DRUG DISPOSITION
Clin. Pharmacokinet. 26 (4): 248-258.1994 0312-5963/94/0004-0248/$05.50/0 © Adis International Limited. All rights reserved.
Clinical Pharmacokinetics of Cefotetan Claude Martin, Laurent Thomachot and Jacques Albanese Anaesthesia Department and Trauma Centre, Hopital Nord, Marseille, France
Contents 248 249 251
251 251 251
253 253 254 254 255 256
Summary
Summary 1. Absorption 2. Distribution 2.1 Apparent Volume of Distribution 2.2 Extravascular Distribution of Cefotetan 2.3 Protein Binding 3. Elimination 3.1 Metabolism 3.2 Excretion 3.3 Half-Life 4. Influence of Disease States on Pharmacokinetics 5. Conclusion
Cefotetan is a 7-o.-methoxy 13-lactam. A long serum half-life and resistance to 13-lactamase hydrolysis have made cefotetan an attractive chemotherapeutic agent, and the results of clinical trials worldwide have demonstrated its efficacy in a wide variety of clinical situations. Cefotetan can be administered intravenously (bolus or infusion) or intramuscularly with lidocaine (lignocaine) 0.5%. Mean peak plasma concentrations are almost linearly related to dose. The volume of distribution is between 8 and 13L and is not different from other cephalosporins. No accumulation is seen after repeated doses and no metabolite has been detected in either plasma or urine. Total body clearance is 1.8 to 2.9 Llh. Renal clearance accounts for about 64 to 84% of a dose, and 75% of a dose is excreted in the urine within 24 hours. The plasma elimination half-life is between 3 and 4 hours after intravenous and intramuscular doses. Half-life is considerably prolonged in patients with renal impairment (up to 10 hours). Cefotetan concentrations are likely to be active against susceptible bacteria in most tissues and body fluids. Breast milk and cerebrospinal fluid concentrations are low. The recommended dosage is Ig every 12 hours, increasing to 2g in severe infections and 3g in life-threatening infections. In surgical prophylaxis, a single dose of2g is given with the induction of anaesthesia; an additional dose of 2g may be administered 12 hours later. In children over 6 months, the recommended dosage is 30 mg/kg given 12-hourly. In patients with a creatinine clearance of 10 to 40 mUmin (0.6 to 2.4 LIh), the dose is halved or the dosage interval is doubled. When creatinine clearance is less than 10 mUmin (0.6 LIh). the dose is quartered or the dosage interval quadrupled.
Cefotetan Pharmacokinetics
Cefotetan is a semisynthetic cephamycin antibiotic administered intramuscularly (1M) or intravenously (IV). It is a 7-a-methoxy B-Iactam, which is structurally related to cefoxitin. Resistance to B-Iactam hydrolysis gives cefotetan a broad spectrum of activity against Gram-negative aerobic and most clinically important Grampositive and anaerobic bacteria. It is generally more active against Enterobacteriaceae than the so-called first and second generation cephalosporins, but cefotetan has little activity against Pseudomonas aeruginosa. A long plasma elimination half-life (3.5 to 4.3 hours) and high achievable serum and tissue concentrations enables cefotetan to be administered on a twice-daily basis in the treatment of mild or severe infections. Cefotetan is also used for the prophylaxis of infection following urologic, gynaecological, obstetric and gastrointestinal surgery. A convenient single-dose prophylaxis schedule has been used in most studies (cefotetan being given at time of the induction of anaesthesia), and the drug was at least as effective as comparative antibacterial prophylaxis with multiple or single doses of cefazolin, cefoxitin, cefuroxime or other cephalosporins. Also, cefotetan appeared to be at least as effective as conventional arninoglycoside and/or imidazole derivative-containing multidrug regimens. On the basis of the findings published in the medical literature, cefotetan has one of the longest plasma elimination and urinary excretion half-lives of the currently available cephalosporins and cephamycins. This could result in both convenience and cost-reduction benefit as a result of reduced pharmacy preparation and nursing administration time.
1. Absorption The pharmacokinetics of cefotetan have been studied after 1M and IV administration in healthy volunteers and surgical patients. The peak serum concentration (C max) of biologically active drug after IV administration appears to vary with the dose and the rate of injection, being higher after a bolus
249
injection of 2g than after an infusion of Ig over a period of 10 to 60 minutes. In dose-ranging studies in healthy volunteers, plasma cefotetan concentrations showed an almost linear increase with dose after a single IV injection of 0.25 to 2.0g (table I). Immediately following an IV bolus dose of l.Og, Cmax values are about 140 to 250 mg/L (Naber et al. 1985; Nakayama et al. 1981; Saito et al. 1982 a,b) [table I]. After an IV bolus of 2.0g, C max values are higher (414 to 491 mg/L) [Martin et a11992; Stahl et al. 1985]. Doses of 1.0 to 2.0g administered by IV infusion over 60 minutes give mean C max values of 70 to 270 mg/L (Nagasawa et al. 1982; Nakagawa et al. 1982; Soejima et al. 1982). No sign of drug accumulation was noted after repeated administration of 1g IV twice daily for 6 days (Koyama et al. 1982). Cefotetan is completely bioavailable after 1M injection (Guibert et al. 1983), and the use of either water or 0.5% lidocaine (lignocaine) does not alter plasma concentrations and pharmacokinetic parameters (Yates et al. 1983b). Mean Cmax values are about 25 to 50% of those achieved after the same dose administered by IV bolus or rapid infusion. After single 1M doses of cefotetan 0.5 to 2.0g, Cmax values are also dose related (23 to 91 mg/L). They are attained after l.5 to 3.0 hours (Guibert et al. 1983; Yates et al. 1983b). With continuous IV administration (75.8 mg/hour), steady-state plasma concentrations (C SS ) of 37.5 mg/L are attained 12 hours after the start of the infusion (Adam et al. 1983). C ss is reached more rapidly with the use of a 0.5g loading dose (Adams et al. 1983). In comparative studies, mean serum Cmax values were 3.0-fold higher than those of cefoxitin, 1.8fold higher than those of latamoxef (moxalactam), 1.6-fold higher than cefotaxime and similar to cefazolin, all at equigravimetric IV doses. From 2 hours postdose, these differences were even more pronounced (Carver et al. 1989; Naber et al. 1985; Nakagawa et al. 1982; Nakayama et al. 1981; Quintiliani et al. 1985). At 8 hours following single IV doses of cefotetan 0.5 and 1.0g in healthy volunteers,
CZin. Pharmacokinet. 26 (4) 1994
250
plasma concentrations ranged from 7.6 to 9.1 mg/L and 13.5 to 16.3 mg/L, respectively (Koyama et al. 1982; Nakagawa et al. 1982; Nakayama et al. 1981; Sawae et al. 1982; Tachibana et al. 1985). With cefazolin 1.0g or latamoxef 1.0g, serum concentrations 8 hours postdose were 1.7 and 3.8 mg/L, respectively (Nakagawa et al. 1982; Nakayama et al. 1981). At 8 hours following a single IV dose of cefotetan 2.0g, the mean plasma concentration was 28.1 mg/L, whereas the mean concentration of cefoxitin after a 2.0g dose had decreased to 0.14 mg/L (Carver et al. 1989). At 12 hours following an IV injection of cefotetan 1.0g, the mean plasma concentration was 7.4 mg/L (Guibert et al. 1983). Mean serum concentrations 12 hours after cefotetan 2.0g or cefoxitin 2.0g were 10.0 and 2.0 mg/L, respectively, in one study (Quintiliani et al. 1985), and 10.6 mg/L and not detectable, respectively, in another (Carver
et al. 1989). After cefotetan 0.5 and l.Og 1M, respective serum concentrations 8 hours postdose were 10.5 (Tachibana et al. 1985) and 10.2 mg/L (Guibert et al. 1983). Serum concentrations of 4.5 and 10.4 mg/L were also recorded 12 hours after a single 0.5 and l.Og 1M dose of cefotetan, respectively (Guibert et al. 1983). Among patients undergoing colorectal surgery, cefotetan serum concentrations were 163, 73 and 64 mg/L, 33, 151 and 216 minutes, respectively, after a single 2.0g IV bolus dose (Martin et al. 1992). Similarly, cefotetan and cefoxitin serum concentrations 80 minutes after administration of single 2.0g IV doses were 108 and 34 mg/L, respectively (Quintiliani et al. 1985). In patients undergoing hysterectomy, after single IV doses of cefotetan 2.0g or cefoxitin 2.0g, serum concentrations were 298 and 101 mg/L after 20 minutes, and 235 and 43 mg/L after 47 minutes, respectively (Quintiliani et al. 1985).
Table I. Pharmacokinetics of cefotetan in healthy volunteers following single-dose parenteral administration References
Route Dose (g)
Cmax (mg/L)
Carver et al. (1989)
IV
2.0
336
Guibertetal. (1983)
IV 1M
1.0 0.5 1.0
179 35 74
Martinetal. (1992)a
IV
2.0
Nakagawaet al. (1982a)
IV
Stahl etal.
IV
(1985a) Yates etal.
IV
(1983a)
Yates etal.
1M
(1983b)
1M 1M
a
tmax (min)
t'l2~
(h) 2.9
Vc (L)
7.7
% Recovery in urine (h)
Assay techniques
3.5
91 (24)
Bioassay
1.8 (plasma)
75(24) 60-65 (24)
Bioassay
10.3 11.0 11.6
414
4.3
16.7
0.5 1.0 1.0
132 253.2 263.9
3.1 3.4 2.8
8.9 8.0 7.2
1.0
3.8 4.2
10.4 11.4
1.9
2.0
229 491
0.25
42
3.0
10.5
0.5 1.0 2.0
79 142 237
3.0 3.5
11.1 13.0 14.8
2.4 2.6
2.0
23.3 51.9 91.0
5 5 5 5
3.6
5.85
CL (Uh)
3.1 3.4-3.7
0.5 1.0
2 82 97
Vd (L)
CLR (Uh)
2.8 3.9 3.9 3.9
HPLC
2.2 1.8
1.8 1.4
HPLC Bioassay TLC
1.2
Bioassay
2.0
2.7 2.9
1.9
66(18)
NS
67(19) 70 (18) 66(18)
HPLC Bioassay
180 180
3.4 4.4
66.5 (18) 61 (18)
180
4.2
61 (18)
NS HPLC Bioassay
Surgical patients.
Abbreviations: CL =clearance; CLR =renal clearance; Cmax =mean maximum plasma or serum concentration; HPLC =high performance
=
=
=
=
=
liquid chromatography; 1M intramuscular; IV intravenous; NS method not specified; t1r,.~ plasma elimination half-life; tmax time to Cmax ; TLC thin-layer chromatography; Vc volume of distribution of the central compartment; Vd apparent volume of distribution.
=
=
=
Cefotetan Pharmacokinetics
In children, C max values are usually comparable with those achieved in adults after administration of comparable doses based on bodyweight. With doses of 10 to 20 mg/kg, C max values of 55 to 216 mg/L are obtained (Aso et al. 1983; Fujii et al. 1983; Nishimuraetal. 1983; Toyonagaet al. 1983). In some situations, plasma concentrations were approximately 20% lower (Iwai et al. 1983); however, the clinical relevance of this finding is unknown.
2. Distribution 2.1 Apparent Volume of Distribution The apparent volume of distribution of cefotetan in healthy adult volunteers is about 8 to 13L after a single IV bolus or 1M dose of 0.5 to 1.0g (table I). After a 2.0g IV dose, a value of 14.8L was recorded in healthy volunteers (Yates et al. 1983a) and 16.7Lin patients undergoing colorectal surgery (Martin et al. 1992). 2.2 Extravascular Distribution of Cefotetan Distribution of cefotetan into a wide range of body tissues and fluids has been determined in humans (table II). Cefotetan enters the vascular circulation and diffuses or is secreted into a variety of sites in the human body in widely differing concentrations. The concentrations achieved in various body sites are the result of a complex set of factors that include, drug protein binding, lipid solubility, ionisation state, passive diffusion, active transport, extravascular site geometry and degree of inflammation. Cefotetan concentrations have been determined in a wide range of body tissues and fluids in man. In most of these tissues and fluids cefotetan concentrations likely to be inhibitory to susceptible bacteria are achieved. Sites of extravascular cefotetan distribution are divided into 4 major categories (table II). 2.2.1 Fluid-Filled Spaces Cefotetan accumulates by means of passive diffusion in fluid-filled spaces of relatively large volume. They are characterised by having a relatively
251
small surface area for diffusion, compared with their volume. This results in slow accumulation of cefotetan with repeated administration, as well as lower peak and higher trough drug concentrations than those of serum. 2.2.2 Fluid Produced by the Excretion or Secretion of Glands and Organs These fluids provide the greatest variability in achievable drug concentrations of all extravascular sites. Since cefotetan is actively secreted into urine and bile, high concentrations are achieved in these fluids. In contrast, some glands pose a substantial barrier to penetration by cefotetan (e.g. into milk and prostatic fluid). 2.2.3 Spaces with Diffusion Barriers As for many other antimicrobials, low cefotetan concentrations are achieved in the cerebrospinal fluid. Active transport from cerebrospinal fluid or removal by bulk cerebrospinal fluid flow may be major reasons for the low concentrations measured. 2.2.4 Body Tissues Body tissue concentrations high enough to inhibit even moderately susceptible bacteria [concentration required to inhibit 90% of tested strains (MIC90) 16 to 64 mg/L] were achieved in intrapelvic genital organs, gallbladder tissue, stomach wall and mucosa, colon and rectal wall and mucosa, renal cortex and mucosa, prostatic tissue and lung tissue (table II). Somewhat lower concentrations were observed in skin, subcutaneous fat, endometrial tissue, ovarian tissue, fascia, muscle and lung in patients with chronic obstructive pulmonary disease (table II).
2.3 Protein Binding Cefotetan is about 78 to 91 % reversibly bound to plasma proteins (Carver et al. 1989; Drumm et al. 1983; Gialdroni Grassi et al. 1983; Komiya et al. 1981; Quintiliani et al. 1985; Tachibana et al. 1985; Wise et al. 1982; Yates et al. 1983a). Owing to slow elimination, the free cefotetan serum concentration at the recommended dosage interval of
Clin. Pharmacokinet. 26 (4) 1994
252
Table II. Cefotetan concentrations in various body fluids and tissues after single-dose administration to patients Body fluid or
Indication
Dose (g)
tissue
Route Mean peak concentration
Fluid or tissue
Reference
to serum
(mg/kg or mg/L) concentration ratio (%)
Fluid-filled spaces Blister fluid
Healthy volunteers
1.0
1M
12.5
19.1
Periti et al. (1983)
Amniotic fluid
Pregnant women
0.5-1.0
IV
8.6-19.1
10.1-12.3
Cho et al. (1982); Seiga et al. (1982); Takase et al. (1982)
Wound secretion
Abdominal infection
2.0
IV
61.8
94
Peritoneal fluid
Abdcminal infection
1.0-2.0
IV
48-80
85
Donovan et al. (1983)
Elective surgery
1.0
IV
32.3
115
Wittke et al (1985)
2.0
IV
120
110
Gruwez et al. (1988); Wise
Wittke et al. (1985)
et al. (1983)
Excretory and secretory fluids Urine
Sputum Bile
Healthy volunteers
1.0
IV
4513
0.5
1M
878 2354
Guibert et al. (1983)
1.0
1M
Chronic bronchitis
0.5-1.0
IV
Lung cancer
2.0
1M
6-13
7-15
Motta et al. (1987)
Post cholecystectomy
1.0
IV
>100 >100
Fujimoto et al. (1982) Owen et al. (1983a,b)
0.74-12
Matsumoto et al. (1982)
2.0
IV
171-408 179-719
Biliary tract infection
1.0-2.0
IV
Up to 1587
>100
Tanimura et al. (1982);
Prostatic fluid
Prostatitis
1.0
IV
0.2-1.32
0.8
Suzuki etal. (1981,1982)
Breast milk
Puerperal women
1.0 1.0
IV
0.10
0.4
IV 1M
0.34 0.59
Wittke et al. (1985)
1.0
Matsuda (1984) Cho et al. (1982) Novelli et al. (1983)
Spaces with diffusion barriers Cerebrospinal fluid
Meningitis (children) Cerebrovascular
54-83 mg/kg 2.03-hourly
IV
1.1-4.8
0.8-3.6
Iwata et al. (1983)
IV
4.5
1.3
Hirayama (1985)
10.0
haemorrhage (adults)
Body tissues Subcutaneous fat
Surgical patients
2.0
IV
14.2-16.4
2.0
IV
17.5
Martin et al. (1992) Orr et al. (1988)
2.0
IV
10.9
16
Wittke et al. (1985)
Endometrial tissue Hysterectomy
2.0
1M
9.9
2.4-22.0
Fraschini et al. (1988)
Intrapelvic genital
30 mg/kg
IV
65-70
22
Cho et al. (1982);
1.0
IV
13.5-45.0
7.5-47.0
Daschner et al. (1985);
2.0
IV
30-158
Surgical patients
organs
Engel et al. (1988); Motomura et al. (1982); Orr et al. (1988); Quintiliani et al. (1988); Vercruysse et al. (1987); Yasuda et al. (1983)
Ovarian tissues
Surgical patients
2.0
1M
6.5
1.9-11.1
Fraschini et al. (1988)
253
Cefotetan Pharmacokinetics
Table II. Contd Body fluid or
Indication
Dose
Route
(g)
tissue
Mean peak
Fluid or tissue
concentration
to serum
Reference
(mg/kg or mg/L) concentration ratio (%) Gallbladder tissue Cholecystectomy,
0.5-2.0
IMIIV
8.0-87.6
0.25-41
biliary tract infections
Furuhata et al. (1988); Owen et al. (1983a,b); Tanimura et al. (1982, 1985); Wittke et al. (1985)
Stomach wall and
Surgical patients
1.0
IV
19-30
9.13
Furuhata et al. (1985)
Surgical patients
2.0
IV
33.3
46
Martin et al. (1982)
Carcinoma
2.0
1M
21.3-22.7
15.3-72.7
Fraschini et al. (1988)
Prostatic hypertrophy
1.0
IV
38
Prostatic adenoma
2.0
1M
13.1
16-86
Fraschini et al. (1988)
mucosa Colon and rectal wall and mucosa Renal cortex and medulla Prostatic tissue Lung
Fascia
Fujimura et al. (1982)
Surgery in cancer
1.0
IV
45
17-34
Imaizumi et al. (1988)
patients COPO
2.0
IV
6.9
2.9-21.0
Fraschini et al (1988)
Surgical patients
2.0
IV
5.0
7.5
Wittke et al. (1985) Wittke et al. (1985) Wittke et al. (1985)
Muscle
Surgical patients
2.0
IV
8.7
13
Skin
Surgical patients
2.0
IV
4.4
6.6
Abbreviations: COPO
=chronic obstructive pulmonary disease; 1M =intramuscular; IV =intravenous.
12 hours is 1.6 mg/L (total concentration 10.6 mg/L) and this enables free serum inhibitory titres against Escherichia coli to be >1 : 8 for 12 hours postdose (Carver et al. 1989). Despite relatively higher protein binding than cefoxitin (52%), cefotetan demonstrates activity 12 hours after administration similar to cefoxitin 6 hours after administration (Carver et al. 1989). Cefotetan is also bound to human liver ligand (glutathione-S-transferase) to a much greater extent than cefazolin, chloramphenicol or gentamicin. This may explain the differences in the extent of biliary excretion ofthese drugs (Komatsu et al. 1981).
3. Elimination 3.1 Metabolism The few published data on the human metabolism of cefotetan (Kuroda et aI. 1982; Saito et al. 1982b) have demonstrated the lack of biologically active metabolites of cefotetan in either plasma or
urine of human healthy volunteers. However, cefotetan, like some other cephalosporins (latamoxef, cefmenoxime and cefoperazone) contains an N-methylthiotetrazole side chain. This side chain in humans gives rise to vitamin KI-2,3 epoxide in response to a dose of vitamin Kl, which may cause hypoprothrombinaernia with an increase in prothrombin time and possible coagulation abnormalities (Andrassy & Koderish 1987; Andrassy et al. 1985). Recently, 11 volunteers were studied for N-methylthiotetrazole formation in vivo (Welage et al. 1990). Mean peak serum concentrations of the parent drug after administration of cefotetan, moxalactam and cefoperazone 2.0g IV were 2.77, 6.69 and 1.19 mg/L, respectively, and in vivo Nmethylthiotetrazole formation was 16.4,41.0 and 58.8mg, respectively. This reflects the difference in parent cephalosporin disposition and may affect the relative incidence of antibiotic associated coagulopathy (Welage et al. 1990).
254
Clin. Pharmacokinet. 26 (4) 1994
Table III. Pharmacokinetics of single doses of intravenous cefotetan in patients with varying degrees of renal impairment References
Creatinine clearance Dose (mllmin/1.73m2)8 (g)
t1h~
(h)
AUC (mgILo h)
Total body
Renal
Recovery in urine
clearance (mllmin)8
clearance
over 24 hours
(mllmin)8
(%)
Browning et al. (1980)
0 0
1.0
Inamatsu et al. (1983)
40
0.5
7.64
Ishito et al. (1983)
>80
0.5
3.0
77.0
9.1
22.8
1.0
34-35 7-15 Ohkawa et al. (1983)
Smith & LeFrock (1984)
38.7
32.3
31.5
20.2
31-68
4.59
427.8
23.9
13.6
8-28
11.09
1171.0
10.1
3.3
0.7
13.11
1452.9
8.3
0.5
4.2
42.3
20.7
7.8
20.8
9.6
42.3
9.9
16.4
5.0
27.2
>80 40-80
0.5
17.1 254 323.8
>80 40-80 50-110
1.0
5.1 8.8 10.1
1.0
0.5
49.4
4.6
78.4
8.0
65
6-11
18.8
8
0-5
35.1
4.9
15-50
a
659
3.0 3.72
>80 69-94
10-39 Wright et al. (1983)
13.0
15.3
10-40 Smith et al. (1986)
15.5 20.4
To convert mllmin to LIh. multiply by 0.06.
Abbreviations: AUC = area under the plasma concentration-time curve; t'hP = plasma elimination half-life.
3.2 Excretion Cefotetan is removed to a considerable extent in the urine, with 60 to 90% of a dose being renally excreted over a period of 6 to 24 hours after administration of a single 1M or IV injection to healthy Caucasian volunteers (table I). During the first 3 hours following administration of cefotetan 0.5 or 1.0g 1M or 1.0g IV, cefotetan concentrations in the urine are 878, 2354 and 4513 mg/L, respectively (Guibert et al. 1983). The drug is still detected in the urine at 12 and 24 hours (77 and 45 mg/L after l.Og IV or 1M, respectively). Urinary excretion half-life is 3.0 to 3.2 hours (Guibert et al. 1983; Nakayama et al. 1981; Yates et al. 1983a,b). Good and rapid biliary penetration after parenteral administration has been documented, with concentrations in bile of the common bile duct exceeding plasma concentrations up to lO-fold
(Fujimoto et al. 1982; Owen et al. 1983a,b; Tanimura et al. 1982). Bile concentrations vary with the functional state of the gallbladder, and penetration into the biliary tree is delayed and lowered in patients with obstructive jaundice (Leaper et al. 1986; Owen et al. 1983a,b). Total body clearance was reported as 1.8 to 3.5 LIh (Carver et al1989; Martin et al. 1992) [table I]. Renal clearance in healthy Caucasians after IV bolus or infusion has been calculated to be about 1.2 to 1.9 LIh and accounts for 64 to 84% of total body clearance. Biliary excretion accounts for about 12% of an IV dose in Caucasian volunteers (Lanzini et al. 1985, 1987). 3.3 Half-Life The apparent elimination half-life of cefotetan in healthy volunteers is 2.8 to 4.3 hours after ad-
Cefotetan Pharmacokinetics
ministration of 0.25 to 2.0g IV, when determined over a period of 8 to 24 hours (table I). There is no tendency for the half-life to increase with a rise in dosage. The elimination half-life is not prolonged in the elderly provided renal function is not impaired (Ripa et al. 1987; Stahl et al. 1985). After 1M injection of equal doses, the elimination halflife is the same as after IV administration (3.4 to 4.4 hours). A slightly shorter elimination half-life of 1.85 to 3.5 hours is reported in paediatric patients (Aso et al. 1983; Fujii et al. 1983; Iwai et al. 1983; Iwata etal. 1983). Alongerhalf-lifeof5.4 hours has been reported in neonates with urinary tract infections (Serra et al. 1985). Among cephalosporins, cefotetan possesses one of the longest half-lives, ceftriaxone alone having a longer half-life of 8 hours. In comparative studies in healthy volunteers, the half-life of cefotetan (4 hours) was considerably longer than that of cefazolin (1.5 hours), latamoxef (1.9 hours), cefoxitin (0.8 hours) and cefotaxime (1.05 hours) [Carver et al. 1989; Kakayama et al. 1982; Naber et al. 1985a,b; Nakayama et al. 1981; Quintiliani et al. 1985]. As for other cephalosporins, the optimal dosage regimen of cefotetan for the treatment of common Gram-positive or Gram-negative bacterial infections is still a matter of debate (Yuk-Choi et al. 1992). Based on the results of early penicillin studies, the goal of a dosage regimen for cephalosporins is to prevent a drug-free interval between doses from being long enough for the bacterial pathogens to resume growth (Craig & Ebert 1992; Eagle et al. 1953). Also, the bactericidal activity of cefotetan and other cephalosporins is characterised by a linear stability over a wide range of concentrations, with minimal enhancement with increasing drug concentrations. The extent of bactericidal activity in various tissues appears to depend more on the duration of exposure to drug concentrations above the MIC than on the magnitude of antibiotic concentrations (Fluckinger et al. 1991; Gerber et a1.1984). The duration of time that concentrations in serum and tissue exceed the MIC has been
255
Table IV. Cefotetan dosage recommendations in patients with varying degrees of renal impairment Creatinine clearance
Dosage
(mVminl1.73m2)8 >40
Interval adjustment
2 g/12h
2 g/12h
10-40
1 g/12h
2 g/24h
<10
0.5 g/12h
2 g/48h
Post-haemodialysis
19
supplement a
To convert mllmin to Uh, multiply by 0.06.
shown to be the major pharmacokinetic parameter correlating with the efficacy of antibiotics in animal models (Craig et al. 1988; Leggett et al. 1989) Since concentrations of cephalosporins in excess of MIC values do not result in a more rapid killing of bacteria, and maximising the time of exposure to therapeutic drug concentrations is the main goal of dosage regimens for ~-lactam antibiotics, the long half-life of cefotetan represents a considerable advantage over other cephalosporins (Yuk-Choi et al. 1992).
4. Influence of Disease States on Pharmacokinetics In the presence of moderate to severe renal impairment there is a direct correlation between total body clearance and creatinine clearance (CLcR) , and thus cefotetan elimination is delayed (table III). In patients with mild renal impairment [CLcR 60 to 100 ml/min (3.6 to 6.0 Lib)] the elimination half-life is increased. With more severe impairment [CLcR < 30 ml/min (1.8 Lib)] the elimination half-life is at least twice the normal value. When CLcRis 10 mllmin (0.6 Lib) or less, the value will exceed 10 hours (Browning et al. 1986; Ohkawa et al. 1983; Wright et al. 1983). As expected, alteration in renal function will result in decreased renal clearance, total body clearance and urinary recovery of the drug (Ishino et al. 1982; Ishito et al. 1983; Ohkawa et al. 1983; Wright et al. 1983). However, renal impairment does not alter the volume of distribution (Ohkawa et al. 1983). A dosage adjustment is desirable when treating patients with altered renal function (table
256
IV). As creatinine clearance decreases, a progressive reduction in dosage or an increase in the dosage interval is recommended. A dose of Ig should be administered after each haemodialysis session.
5. Conclusion Cefotetan, a 7-a-methoxy ~-lactam, has a broad spectrum of activity in vitro against many anaerobic bacteria as well as Gram-positive and Gramnegative bacteria. The drug has a prolonged serum half-life, and mean Cmax values are almost linearly related to dose. The volume of distribution is not different from other cephalosporins. No accumulation is seen after repeated doses and no active metabolite has been detected. The drug is excreted to a considerable extent in the urine, and a dosage adjustment is needed for patients with impaired renal function. Cefotetan concentrations are likely to be active against susceptible bacteria in most tissues and body fluids.
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Correspondence and reprints: Professor Claude Martin, Service de Reanimation, Hopitai Nord, 13915 Marseille Cedex 20, France.
