Drug Disposition
Clin. Pharmacokinet. 17 (4): 223-235. 1989 0312-5963/89/00 10-0223/$06.50/0 © ADIS Press Limited
All rights reserved. CPKOO3231
Clinical Pharmacokinetics of Ceftriaxone Jae H. Yuk, Charles H. Nightingale and Richard Quintiliani The Methodist Hospital, Department of Pharmacy Services, Texas Medical Center, Houston, Texas, Hartford Hospital, Hartford, Connecticut, University of Connecticut School of Pharmacy, Storrs, Connecticut, and University of Connecticut School of Medicine, Farmington, Connecticut, USA
Contents
Summary ................ .................................................................................................................... 223 1. Pharmacokinetics of Ceftriaxone ......................................................................................... 224 1.1 Protein Binding ............................................................................................................... 224 1.2 Serum Concentrations ............. ....................................................................................... 225 1.3 Elimination ......................................................................... ..... ........ ....................... ......... 225 1.4 Distribution .... .............. ............................. ........................ .................................. ....... ..... 227 1.5 Penetration ......................................................................................................................227 1.6 Effect of Disease States .................................................................................................. 229 1.7 Effect of Age .................................................................................................................... 230 2. Clinical Features of Ceftriaxone .......................................................................................... 230 2.1 Clinical Trials ............................................. .....................................................................230 2.2 Adverse Effects ... ................ ............ .............................. .......................... ......................... 231
Summary
Ceftriaxone is a third-generation cephalosporin that exhibits saturable plasma protein binding. which influences its pharmacokinetic parameters depending on the dose. Systemic clearance and volume of distribution of total drug show dependence on both concentration and time. whereas for unbound drug these parameters remain constant. The decrease in renal or non-renal clearance with age or in the presence of disease states is often compensated by the concurrent increase in free fraction. resulting in no apparent changes in half-life and no need for dose adjustment. Because of its unusually long plasma half-life. the availability of intramuscular administration and its high intrinsic activity against many organisms. cefiriaxone has become a popular agent in once-daily therapy of infections in paediatric patients. gonococcal infections and outpatient management of pneumonia and osteomyelitis.
Gin. Pharmacokinet. 17 (4) 1989
224
Like other so-called third-generation cephalosporins, ceftriaxone is highly active against most Enterobacteriaceae (MIC90 < I mg/L) but only moderately active (MIC90 = 32 to 64 mgfL) against Pseudomonas aeruginosa. It is very active against Streptococcus species (MIC90 = 0.1 to 0.2 mg/L), but only moderately so against methicillin-sensitive Staphylococcus species (MIC90 = 2 to 8 mg/ L) and enterococci. Its activity is excellent against Gram-positive anaerobes but moderate against Bacteroides fragilis, with MIC90 usually being> 32 mg/L, and it has no role in the treatment of Listeria monocytogenes or methicillin-resistant staphylococci. Since ceftriaxone, like other (j-Iactams, distributes only into the extracellular space, intracellular pathogens (e.g. mycoplasma, Legionella, mycobacterium, Brucella. Chlamydia. Rickettsia) cannot be treated with this antibiotic.
Glossary of terms
CL CLo CLint CLR CLu CLu.R CLu,NR
fut
kA MBC MIC90
1. Pharmacokinetics of Ceftriaxone 1.1 Protein Binding
Since it is drug which is not bound to plasma protein, i.e. 'free', that is responsible for antimicrobial activity, it appears reasonable that the selection of agents for clinical use should favour those drugs with low protein binding. Although there are a number of studies demonstrating the importance of protein binding in clinical application (Chambers et al. 1984; Dudley et al. 1983), its effect can often be overshadowed by other factors that can affect the penetration profile and in vivo microbiological activity of an antibiotic. Moreover, protein binding is a dynamic equilibrium process, in which the degree of binding varies as a function of concentration. Often the doses administered are so high and the microbiological activity of the drug is so intense that they can overcome the theoretical negative effect of high protein binding. For most antibiotics the percentage of protein binding remains relatively constant throughout the dosing range. However, some drugs, like ceftriaxone, can saturate plasma protein binding sites with
Vss Vt VT,.. VT,.. Vu Vu,.. Vu,z Vz
Terminal elimination rate constant of the drug Systemic clearance of total (bound and unbound) drug Dialysis clearance Intrinsic hepatiC clearance of drug in plasma Renal clearance of drug from plasma Systemic clearance of unbound (free) drug Renal clearance of free drug Non-renal clearance of free drug Fraction of drug secreted into the bile Fraction of dose excreted unchanged in the urine Average free fraction of drug excreted unchanged in the urine Free fraction of drug in plasma Average free fraction of drug in plasma Free fraction of drug in tissue compartment Affinity constant Minimum bacteriCidal concentration Minimum inhibitory concentration for 90% of isolates Capacity constant Liver blood flow Terminal half-life Terminal half-life of free drug Volume of plasma Volume of distribution of total drug at steadystate Corrected volume of distribution of total drug at steady-state Volume of distribution in tissue compartment Steady-state volume of distribution with reference to total drug concentration Corrected steady-state distribution term for total drug concentration Volume of qistribution of free drug Volume of distribution of free drug at steadystate Volume of distribution of free drug in terminal phase Apparent volume of distribution of total drug during terminal phase
the usual dosing range, resulting in non-linearity in various pharmacokinetic parameters. After the administration of ceftriaxone 0.15, 0.5, and 1.5g, total concentrations and areas under the curve (AUC) increase disproportionately (Stoeckel et al. 1981 a, b), and this disproportionality becomes more pronounced with doses greater than 3g (Mc-
Pharmacokinetics of Ceftriaxone
Namara et al. 1982}. In fact, the free fraction increases from 4 to 17% as the serum concentration changes from 0.5 to 300 mgfL. Because ceftriaxone is a drug with low extraction ratio, total (bound and unbound) systemic clearance (CL = QHCLintfu/ QH + CLintfu) and volume of distribution (V z = Vp + Vt • fu/fint) are affected by the changes in free fraction (fu). After doses of ceftriaxone 0.15 and 1.5g, CL and Vz increase from 0.58 to 0.78 L/h and 7.0 to 8.6L, respectively. In contrast, pharmacokinetic parameters based on free concentrations such as systemic clearance offree drug (CLu), renal clearance of free drug (CLu,R), and volume of distribution of free drug (V u) are constant and independent of dose. The disproportionately high free peak concentration available at high ceftriaxone concentrations theoretically provides a greater driving force for drug penetration into tissue, which could possibly improve the chances for a better clinical outcome. Definitive clinical studies supporting this assumption, however, are not available. One of the unfavourable effects of high protein binding is its ability to displace bilirubin-albumin binding. Although cephalosporin with both low and high protein binding can displace bilirubin, clinicians should be aware of the potential of ceftriaxone to competitively displace bilirubin, particularly in paediatric patients such as the jaundiced neonate (Fink et al. 1987; Gulian et al. 1986, 1987; Robertson et al. 1988). 1.2 Serum Concentrations Peak and trough concentrations reported with administration either every 12 hours or daily are presented in table I. After intravenous administration of multiple doses of ceftriaxone 0.5, I, and 2g every 12 hours, the overall accumulation was 30 to 50% compared with 15 to 35% accumulation with 2g daily. Interestingly, trough concentration after 2g every 24 hours was 12 to 20 mg/L (total drug) and 1.2 mg/L (free drug) [fig. I] which provides sufficient antibacterial activity against many organisms despite the high serum protein binding. A single dose of ceftriaxone Ig has also been re-
225
ported to attain a serum concentration of 9.3 mgl L (total drug) and 0.5 mg/L (free drug) 24 hours after the dose, implying that even a regimen of Ig once daily could be effective against the highly susceptible Enterobacteriaceae and Haemophilus injluenzae, which are usually inhibited at concentrations of> 0.2 mgfL. These assumptions have been proven to be true in many recent clinical trials using once-daily dosing regimens. Intramuscular administration is an important mode of ceftriaxone usage. The peak concentrations (C max ) are about half those achieved with intravenous administration and the concentration profile essentially superimposes with that of intravenous administration after 2.5 hours, with a similar t'l2 (fig. 2). Due to higher clearance at the higher concentrations achieved after intravenous administration, comparison of AVCs could overestimate the bioavailability of intramuscular administration. However, the contribution ofthis early phase to the total AVC appears to be insignificant (15 to 20%) and the overall AVCs appear to be similar (Delsignore et al. 1983; Scully et al. 1984a). Subcutaneous administration produces a C max a little lower (37 mg/L after a dose of 0.5g) than that of intramuscular administration (Bomer et al. 1985). 1.3 Elimination As discussed earlier (section 1.1), total systemic clearance increases with dose due to dose-dependent protein binding. It increases by 14% (0.58 to 0.66 L/h) after multiple doses of Ig every 12 hours, and by 18% (0.68 to 0.81 L/h) after multiple doses of 2g every 12 hours, compared with the clearance following single doses of 1 or 2g. Systemic clearance of free drug, however, remains constant, being slightly higher than the glomerular filtration rate. This implies that the major route of renal elimination is via glomerular filtration without any significant renal tubular secretion (and there is, indeed, no interaction with probenecid). This lack of active tubular secretion, together with the high protein binding, allows an unusually long tl/, (6 to 9 hours). Urinary concentration 24 hours after a dose of
226
Clin. Pharmacokinet. 17 (4) 1989
Table I. Concentrations and pharmacokinetic parameters after various doses of ceftriaxone Reference
Single dose Borner et al.
No. of pts
Dose (g)
Route (duration) [min]
Cmaxa (mg/L)
tmax (h)
(h)
CLT (L/h)
Vd (L)
CLR (L/h)
10
2
IV (20)b
258
0.3
6.4
1.32
12.0
0.67
0.5 0.5
IV (20)b SC
83.8 37.1
0.3 2.6
9.9 8.6
0.96 0.95
13.3 11.9
0.46 0.37
1.5
IV (3)e
286
0.25
1.5
1M
167.6
2
C(12)
C(24)
(mg/L)
(mg/L)
8.9
64.0
24.9
8.9
72.0
27.4
tV2
Cmin a (mg/L)
(1985)
Delsignore et al. (1983)
7
8
1.11
12.7
0.73
0.5
5.82
1.19
10.05
0.53
46
15.1
150.7 82
0.5 0.5
6.13 6.3
1.01 0.93
9 8.46
0.4 0.37
28.1 15.3
9.3 5.3
IV (30)b
168
0.5
7.6
0.9
9.1
0.36
32
13.2
0.5
1M 1M
81.2 45.7
2.4 2
8.3 8.3
0.98 0.93
8.38 7.46
0.32 0.32
39.6 21.4
14.9 8.4
6
1.5
IV (5)e
306
7.8
0.78
8.6
6
0.5
IV (5)e
123
7.7
0.61
6.7
6
0.15
IV (5)e
36
8.6
0.58
7
0.420.78 0.360.48 0.36
12
1q12
1M
81/114
29/39
12
0.5q12
1M
49/65
16/24
12
1q12
IV (30)b
145/168
6.5
1.19
11.1
0.39
30/35
12
2q12
IV (30)
255/280
6.7
1.45
13.5
0.53
45/59
12
2q12
IV (30)b
255/280
6.5
1.45
13.5
0.53
45/59
12 12 8
1q12 0.5q12 2q24
IV (30)b IV (30)b IV (30)b
145/168 79/101 239/260
6.4 6.4 6.2
1.19 1.04 1.36
11.1 10.2 12.3
0.39 0.35 0.51
30/35 15/20 13/15
McNamara et al. (1982)
6
3
IV
411
Patel et al.
12
2
IV (30)b
256.9
0.5
IV (30)b IV (30)b
(1981)
Scully et al.
8
(1984)
Stoeckel et al.
(1981)
Multiple dose Holazo et al.
(1986) Patel et al.
(1981) Pollock et al.
(1982)
a Values for multiple dose are given as initial/steady-state. b Infusion. c Bolus. Abbreviations: Cmax = peak plasma drug concentration; t max = time to reach Cmax; tV2 = elimination half-life, CLT = clearance of total drug; Vd = apparent volume of distribution; CLR = renal clearance; C(12) [C(24)] = plasma drug concentration 12[24] hours post dose; Cmin = plasma trough drug concentration; IV = intravenous; 1M = intramuscular; SC = subcutaneous; q12(24) = every
12(24) hours; pts = patients.
227
Pharmacokinetics of Ceftriaxone
ceftriaxone Ig given intravenously remains above 100 mg/L, and 56% of the dose is recovered in the urine: Ceftriaxone also has a substantial non-renal elimination component, 44% being recovered in faeces. In general, about two-thirds of the dose is eliminated renally, while the remaining third undergoes non-renal elimination, mainly through biliary excretion.
200 3100
c;
.5. t.i c
)(
as ·c
:::
B
E
1.4 Distribution
~
CJ)
Ceftriaxone distributes primarily to extracellular water. As mentioned earlier (section l.l), the volume of distribution of total drug (Vz = Dose/ fl· AUC) increases with dose, while that offree drug (Vu) remains constant. None of these traditional volume terms (VT,ss, Vz, Vu,ss, Vu,z) adequately predicts the steady-state situation. Therefore, a new term, VT,ss (VT,ss = fu x Vu,ss), was proposed to characterise the concentration-dependent changes of volume of distribution (McNamara et al. 1983a,b).
50
8 CD 8 10 5
1+---~--~--~--~--~--~
o
4
8
12
16
20
24
Time (h)
Fig. 2. Serum concentration versus time profile of ceftriaxone after doses of Ig given intravenously (-) and intramuscularly (--).
1.5 Penetration 1.5.1 In Vivo Penetration Study Ceftriaxone penetration after single and multiple doses was studied in 12 subjects, using the skin blister fluid model (LeBel et al. 1985). The 11;, of ceftriaxone in the blister was longer than the plasma t'l2 (11.5 vs 8.3h) and the AUC ratio (blister fluid/ plasma) was higher with a dosage regimen of 2g daily than with a dose of Ig every 12 hours (0.51 vs 0.47). However, the Cmax ratio (blister fluid/ plasma) was not higher with the former regimen (0.16 vs 0.22) in this study.
300
200 ~
100
80
:::!. 60 CI
.5.
40 \ \
10
l!!
i
, .... ,, \
\
...... ~~ ...
8 6
.. "1 .... ..........
4
................... ..
U
2
....
...... .........
1+---~--~--~~--~--~--~-
o
4
8
12
16
20
24
Time (h)
Fig. 1. Effect of concentration-dependent protein binding. Total (-) and free (---) drug concentration after multiple doses of ceftriaxone 2 gfday intravenously; (... ) = hypothetical line assuming no change in protein binding. Data extrapolated from reported values.
1.5.2 Biliary Tract/Liver Patients with biliary diseases who underwent cholecystectomy and T -tube drain insertion were studied with varying doses of ceftriaxone (Hayton et al. 1986a, b; Owens et al. 1987). The average bile-to-serum ratio was up to 33 to 69 times and biliary excretion was responsible for elimination of 15% of the dose. Because the albumin concentration in bile is lower than in plasma an even higher
228
free concentration ratio would be achieved. The total fraction of the dose recovered in urine (fe) and bile (fbile) was less than I, however, implying another possible excretory pathway. Concentrations achieved in liver tissue, on the other hand, were relatively low after a dose of ceftriaxone Ig, which might be due to rapid elimination into bile (Lucht et al. 1986). 1.5.3 Cerebrospinal Fluid (CSF) Due to its long t,;" requiring less frequent administration, ceftriaxone has been favoured especially for paediatric patients and has been used in serious infections including meningitis. In vitro and in vivo animal studies were conducted to determine its CSF penetration (Spector 1986, 1987). Despite its size and negative charge, ceftriaxone entered the CSF, possibly through a facilitated transport system at the blood-brain barrier, as effectively as mannitol, which was transported by simple diffusion. Unlike penicillins, or first- and second-generation cephalosporins (which are transported out of the CSF by the weak organic acid transport system of the choroid plexus), ceftriaxone had a minimal affinity for this efflux system; consequently, the drug appeared to maintain effective concentrations in the CSF. This property is, in fact, consistent with its minimal affinity for the renal tubular secretory system, which results in CLR close to glomerular filtration rate. After a loading dose of 75 mg/kg given in 15 paediatric patients, 3 to 25% of the serum concentration was measurable in concurrent CSF (1.1 to 8 mg/L) [Nahata et al. 1986]. With an 80 mg/kg once-daily regimen in 22 paediatric patients, the CSF level 24 hours after the dose averaged 0.64 to 1.4 mg/L, justifying the use of ceftriaxone for the treatment of meningitis even with once-daily dosing (Dankner et al. 1988). 1.5.4 Pleural Fluid Penetration into pleural fluid was studied in 7 patients with pleural effusion (Benoni et al. 1986). After a single dose of ceftriaxone Ig, peak concentration of the drug in pleural fluid reached 7 to 8.7 (total) and 2.3 to 3.8 (free) mg/L in 4 to 6 hours,
Clin. Pharmacokinet. 17 (4) 1989
values which exceed its MICs for most susceptible organisms. The t'l2 in pleural fluid was about 2 to 4 times longer (23 to 46.2h) and a therapeutic concentration was detectable in pleural fluid (1.7 mg/ L of free drug) at least 53 hours after the dose, which is consistent with the previously reported behaviour of other cephalosporins in interstitial fluid containing high protein levels.
1.5.5 Synovial Fluid and Bone Ceftriaxone is an excellent choice for outpatient therapy owing to its capacity for use on a once daily basis. For example, osteomyelitis is an infection which generally requires long term antibiotic therapy. 15 patients undergoing orthopaedic surgery received intravenous ceftriaxone Ig, and synovial fluid samples were obtained at various times (Morgan et al. 1985). The drug was measurable in synovial fluid up to 24 hours after the dose (14 mg! L). No significant correlation was detectable between the degree of penetration and the magnitude of inflammation based on leucocyte count in synovial fluid. After a dose of ceftriaxone 2g, a concentration in bone of 24 J.l.g/g was achieved, which is comparable with other third-generation cephalosporins.
1.5.6 Other Tissues Penetration into lung, tonsil, middle ear mucosa and nasal mucosa was determined following a single dose of ceftriaxone Ig administered intramuscularly (Fraschini et al. 1986a, b). Three hours after this dose, peak tissue concentrations varied between 6 and 10 J.l.g/g, and 24 hours later the concentrations were still above the MICs of most pathogens encountered in infections at these sites. After intravenous administration of a dose of ceftriaxone 2g to 18 women undergoing hysterectomy or annexectomy, tissue concentrations (2.3 to 11.7 J.l.g/g) measured 24 hours after the dose were above its MIC for most aerobic organisms encountered in gynaecological infections (De Grandi et al. 1986).
Pharmacokinetics of Ceftriaxone
1.6 Effect of Disease States 1.6.1 Renal Disease The tlh of ceftriaxone does not change appreciably with moderate renal function impairment, since a significant fraction is eliminated non-renally and the low level of albumin often present in these patients increases its non-renal clearance [CL = fu (CLu,R + CLu,NR)]. Anephric patients with normal extrarenal clearance showed a moderate increase in tlh (14.4 to 17h) with greater Vd (Garcia et al. 1988; Patel et al. 1984; Wise et al. 1985). Anephric patients with concurrent decrease in extrarenal clearance (> 80%), however, showed a significant prolongation of tlh (> 50h), requiring dose adjustment (Stoeckel et al. 1984b). The affinity constant (kA), capacity constant (nP) of albumin and corresponding fu were compared in uraemic patients and healthy subjects by Scatchard plot analysis (Stoeckel et al. 1983). Uraemic patients, in general, had a lower kA (1. 77 vs 3.91 X 10- 4 mol/L-I in healthy subjects) and nP (5.36 vs 5.90 x 104 mol/L in healthy subjects), making fu in these patients double that of healthy subjects. Overall, the increase in fu completely offset the loss of CLR, making the apparent CL comparable with that in healthy subjects. Two uraemic patients in this study, however, also showed a marked decrease in CLNR, which was not detectable with biochemical parameters (ALT, AST, 'Y-glutamyl transferase and bilirubin), indicating that normal liver function does not assure normal CLNR. Ceftriaxone was initially reported to show insignificant pharmacokinetic changes from haemodialysis (Patel et al. 1984; Stoeckel et al. 1983). However, a recent study reported a 41 % reduction in serum concentration (68 to 40 mg/L) and average tlh (16.6 to 4.88h) with 4-hour haemodialysis in II patients with end-stage renal disease (Garcia et al. 1988). At 28 hours after a dose of ceftriaxone Ig including a 4-hour haemodialysis, plasma concentrations were still within the therapeutic range (40 mg/L). On the basis of these results, the authors recommended that ceftriaxone Ig be given every 48 hours at the end of each haemodialysis. Peritoneal dialysis is reported to contribute to
229
the overall clearance by only 3 to 8% (Albin et al. 1986; Koup et al. 1986). In 8 patients undergoing continuous ambulatory peritoneal dialysis (CAPO), ceftriaxone Ig was given intravenously and intraperitoneally. After intravenous administration, only 4.5% was eliminated intraperitoneally over 72 hours, with concurrent renal elimination of 4.3%. However, after intraperitoneal administration, ceftriaxone rapidly appeared in serum (ka = 0.6h- l ) and maintained a plasma concentration of more than 4 mg/L for 36 hours. Overall absorption through the peritoneum was 39%. Both routes of administration of ceftriaxone Ig once daily achieved concentrations adequate for the treatment of bacterial peritonitis. In the presence of peritonitis, dialysate concentration increases due to increased transport across the peritoneal membrane, but the overall change in clearance remains minimal owing to this small fractional change (CLD 0.69 vs CL 10.1 ml/kg· h). 1.6.2 Hepatic Disease The pharmacokinetic profiles of ceftriaxone in 15 subjects with various liver diseases (alcoholic fatty liver, cirrhosis with and without ascites) were compared with those of healthy subjects (Stoeckel et al. 1984a). The kA and nP from the fatty liver or cirrhosis without ascites group were slightly lower than those in healthy subjects (3.52 vs 3.91 x 10- 4 mol/L-i and 5.11 vs 5.90 x 104 mol/ L, respectively). The loss of intrinsic clearance (CLu,NR) was offset by the parallel decrease in plasma protein binding and, therefore, CL did not change in proportion to the loss in intrinsic clearance. In patients with cirrhosis with ascites, however, kA and nP values were significantly lower at 2.13 x 10- 4 mol/L -I and 3.39 x 104 mol/L, respectively, resulting in a marked elevation of fu (0.16 vs 0.05 in healthy subjects). In these patients, the decrease in CLu,NR was overcompensated by the increase in fu, resulting in a CL higher than in healthy subjects. Because the drastic increase in f u also increases Vz and VT,SS in patients with cirrhosis and ascites, the overall tv, does not appear to change (9.7 vs 8.4h). Dose adjustment is not nec-
Clin. Pharmacokinet. 17 (4) 1989
230
essary in patients with chronic liver disease, whereas patients with cirrhosis and ascites should be dosed cautiously due to increased free drug concentrations. With the reduced protein synthesis and the presence of ascites, liver disease can change the pharmacokinetic behaviour of many /'1-lactams. Penetration into ascitic fluid after a dose of ceftriaxone Ig was studied in 12 patients with cirrhosis or peritoneal carcinoma by Benoni et al. (1985). An increase in Vz (0.19 to 0.32 L/kg) and CL (0.016 to 0.02 L/h/kg) was observed in patients compared with healthy subjects. Ascitic fluid concentrations readily equilibrated with those in plasma and the t'l2 in ascitic fluid was slightly longer than that in serum (13.6h in patients vs 8.9h in healthy subjects). Prolongation ofthe t'l2 in ascitic fluid due to high protein binding was previously reported with other cephalosporins (Gerding et al. 1978). Since ceftriaxone already has high serum protein binding, the prolongation in ascitic fluid was not as noticeable as with other cephalosporins.
1.6.3 Other Diseases Pharmacokinetic studies were also conducted in hospitalised patients with various underlying diseases. Leukaemic children with fever and granulocytopenia had increased Vz and CL (1.35 L/kg and 0.1 L/h) due to lower protein binding and a larger volume of extracellular fluid, with a longer t'l2 (9.1 h) [Rossi et al. 1986]. As with other antimicrobial agents, patients with cystic fibrosis tended to have higher Vz (18.26L) and CL (1.77 L/h) [Vangdal et al. 1982]. The pharmacokinetic parameters obtained in 35 cancer patients were comparable with those from healthy subjects (Salvador et al. 1983). 1.7 Effect of Age The change in pharmacokinetic parameters with ageing has been reviewed previously (Hayton et al. 1986; Luderer et al. 1984). Since CL is determined by both glomerular filtration and biliary secretion, both CLR and CLNR are lower in neonates due to lower glomerular filtration rate and poor biliary excretion. Because the biliary system in neonates is not fully developed,
the renally eliminated fraction (fu) of ceftriaxone accounts for as much as 70% of the excretion, compared with 46% in adults. The f u (0.285 vs 0.05 in adults) was more than 400% higher in neonates due to the lower binding constant (2.06 vs 3.91 x 104 mol/L in adults), concentration of binding sites (2.43 vs 5.90 x 10- 4 mol/L-l in adults), and albumin concentrations (3.1 vs 4.3% in adults). Both CLR and CLNR are lower in infants, although these decreases are partially offset by an increased f u (Schaad et al. 1982, 1985). Because protein binding tends to be lower in children less than 6 years old and the renal elimination peaks between 2 and 20 years of age, the apparent CL is highest in children. Vz does not vary much with age, but it is 200 to 300% larger in infants and children on a weight basis. The corrected volume of distribution at steady-state introduced by McNamara (VT,ss) is similar in both the young and adults. The t'l2 does not appreciably change with age except in neonates (l8.6h). The slight change in t'h in elderly subjects (mean age 70.5 years, t'l2 8.9h) is primarily due to changes in CLu,R, although the increased free concentration available for filtration compensates for the decrease in this parameter.
2. Clinical Features of Ceftriaxone 2.1 Clinical Trials Ceftriaxone has been shown to be as effective as various other antibiotics for the treatment of serious infections caused by susceptible bacteria producing bacteraemia, lower respiratory tract infections, osteomyelitis, meningitis, and sexually transmitted infections (Abbate et al. 1986; Bittner et al. 1986; Bradley et al. 1988; Brogden & Ward 1988; Chadwick et al. 1983; Fraschini et al. 1986b; Grassi et al. 1987; Potgieter et al. 1986; Sherman et al. 1987).
2.1.1 Meningitis Numerous studies have been conducted using both 12- and 24-hour dosage regimens in the treatment of patients with meningitis caused by H. injluenzae, Neisseria meningitidis, and Streptococcus
Pharmacokinetics of Ccftriaxonc
pneumoniae. Although a wide range of patient populations has been studied, the majority of those studies were conducted in paediatric populations (Congeni et at. 1986; Dankner et at. 1988; Nahata et at. 1986; Prado et at. 1986; Yogev et at. 1986). The efficacy of ceftriaxone in these infections was comparable with that of traditional antibiotic therapy such as ampicillin and chloramphenicol (Bryan et at. 1985; Girgis et at. 1987). It has excellent in vitro activity against group B streptococci (MIC90 = 0.06 mgjL) and has proved effective in meningitis caused by this organism, which often does not respond to other third generation cephalosporins (Congeni et at. 1986; Hoogkamp-Korstanje 1985; Prado et at. 1986). Ceftriaxone is, however, not active against Listeria monocytogenes, an organism encountered in neonatal meningitis. 2.1.2 Lyme Disease Ceftriaxone displays excellent activity against Borellia burgodorferi (MBC 0.04 mg/L), the agent responsible for Lyme disease (Johnson et al. 1987). Although further clinical trials are needed to determine the most appropriate dosing regimen, doses of I to 2g daily or every 12 hours (up to 4 gjday) for 10 to 14 days have been tried with success. In fact, compared with 24 million units/day of penicillin, ceftriaxone 2 to 4 gjday was more effective for late Lyme disease (5/10 failure with penicillin vs 1/13 failure with ceftriaxone) [Dattwyler 1988]. Not surprisingly, a higher rate of Jarisch-Herxheimer reaction has been reported for ceftriaxone along with the higher efficacy, but the tolerance in general was excellent. It has been effective in Lyme disease complications including neurological, cardiac and arthritic problems (Dattwyler et al. 1987, 1988). Patients who failed to improve with penicillin have also responded to ceftriaxone, suggesting that in moderate to serious Lyme disease ceftriaxone is a promising agent. 2.1.3 Sexually Transmitted Diseases Ceftriaxone is gaining an important role in the treatment of gonorrhoea, since it is usually curative as a single, low intramuscular dose for both
231
penicillinase- and non-penicillinase-producing strains of this organism. Dose range studies (single doses of 500,250, 125 and 50mg by intramuscular injection) were conducted for uncomplicated gonococcal infections with 10 to 20 patients receiving each dose. A 100% cure was observed with all the doses except 50mg. Ceftriaxone 125mg has been shown to be more effective than spectinomycin 2g and procaine penicillin (Collier et at. 1984; Dixon et at. 1986). It has been almost 100% effective for gonococcal ophthalmia neonatorum, pharyngeal, cervical and anal gonococcal infections, including those caused by penicillinase-producing strains (Haase et at. 1986; Judson 1986; Laga et at. 1986). A case of successful treatment of gonococcal endocarditis has been reported (Black et at. 1988). For chancroid, ceftriaxone is also effective at a dose of 250mg intramuscularly (Bowmer et at. 1987; Taylor et al. 1985). For Chlamydia trachomatis, however, even a dose of ceftriaxone Ig administered intravenously was ineffective (Stamm et at. 1986). Further studies need to be conducted to establish definitive effectiveness for the treatment of syphilis, but ceftriaxone has been shown to be effective in vitro (Korting et at. 1986, 1987), and a recent study reports its usefulness for primary, incubating and asymptomatic syphilis (Hook et at. 1986, 1988; Moorthy et at. 1987). 2.2 Adverse Effects Ceftriaxone is in general well tolerated, with a low (7 to 8%) overall incidence of adverse effects (Mostovitz 1984; Oakes et al. 1984). Gastrointestinal complaints, particularly diarrhoea, are the most common. Severe reactions requiring discontinuance occur only in about 1% of cases, although both profound neutropenia (Dankner et at. 1988) and precipitation in the gallbladder (Schaad et at. 1986) have been reported. Concurrent injection of I% lignocaine (lidocaine) can significantly reduce the pain with intramuscular administration (Patel et at. 1982). Finally, bilirubin displacement could be clinically significant, especially in jaundiced neonates.
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Authors' address: Dr Jae H. Yuk, Infectious Disease/Pharmacokinetic Specialist, The Methodist Hospital, Department of Pharmacy Services, 6565 Fannin, MS-DB 109, Texas Medical Center, Houston, TX77030, USA.
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