Patient Variables Associated with Nafcillin Plasma Concentrations and Toxicity.

PRIMARY OBJECTIVE: To retrospectively review nafcillin plasma concentrations (CNAF ) and determine nafcillin clearance (CLNAF ) in a diverse sample of patients treated with nafcillin administered as a continuous infusion. SECONDARY OBJECTIVE: To identify clinical variables associated with CLNAF and nafcillin-related adverse drug reactions (ADRs). METHODS: Retrospective chart review of patients receiving nafcillin via continuous infusion at University of Utah Health Care from 2006 to 2013 who had at least one steady-state CNAF measured. CLNAF was determined by dividing the nafcillin rate of infusion by CNAF . Adverse drug reactions (ADRs) were defined using the National Institutes of Health, Division of Microbiology and Infectious Diseases criteria and scored for probability of association with nafcillin by using Naranjo criteria. Multivariate models were constructed to identify independent variables associated with CLNAF and ADRs. MAIN RESULTS: Seventy-six CNAF from 54 patients were included. Median CLNAF was 13.9 L/hour (range ≤ 4.2 to 36.9 L/hr). Congestive heart failure (p=0.007), hyperbilirubinemia (p<0.0001), and serum creatinine (p<0.0001) were associated with reduced CLNAF , and Hispanic race (p=0.002) was associated with increased CLNAF by multivariate analysis. Twenty patients (37.0%) experienced an ADR. CNAF were significantly higher between patients that experienced an ADR and those that did not (66.0 vs 25.5 mg/L, p<0.001). Individual ADRs associated with CNAF included hepatotoxicity (62.8 vs 27.0 mg/L, p=0.001), nausea/vomiting (80.0 vs 28.5 mg/L, p=0.01), and diarrhea (66.5 vs 26.5 mg/L, p<0.001). Multivariate analysis identified CNAF as being independently associated with ADRs. A putative toxicity relationship between CNAF and predicted probability of ADR was established. CONCLUSIONS: Several patient variables were associated with impaired CLNAF , and elevated CNAF were associated with ADRs. Additional studies assessing the utility of nafcillin therapeutic drug monitoring to minimize toxicity are warranted.

Evidence of an interaction between nifedipine and nafcillin in humans.

AIMS: Nafcillin (Wyeth Laboratories, Philadelphia, PA, USA) has been reported to induce the metabolism of cyclosporin and warfarin, which are known substrates of cytochrome P-450 (CYP). However, there has not been any report to date on its possible interaction with nifedipine, an index substrate of the enzyme, CYP3A4. METHODS: Nine healthy normotensive subjects participated in this randomized placebo-controlled two-way crossover study examining the effects of 5 days' pretreatment of nafcillin 500 mg or placebo four times daily on the pharmacokinetics of an oral dose of nifedipine 10 mg. Plasma nifedipine concentrations were measured by gas chromatography-mass spectro. RESULTS: The area under the plasma nifedipine concentration-time curve (AUC0-alpha) in nafcillin-pretreated subjects (80.9 +/- 32.9 micro g l-1 h-1) was significantly decreased compared with subjects who received only nifedipine (216.4 +/- 93.2 micro g l-1 h-1) (P < 0.001). Total plasma clearance of nifedipine (CL/F) was significantly increased with nafcillin pretreatment (138.5 +/- 42.0 l h-1 vs 56.5 +/- 32.0 l h-1) (P < 0.002). CONCLUSIONS: The results show that nafcillin pretreatment markedly increased the clearance of nifedipine and suggest that nafcillin is a potent inducer of CYP enzyme.

Comparative evaluation of oral levofloxacin and parenteral nafcillin in the treatment of experimental methicillin-susceptible Staphylococcus aureus osteomyelitis in rabbits.

Methicillin-susceptible Staphylococcus aureus (MSSA) is the most common pathogen recovered from osteomyelitis patients. The current standard therapeutic method for acute phase osteomyelitis is parenteral antibiotic therapy. However, parenteral administration has negative aspects, such as secondary infection, patient inconvenience and high cost. The use of single oral antibiotic therapy may alleviate these problems. Therefore, the purpose of this study was to compare the effectiveness of standard once per day dosing of oral levofloxacin with a standard parenteral antibiotic regimen (nafcillin four times daily) for the treatment of experimental MSSA osteomyelitis in rabbits. Nearly all tibias from untreated infected controls (n = 27) revealed positive cultures (93%) for S. aureus, while the levofloxacin-treated group (n = 20) demonstrated significantly lower percentages of S. aureus infection (50%). The infected tibias of the nafcillin-treated group (n = 20) demonstrated significantly lower percentages (10%) of infected tibias than either the controls or the levofloxacin-treated groups (P < 0.05). The inferior efficacy of levofloxacin may have been due to the pharmacokinetic profile of this fluoroquinolone. The serum kinetics demonstrated that following single dose administration, levofloxacin was almost undetectable after 12 h. Studies in which levofloxacin is dosed every 12 h or given at increased doses in order to obtain bactericidal concentrations throughout the treatment regimen are needed.

Displacement of phenytoin from serum protein carriers by antibiotics: studies with ceftriaxone, nafcillin, and sulfamethoxazole.

Increased concentrations of free phenytoin in serum, attributable to the displacement of this anticonvulsant by other drugs, e.g., valproic acid and salicylic acid, have been reported. We observed in vitro and in vivo displacement of phenytoin by the antibiotics ceftriaxone, nafcillin, and sulfamethoxazole. In vitro studies demonstrated statistically significant (P less than 0.05) increases in free phenytoin after the addition of specific antibiotics to patients' sera and to phenytoin-supplemented sera from controls. Concentrations of free phenytoin in vivo, predicted by an equation we have found to be accurate for albumin concentrations greater than or equal to 32 g/L, were consistently underestimated in patients receiving concomitant therapy with the antibiotics studied. The concentrations of free phenytoin decreased towards the predicted values when the antibiotic therapy was discontinued. We conclude that ceftriaxone, nafcillin, and sulfamethoxazole can displace phenytoin from the usual protein carriers found in serum, in vitro and in vivo.

Pharmacokinetics and cerebrospinal fluid concentration of nafcillin in pediatric patients undergoing cerebrospinal fluid shunt placement.

Postoperative infection is among the most common complications in patients with cerebrospinal fluid shunt placement. Nafcillin is often used for prophylaxis but not pharmacokinetic data are available perioperatively in pediatric patients. The objectives of this study were to characterize the pharmacokinetics and determine the cerebrospinal concentrations of nafcillin. Ten patients (mean age 8.0 +/- 5.6 years) received three doses of intravenous nafcillin, 50 mg/kg every 6 h; the first dose was administered 1 h prior to surgery. Multiple blood samples were collected during and after surgery and the cerebrospinal fluid sample was obtained at the time of shunt insertion. Urine samples were collected for 24 h after initiation of nafcillin. Nafcillin was analyzed with an HLPC method. The peak serum concentrations ranged from 22 to 107 micrograms/ml; cerebrospinal fluid concentrations ranged from 0.02 to 0.30 (mean 0.16 +/- 0.11) micrograms/ml. The mean total clearance, renal clearance, apparent volume of distribution, and elimination half-life were 0.90 +/- 0.55 l/kg/h, 0.12 +/- 0.04 l/kg/h, 0.70 +/- 0.52 l/kg, and 0.5 +/- 0.1 h, respectively. 16% of total nafcillin dose was excreted in the urine. A 4-fold variability in total clearance and a 10-fold variation in cerebrospinal fluid concentrations of nafcillin was observed in these patients. Further, the concentrations of nafcillin attained in the cerebrospinal do not appear to be adequate, based on its minimum inhibitory concentration of 0.5 micrograms/ml against very susceptible staphylococci. These data, in addition to the fact that an increasing number of staphylococci are becoming resistant to nafcillin, question the usefulness of prophylactic nafcillin in pediatric patients undergoing shunt procedures.

A rapid analysis of nafcillin using high-performance liquid chromatography.

A simple, rapid, and reproducible high-performance liquid chromatography method is described for the measurement of nafcillin using an internal standard (IS), 5-(p-hydroxyphenyl)-5-phenylhydantoin. A one-step protein precipitation was used for preparation of nafcillin and IS. The mobile phase included 0.02 M ammonium acetate buffered solution and acetonitrile (75:25 vol/vol). An Ultrasphere ODS reversed-phase column was used and the detector was set at 224 nm. The retention time of IS and nafcillin was 4.8 and 6.6 min, respectively. The absolute recovery for nafcillin ranged from 95-98%. The intraday coefficient of variation for the assay was 3.5% at nafcillin concentrations of 1.0 and 60 micrograms/ml. The interday coefficient of variation was 7.1 and 3.1% at the nafcillin concentrations of 1.0 and 60.0 micrograms/ml, respectively. The major advantages of this method include the single-step extraction and the use of a small volume (50 microliter) of serum samples for nafcillin measurement. The serum concentrations of nafcillin in a pediatric patient were determined to demonstrate the application of this method.

Relationship of staphylococcal tolerance, teichoic acid antibody, and serum bactericidal activity to therapeutic outcome in Staphylococcus aureus bacteremia.

A randomized cooperative study of therapy for Staphylococcus aureus bacteremia was conducted in which nafcillin was given for four or six weeks to patients with clinical endocarditis and for two or four weeks to those without evidence of endocarditis. Eighty-four patients were enrolled, and 32 completed treatment, all of whom had bacteriologic cures. Three patients, treated for two weeks, had complications that were undetectable by assay of serum teichoic acid antibody. Data were insufficient to allow conclusions regarding the optimal duration of therapy for patients with or without endocarditis. However, the results suggest that neither clinical nor immunologic methods can reliably detect complications in patients treated for two weeks only. In addition, patients infected with tolerant organisms remained febrile longer than those infected with nontolerant strains but did not require additional antibiotics for cure. Peak serum bactericidal activity at a dilution of 1:8 or greater was present in all patients. Serum bactericidal activity of 1:8 prior to an antibiotic dose was not necessary for cure.

Serum bactericidal titer as a predictor of outcome in endocarditis.

A study was conducted in 89 rabbits with experimental aortic valve endocarditis caused by three different strains of Staphylococcus aureus to determine whether there was a correlation between the peak serum bactericidal titer of the four drugs tested and the vegetation titer. After four days of therapy both the rabbits with and those without sterile vegetations had median peak bactericidal titers of 1 : 8. The mean vegetation titers did not correlate with the mean bactericidal titers. The serum bactericidal test does not measure the relative rate of killing of the bacteria by the drugs. Although the test remains clinically useful for documentation of bactericidal activity, the minimum level of activity necessary for the test to serve as a predictor of outcome remains to be defined.

Comparison of oral penicillinase-resistant penicillins: contrasts between agents and assays.

We observed the comparative serum levels and mean peak serum antistaphylococcal activity in eight fasting adults who received 500 mg each of dicloxacillin, cloxacillin, oxacillin, and nafcillin. Dicloxacillin achieved higher and more prolonged serum levels and greater peak serum antistaphylococcal titers than the other drugs studied. The higher degree of protein binding of dicloxacillin was reflected in a greater disparity between the peak antistaphylococcal activity observed when dilutions were done in serum compared to broth. The lesser protein-bound penicillins showed less disparity, but this effect was offset by the higher serum levels obtained by dicloxacillin. The higher protein binding of dicloxacillin did not prevent its having equal or superior antistaphylococcal activity in serum when the drugs were given in equal doses.

Penetrance of nafcillin into human ventricular fluid: correlation with ventricular pleocytosis and glucose levels.

Fourteen hydrocephalic pediatric patients with suspected shunt infections were studied for penetrance of nafcillin into the ventricular fluid after intravenous administration. In seven patients with bacterial ventriculitis, the concentration of nafcillin in ventricular fluid was 0.8 to 20.4% of the peak concentration in serum. In the remaining seven patients without bacterial ventriculitis, ventricular fluid levels ranged between less than or equal to 0.02 to 4% of peak serum concentrations. Although the degree of pleocytosis correlated poorly with penetrance, ventricular fluid glucose levels correlated inversely with penetrance of nafcillin (r = -0.7275, P less than 0.001).

A rapid high performance liquid chromatographic procedure for the analysis of cloxacillin and/or nafcillin in serum.

A rapid, reliable procedure for the analysis of cloxacillin and/or nafcillin in 100 microliter of serum or plasma is described. Percentage analytical recovery of cloxacillin, nafcillin, and internal standard (5-(p-hydroxyphenyl)-5-phenylhydantoin) were 94, 91, and 85%, respectively. The between-day precision of the method at cloxacillin concentrations of 2, 8, and 20 mg/liter was 14.7, 11.6, and 10.3%, respectively. At identical serum concentrations, the values obtained for nafcillin were 15.3, 12.4, and 12.2%, respectively. The method will be used to study the pharmacokinetics of both drugs in patients with cystic fibrosis who are on long-term therapy. Preliminary data providing the i.v. half-life, clearance, and volume of distribution are presented for two normal individuals.

New rapid assay for nafcillin in serum by spectrofluorometry.

A new, rapid method for measuring serum levels of nafcillin by spectrofluorometry is described. The method involves extraction of 2 ml of acidified serum with n-butyl chloride, subjecting the organic solvent layer to excitation at 340 nm, and measuring the relative intensity of emission fluorescence at 380 nm. An excellent linear correlation exists between serum levels of nafcillin and the relative intensity in a drug concentration range of 0.25 to 150 mug/ml. The results obtained by this spectrofluorometric technique are in complete accord with those obtained by the conventional microbiological assay using Staphylococcus aureus ATCC 6538P. The method is not interfered with by elevated levels of endogenous metabolic products or the presence of other drugs, including a number of antimicrobial agents. The assay is interfered with, however, by the presence of salicylates, for which appropriate correction can easily be made. A salicylate assay employing a spectrofluorometric technique is also described.

Use of the serum bactericidal titer to assess the adequacy of oral antibiotic therapy in the treatment of acute hematogenous osteomyelitis.

Serum bactericidal titers against Staphylococcus aureus were measured in 63 children who were receiving mafcillin or methicillin intravenously, or dicloxacillin, penicillin, or cephalexin orally. The SBTs obtained following unit does of 25 mg/kg of dicloxacillin, 35 mg/kg of penicillin, or 25 mg/kg of cephalexin with probenecid were comparable to those seen following intravenous doses of 40 mg/kg nafcillin or methicillin. Twenty-two children with acute hematogenous osteomyelitis proven or presumed to be due to S. aureus were treated intravenously until point tenderness and fever had resolved, and then with oral therapy. The mean duration of intravenous therapy was 14 days. Oral doses were adjusted so that a peak SBT of greater than or equal to 1:16 and a trough SBT of greater than or equal to 1:2 were obtained in most children. No recurrences occurred. The SBT proved to be a practical means of assessing the adequacy of oral therapy in children with infections due to S. aureus.

Effectiveness of nafcillin, methicillin, and cephalothin in experimental Staphylococcus aureus endocarditis.

Nafcillin, methicillin, and cephalothin (40 mg/kg every 6 h) were all effective in reducing the number of Staphylococcus aureus in vegetations in rabbits with endocarditis. Nafcillin and methicillin reduced the number of S. aureus at a significantly faster rate than did cephalothin. Nafcillin and methicillin also reduced titers of the S. aureus more rapidly than did cephalothin in vitro, both in broth and in rabbit serum.

Antibiotic penetration into normal and inflamed tissues as reflected by peripheral lymph.

The concentration of antibiotic in peripheral lymph reflects the tissue levels. Following microsurgical cannulation of the right lymphatic duct in 28 healthy rabbits, either penicillin-G, nafcillin, erythromycin, or cefazolin was given intramuscularly, and lymph and serum samples obtained at frequent intervals. Penicillin or nafcillin was administered to 14 additional rabbits with cellulitis of the right upper extremity. A serum sample drawn between one and two hours after an intramuscular injection, in general, reflects the peak lymph antibiotic concentration and hence the peak tissue concentration of the drug. After two hours the lymph level remains equal to or greater than the simultaneous serum level. The presence of inflammation did not alter the peak antibiotic levels. However, nafcillin required longer for equilibration in the inflamed state than in the uninflamed state, whereas penicillin-G equilibrated more rapidly in the presence of inflammation.

Prediction of the concentration of penicillins in ascitic fluid from serum kinetics and protein binding of the antibiotics in serum and ascitic fluid of dogs.

Ascites was induced in dogs by partial ligation of the inferior vena cava. Concentrations of ampicillin, penicillin G, oxacillin, cloxacillin, dicloxacillin, nafcillin, and methicillin in ascitic fluid and serum were each determined in three animals. All antibiotics were administered intramuscularly in a dose of 15 mg/kg (dry weight) for both single-dose and multiple-dose (eight doses at 4-hr intervals) studies. Binding of antibiotics to serum and ascitic fluid proteins was measured by ultracentrifugation. After single doses the highly protein-bound drugs (oxacillin, cloxacillin, dicloxacillin, and nafcillin) had lower percentages of penetration (ratio of peak in ascitic fluid to that in serum, multipled by 100) than did methicillin, ampicillin, and penicillin G, which have a lower degree of protein binding. The effect was partially overcome by repetitive doses, but five to six doses were usually required to reach equilibrium. In addition to protein binding, serum kinetics (particularly the log mean total concentration of drug in serum after multiple doses) were important determinants of antibiotic concentrations in ascitic fluid. The total antibiotic concentration in ascitic fluid at equilibrium can be accurately calculated from the log mean serum concnetration and the percentages of protein binding in serum and ascitic fluid.

Disposition of nafcillin in patients with cirrhosis and extrahepatic biliary obstruction.

Nafcillin, a semisynthetic penicillin effective against penicillinase-producing staphylococci, is eliminated largely in man via the liver. This study assessed the effect of cirrhosis and extrahepatic biliary obstruction in man on the pharmacokinetics of nafcillin. The plasma clearance of nafcillin controls was 583 +/- 144.2 ml per min (mean +/- SD) and fell strikingly to 291 +/- 147.6 and 163 +/- 56.3 ml per min in patients with cirrhosis and extrahepatic obstruction, respectively (P less than 0.001). In the latter two groups nafcillin excreted in urine increased from about 30 to 50% of administered dose (P less than 0.02), suggesting that renal disease superimposed on hepatic disease would further decrease over-all nafcillin clearance. The depression of nafcillin clearance with hepatobiliary disease did not correlate with any conventional liver laboratory test. The initial volume of distribution of nafcillin (V1) was unaltered but at steady state (Vd()) there was a significant reduction in the distribution volume in the patients with liver disease. Accordingly, the impairment in drug elimination, as assessed by its clearance from plasma, was underestimated by the prolongation of the nafcillin elimination half-life (t1/2(beta)) which was 1.02 +/- 0.20 hr in controls, and 1.23 +/- 0.31 (P greater than 0.05) and 1.73 +/- 0.44 hr (P less than 0.03), respectively, in patients with cirrhosis and extrahepatic obstruction.

Nafcillin concentration in cerebrospinal fluid during treatment of staphylococcal infections.

The nafcillin concentration of simultaneous cerebrospinal fluid (CSF) and serum specimens from nine patients being treated with parenteral nafcillin for staphylococcal infection were measured. Marked variations in the ratio of CSF/serum nafcillin concentration were observed. However, the concentration of nafcillin in the CSF was greater than the minimum lethal concentration (MLC) for Staphylococcus aureus in eight of the nine patients. In five patients with CSF pleocytosis, the nafcillin concentration was three to 100 times the MLC. These results support the recommendation to use nafcillin in doses of at least 100 to 200 mg/kg body weight-day for treatment of meningitis caused by S. aureus.