Ceftriaxone A Review of its Antibacterial Activity, Pharmacological Properties and Therapeutic Use

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Abstract
Synopsis: Ceftriaxone 1 is a new ‘third generation’ semisynthetic cephalosporin with a long half-life which has resulted in a recommended once daily administration schedule. It is administered intravenously or intramuscularly and has a broad spectrum of activity against Gram-positive and Gram-negative aerobic, and some anaerobic, bacteria. The activity of ceftriaxone is generally greater than that of the ‘first’ and ‘second generation’ cephalosporins against Gram-negative bacteria, but less than that of the earlier generations of cephalosporins against many Gram-positive bacteria. Although ceftriaxone has some activity against Pseudomonas aeruginosa, on the basis of present evidence it cannot be recommended as sole antibiotic therapy in pseudomonal infections. Ceftriaxone has been effective in treating infections due to other ‘difficult’ organisms such as multidrug-resistant Enterobacteriaceae. Ceftriaxone was effective in complicated and uncomplicated urinary tract infections, lower respiratory tract infections, skin, soft tissue, bone and joint infections, bacteraemia/septicaemia, and paediatric meningitis due to susceptible organisms. In most of these types of infections once-daily administration appears efficacious. Results were also encouraging in a few patients with ear, nose and throat, intra-abdominal, obstetric and gynaecological infections, and adult meningitis, but conclusions are not yet possible as to the efficacy of the drug in these indications due to limited experience. A single intramuscular dose of ceftriaxone has been compared with standard therapy for gonorrhoea due to non-penicillinase-producing and penicillinase-producing strains of Neisseria gonorrhoeae and shown to be highly effective. In a few small trials the comparative efficacy of ceftriaxone and other antibacterials has been assessed in other types of infections and in perioperative prophylaxis in patients undergoing surgery. Few significant differences in response rates were found between therapeutic groups in these comparative studies, but larger well-designed studies are needed to more clearly assess the comparative efficacy of ceftriaxone and other antimicrobials, especially the aminoglycosides and other ‘third generation’ cephalosporins, and to confirm the apparent lack of serious side effects with ceftriaxone. If more widespread use confirms the safety and efficacy of ceftriaxone, it will offer an important alternative, particularly for the treatment of serious infections due to multidrug-resistant Gram-negative bacteria and in situations where the long half-life of the drug could result in worthwhile convenience and cost benefits. Antibacterial Activity: Ceftriaxone has a broad spectrum of activity in vitro which includes Gram-positive and Gram-negative aerobic and some anaerobic bacteria. Both penicillin-sensitive and -resistant strains of Staphylococcus aureus are sensitive to ceftriaxone (MIC90s 3 to 7 mg/L), but the drug is poorly active against methicillin- and oxacillin-resistant strains. Ceftriaxone is similar in activity to benzylpenicillin against Streptococcus pneumoniae and pyogenes, and is also active in low concentrations against other Streptococcus species (Str. agalactiae and viridans streptococci). However, Staphylococcus epidermidis is at most only moderately sensitive (MIC90s 11.9 to 50 mg/L) and Streptococcus faecalis is resistant to ceftriaxone. Cephalothin and cefamandole tend to be more active than ceftriaxone against most Gram-positive bacteria. Ceftriaxone exhibits both a wider spectrum and greater activity against Gram-negative aerobic bacteria than ‘first generation’ and ‘second generation’ cephalosporins, is generally more active than cefoperazone except against Pseudomonas aeruginosa, and is similar in activity to cefotaxime and moxalactam (latamoxef). 90% of tested strains of most Enterobacteriaceae were inhibited by a ceftriaxone concentration of ⩽ 1 mg/L, but Enterobacter cloacae is less sensitive than most other Enterobacteriaceae (MIC90s 0.5 to 25 mg/L). The reported activity of ceftriaxone against Pseudomonas aeruginosa varies widely, but generally at least 32 mg/L is required to inhibit most strains, and strains resistant to other antibiotics are even less sensitive. The combination of ceftriaxone and an aminoglycoside (amikacin, gentamicin, netilmicin or tobramycin) is synergistic against P. aeruginosa in vitro (20 to 80% of tested strains). However, synergy is less common against aminoglycoside-resistant and/or multidrug-resistant strains. The combination of ceftriaxone and cefoxitin was found to be antagonistic against P. aeruginosa and E. cloacae having inducible β-lactamases. Ceftriaxone is also active at very low concentrations against β-lactamase-positive and -negative strains of Haemophilus influenzae and Neisseria gonorrhoeae and meningitidis. Clostridium difficile and several species of Bacteroides, including B. fragilis, are only moderately sensitive or insensitive to ceftriaxone, but some other anaerobic bacteria are inhibited by the drug. In general, the β-lactamase stability pattern of ceftriaxone is similar in rate and percentage of inactivation to that of cefotaxime and cefuroxime, which are inactivated by fewer β-lactamases than cefamandole, cephalothin and cephaloridine, but by more β-lactamases than moxalactam and cefoxitin. Thus, ceftriaxone is highly stable to inactivation by β-lactamases produced by many bacteria, but not to those produced by B. fragilis or by some strains of Klebsiella species, Proteus vulgaris and Pseudomonas cepacia. Pharmacokinetics: Mean peak plasma ceftriaxone concentrations of 82.0, 150.7 and 256.9 mg/L were obtained after 30-minute infusions of 0.5, 1 and 2g, respectively. When the drug was administered 12-hourly by intravenous infusion, steady-state plasma concentrations were achieved within 4 days. The bioavailability of an intramuscular dose of ceftriaxone, alone or in combination with lignocaine (lidocaine), is similar to that following intravenous administration although mean peak plasma concentrations are lower. Peak plasma concentrations occur from 1 to 3 hours following intramuscular administration. The apparent volume of distribution of total ceftriaxone during the terminal elimination phase (Vdβ) is small due to the high degree of plasma protein binding, and increases with increasing dose (10.16, 11.06 and 13.52L following 30-minute infusions of 0.5, 1.0 and 2.0g, respectively). However, the volume of distribution (Vdβ) of the free ceftriaxone fraction remains constant with increasing dose. Concentrations of ceftriaxone inhibitory for most Gram-negative bacteria are attained in inflamed or non-inflamed meninges, in purulent sputum, and in synovial, prostatic, and pleural fluid. Concentrations likely to be effective against most sensitive organisms are similarly attained in blister and peritoneal fluid, bone, myometrium, endometrium and salpinges tissue. Ceftriaxone is excreted in breast milk (AUC in milk is approximately 3 to 4% of the AUC in serum). High concentrations of ceftriaxone are attained in bile. Ceftriaxone is highly bound to human serum protein, probably albumin, the extent of binding decreasing from 96% to 83% over the concentration range 0.5 to 300 mg/L. This concentration-dependent serum protein binding is responsible for the non-linear dose-dependent pharmacokinetics of the drug. The elimination half-life of ceftriaxone (6 to 9 hours) is much longer than that for most cephalosporins and it does not vary significantly with dose. The main routes of elimination of ceftriaxone are urine (40 to 60%) and bile (11 to 65%). As the pharmacokinetics of ceftriaxone are unaffected by probenecid, glomerular filtration and not tubular secretion appears to be the mechanism of renal excretion. In infants and children, decreased plasma albumin levels result in decreased plasma protein binding. The greater percentage of free ceftriaxone at a given plasma concentration is the likely cause of the several-fold greater volume of distribution and plasma clearance and somewhat shorter half-life (4 to 6.5 hours) in infants and children as compared with adults. Among neonates, the elimination half-life is prolonged compared with adults. In patients with severe renal dysfunction, non-renal elimination may compensate for the loss of the renal elimination pathway. However, in some such patients, a concomitant defect in non-renal pathways of elimination not revealed by standard liver function tests may result in a greatly prolonged elimination half-life. In decompensated liver cirrhosis (ascites), both the volume of distribution and serum clearance are increased, but the half-life of elimination is unchanged. Therapeutic Trials: As ceftriaxone was first synthesised only in 1978, the efficacy of the drug in some therapeutic areas remains to be assessed fully. However, published studies and summaries of clinical experience have documented the efficacy of ceftriaxone (usual dosage, 1 to 3 g/day at 12-hourly intervals) in a wide range of infections caused by Gram-positive and Gram-negative aerobic bacteria, and in a few cases anaerobic bacteria. Efficacy has also been demonstrated with a once daily dosage schedule in several types of infection. Ceftriaxone has been used successfully in patients who had failed to respond to other antibiotics, and in urinary tract infections caused by Enterobacteriaceae resistant to usual therapy. Also, ceftriaxone appears to be effective in uncomplicated gonorrhoea due to penicillinase-producing and non-penicillinase-producing Neisseria gonorrhoeae. Although ceftriaxone alone was effective in some patients with pseudomonal infections, on the basis of present evidence it cannot be recommended as the sole antibiotic for suspected or confirmed pseudomonal infections. The development of resistance and/or superinfection has been reported (e.g. due to Streptococcus faecalis, Pseudomonas aeruginosa, Enterobacter and Serratia species, and Bacteroides fragilis) following treatment of infections with ceftriaxone. In open or controlled studies, generally from 80 to 100% of infecting strains of ceftriaxone-sensitive Gram-positive and Gram-negative organisms were eradicated from patients with complicated or uncomplicated urinary tract infections immediately following treatment, P. aeruginosa and Str. faecalis were eliminated less successfully than Enterobacteriaceae. Dosages of 0.25 to 1g administered once daily appear to be equally effective as multiple daily injections in treating urinary tract infections. Ceftriaxone has been studied in many hospitalised patients with lower respiratory tract infections, usually caused by Streptococcus pneumoniae and Haemophilus influenzae (although several patients were infected with Enterobacteriaceae). 75 to 100% of patients showed complete resolution or improvement in clinical signs and symptoms and chest radiographs at the end of therapy. Once-daily administration (1 to 2g) with ceftriaxone also appears effective in lower respiratory tract infections. Bacteriological results were reported for only a few patients with septicaemia/bacteraemia who were treated with ceftriaxone, but ceftriaxone-sensitive Enterobacteriaceae (Escherichia coli, Proteus mirabilis, Serratia marcescens, Klebsiella pneumoniae, Enterobacter aerogenes and Citrobacter species) were isolated most frequently and all of the isolated strains were eradicated. Combined clinical and bacteriological ‘cure’ (definition varied) was reported in 43 to 91% of patients. However, the cure rate varied with the site of origin of the bacteraemia/septicaemia. Only limited experience has been reported with a once daily dosage schedule in bacteraemia/septicaemia. Satisfactory clinical responses were obtained in over 88% of patients treated with ceftriaxone (usual dosage 2 g/day as 1 to 2 administrations daily) often in conjunction with surgical procedures for skin, soft tissue, bone or joint infections caused by Gram-positive aerobes (e.g. Staphylococcus aureus), Gram-negative aerobes and in a few cases, anaerobes. Similar cure rates were reported in patients who received ceftriaxone 2g as a once daily injection. Infants and children with meningitis, due in most cases to Haemophilus influenzae, Streptococcus pneumoniae, Neisseria meningitidis or group A or B streptococci, generally had negative cerebrospinal fluid cultures within 24 hours of the initiation of ceftriaxone 25 to 50 mg/kg twice daily (or in a few patients 50 to 100 mg/kg once daily). Encouraging results have also been reported in patients with paediatric ventriculitis. While encouraging results have been obtained in a few patients with ear, nose and throat, intra-abdominal, obstetric and gynaecological infections and adult meningitis, published experience is limited and thus firm conclusions are not yet possible as to the efficacy of ceftriaxone in these important areas. In a few small studies, ceftriaxone has been compared with gentamicin, cefazolin, cefuroxime and tobramycin in treating urinary tract infections; amoxycillin, ampicillin, cephalothin, cefotaxime and doxycycline in treating lower respiratory tract infections; and amoxycillin, ampicillin and chloramphenicol in treating meningitis. In uncomplicated gonorrhoea a single intramuscular dose of ceftriaxone (usually 125mg to 500mg) has been compared with spectinomycin, kanamycin, and with probenecid in combination with penicillin, or cefoxitin. In controlled studies of perioperative prophylactic use ceftriaxone was compared with untreated controls, cefazolin and cefuroxime. In those comparative studies ceftriaxone usually appeared to be similar in efficacy to the alternative antibacterials, but most of the trials either did not analyse the results statistically, or included too few patients to distinguish at a statistically significant level any small potential differences between treatments. Thus, a few larger well-designed comparative studies are needed to define more clearly the comparative efficacy of ceftriaxone as related to other antimicrobials, especially the aminoglycosides and other ‘third generation’ cephalosporins. Side Effects: Ceftriaxone has generally been well tolerated by adults and children following intravenous and intramuscular injection. The most commonly reported adverse effects were diarrhoea, exanthema, rash or pruritus, and reactions at the injection site such as phlebitis and pain on intramuscular injection. Variations in laboratory test results, including transient eosinophilia and elevations of renal and liver function tests, have occurred, but symptomatic drug-related nephrotoxicity or hepatotoxicity have not been reported. Three reports of haematoma or haemorrhage, and 1 report of hypopro-thrombinaemic bleeding (rapidly corrected by vitamin K administration) in a chronic dialysis patient have appeared. Dosage and Administration: Ceftriaxone can be administered intravenously or intramuscularly. For adults the recommended dosage is 1 to 2g once (or in some countries once or twice) daily, although in some types of infections only limited experience with once daily administration has been reported. In severe infections and in cases in which the pathogens are only moderately sensitive to ceftriaxone, the dosage may be increased, in exceptional cases to 4g or higher daily (dosages larger than 4 g/day should be administered at 12-hourly intervals). The recommended daily dosage in infants and young children is 20 to 80 mg/kg, but in cases of premature birth the daily dosage should not exceed 50 mg/kg.