Cephalothin Sodium
A white to off-white, almost odourless, crystalline powder. 1.06 g of monograph substance is approximately equivalent to 1 g of cephalothin. Each % s>{ monograph substance represents 2.39 mmol of sodium.
Freely soluble in water; slightly soluble in dehydrated alcohol; freely soluble in 0.9% sodium chloride solution and in glucose solutions; practically insoluble in ether, and most other organic solvents. A 10 or 25% solution in water has a pH of 4.5 to 7.0. Store at a temperature not exceeding 30° in airtight containers. Protect from light.
Cephalothin sodium has been reported to be incompatible with aminoglycosides and with many other drugs. Precipitation may occur in solutions with a pH of less than 5.
Adverse Effects
The adverse effects associated with cephalothin and other cephalosporins are broadly similar to those described for penicillins. The most common are hypersensitivity reactions, including skin rashes, urticaria, eosinophilia. fever, reactions resembling serum sickness, and anaphy-laxis.
There may be a positive response to the Coombs' test although haemolytic anaemia rarely occurs. Neutropenia and thrombocytopenia have occasionally been reported. Agranulocytosis has been associated rarely with some cephalosporins. Bleeding complications related to hypoprothrombinaemia and/or platelet dysfunction have occurred especially with cephalosporins and cephamycins having a methylthiotetrazole side-chain, including cepha-mandole. cefbuperazone, cefmenoxime. cefmeta-zole, cefonicid. cefoperazone. ceforanide. cefotetan. cefpiramide. and latamoxef. The presence of a methylthiadiazolethiol side-chain, as in cephazolin, or a methylthiotriazine ring, as in ceftriaxone. might also be associated with such bleeding disorders. Nephrotoxicity has been reported with cephalothin although it is less toxic than Cephaloridine. Acute renal tubular necrosis has followed excessive dosage and has also been associated with its use in older patients or those with pre-existing renal impairment, or with the concomitant administration of nephrotoxic drugs such as aminoglycosides. Acute interstitial nephritis is also a possibility as a manifestation of hypersensitivity.
Transient increases in liver enzyme values have been reported. Hepatitis and cholestatic jaundice have occurred rarely with some cephalosporins. Convulsions and other signs of CNS toxicity have been associated with high doses, especially in patients with severe renal impairment.
Gastro-intestinal adverse effects such as nausea, vomiting, and diarrhoea have been reported rarely. Prolonged use may result in overgrowth of non-susceptible organisms and, as with other broad-spectrum antibiotics, pseudomembranous colitis may develop.
Theft; may be pain at the injection site following intramuscular administration, and thrombophlebitis has occurred following intravenous infusion of cephalosporins. Cephalothin appears to be more likely to cause such local reactions than other cephalosporins.
Antibiotic-associated colitis. Pseudomembranous colitis has been associated with the use of most antibiotics, including the cephalosporins. The newer broad-spectrum cephalosporins have also been implicated and in the UK the Committee on Safety of Medicines (CSM)4 has warned of the dangers of pseudomembranous colitis with the newer, as well as the older, oral cephalosporins. In addition to 33 reports of pseudomembranous colitis associated with cephalcxin. ce-phradine. cefadroxil, and cefaclor, 6 of which proved fatal, they had received 12 reports of probable or confirmed cases with cefuroxime axetil and 15 with cefixime, one of them fatal. In clinical trials of cefuroxime axetil and cefixime, diarrhoea and pseudomembranous colitis appeared to be dose-related and therefore the CSM recommended that higher doses should be reserved for severe infections. In any event they advised that treatment should be discontinued if symptoms suggestive of pseudomembranous colitis arise. For further discussion of the management of this condition.
Precautions
Cephalothin should not be given to patients who are hypersensitive to it or to other cephalosporins. About 10% of penicillin-sensitive patients may also be allergic to cephalosporins although the true incidence is uncertain; great care should be taken if cephalothin is to be given to such patients. Care is also necessary in patients with known histories of allergy.
Cephalothin should be given with caution to patients with renal impairment; a dosage reduction may be necessary. Renal and haematological status should be monitored especially during prolonged and high-dose therapy. Cephalothin and some other cephalosporins and cephamycins (ceforanide, cefotetan, cefoxitin. and cefpirome) may interfere with the Jaffe' method of measuring creatinine concentrations and may produce falsely high values; this should be borne in mind when measuring renal function. Positive results to the direct Coombs' test have been found during treatment with cephalothin and these can interfere with blood cross-matching. The urine of patients being treated with cephalothin may give false-positive reactions for glucose using copper-reduction reactions.
Interactions
The concomitant use of a nephrotoxic drug such as the aminoglycoside gentamicin may increase the risk of kidney damage with cephalothin. There is also some evidence for enhanced nephrotoxicity with a loop diuretic like frusemide, but this is less certain than with frusemide and Cephaloridine. Similarly to the penicillins, the renal excretion ofcepha-lodiin and many other cephalosporins is inhibited by probenecid. There may be antagonism between cephalothin and bacteriostatic antibacterials.
Antimicrobial Action
Cephalothin is a beta-lactam antibiotic. It is bactericidal and acts similarly to benzylpenicillin by inhibiting synthesis of the bacterial cell wall. It is most active against Gram-positive cocci, and has moderate activity against some Gram-negative bacilli.
Sensitive Gram-positive cocci include both penicil-linase- and non-penicillinase-producing staphyloco-cci, although methicillin-resistant staphylococci are usually resistant; most streptococci are also sensitive, but not penicillin-resistant Streptococcus pneu-moniae; enterococci are usually resistant. Some Gram-positive anaerobes are also sensitive. Cephalothin is usually inactive against Listeria monocy-togenes.
Among Gram-negative bacteria cephalothin has activity against some Enterobacteriaceae including strains of Escherichia coli, Klebsiella pneumoniae, Proteus mirahilis, Salmonella, and Shigella spp., but not against Enterobacter, indole-positive Proteus, or Serratia spp. It is also active against Haemophilus influenzae, Moraxella (Branhamella) catarrhalis, and Neisseria spp. Bacteroides fragilis and Pseu-domonas aeruginosa are not sensitive, neither are mycobacteria, mycoplasma, and fungi. The minimum inhibitory concentrations of cephalothin for susceptible Gram-positive cocci range from about 0.1 to 1 ng per mL; for the majority of susceptible Gram-negative bacteria concentrations of 1 to 16 u,g or more per mL are usually required. Resistance of bacteria to cephalothin may be due to several mechanisms: the drug may be prevented from reaching its site of action, for example in some Gram-negative organisms the cell wall may be a potential barrier, the target penicillin-binding proteins may be altered so that cephalothin cannot bind with these proteins; or, most importantly, the organism may produce beta-lactamases (cephalosporinases). Cephalothin is relatively resistant to hydrolysis by staphylococcal beta-lactamase, but is inactivated by a variety of beta-lactamases produced by Gram-negative organisms; resistance of Gram-negative organisms often depends on more than one factor. Resistance can be chromosomally or plasmid-mediated and may sometimes be inducible by cephalosporins.
Certain strains of bacteria may be inhibited but not killed by cephalosporins or penicillins and in such cases the minimum bactericidal concentration (MBC) is much greater than the minimum inhibitory concentration (MIC); this is known as tolerance. As well as with other cephalosporins, some cross-resistance may occur between cephalothin and the penicillinase-resistant penicillins.
Pharmacokinetics
Cephalothin is poorly absorbed from the gastro-in-testinal tract. After intramuscular injection peak plasma concentrations of about 10 and 20 u,g per mL are achieved within 30 minutes of doses of 0.5 and 1 g, respectively. A concentration of 30 ng per mL has been reported 15 minutes after the intravenous injection of'a 1-g dose; a range of 14 to 20 u,g per mL has been achieved by the continuous intravenous infusion of 500 mg per hour. Cephalothin is widely distributed in body tissues and fluids except the brain and CSF where the concentrations achieved are low and 'unpredictable. It crosses the placenta into the fetal circulation and low concentrations have been detected in breast milk. The plasma half-life varies from about 30 to 50 minutes, but may be longer in patients with renal impairment, especially that of the metabolite. About 70% of cephalothin in the circulation is bound to plasma proteins.
Approximately 20 to 30% of cephalothin is rapidly deacetylated in the liver and about 60 to 70% of a dose is excreted in the urine by the renal tubules within 6 hours as cephalothin and the relatively inactive metabolite, desacetylcephalothin. High urine concentrations of 0.8 and 2.5 mg per mL have been observed following intramuscular doses of 0.5 and 1 g, respectively. Probenecid blocks the renal excretion of cephalothin. A very small amount is excreted in bile.
Uses and Administration
Cephalothin is a first-generation cephalosporin antibiotic that has been used in the treatment of infections due to susceptible bacteria, particularly staphylococci, but has generally been replaced by cephazolin or cephradine: these in turn are being replaced by newer cephalosporins. Cephalothin is given as the sodium salt by slow intravenous injection over 3 to 5 minutes or by intermittent or continuous infusion. It may be given intramuscularly but this route is painful. Doses are expressed in terms of the equivalent amount of cephalothin. The usual dose has been 0.5 to 1 g of cephalothin every 4 to 6 hours; up to 12 g daily has been given in severe infections. Reduced doses are recommended if cephalothin has to be given to patients with impaired renal function.