Cephalothin and Cefazolin: Antimicrobial Activity, Susceptibility, Administration and Dosage, Clinical Uses etc.

Cephalothin (also spelt cefalothin) and cefazolin (also spelt cephazolin) are semisynthetic cephalosporins derived from cephalosporin C, a natural antibiotic produced by a strain of the fungus Acremonium chrysogenum (previously known as Cephalosporium acremonium) (Griffith and Black, 1964). The cephalosporin C nucleus, 7-ACA, is closely related but not identical to the penicillin nucleus, 6-APA. Although very similar compounds (Wick and Preston, 1972), cefazolin was introduced after cephalothin with the practical advantage of maintaining higher serum levels because of its longer half-life. Both cephalothin and cefazolin are described as first-generation cephalosporins.

These antibiotics are widely used in perioperative prophylaxis. Their future utility will be likely limited by the spread of methicillin-resistant Staphylococcus aureus (MRSA). However, at the present time, few studies show any decline in benefit of the first-generation cephalosporins despite the advent of MRSA (Bolon et al., 2004). The other major place in therapy is in therapy of cellulitis and potentially osteomyelitis – interventions using outpatient continuous intravenous infusions have been recently described (Grayson et al., 2002; Zeller et al., 2009). The molecular weight of cephalothin is 418.4 and its formula is C16H15N2NaO6S2. The molecular weight of cefazolin is 476.5 and its formula is C14H14N8O4S3. The chemical structures of these compounds are illustrated in Figure 18.1.

Figure 18.1 Chemical structure of cephalothin and cefazolin.

ANTIMICROBIAL ACTIVITY

a. Routine susceptibility

Cephalothin and cefazolin are both active against a range of Grampositive and Gram-negative bacteria, predominantly aerobes (see Table 18.1).

Gram-positive aerobic bacteria

Cephalothin and cefazolin are highly active against staphylococci, except MRSA and methicillin-resistant coagulase-negative staphylococci (Richmond et al., 1977; Laverdiere et al., 1978; John and McNeill, 1980; Chambers et al., 1984). Cephalothin has been shown to be minimally affected by staphylococcal penicillinase, although cefazolin may be affected to some degree (Lacey and Stokes, 1977; Goldman and Petersdorf, 1980). Most beta-hemolytic streptococci are also susceptible to these two cephalosporins.

Gram-negative aerobic bacteria

‘‘Wild-type’’ Escherichia coli is usually susceptible, but resistant strains are now common, especially in the hospital environment (Yoshioka et al., 1977). Typically, cefazolin has greater activity than cephalothin against E. coli. Susceptibility of the Klebsiella spp. varies; wild-type K. pneumoniae is usually susceptible, with cefazolin having greater activity than cephalothin. However, strains that are highly ampicillin resistant (MIC W500 mg/l) are also likely to be cephalothin and cefazolin resistant (Greenwood and O’Grady, 1975). Wild-type Proteus mirabilis is usually sensitive. For all of these Enterobacteriaceae, production of extended-spectrum beta-lactamases (ESBLs), or over-production of TEM-1 or SHV-1, resultsb in resistance to the first-generation cephalosporins.

Anaerobic bacteria

Anaerobic Gram-positive cocci, such as Peptostreptococcus spp. and anaerobic streptococci, are likely to be sensitive to cephalothin and cefazolin (Tally et al., 1975; Sutter and Finegold, 1976). Similarly, anaerobes, such as Clostridium perfringens, C. tetani, and the Lactobacillus and Actinomyces spp., are usually cephalothin and cefazolin sensitive (Sutter and Finegold, 1976; Schwartzman et al., 1977; Bayer et al., 1978). Bacteroides fragilis is resistant to cephalothin and cefazolin. Prevotella melaninogenica and some strains of other Bacteroides spp. may be inhibited by therapeutically achievable concentrations of cephalothin or cefazolin (Tally et al., 1975; Sutter and Finegold, 1976).

Other bacteria

Treponema pallidum and Leptospirae may be susceptible to cephalothin and cefazolin. Mycobacteria, Mycoplasma, Nocardia, Rickettsiae, Chlamydia, fungi, and protozoa are resistant (Thompson and Dretler, 1982; Gutmann et al., 1983).

MODE OF DRUG ADMINISTRATION AND DOSAGE

Cephalothin and cefazolin can only be given parenterally as absorption after oral administration is negligible. Cephalothin and cefazolin can be administered i.v. by either continuous infusion, intermittent infusions (via a pediatric buretrol or separate secondary i.v. bottles), or by direct i.v. injections. The continuous infusion method may have some pharmacodynamic advantages; when resultant serum levels are graphed, it produces a greater area under the curve and also biliary levels are more sustained (Thys et al., 1976).

a. Adults

Cefazolin can be administered i.m. as well as i.v. and the usual adult dosage is 0.5 g every 8 hours (Reller et al., 1973). The total daily dose can be varied widely according to the nature and severity of the infection. Daily doses ranging from 1 to 4 g (occasionally up to 12 g) administered in two, three, or four divided doses, have been used (Reinarz et al., 1973; Ries et al., 1973). Thrombophlebitis can sometimes be a problem when cephalothin is used i.v., and this may be reduced if the acid pH of the cephalothin solution is buffered by sodium bicarbonate (Bergeron et al., 1976). Cefazolin causes less pain on i.m. injection than cephalothin, and is associated with less thrombophlebitis when used i.v. (Shemonsky et al., 1975).

b. Newborn infants and children

The same dose for cephalothin and cefazolin is used – dosage for children is 25–50 mg/kg body weight per day, given in three or four divided doses (Pickering et al., 1973). Total daily dosage may be increased to 100 mg/kg/day for the treatment of severe infections. For newborn and premature infants, aged 0–7 days and weighing less than 2000 g, a dosage of 20 mg/kg every 12 hours is recommended (total daily dose 40 mg/kg). For infants weighing more than 2000 g or who are older than 7 days, a dosage of 20 mg/kg 8-hourly (total daily dose 60 mg/kg) is recommended (McCracken and Nelson, 1983). Few data exist to guide dosing in premature neonates.

PHARMACOKINETICS AND PHARMACODYNAMICS

a. Bioavailability

Cephalothin and cefazolin both have poor bioavailability whereby oral administration for systemic effect is not useful. Both have high bioavailability after i.m injection (cefazolin 98%; Anderson et al., 1976). Both drugs are considered to have a low volume of distribution, cephalothin 0.21–0.26 l/kg and cefazolin 0.13–0.22 l/kg (Kirby and Regamey, 1973). Cephalothin is 50–60% serum protein bound (Kunin, 1967), whereas cefazolin is approximately 80%. The high protein binding of cefazolin and longer half-life are partly responsible for its high serum levels, given that most studies report total antibiotic concentrations.

b. Drug distribution

After i.m. injection of 0.5 g to adults, the peak serum level of cephalothin is attained after 30 minutes, and it is about 10 mg/ml. The cephalothin level with this dose falls below 2 mg/ml after 4 hours, and at 6 hours the drug is undetectable (Benner et al., 1966); however, for cefazolin, a peak serum level as high as 34 mg/ml is attained 1 hour after a 0.5 g i.m. dose of cefazolin and 6 hours later the level is about 6 mg/ml (Ishiyama et al., 1971). These levels are about four times as high as those after cephalothin. In addition, measurable levels of cefazolin may still be present 12 hours after this dose (Ries et al., 1973). For both drugs, doubling the dose usually doubles the serum concentration.

c. Clinically important pharmacokinetic and pharmacodynamic features

As with other b-lactam antibiotics, cephalothin and cefazolin show time-dependent antibiotic killing, and their bactericidal activity relates most to the time that serum drug concentrations remain above the MIC (TWMIC) for a given organism. In vitro and animal in vivo studies have shown that cephalosporins require a TWMIC of 60–70% of the dosing interval (Craig, 1998). Retrospective data using third- (ceftazidime) and fourth-generation (cefepime) cephalosporins administered to critically ill patients suggests that a TWMIC of 100% is associated with superior bacteriologic cure and clinical cure, although these results have not been shown prospectively, nor for cephalothin or cefazolin (McKinnon et al., 2008).

d. Excretion

Cephalothin and cefazolin are rapidly excreted via the kidney (Saslaw, 1970). Whereas cephalothin is primarily excreted by tubular secretion, cefazolin is excreted primarily by glomerular filtration and, to a lesser degree, by tubular secretion. Both drugs may have excretion reduced and serum levels elevated by concomitant administration of probenecid (Kirby and Regamey, 1973). Renal clearance of cefazolin is slower than that of cephalothin, and this explains its higher and more prolonged serum levels. For cefazolin, high urinary concentrations (4000 mg/ml) of the active drug are attained, and about 60% of an i.m. administered dose is excreted in the urine during the first 6 hours (Ishiyama et al., 1971). Its renal clearance is about 80% of the simultaneous creatinine clearance, and nearly all of a given dose can be recovered from the urine in 24 hours (Reller et al., 1973; Rattie and Ravin, 1975).

Augmented renal clearance (ARC) refers to the enhanced renal elimination of circulating drugs. From a pharmacokinetic point of view, ARC will result in elevated renal elimination of drugs normally excreted by the kidneys, resulting in subtherapeutic serum concentrations toward the end of a routine dosing interval (Udy et al., 2010). In patients with ARC, cephalothin and cefazolin will have increased clearances and hence dosing should be individualized (Udy et al., 2010).

e. Drug interactions

Probenecid is reported to interact with cephalothin, and cefazolin resulting in prolonged serum concentrations (Saslaw, 1970; Grayson et al., 2002). This drug interaction can be used therapeutically to maintain serum concentrations for extended periods, enabling reduced frequency of antibiotic dosing. Furosemide has also been reported to decrease the renal excretion of both cephalothin and cefazolin, although another study reported no significant effect on renal clearance of cephalothin in humans (Tice et al., 1975; Iakovlev et al., 1981).

TOXICITY

a. Hypersensitivity reactions

Perioperative anaphylaxis has occurred in patients receiving first generation cephalosporins for surgical prophylaxis (Culp et al., 2007). On the assumption that it is not cross-allergenic with the penicillins, the first-generation cephalosporins are frequently recommended for the treatment of infections in penicillin-allergic patients. In some clinical studies, allergic reactions have not been observed in penicillin-allergic patients treated with cephalothin (Perkins and Saslaw, 1966; Rahal et al., 1968). Occasionally, penicillin-sensitive patients have reacted to cephalosporin C derivatives. Immediate severe reactions to cephalothin in penicillin-allergic patients have been described (Rothschild and Doty, 1966; Scholand et al., 1968; Spruill et al., 1974). A skinsensitizing antibody to cephalothin and 7-ACA was demonstrated in one patient who had suffered an anaphylactic reaction to penicillin G five months previously (Grieco, 1967).

b. Nephrotoxicity

Cephalothin, its metabolite desacetylcephalothin, or both may be responsible for the nephrotoxicity observed with its prescription. Serum concentrations of the metabolite are very high in patients with renal failure, even when the cephalothin dose is suitably reduced (Nilsson-Ehle and Nilsson-Ehle, 1979). In most reports of nephrotoxicity there was evidence either of preexisting renal damage or that the cephalothin dosage was unusually large, such as 8–24 g daily for 8– 35 days (Rahal et al., 1968; Benner, 1970; Hansten, 1973; Engle et al., 1975; Barrientos et al., 1976). Some instances of cephalothin nephrotoxicity appear to be due to direct toxicity of the drug, and this has a histologic picture of acute tubular necrosis. Pathology in other cases resembles hypersensitivity interstitial nephritis, similar to that caused by the penicillins (Barza, 1978; Durham and Ibels, 1981).

Nephrotoxicity appears to be rare, mild, and reversible with cefazolin (Moellering and Swartz, 1976). Cefazolin has been used in doses as high as 12 g daily, without evidence of nephrotoxicity (Reinarz et al., 1973). Cefazolin produces renal tubular damage in experimentalb animals, but the lesions are relatively mild (Silverblatt et al., 1973).

c. Hematologic side-effects

Cefazolin-induced hemolytic anemia is rare, but needs to be considered in patients who develop hemolytic anemia postoperatively (Cerynik et al., 2007). A positive direct Coombs’ test occurs in many patients receiving cephalothin (Molthan et al., 1967; Gralnick et al., 1971; Rubin and Burka, 1977). In a patient with hemolytic anemia due to penicillin G, the disease worsened when cephalothin was substituted, but full recovery occurred 12 days after cephalothin was stopped (Medical News, 1968). Circulating antibodies in this patient were identical to those of another patient who had hemolysis caused by penicillin G only, in that the sera of both patients were equally reactive with penicillin- and cephalothin-coated red cells. A severe cephalothin-induced hemolytic anemia occurred in a patient following aortic valve replacement (Lemole et al., 1972). Cephalothin usually causes an aggregation-type hemolytic anemia – it binds to the red cells, but during this process serum proteins are also aggregated. In this condition either the IgG Coombs’ test, or the C3 Coombs’ test, or both, may be positive (Garratty and Petz, 1975).

d. Gastrointestinal side-effects

Clostridium difficile infection may occur after a single prophylactic dose of a first-generation cephalosporin (Carignan et al., 2008). 

e. Hepatotoxicity

Transient elevations of transaminases or serum alkaline phosphatase have been noted during treatment with cefazolin (Ries et al., 1973). No cases of serious hepatoxicity have been reported.

f. Encephalopathy

As with the penicillins and other beta-lactams, encephalopathy may occur if very high serum levels are reached. A patient reported by Gardner et al. (1978) who had renal functional impairment, and who was initially treated with inappropriately high doses of cefazolin (12 g/ day), developed repeated convulsions while undergoing hemodialysis. A post-dialysis serum cefazolin level was greater than 512 mg/ml.

g. Other side-effects

Intramuscular administration of cefazolin is reported to be less painful than that of cephalothin (Kirby and Regamey, 1973). Bacterial meningitis occurred in five patients receiving cephalothin for other severe infections (Mangi et al., 1973). Two patients had pneumococcal meningitis and the other three were due to a meningococcus, a Klebsiella spp., and L. monocytogenes, respectively. Freij et al. (1975) reported another patient who developed pneumococcal meningitis during cephalothin treatment for pneumococcal septicemia. The occurrence of meningitis in these circumstances was erroneously described as a specific complication of cephalothin therapy. Meningitis is not an uncommon association of any septicemia. Furthermore, it may develop during treatment, particularly if the antibiotic used, such as cephalothin, does not easily pass into the CSF and if the bacterial species involved is not highly susceptible. This has also occurred with other cephalosporins.

h. Use in pregnancy

Teratogenicity in humans due to cephalothin has not been described (Williams and Smith, 1973). Similar to penicillins, cephalosporins can probably be safely used during the first trimester of pregnancy. No adverse effects, such as hemolytic anemia in the newborn, have been detected with cephalothin administration to mothers near term (Hirsch, 1971).

CLINICAL USES OF THE DRUG

a. Perioperative prophylaxis in surgical patients

Cephalothin and cefazolin have long been used for perioperative surgical prophylaxis in a wide variety of situations. It could be contended that cefazolin is more suitable for this purpose than cephalothin, as single intravenous injections result in more prolonged serum levels.

b. Streptococcal and pneumococcal infections

Cephalothin and cefazolin have been used as an alternative to penicillin G for the treatment of infections such as cellulitis (Reinarz et al., 1973; Reller et al., 1973; Fass, 1978; Symonds and Geddes, 1987).

Streptococcus pyogenes infections, such as pharyngitis, scarlet fever and cellulitis, and pneumococcal pneumonia respond well to cephalothin and cefazolin (Reinarz et al., 1973; Reller et al., 1973; Fass, 1978; Neu, 1980). A randomized trial has been performed comparing once-daily intravenous cefazolin, ‘‘boosted’’ by oral probenicid with once-daily ceftriaxone for management of moderate to severe cellulitis in adults (Grayson et al., 2002). Clinical cure was observed in 86% of 59 patients treated with cefazolin–probenicid and 96% of 57 patients treated with ceftriaxone (p = 0.11). Nausea was more common in the cefazolin– probenicid group (Grayson et al., 2002).

c. Staphylococcal infections

Cephalothin is a satisfactory anti-staphylococcal agent. Clinical efficacy of cephalothin in severe staphylococcal sepsis is probably about the same as that of the parenteral penicillinase-resistant penicillins.

Cephalothin is effective in experimental S. aureus endocarditis in animals (Carrizosa et al., 1982). It may be used for the treatment of severe staphylococcal infections such as septicemia and endocarditis in penicillin-allergic patients, although some clinicians prefer vancomycin (Sande and Scheld, 1980; Kaplan and Tenenbaum, 1982).

d. Urinary tract infections and gonorrhoea

Cephalothin and cefazolin are effective in eradicating sensitive strains of E. coli and P. mirabilis from urine, but results are less satisfactory with infections due to Klebsiella and Enterobacter spp. (Ries et al., 1973; Benner et al., 1975). In chronic infections, associated with urinary tract abnormalities, results of treatment with cephalothin and cefazolin are likely to be unsatisfactory.

Uncomplicated gonorrhoea and gonococcal arthritis historically responded to a course of cefazolin (Karney et al., 1973). Single-dose treatment for uncomplicated gonorrhoea, using an i.m. dose of 2 g with or without probenecid, is unsatisfactory (Duncan, 1974). In the current era, ceftriaxone would be preferred to earlier generation cephalosporins for gonorrhoea.

e. Actinomycosis

A few patients with this disease have been successfully treated with cephalothin (Caldwell, 1971).

References

Abrutyn E, Lincoln L, Gallagher M, Weinstein AJ (1978). Cefalotin-gentamicin synergism in experimental enterococcal endocarditis. J Antimicrob Chemother 4: 153.
Adam D, Hofstetter AG, Jacoby W, Reichardt B (1975). Studies on the diffusion of cephradine and cefalotin into human tissue. Proceedings of 9th International Congress of Chemotherapy, Abstract M-69.
Allegaert K, van Mieghem T, Verbesselt R et al. (2009). Cefazolin pharmacokinetics in maternal plasma and amniotic fluid during pregnancy. Am J Obstet Gynecol 200 (170): e1.
Alveyn CG (1993). Antimicrobial prophylaxis during biliary endoscopic procedures. J Antimicrob Chemother 31 (Suppl B): 101.
Brown EM (1987). Systemic antimicrobial prophylaxis in hysterectomy. J Antimicrob Chemother 20: 143.
Brown EM (1993). Antibiotic prophylaxis in neurosurgery. J Antimicrob Chemother 31 (Suppl B): 49.
Bryant RE, Alford RH (1977). Unsuccessful treatment of staphylococcal endocarditis with cephazolin. JAMA 237: 569.
Bryant RE, Alford RH (1978). Treatment of staphylococcal endocarditis. JAMA 239: 1130.
Caldwell JL (1971). Actinomycosis treated with cefalotin. South Med J 64: 987. Carignan A, Allard C, Pepin J et al. (2008). Risk of Clostridium difficile infection after perioperative antibacterial prophylaxis before and during an outbreak of infection due to a hypervirulent strain. Clin Infect Dis 46: 1838.
Carrizosa J, Santoro J, Kaye D (1978). Treatment of experimental Staphylococcus aureus endocarditis; comparison of cefalotin, cephazolin, and methicillin. Antimicrob Agents Chemother 13: 74.
Carrizosa J, Kobasa WD, Snepar R et al. (1982). Cephazolin versus cefalotin in beta-lactamase-producing Staphylococcus aureus endocarditis in a rabbit experimental model. J Antimicrob Chemother 9: 387.
Drake TA, Sande MA (1983). Studies of the chemotherapy of endocarditis: correlation of in vitro, animal model, and clinical studies. Rev Infect Dis 5 (Suppl 2): 345.
Duncan WC (1974). Treatment of gonorrhea with cephazolin plus probenecid. J Infect Dis 130: 398.
Durham DS, Ibels LS (1981). Cefalotin-induced acute allergic interstitial nephritis. Aust NZ J Med 11: 266.
Earnshaw JJ (1989). Prevention of infection after vascular reconstruction. J Antimicrob Chemother 23: 480.
Ellis BW, Standbridge RdeL, Sikorski JM et al. (1975). Penetration into inflammatory exudate and wounds of two cephalosporins for the prevention of surgical infections. J Antimicrob Chemother 1: 291.
Engle JE, Drago J, Carlin B, Schoolwerth AC (1975). Reversible acute renal failure after cefalotin. Ann Intern Med 83: 232.

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