.5 113 ± 35.5 9.7 ± 1.8 9
9 500 PO S 100 0.61 ± 0.15 159 ± 48 7.0 ± 1.1 16
5 500 PO S 11.5 ± 5.6 9.1 ± 0.54 10
9 500 PO S 111 9.0 ± 0.5 122 ± 10.3 8.9 ± 0.6 17
12 500 PO S 12.7 ± 2.0 133 ± 43.1 18
9 500 PO S 15.6 ± 0.92 142 ± 17.9 19
5 500 PO S 10.1 ± 0.9 0.60 ± 0.01 115 ± 7.8 7.4 ± 0.3 20
4 750 PO S 11.9 8.4 ± 1.5 21
11 800 PO S 98.5 ± 14 18.0 ± 3.9 0.56 ± 0.13 192 ± 30 6.6 ± 1.5 4.1 ± 0.50 22
10 1000 PO S 16.3 ± 2.4 214 ± 35.5 9.31 ± 2.2 9
10 1000 PO S 19.6 ± 3.8 0.76 ± 0.13 282 ± 75 7.8 ± 1.3 3.9 ± 0.96 23
8 2000 PO S 96 427 ± 53 7.6 ± 0.9 15
4 2000 PO S 40.6 ± 9.3 0.55 ± 0.04 621 ± 146 8.8 ± 1.1 2.9 ± 0.9 23
9 250 IV S 0.67 ± 0.14 48.4 ± 19.3 6.0 ± 1.3 6.4 ± 2.5 24
7 400 IV S 1.1 ± 0.15 81.6 ± 8.12 8.3 ± 0.4 5.2 ± 0.42 11
10 400 IV S 98 ± 22 8.3 ± 3.0 12
8 500 IV S 0.74 ± 0.10 101 ± 17.0 7.3 ± 0.9 5.0 ± 0.84 15
9 500 IV S 0.64 ± 0.14 151 ± 42 7.3 ± 1.0 16
6 500 IV S 9.4 ± 0.5 0.69 ± 0.016 107 ± 10.7 7.9 ± 0.6 4.8 ± 0.31 17
5 500 IV S 11.7 ± 0.6 0.65 ± 0.05 136 ± 16.6 7.7 ± 0.8 3.9 ± 0.44 14
11 800 IV S 0.66 ± 0.084 198 ± 25.2 6.6 ± 0.49 4.1 ± 0.50 22
9 1000 IV S 0.53 ± 0.05 257 ± 58.4 8.1 ± 1.2 3.6 ± 0.84 24
22 1500 IV S 0.51 ± 0.16 680 ± 282 9.4 ± 1.9 2.1 ± 0.9 25
8 1500 IV S 46.5 0.56 ± 0.044 506 ± 13.5 8.5 ± 1.1 3.3 ± 1.1 26
8 2000 IV S 0.74 ± 0.12 447 ± 67.0 7.7 ± 1.7 4.4 ± 0.72 15
9 2000 IV S 0.58 ± 0.08 532 ± 104 8.8 ± 1.2 3.5 ± 0.84 24
10 500 PR S 86.2b 7.94 ± 2.9 89.1 ± 24.2 10.5 ± 6.1 9
10 1000 PR S 88.5b 15.0 ± 4.8 188 ± 47.2 8.8 ± 2.2 9
11 1000 PR S 61.9 ± 16 10.1 ± 2.8 0.59 ± 0.23 152 ± 42.2 6.8 ± 2.5 4.1 ± 0.50 22
6 1000 PR S 53b 8.8 ± 1.1 130 ± 18.6 8.8 ± 0.4 17
10 2000 PR S 24.8 ± 11.3 281 ± 109 9.5 ± 3.7 9
12 37.5 IG S 0.24 ± 0.07 5.0 ± 2.67 18
6 500 IG S 25b 1.9 ± 0.2 31.0 ± 5.0 17
9 500 IG S 23b 1.9 ± 0.21 32.4 ± 38.4 19
5 500 IG S 19 ± 3 1.1 ± 0.02 0.65 ± 0.05 24.2 ± 2.3 3.9 ± 0.44 14
6 250 PO M 0.73 ± 0.09 70.6 ± 22.1 9.5 ± 2.1 3.9 ± 0.66 27
13 250 PO M 5.1 ± 1.7 0.62 ± 0.17 50.2 ± 30 5.9 ± 3.9 4.3 ± 0.9 23

© Adis International Limited. All rights reserved. Clin Pharmacokinet 1999 May; 36 (5)
Nitroimidazole Antimicrobials
Table I. Contd
n Dose Schedule F Cmax Vss
(mg) (%) (mg/L) (L/kg)
7 400 PO M 11.2 ± 1.6
13 400 PO M 13.0 ± 2.8
7 500 PO M 100 ± 23
a Normalised to a bodyweight of 70kg.
b Compared with equivalent oral doses.
AUC = area under the drug concentration-time curve; Cmax = peak plasma drug concentration; CL = total body clearance; F = bioavailability;
IG = intravaginal; IV = intravenous; M = multiple; n = number of participants; PO = oral; PR = rectal; S = single; t1⁄2β = elimination half-life;
Vss = volume of distribution at steady state.
3.1.1 Oral
The oral absorption of metronidazole is excel-
lent, with bioavailability often reported as
>90%.[9,11-13,15,16,22,26] The peak plasma drug con-
centration (Cmax) after a single dose of 500mg is
approximately 8 to 13 mg/L, with a corresponding
time to Cmax (tmax) of 0.25 to 4h.[9,10,12,17]
A suspension formulation of benzoylmetro-
nidazole, equivalent to 400mg and 2g single doses
of metronidazole, was administered to healthy
males, yielding mean peak metronidazole serum
concentrations of 4.6 mg/L (400mg dose) and 17
mg/L (2g dose) with mean tmax values of 3.2 to
5.1h. Compared with metronidazole, this formula-
tion has a 20% lower bioavailability and approxi-
mately 45% lower Cmax.[13]
Single 2g oral doses given to healthy females
yielded mean Cmax values of 40 mg/L with a tmax
of 1 to 2h; values varied depending on whether
HPLC or bioassay was used for serum concentra-
tion analysis.[29] Pregnant women in their second
trimester were administered metronidazole orally
at dosages of 250mg twice daily for 6 to 10 days
or a 1g dose given only once or twice.[30] Serum
concentrations with these doses reached peak val-
ues of 4.6 and 17.4 mg/L for the 250mg and 1g
doses, respectively.
Seven patients with known or presumed mixed
aerobic-anaerobic infections received metronidazole
as an initial intravenous loading dose of 1g followed
by 500mg every 8 hours either intravenously or
orally, with or without other antimicrobial thera-
pies.[28] Mean absorption parameters after oral ad-
© Adis International Limited. All rights reserved.
357
AUC t1⁄2β CL Reference
(mg/L • h) (h) (L/h)a
82.3 ± 12.7 8.3 ± 0.4 11
13
8.3 4.9 ± 1.7 28
ministration of metronidazole were 100% of the
intravenous parameters.
3.1.2 Rectal
Rectal administration of metronidazole 500mg
produced Cmax values of approximately 4 to 5.5 mg/L,
at tmax values ranging from 0.5 to 1h for a retention
enema to 4 to 12h for suppositories.[9,22,31,32] Metro-
nidazole absorption from the rectum has been re-
ported as being approximately 67 to 82% based upon
calculations with equivalent intravenous doses
used as a reference.[32]
3.1.3 Intravaginal
Intravaginal absorption of metronidazole displays
substantial variation depending on which vehicle
is utilised. The 0.75% metronidazole intravaginal
gel at a dose of 5g produced Cmax values of 0.2 to
0.3 mg/L with tmax values of 8.3 to 8.5h.[18] Vaginal
suppositories and inserts containing metronidazole
500mg produced Cmax values of approximately 1.1
to 1.9 mg/L with corresponding tmax values of 7.7
to 20h.[14,17,19]
Metronidazole vaginal suppositories have a bio-
availability that is approximately 20 to 25% of an oral
500mg dose; the bioavailability from a vaginal gel
was reported as being 56% when compared with a
500mg intravenous dose.[17,18]
3.1.4 Topical
Metronidazole gel 0.75% has low systemic ab-
sorption. The resulting serum concentrations in
adults with rosacea after 1g of the gel was applied
ranged from undetectable to 66 μg/L in the sub-
sequent 24 hours.[33,34]
Clin Pharmacokinet 1999 May; 36 (5)
358 Lamp et al.

Table II. Tissue and fluid penetration of metronidazole

Dose (mg/day) n Route Tissue/fluid Penetration (%)a Reference
120 1 IV CSF 70-103 35
1000 1 PO CSF 90-133 36
1000 1 PO CSF 18 37
500 16 IV Umbilical cord plasma 84 38
200 NR PO Placenta 0-20 39
400 8 PO Fallopian tube 93-97 40
1000 8 PR Fallopian tube 83-96 40
400 8 PO Uterus 90-94 40
1000 8 PR Uterus 82 40
500 10 IV Peritoneal fluid 74 41
500 5 IV Pancreatic juice 57 42
500 8 IV Pancreatic tissue 60 42
500 1 IV Pancreatic tissue 99 43
500 1 IV Pancreatic tissue 63 43
1000 12 IV Rectal muscle 94 44
1000 12 IV Colonic mucosa 76 44
1000 11 IV Colonic mucosa 42 45
1000 12 IV Adipose tissue 21 44
1000 11 IV Adipose tissue 13 45
1000 13 IV Alveolar bone 75 46
a Ratio of metronidazole concentration in sample to concentration in blood at the same time point.
CSF = cerebrospinal fluid; IV = intravenous; n = number of participants; NR = not reported; PO = oral; PR = rectal.

3.1.5 Hydroxy-Metronidazole
Peak serum concentrations of the hydroxy meta-
bolite range from 2.4 mg/L after a 500mg intrave-
nous dose to 7.6 mg/L after a 2g intravenous dose
of metronidazole.[13,15,22,32]
3.2 Distribution
The penetration and distribution of metronidazole
into assorted tissues and body fluids has been ade-
quately documented (table II). Its protein binding
is <20%.[10,21,47] The reported volumes of distribu-
tion (Vd) in various studies have ranged from 0.65
to 0.71 L/kg in newborn infants[48] to 0.51 to 1.1 L/kg
in adults.[11,15-17,20,22,24-27]
Single-dose studies with oral or intravenous
metronidazole 500mg have determined the area un-
der the serum concentration-time curve (AUC) to
be approximately 100 to 159 mg/L • h.[15-17] Oral
or intravenous doses of 1000mg generate AUCs of
214 to 257 mg/L • h, suggesting a linear relation-
ship with dose.[9,23,49] Pregnant women tend to
have AUCs that also fall into this range,[30] but chil-
dren and infants may have higher AUCs depending
on the dose utilised.[13,32,50]
A study in 54 Asian patients undergoing surgery
who received metronidazole 500mg intravenously
every 8 hours demonstrated mean peak and Vd values
that were consistent with values reported in other
studies.[51]
The pharmacologically active hydroxy metabo-
lite of metronidazole has AUC values of 42 to 50
mg/L • h after an oral 400mg dose of metronidazole,
40.8 mg/L • h after 250mg intravenously and up to
239 mg/L • h after 2g intravenously.[13,15,24,32]
3.2.1 Polymorphonuclear Leucocytes
The concentration of metronidazole in polymor-
phonuclear leucocytes has been demonstrated to be
equal to the concentration found in extracellular
fluid.[52]
3.2.2 Central Nervous System
Metronidazole has generally been reported to
have good penetration into the cerebrospinal fluid
(CSF) and central nervous system (CNS). A patient

© Adis International Limited. All rights reserved. Clin Pharmacokinet 1999 May; 36 (5)
Nitroimidazole Antimicrobials
with Fusobacterium meningitis had CSF concen-
trations of 13.9 and 11 mg/L with concurrent serum
concentrations of 15.4 and 8.3 mg/L at 2 and 8
hours, respectively, after administration of oral
500mg doses twice daily.[36] Another case report
by Soriano et al.[53] reported a CSF concentration
of 23.8 mg/L on the 14th day of treatment with
metronidazole 500mg every 6 hours, but no con-
comitant serum concentration was reported. Feld-
man[54] reported an infant patient weighing 2kg
with B. fragilis ventriculitis and meningitis who
received oral metronidazole 15 mg/kg twice daily.
This patient had ventricular fluid concentrations of
15 mg/L at 2 hours and 18mg/L at 2.5 hours after
the dose, but again concurrent serum concentra-
tions were not obtained. A similar case report, by
Warner et al.,[35] involved treatment of a 1.16kg
premature infant with metronidazole 40mg intra-
venously every 8 hours, giving ventricular CSF
concentrations of 56.7 to 71.5 mg/L with serum
concentrations ranging from 69.7 to 84.1 mg/L over
the same 4-hour time period.
Davies[37] administered metronidazole 1g orally
every 6 hours to 3 patients with neurosyphilis. One
patient had a CSF concentration of 80.4 mg/L ob-
tained approximately 2.5 hours after the fifth dose,
with serum concentrations that ranged from 15 to
72 mg/L.
Metronidazole penetration into CNS abscesses
has been reported by George and Bint.[55] They ob-
tained a pus concentration of 42 mg/L in a 3-year-
old patient receiving oral metronidazole 8 mg/kg 4
times daily. Ingham and colleagues[56] obtained metro-
nidazole concentrations of 21 to 45 mg/L from ce-
rebral abscesses in 3 patients who received metro-
nidazole 400 to 600mg orally or intravenously
every 8 hours.
3.2.3 Placenta
16 pregnant women about to undergo caesarean
sections received a single intravenous dose of met-
ronidazole 500mg.[38] Arterial cord blood concen-
trations at the time of caesarean ranged from 8.9 to
16.4 mg/L, although the precise time in relation
to administration of the metronidazole was not ev-
ident. Placental tissue concentrations have been
© Adis International Limited. All rights reserved.
359
reported as being relatively low (0 to 1.4 mg/L)
compared with serum concentrations of 3 to 6.9
mg/L when obtained 4 to 5 hours after a single oral
dose.[39]
3.2.4 Pelvic Tissue and Peritoneal Fluid
Elder and Kane[40] studied the concentrations of
metronidazole administered as single 400mg oral
doses, or 4 × 400mg doses given every 8 hours, in
30 women who required hysterectomies for benign
conditions. Serum and tissue samples from the fal-
lopian tubes and uterus were obtained at approxi-
mately 3 to 4 hours after administration. In the sin-
gle-dose regimen, the concentrations in the uterus
and fallopian tubes were 94 and 97.3% of serum
concentrations, respectively. The multiple oral
doses resulted in 90.1 and 92.7% penetration into
the uterus and fallopian tubes, respectively.
30 women undergoing laparoscopy received
metronidazole 500mg intravenously as part of a
prophylaxis regimen.[41] The average time elapsed
from infusion of metronidazole until simultaneous
sampling of peritoneal fluid and blood was 55 min-
utes. Serum concentrations at this time averaged
10.7 mg/L and the peritoneal fluid concentration
was 7.2 mg/L.
3.2.5 Pancreas
The median pancreatic tissue concentration in 8
patients with either chronic pancreatitis or pancre-
atic carcinoma who received metronidazole 500mg
intravenously prior to laparotomy was 5.1 mg/L.[42]
In 5 patients, the median concentration in pancre-
atic juice was 8.5 mg/L. 12 patients with necrotis-
ing pancreatitis had serum and necrotic tissue sam-
ples obtained to determine tissue penetration.[43]
The penetration of metronidazole was 99%, with a
concentration of 8.4 μg/g of tissue.
3.2.6 Colorectal Tissue
12 patients undergoing colorectal surgery re-
ceived metronidazole 1g intravenously for prophy-
laxis.[44] Tissue sampling of rectus abdominus
muscle and colonic mucosa at the time of intestinal
resection and at abdominal wound closure revealed
metronidazole median tissue : serum concentra-
tion ratios of 0.94 and 0.76, respectively. Another
Clin Pharmacokinet 1999 May; 36 (5)
360
study involving 11 patients undergoing elective
colorectal surgery also administered metronidazole
1g intravenously for prophylaxis.[45] At a mean
time of 38 minutes following administration, the
abdominal wall fat-to-serum ratio was 0.1 and for
epiploic fat was 0.08. Anastomosis occurred at a
mean time of 156 minutes following administration
and resulted in a mean concentration of 8.9 mg/kg
in colonic wall tissue.
17 patients undergoing colorectal surgery re-
ceived 1.5g of metronidazole intravenously and
had serum samples taken from 0.17 to 72 hours
after infusion, and tissue samples (colon, perito-
neum, ileum, muscle, omentum, appendix and sub-
cutaneous fat) taken from 0.5 to 4.5 hours after
infusion.[57] Concentrations of metronidazole and
the hydroxy metabolite were assayed from these
samples. The mean concentration of metronidazole
in the various tissues was in the 10 to 30 mg/g [sic]
range. For the hydroxy metabolite the concentra-
tions were <5 mg/g [sic], although there was consid-
erable variability for both the parent compound and
the metabolite.
3.2.7 Alveolar Bone
A series of 13 patients undergoing the removal
of impacted mandibular third molar teeth were
given rectal metronidazole 1g suppositories 3 hours
prior to extraction.[46] Molar tooth concentrations
taken at the time of extraction were 75% of those
found in plasma.
3.2.8 Saliva and Gingival Fluid
Van Oosten et al.[58] administered metronida-
zole 750mg orally to 4 healthy volunteers to mea-
sure concentrations in saliva and gingival crevice
fluid. Plasma Cmax, as measured by bioassay,
ranged from 8.7 to 18.4 mg/L, whereas Cmax for
gingival crevice fluid and saliva ranged from 10.5
to 41.3 and from 11.3 to 13.8 mg/L, respectively.
Overall, concentrations appeared to be similar be-
tween the 3 body fluids.
3.3 Metabolism
Metronidazole is metabolised by the liver into 5
metabolites. The hydroxy metabolite, 1-(2-hydroxy-
© Adis International Limited. All rights reserved.
Lamp et al.
ethyl)-2-hydroxy methyl-5-nitroimidazole, is clin-
ically significant with antimicrobial activity approx-
imately 30 to 65% that of metronidazole.[59-62] The
acid metabolite, 1-acetic acid-2-methyl-5-nitro-
imidazole, has only 5% of the activity of the parent
drug and is only detectable in patients with renal
dysfunction.[61] Glucuronide and sulphate conjugates
and an oxidation product of the hydroxy metabolite
have also been detected.[63]
3.4 Elimination
Experiments utilising 14C-labelled metronida-
zole demonstrate that the majority of metronida-
zole and its metabolites is eliminated in urine. Ap-
proximately 77 and 14% of the dose was collected
in urine and faeces, respectively, over 5 days.[21]
Unchanged metronidazole in urine represents only
7 to 12% of the dose.[3,9,16] The total of metronida-
zole and metabolites (as measured by chromato-
graphic methods) excreted in urine averages 33 to
44% of the dose.[3,13,16] The hydroxy metabolite
contributes 14 to 24.1% of the total administered
dose excreted in urine, and the acid metabolite ac-
counts for 9.6 to 12%.[3,13] The radioactivity unac-
counted for in urine probably represents metabo-
lites not identified by HPLC assay techniques.
The total clearance (CL) of metronidazole from
serum has been reported to range from 2.1 to 6.4
L/h/kg bodyweight (table I).[11,14,15,17,22-28] Metro-
nidazole appears to exhibit dose-dependent clear-
ance at doses ranging from 250 to 2000mg.[24,51]
The elimination half-life (t1⁄2β) for metronidazole
ranges from 6 to 10h,[22,24] with most studies re-
porting values in the 8h range (table I). On the basis
of the log-linear pharmacokinetic properties of
metronidazole, Loft and colleagues[64] calculated
the CL of metronidazole as dose divided by AUC
and also determined that the CL of metronidazole
could be determined from a single plasma sample
using the dose and an estimated Vd.
Thiercelin et al.[65] noted that metronidazole
500mg orally every 8 hours resulted in steady-state
AUC (AUCss) values 51% higher than the same
dosage administered intravenously, even though
the t1⁄2β (6h) was virtually the same for both routes,
Clin Pharmacokinet 1999 May; 36 (5)
Nitroimidazole Antimicrobials
a phenomenon also observed in a study by Mattila
et al.[17] Thiercelin et al.[65] noted that, excluding
other possibilities, for AUCss,PO/AUCss,IV to be
greater than 1, CL must have diminished when
switching from oral to intravenous administration.
Two proposed hypotheses by the authors that may
explain this phenomenon were: (i) metronidazole
inhibits its own metabolism by gut microsomal
mono-oxygenases; or (ii) oral administration leads
to excessive glucuronidation with resulting entero-
hepatic recirculation.
The t1⁄2β of the hydroxy metabolite is longer than
that of metronidazole, and ranges from 8.5 to 19.2h
in patients with normal renal function, with most
studies reporting values of 11 to 13h.[22,24-26,57,66]
4. Special Populations
4.1 Renal Dysfunction
Several investigations have been published on
the effect of reduced renal function on the disposi-
tion of metronidazole and its metabolites. In 1
study, 6 patients, 23 to 75 years of age, with acute
renal failure [creatinine clearance (CLCR) ≤0.6 L/h
(10 ml/min)] received either metronidazole 500mg
intravenously over 30 minutes as a single dose or
as a multiple dose twice daily for 4 days or longer.
The Vd was 0.65 L/kg, t1⁄2β was 9.5h, and total
plasma clearance and nonrenal clearance were 3.3
and 3.2 L/h, respectively. The hydroxy metabolite
reached an average steady-state concentration
(Css) of 17.4 mg/L while the acetic acid metabolite
only reached a Css of 1.2 mg/L.[67]
A single intravenous dose of metronidazole
500mg was given to 29 patients with CLCR values
less than 3 L/h (50 ml/min). None of the pharmaco-
kinetic parameters of metronidazole were changed
when compared with a previous group of healthy
volunteers except for renal clearance, which de-
creased from 0.41 L/h to 0.14 to 0.16 L/h. The
hydroxy and acetic acid metabolites reached higher
concentrations in the patients with reduced renal
function, but this would not significantly alter the
combined biological activity of metronidazole and
metabolites.[68]
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361
A further study was conducted in 10 healthy
volunteers and 24 patients with CLCR of 0 to 3.9
L/h (0 to 65 ml/min). They received a single intra-
venous dose of metronidazole 500mg over 30 min-
utes. Half-life, Vd and total body clearance for
metronidazole were not affected by renal dysfunc-
tion. The metabolite : metronidazole ratios for both
metabolites were increased with decreasing renal
function secondary to decreased renal clearance of
metabolites. The acetic acid metabolite was more
dependent on renal clearance than the hydroxy me-
tabolite; however, clearance was not measured di-
rectly for the metabolites. The Cmax for the hydroxy
metabolite in patients with renal failure was re-
duced compared with healthy volunteers, 4.3 ver-
sus 6.1 mg/L. The t1⁄2β was also prolonged for the
hydroxy metabolite from 18 to 32.3h. The AUC of
the acetic acid metabolite was increased with de-
creasing renal function from 15.7 mg/L • h [CLCR
of 0.6 to 1.8 L/h (10 to 30 ml/min)] to 51 mg/L • h
[CLCR <0.6 L/h (<10 ml/min)]. The t1⁄2β increased
from 22.3 to 28.4h for the same change in CLCR.[69]
The pharmacokinetics of metronidazole are not
significantly affected by alterations in renal func-
tion. The accumulation of metabolites has led to
recommendations of monitoring metabolite con-
centrations for patients with CLCR <1.8 L/h (<30
ml/min) and avoiding metronidazole when CLCR is
<0.6 L/h (<10 ml/min).[69] The metabolites have
not shown toxicity when administered in large
doses to animals.[68]
4.2 Haemodialysis
The influence of haemodialysis has also been
evaluated for metronidazole and its metabolites.
Metronidazole 500mg was administered intrave-
nously to 5 volunteers with normal renal function,
4 patients with renal failure and 5 patients requiring
haemodialysis. The pharmacokinetic parameters
were not altered by the presence of renal failure.
The mean t1⁄2β, Vss and CL were 6.57h, 1.29 L/kg
and 11.02 L/h for the normal group; 6.13h, 1.38 L/kg
and 9.10 L/h for the renal failure group not receiv-
ing dialysis; and 6.8h, 1.44 L/kg and 11.02 L/h for
the dialysis group, respectively. Metabolite concen-
Clin Pharmacokinet 1999 May; 36 (5)
362
trations increased 3-fold in the group with renal
failure. Researchers noted that clearance through
cuprophan dialyser membranes was faster than
through polyacrylamide membranes for metroni-
dazole (5.1 versus 2.8 L/h) and the hydroxy meta-
bolite (5.2 versus 3.3 L/h). An 8-hour dialysis ses-
sion was estimated to remove 50% of a dose of
metronidazole; however, the resulting serum con-
centration at the end of a 12-hour dose interval
would still be above the MIC for many anaerobic
isolates. These investigators recommended that a
dosage reduction may be necessary because of the
potential accumulation of metabolites.[70]
To further study of the influence of dialyser
membrane type, regenerated cellulose and cuprophan
dialyser membranes were used in 9 patients with
renal failure. Metronidazole 500 to 750mg was
given either intravenously or orally to reach thera-
peutic concentrations. The regenerated cellulose
membrane attained a higher clearance than the cupro-
phan membrane (6.36 versus 4.32 L/h, p < 0.001).
A similar difference was noted for the hydroxy me-
tabolite. Haemodialysis over 4 hours was estimated
to remove 24 to 35% of the total body stores of
metronidazole and supplementation might be needed
in seriously ill patients undergoing dialysis with
high-clearance membranes.[71]
4.3 Continuous Ambulatory
Peritoneal Dialysis
5 patients receiving continuous or intermittent
peritoneal dialysis (CAPD) received a single intra-
venous dose of metronidazole 500mg. Peritoneal
dialysis was begun 1 hour later and concentrations
were measured for 6 hours. The t1⁄2β and Vd were
5.6h and 39L, respectively, which were similar to
values obtained in individuals with normal renal
function. Peritoneal dialysis clearance (0.96 L/h)
was approximately 20% of total body clearance
(4.8 L/h). Although no information was presented
on metabolite clearance, the authors did not recom-
mend a change in dosage.[72]
A study of 5 CAPD and 5 haemodialysis patients
provides data on both metronidazole and its meta-
bolites. All patients received metronidazole 750mg
© Adis International Limited. All rights reserved.
Lamp et al.
as a single intravenous dose. Patients on haemo-
dialysis served as the control group, receiving met-
ronidazole on nondialysis days. Peritoneal dialysis
contributed less than 9% of total body clearance of
metronidazole or its metabolites. The t1⁄2β and Vd
were not different between the 2 groups. The authors
recommended that metronidazole dosage alter-
ations would not be required unless metabolite ac-
cumulation is shown to lead to toxicity.[73]
4.4 Liver Dysfunction
On the basis of the extensive metabolism of met-
ronidazole, liver disease would be expected to have
a profound effect on its pharmacokinetics. A small
study compared 6 patients with histologically con-
firmed cirrhosis with 5 healthy individuals. After a
single oral dose of 500mg, concentrations of met-
ronidazole and the hydroxy metabolite were as-
sessed for 24 hours. Although the t1⁄2β increased
from 7.4 to 10.8h, Vd increased from 0.6 to 0.74
L/kg and plasma clearance increased slightly from
4.45 to 4.83 L/h/70kg, no significant differences
were found. The AUC of the hydroxy metabolite
was unchanged.[20]
Another small study of 9 patients with cirrhosis
and encephalopathy compared the disposition of
metronidazole 500mg intravenously over 20 min-
utes with that in healthy individuals. Vd was not
changed by the presence of cirrhosis and encephalo-
pathy; however, the t1⁄2β was increased from 7.3 to
20h (p < 0.001). Total body clearance of metroni-
dazole was reduced from 4.98 to 1.74 L/h (p < 0.001)
and the renal clearance of the hydroxy metabolite
was decreased from 2.68 to 0.82 L/h (p < 0.001).
The tmax for the hydroxy metabolite was prolonged
compared with controls, but the increased AUC (65
to 113 mg/L • h) failed to reach statistical signifi-
cance. Metronidazole 500mg intravenously every
24 hours for 6 days in a subgroup of 3 patients pro-
duced trough metronidazole concentrations ranging
from 4.3 to 9.5 mg/L, which should be above the
MIC90 for most anaerobic species.[74]
A study of 8 patients with alcoholic liver disease
with or without cirrhosis demonstrated increased
metronidazole t1⁄2β (18.3h), Vd (0.77 L/kg) and de-
Clin Pharmacokinet 1999 May; 36 (5)
Nitroimidazole Antimicrobials
creased total body clearance (2.14 L/h/70kg) com-
pared with literature values for healthy controls.
The authors estimated that a dose of 500mg every
12 hours would produce metronidazole serum con-
centrations >15 mg/L, substantially higher than the
MIC90.[75]
The Child-Pugh criteria for grading patients
with cirrhosis are capable of predicting the phar-
macokinetics of metronidazole. 7 healthy volunteers
and 35 patients with cirrhosis received a single intra-
venous dose of metronidazole 500mg over 20 min-
utes. The t1⁄2β increased from 7.4h in the control
group to 10.7, 13.5 and 21.5h in patients in Child-
Pugh class A, B and C, respectively. Metronidazole
clearance was decreased from 6.43 L/h/70kg in the
control group to 3.57, 3.32 and 2.35 L/h/70kg in
Child-Pugh class A, B and C, respectively. The Vd
of metronidazole and the AUC24h of the hydroxy
metabolite were not altered.[76]
Two studies have evaluated the influence of schis-
tosomiasis and found disparate results. The larger
study[76] found that the CL of metronidazole was
reduced from 6.43 to 3.91 L/h/70kg and the t1⁄2β
prolonged from 7.4 to 10.2h compared with the
control group, whereas the other found no differ-
ence.[20,76] No dosage adjustment appears neces-
sary for patients with schistosomiasis.
4.5 Infants and Children
Metronidazole, at a dosage of approximately 10
to 20 mg/kg, was administered orally twice daily
to 20 paediatric patients being treated for tricho-
monal or anaerobic infections. Serum concentra-
tions were measured for 24 hours after a dose using
a polarographic method which does not discrimi-
nate between parent drug and metabolites. Given
these limitations, the authors found no differences
in any parameter between children and adults. One
infant was studied at 6 weeks of age and a slightly
higher t1⁄2β (10.7 versus 8.3h) and Vd (0.87 versus
0.76 L/kg) were noted, although within the range
seen in adults. Clearance values were similar when
adjusted for bodyweight, at 3.95 versus 4.49
L/h/70kg.[50]
© Adis International Limited. All rights reserved.
363
Although metronidazole pharmacokinetics are
not altered in healthy children, severe malnutrition
does change these parameters. A group of 10 chil-
dren with severe protein malnutrition were com-
pared with 10 children recovered from severe mal-
nutrition. Metronidazole was given as a single oral
dose of 30 mg/kg. Clearance was reduced in chil-
dren with severe malnutrition (0.094 versus 0.187
L/kg/h, p < 0.01) and t1⁄2β was longer (11.73 versus
5.68h, p < 0.01).[77] The authors recommended
strict monitoring of serum concentrations and in-
dividualised dosage regimens, although no specific
serum concentrations were proposed.
4.6 Pregnancy
Following the administration of either 250mg or
1g of metronidazole to pregnant and nonpregnant
women, no significant differences in pharmacokinet-
ics have been seen and thus no dosage changes are
needed.[30]
4.7 Enteric Disease
The pharmacokinetics of metronidazole were
evaluated in 12 patients with either Crohn’s disease
or ulcerative colitis. Metronidazole 400mg was given
orally or intravenously over 20 minutes. The bio-
availability was very good in both patient groups,
90% in the patients with ulcerative colitis and 97%
in those with Crohn’s disease. There were no differ-
ences in t1⁄2β, Vd or plasma clearance between the
groups and the values were consistent with those
reported in healthy volunteers.[78]
Another study evaluated the influence of ulcer-
ative colitis, Crohn’s disease, jejunoileal shunt, ile-
ostomy and coeliac disease on metronidazole.
Only the ileostomy patients demonstrated any dif-
ferences compared with healthy controls. Half-life
was increased to 11.9h compared with 8.3h in the
control group and clearance decreased to 1.94 L/h
compared with 5.43 L/h. The authors recommended
that metronidazole be administered at two-thirds
of the normal dose in ileostomy patients.[79]
Clin Pharmacokinet 1999 May; 36 (5)
364
4.8 Critically Ill Patients
14 critically ill patients with renal or liver dys-
function received metronidazole 500mg intrave-
nously every 6 to 8 hours for the treatment of sus-
pected or proven anaerobic infections. The patients
were divided into different groups based on renal
and liver function. The small size of this study and
variability of results precluded any direct statistical
comparison. In patients with normal liver function,
those with CLCR <0.9 L/h (<15 ml/min) had longer
t1⁄2β (12.3 versus 6.73h) and decreased clearance
(3.26 versus 4.54 L/h/70kg) compared with those
with CLCR >1.8 L/h (>30 ml/min). The presence of
obstructive liver disease produced longer metroni-
dazole t1⁄2β (9.15 to 20.1h) than hepatocellular liver
disease (8.6 to 12.1h). The longest t1⁄2β values were
seen in patients with both renal and liver dysfunc-
tion. Metabolite concentrations were predictably
higher in patients with renal dysfunction. This
study had a small number of patients and, there-
fore, no firm recommendations can be made on the
proper dosage of metronidazole in this popula-
tion.[80]
5. Pharmacodynamics
5.1 Bactericidal Effect
Metronidazole appears to have an extremely
rapid rate of killing against susceptible anaer-
obes.[81,82] Time-kill kinetic studies of ciprofloxacin
alone (concentration 0.5 mg/L; MIC 0.25 mg/L)
compared with a combination of ciprofloxacin with
metronidazole (10 and 40 mg/L) displayed more
rapid killing with the combined antimicrobials
against C. perfringens, with undetectable C. per-
fringens colony-forming units (CFU) at 1.5 to 2
hours post-exposure compared with 24 hours with
metronidazole alone.[83]
Treatment of mixed aerobic-anaerobic infections,
such as intra-abdominal infections, has yielded
excellent results in terms of bacterial eradication
when an anti-anaerobic agent such as metronida-
zole was included as part of the therapeutic regi-
men.[28,84]
© Adis International Limited. All rights reserved.
Lamp et al.
5.2 Post-Antibiotic Effect and
Concentration-Dependent Killing
Like aminoglycosides and fluoroquinolones,
metronidazole also appears to exhibit a concentra-
tion-dependent killing effect against anaerobes and
has a post-antibiotic effect (PAE) for more than 3
hours.[85]
Nix et al.[86] discovered that metronidazole had
a concentration-dependent killing effect against
T. vaginalis under anaerobic conditions at concen-
trations that ranged from 0.1 to >8 mg/L. If this
concentration-dependent effect truly exists for
metronidazole it would suggest that in general the
optimal dosage strategy for metronidazole against
organisms like T. vaginalis and B. fragilis would
be to give higher doses less frequently, rather then
smaller doses more frequently, similar to the use of
aminoglycosides and fluoroquinolones against
susceptible Gram-negative aerobic bacteria.[87]
5.3 Serum Bactericidal Titres
Serum bactericidal titres (SBTs), a susceptibil-
ity method of determining bactericidal activity of
antimicrobials which uses human serum instead of
broth growth media, have been used in studies as
an ex vivo method of assessing the effect of metro-
nidazole on anaerobes, primarily B. fragilis. Re-
sults from an SBT study reported a median metro-
nidazole SBT of 1 : 2 against various Bacteroides
species at 0.5, 1 and 6 hours after administration of
a single dose of metronidazole 500mg intrave-
nously.[88] Results with metronidazole against 2
strains of B. fragilis at the 6-hour time-point were
<1 : 2, but titres related to Fusobacterium, Pep-
tostreptococcus and Eubacterium lentum were all
>1 : 8 at all time-points.
Fluoroquinolones have often been studied for
use in combination with metronidazole for antibac-
terial activity against Gram-negative aerobes and
anaerobes.[89,90] Boeckh et al.[90] studied the effect
of fluoroquinolones (ofloxacin, ciprofloxacin, en-
oxacin and fleroxacin) in combination with anti-
anaerobic antimicrobials, including metronidazole,
by determining SBTs. SBT assays were performed
Clin Pharmacokinet 1999 May; 36 (5)
Nitroimidazole Antimicrobials
from serum samples obtained at 1, 2, 6 and 8 hours,
depending upon the antimicrobial combination,
against various Gram-positive and Gram-negative
aerobic pathogens, as well as strains of B. fragilis
and B. thetaiotaomicron. None of the combinations
appeared to interfere with the antibacterial activity
of the individual antimicrobials, and mean SBTs
for the ciprofloxacin/metronidazole, ofloxacin/metro-
nidazole, enoxacin/metronidazole and fleroxacin/
metronidazole combination were all in the 1 : 2 to
1 : 4 dilution range for the various strains and spe-
cies of Bacteroides. Similarly, Pefanis et al.[91] es-
tablished the effectiveness of fleroxacin plus met-
ronidazole in eradicating mixed aerobic-anaerobic
Gram-negative pathogens from experimentally in-
duced abscesses in a rat model based upon reduced
CFU counts.
SBT studies involving the combination of met-
ronidazole 1g with extended-spectrum cephalospo-
rins have also yielded results in the 1 : 4 to 1 : 8 range
for B. fragilis at the end of 12 or 24 hours for
ceftizoxime or ceftriaxone, respectively.[92-94]
6. Drug Interactions
Metronidazole is characterised by a low incidence
of drug interactions. Its well-known propensity to
cause disulfiram-like reactions when administered
with alcohol (ethanol) and other drug interaction
studies have been reviewed extensively.[49,63]
More recent studies have focused on under-
standing the synergistic effect of proton pump in-
hibitors and antimicrobial regimens, including
metronidazole, in the treatment of H. pylori infec-
tions. Several studies have been undertaken to
evaluate the effect of omeprazole on the pharmaco-
kinetics of metronidazole in plasma and gastric
juice. 24 healthy men received metronidazole
400mg intravenously as a single dose while taking
placebo or omeprazole. Omeprazole had no influence
on the plasma pharmacokinetics of metronidazole.
However, metronidazole AUC4h in gastric juice was
reduced from 120.3 to 29.6 mg/L • h (p = 0.001)
and Cmax in gastric juice was decreased from 33.6
to 8.3 mg/L (p = 0.0001).[95]
© Adis International Limited. All rights reserved.
365
A similarly designed study was also carried out
in 8 volunteers receiving metronidazole 400mg
intravenously both with and without omeprazole.
Omeprazole significantly reduced the AUC and
Cmax of both metronidazole and its hydroxy meta-
bolite in gastric juice.[96] These results are consis-
tent with the theory that low pH ionises metroni-
dazole and the hydroxy metabolite, leading to high
concentrations in gastric fluid that are reduced
when gastric pH is lowered by omeprazole. How-
ever, in both these studies the concentrations of the
antimicrobial remained above the MIC for H. py-
lori.
7. Other Nitroimidazoles
7.1 Tinidazole
Tinidazole, 1-[2-(ethylsulphonyl)ethyl]-2-methyl-
5-nitroimidazole, is another member of the 5-nitro-
imidazole class of antimicrobial agents with
amoebicidal, giardiacidal, trichomonicidal and an-
aerobic activity. Tinidazole is used most frequently
for giardiasis, nonspecific vaginitis and urogenital
trichomoniasis. As with others in the class, chem-
ical substitutions at side chains result in class dif-
ferences in pharmacokinetics and antimicrobial ac-
tivity.[97] Most published studies requiring analysis
have utilised HPLC or bioassay.[17,25,26,60,98-107]
Analysis of tinidazole concentrations in numerous
tissues and serum by both methods have been re-
ported.
Very few studies have focused on the mode of
action of tinidazole.[107] The proposed mechanism
is similar to metronidazole. Generally, the drug dif-
fuses into the organism, is reduced to intermediates
which cause cytotoxicity, probably damage DNA,
and, therefore, prevent further DNA synthesis.
The pharmacokinetics of tinidazole were docu-
mented in the early 1980s.[17,25,26,57,98-106] Other
than the initial phase I studies, most pharmaco-
kinetic studies involved either surgical prophylaxis
or mixed anaerobic infections. The pharmaco-
kinetic studies are summarised in table III.
The absorption of tinidazole has been studied
using oral tablets at various doses and following
Clin Pharmacokinet 1999 May; 36 (5)
366 Lamp et al.

Table III. Pharmacokinetics of tinidazole

Dose n Schedule F Cmax Vss AUC t1⁄2β CL Reference
(mg) (%) (mg/L) (L/kg) (mg/L • h) (h) (L/h)
500 PO 22 S 7.5 17
2000 PO 23 S 36.7 863 HV 15.6 HV 98
50.8 RF 1370 RF 18.4 RF 4.27 HD
500 IV 22 S 10.1 57L 175.8 14.0-14.7 2.42-2.86 17
800 IV 16 S 15.3 14 98
800 IV 23 S 14.9 0.8 363 HV 17.1 HV 2.27 HV 99
25.5 RF 0.69 RF 435 RF 16.9 RF 1.85 RF
800 IV 2 S 15.9 0.74 11.6 3.15 101
1500 IV 22 S 40 41.3L 847.5 17.6 1.6 25
1600 IV 16 S 32 13.2 98
1600 IV 8 S 38.1 38.8L 810 14.2 NR 26
1600 IV 5 S 8.7-13.1 100
1000 PR 22 S 7.9 17
500 IG 22 S 1.0 17
500 PO 6 S, M 99 (80-129) 11.9 S 0.65 134.1 IV 12-13 2.34 IV 102
5 mg/kg IV 12.5 M 102
2000 PO 21 S, M 36.2 56.3L 897 17.0 2.3 (2g) 103
250 q12h
AUC = area under the concentration-time curve; CL = total body clearance; Cmax = peak plasma drug concentration; F = bioavailability;
HD = haemodialysis; HV = healthy volunteers; IG = intravaginal; IV = intravenous; M = multiple; n = number of participants; NR = not
reported; PO = oral; PR = rectal; q12h = every 12 hours; RF = renal failure; S = single; t1⁄2β = elimination half-life; Vss = volume of distribution
at steady state.

vaginal and rectal administration.[17,99,102,103] Oral
absorption is excellent, with bioavailability often
reported as >90% relative to intravenous, and has
even been reported as >100% as a result of its entero-
hepatic circulation (90 to 108%).[102] Cmax after
oral doses of 2g occurs around 2 hours after admin-
istration, reaching concentrations between 40 and
58 mg/L.[17,99,102,103] Concentrations fall to 10 mg/L
at 24 hours and to 2.5 mg/L at 48 hours. Trough
concentrations are 8 mg/L with repeated daily doses
of 1g. Compared with metronidazole, the concen-
trations are approximately doubled and persist
longer because of the longer t1⁄2β of 12 to 14h. Serum
Cmax values following rectal administration of 1g
and intravaginal 500mg suppositories were 7.9 and
1 mg/L, respectively.[17]
Tinidazole is about 12% protein bound and dif-
fuses into most tissues.[107] Concentrations were
proportionately higher with increased doses.[98]
Tissue concentrations have been determined for
CSF, abdominal sites (bile, intestinal mucosa and
peritoneal), gynaecological sites (vaginal secre-
tions, uterine and fallopian tube), dental bone and
saliva. Most tissue site concentrations are similar
to the corresponding blood concentrations. CSF pen-
etration is excellent (30 mg/L versus blood of 38
mg/L) even without inflamed meninges.[108]
The Cmax values in blisters (36.2 versus 29.1
mg/L) were comparable with serum but the tmax was
longer (6 versus 2h).[103] Tinidazole was minimally
detectable in breast milk in some patients at 72 hours
following a single dose of 1600mg intravenously.[100]
A single intravenous infusion of 500mg resulted in
detectable concentrations of 13.2 mg/L in maternal
venous blood, 4.9 mg/g in placenta tissue and 7.6
mg/g in aborted fetus tissue.[106]
The metabolism and elimination of tinidazole in
humans is not totally clarified. In humans, around
37% of an intravenous dose is recovered in the
urine with 25% as unchanged drug, and 2% as the
2-hydroxymethyl metabolite and its glucuronide
conjugate. The t1⁄2β is around 12 to 13h in healthy
volunteers following a 2g oral dose. intravenous

© Adis International Limited. All rights reserved. Clin Pharmacokinet 1999 May; 36 (5)
Nitroimidazole Antimicrobials
doses of 800 to 1600mg in healthy individuals re-
sulted in t1⁄2β values of 12 to 14h.[108]
No studies examining the concentration-depend-
ent killing activities of tinidazole have been pub-
lished. It is reasonable to assume that the pharmaco-
dynamics of tinidazole would be similar to those
of metronidazole. Based on normal dosage re-
gimens, concentrations at most sites of infection
would exceed the MIC of susceptible organisms.
The active hydroxymethyl metabolite of tinidazole
has insignificant antimicrobial activity because of
very low serum concentrations.[107,109]
Tinidazole is bactericidal against Gram-negative
and -positive anaerobes at concentrations 1- to 2-fold
above the MIC.[107] Most mimimum bactericidal
concentrations (MBCs) determined for B. fragilis
are the same or 1 dilution above the MIC. Some
Bacteroides sp. have MBCs 2- to 3-fold greater than
the MIC. Tinidazole is relatively more active against
anaerobes, on the basis of the MIC90 values for
B. fragilis (0.5 to 3 mg/L), Fusobacterium (0.4 to
4 mg/L) and C. perfringens (0.5 to 1 mg/L) than
for B. melaninogenicus (12 to 16 mg/L) and Pepto-
streptococcus sp. (0.8 to 25 mg/L).
The pharmacokinetics of tinidazole have been
documented in patients with renal failure and in
patients on haemodialysis (table III).[102] After
800mg oral or intravenous doses, serum concentra-
tions in healthy volunteers were compared with
those in male and female patients on haemodialysis
or with reduced renal function. Haemodialysis pa-
tients received a dose of 2g. The t1⁄2β (17.1 versus
16.9h for intravenous or 15.6 versus 18.4h for
oral), Vd (0.8 versus 0.69 L/kg) and clearance
(2.27 versus 1.85 L/h) did not change significantly
with either patient subset or if the drug was given
orally or intravenous in healthy volunteers or in pa-
tients with renal failure. This study only evaluated
a single oral or intravenous dose. The authors sug-
gested using a normal dose following dialysis and
no adjustment for renal failure unless the patient is
expected to receive multiple doses over time. Non-
renal metabolism and elimination played a impor-
tant role in both groups of patients.
© Adis International Limited. All rights reserved.
367
There are no studies evaluating the pharmaco-
kinetics of tinidazole in CAPD or in the elderly. There
are no documented drug interactions, but they
would be expected to be similar to those of metro-
nidazole. Because of a disulfiram-like reaction, al-
cohol-containing products should be avoided for
72 hours after discontinuing tinidazole.
In summary, the pharmacokinetics of tinidazole
have been extensively studied but there is very lim-
ited pharmacodynamic information. Tinidazole is
well absorbed and has a long half-life, allowing
once daily administration with serum concentrations
exceeding the MIC90 of most of the anaerobic or-
ganisms it is used to eradicate. Dosage may need
to be adjusted for patients with decreased renal
function receiving multiple doses.
7.2 Ornidazole
Ornidazole [α-(chloromethyl)-2-methyl-5-nitro-
imidazole-1-ethanol] is structurally similar to met-
ronidazole and tinidazole. This agent is not approved
for use in the US, but is used in several European
countries including Belgium, France, Italy, Spain
and Switzerland.
Owing to its similar chemical properties, ornid-
azole shares the same mechanism of action and
spectrum of microbiological activity as other nitro-
imidazole agents against anaerobes and protozoa.
Therefore, it is used for the treatment of a variety
of clinical conditions including intestinal amoebi-
asis, amoebic liver abscesses, anaerobic infections,
Crohn’s disease, duodenal ulcers, giardiasis, surgical
prophylaxis, trichomoniasis and vaginitis.[110-112]
Heizmann and colleagues[113] have described
procedures for HPLC quantification of ornidazole
and its major metabolites, M1 and M4, in plasma,
urine, vaginal fluid and CSF.
The pharmacokinetics of oral and intravenous
ornidazole have been studied in a variety of popula-
tions, including healthy individuals, neonates and
infants, those with renal and hepatic dysfunction,
and those receiving single therapeutic doses for
various clinical conditions (table IV). Oral absorp-
tion of ornidazole is almost complete, with bioavail-
ability of >90% and tmax ranging between 2 and
Clin Pharmacokinet 1999 May; 36 (5)
368 Lamp et al.

Table IV. Pharmacokinetics of ornidazole

Dose (mg) n Schedule F (%) Cmax Vss AUC24h t1⁄2β (h) CL (L/h)a Reference
(mg/L) (L/kg) (mg/L • h)
1500 PO 50 S 23.6 (1h) 10.9 110
1000 IV 14 S 24 0.9b 14.1 2.82 111
750 PO 4 S 10.9 0.87 14.4 21
1500 PO 5 S 31.5 13.8 114
1000 IV 10 S 0.86 14.1 3.04 115
20 mg/kg IV 12 (neonates/infants) S 0.96 511 14.7 0.80 116
ml/min/kg
1000 IV or PO 8 (with variable renal function) S 102 (n = 6) 0.70 371 (PO) 12.7 2.94 117
500 IV 8 (CRF, no dialysis) S 0.73 185.0c 10.8 2.78 118
500 IV 7 (dialysis) S 3.84 118
1000 IV or PO 6 (dialysis) S 97 (n = 2) 0.78 308 11.0 3.91 117
500 IV 5 (CAPD) S 0.79 185.6c 11.8 2.87 118
500 IV 10 (cirrhosis) S 0.84 21.9 2.09 115
500 IV 10 (cirrhosis) S 0.81 19.3 2.24 119
500 IV 10 (hepatitis) S 0.90 19.3 2.01 119
500 IV 10 (CA) S 0.74 17.4 1.57 119
500 IV 11 (liver transplant) S 9.11 120
1000 IV 5 (PG) M 20.71 0.79 375c 15.22 3.4 121
a Normalised to a bodyweight of 70kg.
b Approximate value.
c AUC from zero to infinity.
AUC24 = area under the concentration-time curve over 24 hours; CA = pancreatic cancer; CAPD = continuous ambulatory peritoneal
dialysis; CL = total body clearance; Cmax = peak plasma drug concentration; CRF = chronic renal failure; F = bioavailability; IV = intravenous;
M = multiple; n = number of participants; PG = pregnant; PO = oral; S = single; t1⁄2β = elimination half-life; Vss = volume of distribution at steady
state.

4h.[21,117] Protein binding is approximately 11 to
13%, which is slightly higher than that reported for
metronidazole in one study.[21] Reported Vd values
range from 0.73 to 0.90 L/kg with AUC values for
single intravenous 500mg doses of 185 mg/L • h
and for 1g doses of 375 mg/L • h.[111,118,119,121] Al-
though ornidazole concentrations in CSF have only
been assessed in animal models, it is expected that
it should penetrate the CNS as well as metronida-
zole.[122]
Ornidazole concentrations have been measured
in the colonic (8.7 μg/g) and abdominal (3.6 to 4.4
μg/g) walls and epiploic fat (3.4 to 4.7 μg/g) through-
out colorectal surgery in those receiving a 1g intra-
venous dose for surgical prophylaxis.[111] In another
study,[120] concentrations were measured in epiploic
fat (2.48 to 4.64 μg/g) throughout liver transplan-
tation after a 500mg intravenous dose was given
together with ceftriaxone 1g for surgical prophy-
laxis. Penetration rates for this study compared with
plasma concentrations ranged between 50 and 70%.
Ornidazole is metabolised to 5 metabolites. Two
of the major active metabolites are M1 and M4,
with M1 stemming from an oxidative pathway and
M4 via hydrolysis.[123] Ornidazole and its metabo-
lites are primarily excreted in the urine. Between
43 and 63% of the dose was recovered from urine,
with <4% of the dose recovered as unchanged
drug.[123] Biliary excretion is another elimination
pathway for ornidazole and its metabolites, with
22% or more of the dose recovered in the faeces of
healthy volunteers.[21,123] The t1⁄2β is approximately
1.7 times longer than that of metronidazole, with
reported values ranging between 11 and 14h in
individuals without liver dysfunction.[21,110,117]
The pharmacokinetics of ornidazole are not influ-
enced by any degree of renal dysfunction. As shown
in several studies,[117,118] the t1⁄2β of ornidazole in

© Adis International Limited. All rights reserved. Clin Pharmacokinet 1999 May; 36 (5)
Nitroimidazole Antimicrobials
patients with renal dysfunction is similar to that
observed in those with normal renal function. Or-
nidazole is easily removed during haemodialysis
because of its low molecular weight and low pro-
tein binding.[117,118] It is recommended that doses
be administered after dialysis. In regard to patients
on peritoneal dialysis, one study showed that 6.2%
of an administered dose of ornidazole is found in
peritoneal dialysis fluids after 48 hours.[118] Vd,
plasma CL and t1⁄2β in patients receiving CAPD are
similar to those for patients with chronic renal fail-
ure. Thus, no dosage changes are needed for pa-
tients with renal dysfunction or those receiving
CAPD.
As with metronidazole, the elimination of ornid-
azole is impaired in patients with severe liver dis-
ease.[115,119] As compared with healthy volunteers,
plasma clearance is reduced from 3.04 to 1.57 L/h
in patients with pancreatic cancer, 2.01 L/h in pa-
tients with acute viral hepatitis, 2.09 L/h in patients
with severe alcoholic cirrhosis, and 2.34 L/h in pa-
tients with biopsy-proven liver cirrhosis.[115,119]
The t1⁄2β is also extended in patients with liver dis-
ease, with values ranging between 19 and 21h as
compared with 11 to 14h in those without impair-
ment.[21,115,119]
In vitro susceptibility studies have shown that,
compared with metronidazole, ornidazole has sim-
ilar or slightly lower MIC values against a variety
of anaerobic bacteria and protozoa.[124-127] Compared
with tinidazole, ornidazole MIC values are either
similar or slightly higher.[124,127] After 1g intrave-
nous doses, plasma ornidazole concentrations at 24
hours were above the MIC values of sensitive an-
aerobic organisms in a study of pregnant women
with chorioamnionitis or pyelonephritis and in in-
dividuals undergoing colorectal surgery.[111,121] Ad-
ditionally, adequate tissue concentrations were
found at almost 4 hours after the end of a 1g intra-
venous dose in abdominal wall fat, and for the ma-
jority of patients in epiploic fat samples.[111]
The SBT activity of ornidazole has been studied
in combination with fleroxacin against B. fragilis
and B. thetaiotaomicron.[90] At 2 and 8 hours after
administration of a 500mg oral dose of ornidazole,
© Adis International Limited. All rights reserved.
369
SBT values were 1 : 2 for both isolates at each time
point.
In summary, ornidazole shares many of the
properties of metronidazole. When not used as a
single dose and depending upon the clinical indi-
cation, the usual dosage of ornidazole is 500mg
every 12 hours. Adjustment of the dose for renal
dysfunction is not required. Owing to its long half-
life, up to 14 hours, and typical MIC values for
susceptible bacteria, a 24-hour dosage interval
could be considered appropriate for this agent
when multiple doses are required.
7.3 Secnidazole
Secnidazole [1-(2-hydroxypropyl)-2-methyl-5-
nitromidazole] is a structural analogue of the 5-
nitroimidazoles and has been evaluated for the
treatment of giardiasis, amoebiasis, trichomoniasis
and bacterial vaginitis. Its spectrum of activity is
similar to that of the other nitroimidazoles, with
comparable activity against B. fragilis, T. vaginalis,
E. histolytica and approximately 10 times greater
activity than metronidazole against Giardia duo-
denalis. Secnidazole shares the same mechanism
of action as other 5-nitroimidazoles.[128]
Pharmacokinetic data for secnidazole are lim-
ited. It is absorbed completely after oral adminis-
tration of 0.5 to 2g. A 2g oral dose achieves Cmax
values of 35.7 to 46.3 mg/L.[128,129] Protein binding
is approximately 15% and Vd is 49.2L.[128] The
t1⁄2β is longer than that of metronidazole and ranges
from 17 to 28.8h.[128,129] Excretion of secnidazole
in females was reported to be greater than in males
(approximately 26 versus 17.5%) and consequently
the t1⁄2β was only 14h in females compared with 20h
in males in that study.[128] After a single 2g oral
dose, plasma concentrations are maintained above
the MIC of protozoal pathogens for longer than 48
hours.[128,129] In gingival crevicular fluid, the Cmax
was 74% of the corresponding serum Cmax.[129]
Secnidazole is oxidised by the liver to a hydr-
oxyethyl metabolite. Two studies have reported
varying data on the amount of secnidazole and me-
tabolites excreted in urine. Between 10% and 50%
of an administered dose appears in urine over 72 to
Clin Pharmacokinet 1999 May; 36 (5)
370
96 hours.[128] Similarly to metronidazole, secnid-
azole does not induce or inhibit cytochrome P450
(CYP) enzymes.[130]
No information is available on the disposition
of secnidazole in patients with renal or hepatic dys-
function, or other special populations. Secnidazole
is also prone to cause a disulfiram-like reaction
when administered with alcohol-containing prod-
ucts.[128]
In summary, secnidazole is an effective single-
dose treatment for patients with amoebiasis, tricho-
moniasis, giardiasis and bacterial vaginosis, with
similar efficacy as multiple doses of metronidazole.
In areas where patient compliance is problematic,
single-dose therapy with secnidazole may offer a
useful alternative.
8. Therapeutic Considerations
The main distinguishing features of tinidazole,
ornidazole or secnidazole are their prolonged t1⁄2β
values compared with metronidazole. The choice
of nitroimidazole may be influenced by the longer
dosage intervals with other members of this class;
however, metronidazole remains the predominant
antimicrobial for anaerobic and protozoal infec-
tions.
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Correspondence and reprints: Dr Kenneth Lamp, University
of Missouri-Kansas City, M3-C19 Medical School Building,
2411 Holmes Street, Kansas City, MI 64108, USA.
E-mail: lampk@umkc.edu
Clin Pharmacokinet 1999 May; 36 (5)