|
 
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| REVIEW ARTICLE |
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| Year : 2022 | Volume
: 1
| Issue : 4 | Page : 196-202 |
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Clinical pharmacology of cefazolin
Gian Maria Pacifici
via Sant’Andrea 32, Pisa, Italy
| Date of Submission | 05-May-2022 |
| Date of Decision | 24-Aug-2022 |
| Date of Acceptance | 28-Aug-2022 |
| Date of Web Publication | 31-Oct-2022 |
Correspondence Address:
Prof. Gian Maria Pacifici
via Sant’Andrea 32, 56127 Pisa
Italy
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/abhs.abhs_31_22
Cefazolin is a first-generation cephalosporin that is active against gram-positive bacteria and has modest activity against gram-negative organisms, and cefazolin is excreted by glomerular filtration. The efficacy and safety of cefazolin and cefazolin concentration in body tissues have been described. Cefazolin pharmacokinetics have been studied; six patients received cefazolin at a dose of 1 g thrice daily and one patient received cefazolin at a dose of 2 g once daily and this patient had acute kidney injury. The pharmacokinetics of cefazolin have been studied. The prophylaxis, treatment, and trials with cefazolin have been reported. The penetration of cefazolin into the cerebrospinal fluid has been studied. Cefazolin treats the meningitis caused by Staphylococcus meningitis or by methicillin-susceptible S. aureus and cefazolin may become resistant to bacteria. Cefazolin freely crosses the human placenta and poorly migrates into the breast milk. The aim of this review was to describe cefazolin efficacy and safety, tissue concentration, pharmacokinetics, prophylaxis, treatment, trials, penetration into the cerebrospinal fluid, treatment of bacterial meningitis, resistance, transfer across the human placenta, and migration into the breast milk. Keywords: Breast milk, cefazolin, cerebrospinal-fluid, efficacy-safety, meningitis, pharmacokinetics, placenta, prophylaxis, resistance, tissue-concentration, treatment, trials
How to cite this article:
Pacifici GM. Clinical pharmacology of cefazolin. Adv Biomed Health Sci 2022;1:196-202 |
| Introduction | |  |
Cefazolin is a first-generation cephalosporin and is relatively well tolerated after either intramuscular or intravenous administration. Cefazolin is excreted by glomerular filtration and is bound approximately 85% bound to plasma protein. Cefazolin is the only parenteral first-generation cephalosporin market in the United States. Cefazolin has good activity against gram-positive bacteria and modest activity against gram-negative microorganisms. Most gram-positive cocci (with the exception of enterococci, methicillin-resistant Staphylococcus aureus, and Streptococcus epidermidis) are susceptible. Most oral cavity anaerobes are sensitive, but Bacillus fragilis group is resistant. Cefazolin is a useful drug but has modest activity against Moraxella catarrhalis, Escherichia coli, Klebsiella pneumonia, and Proteus mirabilis [1]. Cefazolin is a first-generation cephalosporin and is active against gram-positive bacteria and has modest activity against gram-negative microorganisms.
Cefazolin molecular structure (molecular weight = 454.51 g/mole)
Literature search
The literature search was performed electronically using the PubMed database as a search engine and the following keywords were used: “cefazolin efficacy, safety,” “cefazolin tissue concentration,” “cefazolin pharmacokinetics,” “cefazolin prophylaxis,” “cefazolin treatment,” “cefazolin trials,” “cefazolin CSF,” “cefazolin meningitis,” “cefazolin resistance,” “cefazolin placental transfer,” and “cefazolin breast-milk” and 44 articles have been reviewed.
| Results | | |
Efficacy and safety of cefazolin
Cefazolin is efficacy and safe in the treatment of methicillin-susceptible S. aureus and cefazolin is better tolerated than anti-Staphylococcus penicillins [2]. Cefazolin is an efficacy and safe first-line option in patients with methicillin-susceptible S. aureus infection and the efficacy is similar to that of antistaphylococcal penicillin therapy [3]. Cefazolin is efficacy and safe in the treatment of bacteremia caused by methicillin-susceptible S. aureus [4]. Cefazolin is efficacy and safe in the treatment of skin and skin structure caused by methicillin-resistant S. aureus [5]. Cefazolin is efficacy and safe as cloxacillin in the treatment of infection caused by methicillin-susceptible S. aureus [6]. Three grams daily of cefazolin is efficacy and safe as 2 g daily of cefazolin in the treatment of surgical infection caused by Clostridium difficile [7].
Concentration of cefazolin in body-tissues
After a dose of 4 g daily of cefazolin to 116 obese patients, the concentration of cefazolin in fatty tissue is above 4 μg/g and cefazolin provides adequate tissue concentration during bariatric surgery [8]. Then children submitted to surgery received a cefazolin dose of 30 mg/kg daily and the peak concentration in skeletal muscle reached a median of 40.5 µg/g within 30 to 60 min [9]. Twenty-two patients undergoing surgery received cefazolin at a dose of 1 g daily and the mean concentration of cefazolin in subcutaneous fat was 186 µg/g and in the intraosseous was 11 µg/g [10]. Twenty obese women undergoing caesarean delivery received cefazolin at a dose of 4 g daily and the myometrial cefazolin concentration was 40.1 ± 24.1 µg/g [11]. Twenty-eight obese women undergoing caesarean delivery received 3 g daily of cefazolin 30 to 60 min before skin incision and the median concentration of cefazolin in the body fat was 4.7 μg/g [12].
Pharmacokinetics of cefazolin in patients with lower extremity wound infections
Bhalodi et al.[13] studied the pharmacokinetics of cefazolin in seven patients with lower extremity wound infections and cefazolin was administered intravenously at a dose of 1 g thrice daily (n = 6) and at a dose of 2 g once daily (n = 1). Patients had uncontrolled diabetes with elevated glycosylated hemoglobin levels due to a long-stating history of noncompliance. Patients had severe chronic foot wound infection requiring surgical intervention such as debridement or amputation in addition to intravenous antibiotics. Patients also had decreased blood flow at their extremities which can make it difficult to achieve adequate cefazolin concentration at the site of infection. One of the seven patients did have significant neuropathy that resulted in his foot infection. Inadequate treatment of lower extremity wound infections can lead to increased resistance, chronic infection, and subsequently foot amputation. [Table 1] summarizes the demographic characteristics of the patients included in this study and [Table 2] summarizes the pharmacokinetic parameters of cefazolin. | Table 1: Demographic characteristics of patients included in the study.
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 | Table 2: Pharmacokinetic parameters of cefazolin are obtained at steady state.
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[Table 2] shows that cefazolin is rapidly eliminated in patients who received cefazolin at a dose of 1 g thrice daily. In the patient who received cefazolin at a dose of 2 g once daily, the elimination half-life is longer because this patient had an acute kidney injury. In this patient, the area under the concentration–time (AUC) is greater than that obtained in the other patients. In six patients, who received cefazolin at a dose of 1 g thrice daily, the pharmacokinetic parameters remarkably vary, and the variability is accounted for by the differences in each patient's individual pharmacokinetics as well as by the severity of the disease. The minimum cefazolin concentration in lower extremity wounds is lower than that in serum, whereas the AUC is similar in tissue and in serum and it is sufficient to control the infection. Cefazolin tissue concentrations remained above 1 µg/mL for 60% of the dosing interval in one patient and for 100% of the dosing interval in six patients who received 1 g of cefazolin thrice daily. The mean penetration rate of cefazolin into the infected tissue for all patients was 1.06 ± 0.78. The tissue cefazolin concentrations appear sufficient as the minimum inhibitory concentration (MIC)50/90 values of cefazolin, against methicillin-susceptible S. aureus, are ≤0.5 and ≤1 µg/mL, respectively.
Prophylaxis with cefazolin
Cefazolin prevents infections in patients undergoing surgery [14], and prevents surgical infection in women undergoing caesarean section [15]. Prophylaxis with cefazolin prevents surgical site infection in women undergoing hysterectomy [16]. The addition of teicoplanin to cefazolin, for the prophylaxis of arthroplasty surgery, was associated with a reduction in the incidence of prosthetic joint infection caused by gram-positive bacteria [17]. Prophylaxis with cefazolin prevents infection in patients undergoing skin surgery [18]. Prophylaxis with cefazolin prevents infection in patients with ulcerated non-melanocytic skin tumor undergoing surgery [19]. Prophylaxis with cefazolin prevents the infection caused by gram-positive aerobic and anaerobic cocci as well as gram-negative bacilli in patients undergoing maxillofacial surgery [20]. Cefazolin was administered 1 h before skin incision in patients undergoing neurosurgery and prophylactic cefazolin prevented the infection in these patients [21].
Treatment of bacterial infections with cefazolin
Cefazolin is active against gram-positive and gram-negative bacteria. Cefazolin reduced the length of hospital stay, and the mortality-rate, and cured patients with bacteremia caused by methicillin-susceptible S. aureus [22]. In patients with endocarditis, cefazolin is effective as an anti-Staphylococcal penicillin while being associated with less nephrotoxicity [23]. Cefazolin is efficacious in treating bacteremia caused by E. coli, Klebsiella species, or P. mirabilis [24]. Cefazolin is similar to oxacillin in the treatment of complicated bacteremia caused by methicillin-susceptible S. aureus [25]. Cefazolin administered by a continuous and prolonged infusion treated patients with bone and joint infections [26]. Serious infections caused by methicillin-susceptible S. aureus were successfully treated with cefazolin [27]. Acute enteric fever caused by Salmonella typhi was successfully treated by cefazolin [28]. In conclusion, cefazolin has good activity against gram-positive bacteria and modest activity against gram-negative microorganisms.
Trials with cefazolin
In patients undergoing hemodialysis, a solution containing gentamicin 7 mg/mL plus cefazolin 12 mg/mL plus heparin 3500 IU/mL) effectively treated the catheter-related bloodstream infection [29]. Cefazolin was associated with significant reductions in all-cause mortality and clinical failure in patients with infection caused by methicillin-susceptible S. aureus [30]. Cefazolin successfully treated bacteremia caused by methicillin-susceptible S. aureus [31]. Prophylaxis with cefazolin plus azithromycin during caesarean delivery is efficacy, well tolerated, and decreased postoperative infections [32]. Intraoperative continuous infusions of cefazolin increased the achievement of target plasma concentrations even with lower infusion doses [33]. Continuous infusions of cefazolin achieved a better probability of target attainment and fractional target attainment than intermittent dosing and reduced the incidence of perioperative infections [34]. Intravenous cefazolin, administered at a dose of 2 g daily plus oral probenecid administered at a dose of 1 g daily, is an effective regimen in the treatment of skin and soft tissue infections [35].
Penetration of cefazolin into the cerebrospinal fluid
Grégoire et al.[35] investigated the penetration of cefazolin into the cerebrospinal fluid (CSF) in 10 patients with severe methicillin-susceptible S. aureus infection and cefazolin was administered by intravenous infusion at a dose of 10 g daily or 8 g daily. The methicillin-susceptible S. aureus had a minimum inhibitory concentration of ≤1 µg/mL.
[Table 3] shows that cefazolin penetrates into the CSF in significant amounts and the unbound cefazolin concentration in the CSF is greater than the minimum inhibitory concentration of methicillin-susceptible S. aureus (≤1 µg/mL); thus, this pathogen was eradicated from the CSF. | Table 3: Cefazolin concentrations in plasma and in cerebrospinal fluid (CSF) which are obtained after the continuous intravenous infusion of cefazolin at a dose of 10 or 8 g daily.
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Novak et al.[36] studied the pharmacokinetics of cefazolin in the CSF of 15 critically ill patients, aged 56 years (range, 51 to 60), with subarachnoid hemorrhage and cefazolin was administered by intravenous infusion at a dose of 2 g thrice daily.
[Table 4] shows that cefazolin is slowly eliminated from the CSF as the median elimination half-life of cefazolin is 6.5 h in all patients. The minimum inhibitory concentration of methicillin-susceptible S. aureus is ≤1 µg/mL and cefazolin peak and minimum concentration are higher than 1 µg/mL; thus, cefazolin achieves significant amounts in the CSF and the methicillin-susceptible S. aureus should be eradicated from the CSF. The elimination half-life of cefazolin in the CSF is longer in patients with creatinine clearance >0.5 mL/min than in all patients; thus, the cefazolin trough concentration is lower in patients with creatinine clearance >0.5 mL/min that in all patients. The CSF to serum AUC ratio is lower in patients with high creatinine clearance than in all patients. | Table 4: Pharmacokinetic parameters of cefazolin obtained in both serum and cerebrospinal fluid.
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Treatment of bacterial meningitis with cefazolin
Cefazolin was administered at a mean dose of 8 g daily (range, 6 to 12) to 17 patients with meningitis caused by S. meningitis. Cefazolin mean concentration in the CSF was 2.8 µg/mL (range, 2.1 to 5.2). This cefazolin concentration is higher than the minimum inhibitory concentration (≤1 µg/mL) of S. meningitis and the meningitis was cured in all patients [37]. Six-hundred four patients had the meningitis caused by methicillin-susceptible S. aureus and were treated with intravenous cefazolin at a dose of 2 g thrice daily. The mean concentration of cefazolin in the CSF was 2.8 µg/mL. This concentration is higher than the minimum inhibitory concentration (≤1 µg/mL) of methicillin-susceptible S. aureus and the meningitis was cured in most patients [38].
Bacterial resistance to cefazolin
Some bacteria may become resistant to cefazolin. The susceptibility rate of E. coli to cefazolin was 62% to 73% from the 2003 to 2010 but it dropped to 23% in 2011, 15% in 2012, and dramatically decreased to 10% in 2010. Thus, E. coli may become resistant to cefazolin [39]. Fecal samples were obtained from 180 patients on hospital admission and from 108 patients at discharge and the samples were analyzed for the degree of resistance of cefazolin to E. coli and enterococci. The resistance rate to cefazolin was observed in 35% of E. coli and in 27% of enterococci. Thus E. coli and enterococci had a considerable resistance rate to cefazolin [40]. Of the 485 cultures analyzed, 66.4% (322 cultures) were positive for coagulase-negative Staphylococcus or for methicillin-susceptible S. aureus. The resistance rate was 13% for coagulase-negative Staphylococcus and 23% for methicillin-susceptible S. aureus [41]. Thus cefazolin may become resistant to different bacteria.
Transfer of cefazolin across the human placenta
Six women at delivery received a single oral cefazolin at a dose of 4 g. The mean serum cefazolin concentration was 18.0 ± 3.4 µg/mL in the maternal serum. The mean cefazolin concentration was 21.0 ± 17.8 in the cord serum of hydropic fetuses and 21.2 ± 17.8 µg/mL in the cord serum of non-hydropic fetuses. Thus cefazolin freely crossed the human placenta [42]. Cefazolin was administered intravenously at a dose of 0.5 g daily to 70 pregnant women undergoing a selective abortion. Cefazolin promptly crossed the placental barrier however the cefazolin concentrations in the fetus were considerably lower than those observed in the second and third trimesters of pregnancy [43].
Secretion of cefazolin into the breast milk
In the literature, there is only one study on the secretion of cefazolin into the breast milk and it has been reported by Yoshioka et al. [44]. Cefazolin was administered by intravenous infusion at a dose of 2 g daily to 20 lactating women and the cefazolin daily content in the breast milk was 0.75% of the maternal dose. This finding is consistent with the view that cefazolin poorly migrates into the breast milk.
| Discussion | | |
Cefazolin is a first-generation cephalosporin that is active against gram-positive bacteria, has modest activity against gram-negative organisms, and is excreted by glomerular filtration [1]. The efficacy and safety of cefazolin have been described [2],[3],[4],[5],[6],[7]. Cefazolin is efficacy and safe in the treatment of methicillin-susceptible S. aureus infection and is better tolerated than anti-Staphylococcus penicillins [2], cefazolin is a first-line option in infection caused by methicillin-susceptible S. aureus and the efficacy is similar to that of antistaphylococcal penicillin therapy [3], cefazolin is efficacy and safe in the treatment of bacteremia [4] and skin and skin structure caused by methicillin-susceptible S. aureus [5], cefazolin is efficacy and safe as cloxacillin in treatment of methicillin-susceptible S. aureus [6], and 3 g daily of cefazolin are efficacy and safe as 2 g daily of cefazolin in treatment of infection caused by Clostridium difficile [7]. The concentration of cefazolin in body tissues has been reported in five studies [8],[9],[10],[11],[12]. Following a cefazolin dose of 4 g daily, the cefazolin concentration in fatty tissues is above 4 µg/kg [8], after a cefazolin dose of 30 mg/kg daily to children, the median concentration of cefazolin in skeletal muscle is 40.5 µg/g within 30 to 60 min after dosing [9], cefazolin was administered at a dose of 1 g daily and the mean concentration of cefazolin in subcutaneous fat is 186 µg/g [10]. Cefazolin was administered at a dose of 4 g daily to obese women undergoing Caesarean delivery and the cefazolin mean concentration in the myometrial is 40.1 µg/g [11], and obese women undergoing caesarean delivery received 3 g daily of cefazolin and the median cefazolin concentration in body-fat is 4.7 µg/g [12]. The pharmacokinetics of cefazolin have been investigated in 7 patients with lower extremity wound infections and diabetes [13]. Six patients received cefazolin at a dose of 1 g thrice daily and 1 patient received cefazolin at a dose of 2 g once-daily and this patient also had acute kidney injury. The elimination mean half-life of cefazolin is 3.51 h in 6 patients and 39.82 h in the patient with acute kidney injury. Cefazolin is cleared from the body by the renal route and the elimination half-life is longer in the patient with acute kidney injury. The prophylaxis with cefazolin has been extensively described [14],[15],[16],[17],[18],[19],[20],[21]. Prophylaxis with cefazolin prevents infections in patients undergoing surgery [14], prevents infection in women undergoing Caesarean delivery [15], and in women undergoing hysterectomy [16]. The prophylaxis with teicoplanin plus cefazolin reduces the incidence of prosthetic joint infection caused by gram-positive bacteria [17]. Prophylaxis with cefazolin prevents the infection in patients undergoing skin surgery [18], prevents the infection in patients with skin tumors undergoing surgery [19], prevents the infection caused by aerobic and anaerobic gram-negative bacilli in patients undergoing maxillofacial surgery [20], and prevents the infection in patients undergoing neurosurgery [21]. The treatment of bacterial infections with cefazolin has been reported [22],[23],[24],[25],[26],[27],[28]. Cefazolin cures the bacteremia caused by methicillin-susceptible S. aureus [22], cures the endocarditis and cefazolin is effective as an anti-staphylococcal penicillins and is associated with less nephrotoxicity [23], cefazolin effectively treats the bacteremia caused by E. coli, Klebsiella species, or P. mirabilis [24], cefazolin is effective as oxacillin in treatment of complicated bacteremia caused by methicillin-susceptible S. aureus [25], continuous and prolonged infusion of cefazolin treats bone and joint infections [26], cefazolin treats serious infections caused by methicillin-susceptible S. aureus [27], and cefazolin treats acute enteric fever caused by S. typhi [28]. Trials with cefazolin have been reported [29],[30],[31],[32],[33],[34],[35]. A solution containing gentamicin 7 mg/mL plus cefazolin 12 mg/mL plus heparin 3500 IU/mL treats catheter-related bloodstream infection in patients undergoing hemodialysis [29], cefazolin reduces all-cause mortality and clinical failure in patients infected by methicillin-susceptible S. aureus [30], and cefazolin treats bacteremia caused by methicillin-susceptible S. aureus [31], cefazolin plus azithromycin decreases postoperative infections during caesarean delivery [32]. Intraoperative continuous infusion of cefazolin achieves target plasma concentrations even with lower doses [33], continuous infusion of cefazolin is more efficacy than intermittent infusion in reducing the incidence of perioperative infections [34], and intravenous cefazolin, administered at a dose of 2 g daily plus oral probenecid administered at a dose of 1 g daily, treats skin and soft tissue infections [35]. The penetration of cefazolin into the CSF has been reported in two studies [35,36]. Following continuous infusion of cefazolin at a dose of 10 g daily or 8 g daily to patients with severe infection caused by methicillin-susceptible S. aureus, the mean unbound cefazolin concentration in the CSF is 11.9 and 6.1 µg/mL, respectively, and these concentrations are higher than the minimum inhibitory concentration (≤1 µg/mL) of methicillin-susceptible S. aureus [35]. The pharmacokinetics of cefazolin in the CSF have been studied in 15 patients with subarachnoid hemorrhage and cefazolin was intravenously infused at a dose of 2 g thrice daily. The mean peak cefazolin concentration in the CSF is approximately 3 µg/mL and this concentration is higher than the minimum inhibitory concentration (≤1 µg/mL) of methicillin-susceptible S. aureus which is the infective organism. Cefazolin mean elimination half-life in the CSF is 6.5 h in all patients. Thirteen of these patients had a creatinine clearance >50 mL/min and cefazolin mean elimination half-life is 0.08 h in these patients [36]. The treatment of bacterial meningitis has been reported in 2 studies [37,38]. Following the administration of cefazolin at a mean dose of 8 g daily to patients with meningitis caused by S. meningitis the mean cefazolin concentration in the CSF is 2.8 µg/mL and this concentration is higher than the minimum inhibitor concentration (≤1 µg/mL) of the infective organism and the meningitis was cured in all patients [37]. Patients, with meningitis caused by methicillin-susceptible S. aureus, were treated with cefazolin at a dose of 2 g thrice daily. The mean cefazolin concentration in the CSF is 2.8 µg/mL, this concentration is higher than the minimum inhibitory concentration (≤1 µg/mL) of the infective organism, and the meningitis was cured in most of the patients [38]. The bacterial resistance to cefazolin has been described in 3 studies [39],[40],[41]. The susceptibility rate of E. coli decreased from 2003 to 2012 [39], E. coli and enterococci were isolated from fecal samples and the resistance rate to cefazolin is 35% and 27%, respectively [40], the resistance-rate to coagulase-negative Staphylococcus and to methicillin-susceptible S. aureus is 13% and 23%, respectively [41]. The transfer of cefazolin across the human placenta has been reported in 2 studies [42,43] and cefazolin freely crossed the human placenta. The secretion of cefazolin into the breast milk has been documented in a study and cefazolin poorly migrates into the breast milk [44].
In conclusion, cefazolin is a first-generation cephalosporin that is active against gram-positive bacteria has modest activity against gram-negative organisms, and is eliminated by glomerular filtration. The efficacy and safety of cefazolin have been reported and cefazolin concentrates in body tissues in significant amounts. The pharmacokinetics of cefazolin, the prophylaxis, treatment, and trials with cefazolin have been reported. Cefazolin penetrates into the CSF in significant amounts and treats bacterial meningitis. Cefazolin may become resistant to bacteria, freely crosses the human placenta, and poorly migrates into the breast milk. The aim of this review was to review the clinical pharmacology of cefazolin. Cefazolin is a first-generation cephalosporin and is active against gram-positive bacteria and has modest activity against gram-negative microorganisms.
Acknowledgement
The author thanks Dr. Patrizia Ciucci and Dr. Francesco Varricchio, of the Medical Library of the University of Pisa, for retrieving the scientific literature.
Financial support and sponsorship
Not applicable.
Conflicts of interest
The authors declare no conflicts of financial interest in any product or service mentioned in the manuscript, including grants, equipment, medications, employments, gifts, and honoraria. This article is a review and drugs have not been administered to men or animals.
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[Table 1], [Table 2], [Table 3], [Table 4]
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