penicillanic acid, is a semisynthetic, narrow-spectrum b-lactam
antibiotic  derived from the penicillin nucleus, 6-aminopenicillanic acid. As
a b-lactamase-resistant penicillin, it is used to
treat infections caused by Gram-positive bacteria, in particular, species of
staphylococci that are resistant to other penicillins. Developed in 1961, it has
since been widely used in the United States and a small number of other
countries for the parenteral treatment of serious b-lactamase-producing
Nafcillin is indicated in the treatment of staphylococcal infections, except those caused by MRSA. U.S. clinical practice guidelines recommend either nafcillin or oxacillin as the first-line treatment of choice for staphylococcal endocarditis in patients without artificial heart valves .
S. aureus infections
Parenteral nafcillin has been used successfully for the
treatment of severe S. aureus infections, such as septicemia,
endocarditis, osteomyelitis, septic arthritis, pneumonia, meningitis, skin and
skin structure infections, and pyomyositis [4-12]. In the USA, nafcillin is
Although the synergistic combination of nafcillin plus gentamicin has usually demonstrated superior therapeutic effect, compared with nafcillin alone, in experimental animals , it remains somewhat uncertain whether this synergistic nafcillin–gentamicin combination is clinically superior to nafcillin alone for the treatment of human endocarditis caused by tolerant or nontolerant S. aureus strains. It may be reasonable to initiate combination therapy in patients with S. aureus endocarditis, but the aminoglycoside should be stopped after clearance of bacteremia (3–5 days) and that nafcillin alone be continued for a total of 6 weeks .
The high prevalence of S. aureus as a cause of acute and chronic osteomyelitis means that nafcillin is widely used for initial treatment of this condition [17-18]. A rifampicin–nafcillin combination has been used to treat chronic staphylococcal osteomyelitis, with a trend towards better outcomes; however, the advantages of this combination are not deﬁnitive .
In Australia and in Europe, one of the parenteral isoxazolyl penicillins, such as cloxacillin or ﬂucloxacillin, is commonly used, while in the USA, oxacillin is an effective alternative. The response obtained in severe staphylococcal infections is about the same with all of these drugs, provided they are given parenterally in appropriate doses.
Because of its better penetration into the CSF, some authors regard nafcillin as the drug of choice for staphylococcal meningitis [20-21]. If nafcillin is used for this purpose, the parenteral dose should be at least 2 g 4 hourly for adults [22-23]. For the treatment of staphylococcal meningitis, a nafcillin–rifampicin combination may prove to be more effective .
Infections due to coagulase-negative staphylococci
Nafcillin can be used to treat severe hospital-acquired infections caused by these organisms, such as prosthetic valve endocarditis, provided the strain is methicillin sensitive. The addition of either gentamicin or rifampicin, or both, to the nafcillin regimen may improve the results of treatment . If the strain is methicillin resistant, which is frequent if the infection is hospital acquired, vancomycin should be used and the addition of either rifampicin or gentamicin, or both, may be of beneﬁcial [26-27]. Chemoprophylaxis with nafcillin plus rifampicin has been used for patients undergoing cardiac valve surgery. However, in one study, more than half of the patients receiving such chemoprophylaxis became colonized by S. epidermidis strains resistant to methicillin, gentamicin, and rifampicin .
Dosage and Administration
Nafcillin comes as a 1- and 2-g parenteral formulation for intravenous and intramuscular use.
Owing to low and unpredictable absorption, nafcillin is not recommended for oral administration. Nafcillin can be given either i.m. or i.v. Intramuscular administration results in a peak concentration of 5–8 mg/ml after 500-mg to 1-g doses. The usual adult i.v. dosage is 1 g 4-hourly, but this can be doubled for the treatment of severe infections, in particular endocarditis. Doses of up to 18 g i.v. daily have been given to adults with no ill effects. The drug should be given i.v. using techniques as described for penicillin G. Nafcillin has been given prophylactically directly into surgical wounds at the time of closure  and can be used to treat continuous ambulatory peritoneal dialysis-associated peritonitis by instillation in the dialysate at a concentration of 125 mg/l . Nafcillin is quite stable in peritoneal dialysate solutions .
Newborn infants and children
The usual parenteral pediatric dose is 25 mg/kg 4-hourly; higher doses of 50 mg/kg 4-hourly can be given safely. In newborns, the recommended dosage for severe infection is 100 mg/kg/day, given in two divided doses for infants less than 7 days of age, and in three divided doses for those older than 7 days . In those with birth weights less than 2000 g, a dose of 20 mg/kg body weight, administered 8-hourly, is probably sufﬁcient .
Impaired renal function
Nafcillin is eliminated from the body rapidly and primarily by nonrenal mechanisms , so that dosage reduction is not needed in patients with renal impairment. The plasma nafcillin elimination half-life is unaltered in anuric patients during hemodialysis and in the interval between dialyses, so that patients can be treated by a nafcillin dosage used for patients with normal renal function .
Impaired hepatic function
As nafcillin is normally cleared through the liver, impaired hepatic function alters kinetics. Cirrhosis and extrahepatic biliary obstruction alter clearance to some extent, although there is at least partial compensation through increased renal clearance 35]. Thus, serum levels may need to be monitored in patients with severe hepatic impairment, and dosage adjustments need to be made accordingly. There are no formal recommendations for dosage reduction, with each patient’s individual situation requiring consideration.
Serious toxicity is unlikely following large doses of nafcillin. Acute ingestion of large doses of nafcillin may cause nausea, vomiting, diarrhea and abdominal pain. Acute oliguric renal failure and hematuria may occur following large doses.
Overall adverse reaction rates to nafcillin when used as deﬁnitive treatment are approximately 20–30% [36-37]. Different rates, either higher or lower, have been recorded when used for prolonged periods, such as for outpatient treatment [38-39]. Serious reaction rates are <5%.
Nafcillin, like other penicillins, may cause the same hypersensitivity reactions that occur with penicillin G. Most common is skin rash . The drug is contraindicated in any patient with a history of penicillin sensitivity. Rash is less likely with nafcillin than with oxacillin .
A patient who developed renal damage due to methicillin, resolved when lincomycin was substituted . Later, when therapy was changed to nafcillin, the hypersensitivity nephritis recurred. Nephropathy has been reported on many occasions with methicillin, but less commonly with other penicillinase-resistant penicillins. If nephropathy develops after the use of one penicillin analog, it is likely to recur if any other penicillin is subsequently used.
Nafcillin administered in large doses i.v. (200 mg/kg/day) can cause hypokalemia and associated alkalosis . Nafcillin acts as a non-reabsorbable anion and increases passive renal distal tubular potassium excretion. This is similar to what occurs with other penicillins used in large doses, such as penicillin G. Hypokalemia may resolve when the nafcillin dose is reduced .
Nafcillin in the urine can cause a false-positive urine reaction for protein when the sulfasalicylic test is used, but not with the dipstick test. Unrecognized, this may lead to unnecessary cessation of the drug and even renal biopsy . Penicillin G and oxacillin can also cause false-positive urine protein determinations, but to a lesser degree.
Neutropenia with concomitant fever occurred in one patient receiving a daily dose of 12 g i.v. nafcillin. This complication resolved when the drug was stopped . In another patient, i.v. nafcillin therapy (12 g daily) was associated with the development of agranulocytosis, which only improved after the drug was discontinued . Four of 29 patients with serious staphylococcal infections treated with nafcillin had fever rash and neutropenia . Neutropenia appears to be a common complication of prolonged outpatient intravenous therapy . Two patients treated with high daily doses of nafcillin i.v. (12–14 g) developed abnormal bleeding times and one had a bleeding episode. This was due to platelet dysfunction, similar to that described with penicillin G .
Skin and tissue necrosis
This can occur after accidental subcutaneous extravasation of i.v. nafcillin, and may necessitate multiple tissue debridements and skin grafting. In animals, tissue necrosis occurs after subcutaneous inoculation of nafcillin, but not with oxacillin, methicillin, and cephalothin . In humans, nafcillin-induced tissue injury can be prevented by prompt administration of hyaluronidase into the site of extravasation .
Hepatotoxicity has been described with all the antistaphylococcal penicillins. Rates of toxicity, at least in the setting of outpatient intravenous therapy, are signiﬁcantly lower for nafcillin than oxacillin .
Nafcillin is comparatively poorly and inconsistently absorbed from the gastrointestinal tract compared with the isoxazolyl penicillins . Doses of 500 mg and 1 g orally yield peak concentrations of 3.2 ± 1.9 mg/ml and 7.7 ± 2.7 mg/ml, respectively; thus, serum levels following oral nafcillin are low and irregular. Administration with food halves absorption [50-52]. Therefore, oral administration of nafcillin is not recommended. The elimination half-life of nafcillin in normal adults ranges from 0.7 to 1.4 hours [33, 53-54]; in children, it is 0.76 ± 0.03 hours and is little inﬂuenced by age . Nafcillin has a high degree of protein binding to serum albumin, depending on the type of assay, binding ranges from 79% to 90% with an average of around 88% .
Following i.v. infusion of a 0.5 g dose of nafcillin over 15 minutes to adults, the serum level is 11 mg/ml at the end of the infusion and 0.5 mg/ml at 6 hours . After an i.m. injection of 1 g nafcillin, a peak serum level of about 8 mg/ml is reached 1 hour later; it falls to about 0.5 mg/ml at 6 hours . Concomitant oral administration of probenecid increases and prolongs nafcillin levels, similar to other penicillins . Probenecid reduces urinary recovery by 50%, decreases both renal and nonrenal clearance, and doubles the AUC .
In children with active infection administered 37.5 mg/kg of nafcillin 6-hourly, infused over 15 minutes, concentrations at 30 minutes (near peak) were around 50 mg/ml , whereas in children having cerebrospinal ﬂuid (CSF) shunt replacement, peaks after 50 mg/kg were 22–107 mg/ml. The kinetics of nafcillin in children are summarized in Table 1.
Table 1. Nafcillin kinetics in children.
About 30% of an i.m. administered dose of nafcillin can be recovered from the urine where concentrations reach as high as 1000 mg/ml. A considerably smaller amount of active nafcillin (about 19% of the administered dose) is recovered from the urine after i.m. administration if it is given with probenecid [58-59]. A small amount of active drug, probably only about 8% of an i.m. dose, is eliminated via the bile . The remainder of administered nafcillin appears to be inactivated in the liver .
There is evidence that it induces
cytochrome P-450 enzymes .
Mechanism of Action
Penicillinase-resistant penicillins exert a bactericidal action against penicillin-susceptible microorganisms during the state of active multiplication. All penicillins inhibit the biosynthesis of the bacterial cell wall. It acts like other penicillins in the penicillin-binding proteins, principally PBPs 1a, 1b, and 2.
The in vitro susceptibility of key pathogens to nafcillin are summarized in Tables 2 and 3.
Table 2. In vitro activity of nafcillin.
Table 3. Minimum inhibitory concentration (MIC) distributions for nafcillin among key species.
Nafcillin has a very similar antibacterial spectrum to the isoxazolyl penicillins (Isoxazolyl Penicillins: Oxacillin, Cloxacillin, Dicloxacillin and Flucloxacillin). It is about as active as oxacillin against both penicillin G-susceptible and penicillin G-resistant Staphylococcus aureus strains . Stability of nafcillin in the presence of staphylococcal b-lactamase (penicillinase) is similar to that of methicillin and greater than that of the isoxazolyl penicillins. Nafcillin shows superior activity to glycopeptides in an animal model of subcutaneous abscesses induced by methicillin-susceptible S. aureus . Methicillin-resistant S. aureus strains are resistant to all penicillinase-resistant penicillins, including nafcillin [68-69]. Both penicillin G-susceptible and b-lactamase-producing strains of coagulase-negative staphylococci are nafcillin susceptible. In many settings, over 50% of coagulase-negative staphylococci are methicillin-resistant, and these are resistant to nafcillin . Penicillin tolerant S. aureus and coagulase-negative staphylococci are usually also tolerant to nafcillin.
As with isoxazolyl penicillins, this may vary in vivo
in different parts of the body. Thus, in the presence of
polyvinylchloride catheters, the minimum bactericidal concentrations (MBCs) of
nafcillin for coagulase-negative staphylococci are considerably higher than in
the absence of such catheters . Nafcillin and gentamicin (and other
aminoglycosides) are synergistic in vitro against most S. aureus
Other pharmacological effects
Nafcillin is a semisynthetic antibiotic substance derived from 6-amino-penicillanic acid. The drugs in this class are highly resistant to inactivation by staphylococcal penicillinase and are active against penicillinase-producing and non penicillinase-producing strains of Staphylococcus aureus. The penicillinase- resistant penicillins are active in vitro against a variety of other bacteria.
Like other penicillins, the antistaphylococcal penicillins show only slight concentration-dependent killing, with maximum effects reached at concentrations 3- to 4-fold higher than the MIC . The in vitro postantibiotic effect of antistaphylococcal penicillins against S. aureus is moderate at most, of the order of 1.5-2 hours depending on concentration and time of exposure . In vivo, the postantibiotic effect is somewhat longer, for example 3 hours for nafcillin against S. aureus .
CAS number: 147-52-4 EINECS: 205-690-9
Molecular Formula: C21H22N2O5S
Average mass: 436.457
Monoisotopic mass: 436.106887157
Systematic name: (2S,5R,6R)-6-(2-ethoxynaphthalene-1-amido)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid
Std. InChI: 1S/C21H22N2O5S/c1-4-28-13-10-9-11-7-5-6-8-12(11)14(13)17(24)22-15-18(25)23-16(20(26)27)21(2,3)29-19(15)23/h5-10,15-16,19H,4H2,1-3H3,(H,22,24)(H,26,27)/t15-,16+,19-/m1/s1
Solubility: soluble in water
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