- Email: [email protected]
Clinical and pharmacokinetic evaluation of nafcillin in infants and children
PEDIATRIC PHARMACOLOGY AND THERAPEUTICS Paul S. Lietman, Editor
Clinical and pharmacokinetic evaluation of nafcillin in infants and children Nofcllltn (150 mg/kg/day, divided every six hours) was administered intravenously to 46 patients ranging
from 5 to 163 months of age with suspected or proved bacterial infections. Thirteen of 15 patients with bacteriologically proved infection responded to nafcillin. Two patients with cellulitis due to Escherichia coli or to Hemophilus influenzae type b did not improve with nafcillin therapy. A mean serum nafcilltn
concentration of 48 p.g/ml was observed 30 minutes after a dose of 37.5 mg/kg. The mean serum half-life was 0.76 hours. There was no significant relation between age and serum half-life, volume of distribution, or plasma clearance rate. Two patients developed neutropenia and six other patients developed an eosinophilia> 400/mm 3 while receiving nafcillin. No significant toxic effect of nafcillin on liver or renal function was observed. One patient had phlebitis. There was a significant correlation between nafcillin concentrations and serum inhibitory and bactericidal titers (P
< 0.001). Results from this study indicate
that nafcillin is a safe and effective antibiotic for the treatment of infections due to susceptible bacteria in the dosage tested.
William E. Feldman, M,D., John D. Nelson, M.D.,* and Lawrence R. Stanberry, M.D., Dallas, Texas
METH I CILLIN has been widely used for the treatment of serious infections due to penicillin-resistant Staphylococcus aureus. There is a substantial incidence of adverse reactions associated with methicillin treatment, including nephrotoxicity,':" hemorrhagic cystitis;' neutropenia,' and thrombocytopenia" Nephrotoxicity appears to be more likely to occur in older patients than in infants, in those who receive dosages greater than 200 mg/kg/day, and in those treated for longer than 10 days,'- 3 Because children with staphylococcal pneumonia or osteomyelitis require prolonged antibiotic therapy with large dosage, an alternative penicillinase-resistant penicillin with less toxicity than methicillin would be desirable. Nafcillin (sodium 6-[2-ethoxy-l-naphthamido] penicillinate) is a semi-synthetic, penicillinase-resistant penicillin with a similar spectrum of activity to that of methicillin. Furthermore, it is quantitatively more active than is
From the Department of Pediatrics, The University of Texas Southwestern Medical School at Dallas. Supported by a grant from Wyeth Laboratories. "Reprint address: 5323 Harry Hines Blvd.. Dallas, TX 75235. Reprints available only 10 persons outside the United States.
0022-3476/781121029+05$00.50/0
e
1978 The C. V. Mosby Co.
methicillin against staphylococci.' It is unusual among the penicillins in that only 10% of parenterally administered nafcil1in is excreted in the urine and 90% is excreted in the bile," whereas the reverse is true of other penicillin derivatives. Although the pharmacokinetics and dosage have been defined for adult patients and the drug is currently in general usage, few data are available about efficacy, pharmacokinetics, or toxicity in infants or children.·· ' 2 Abbreviations used MIC: minimal inhibitory concentration MBC: minimal bactericidal concentration SGOT: serum glutamic oxalacetic transaminase
SUBJECTS AND METHODS Subjects. The 46 patients included in this study were admitted to Parkland Memorial Hospital or Children's Medical Center, Dallas, for treatment of suspected or proved staphylococcal infections. Children with a history of penicillin allergy, liver disease, or coagulopathy were excluded from the study. Signed, informed consent to collect serum samples was obtained from the parent or The Journal of P E D [ A T R [ C S Vol. 93, No.6, pp. 1029-1033
1029
1030
The Journal of Pediatrics December 1978
Feldman, Nelson, and Stanberry
80
...
• A
••
Table I. Clinical evaluation of 46 patients tr eated with nafcillin parenterally
• .\
•
A
40
...I
A Vl
z o ;:: «
20
t Clinical diagnosis
•
A
Cellulitis Septicemia] or endocarditis Osteomyelitis or pyarthrosis Meningitis and/or ventriculitis Pneumonia'[ with or without empyema Abscess in skin Lymphadenitis Infected skin laceration
~
ffiu z oL)
[0
8 6 4
•
A
• A
2
• - INHIBITORY
Total
A - BACTERICIDAL
J. 2
.1. 4
I
"8
I
Th SERUM
Clinical improvement
I 32
I
64
I
128
2:.L
256
TI TERS
Figure. Correlation of concentrations of nafcill in in serum (30 minutes after a dose) with serum inhibitory and bactericidal titers. The regression line relating serum concentrations with inhibitory titers is y == 0.257 + O.152X; correlation coefficient r = 0.876, P < 0.00 I. The regression line relating serum concentrationswith bactericidal titers is y "" 0.294 + 0.167X; r == 0.802, P < 0.001.
guardian of each child. Surgical drainage was used as an adjunct to medical therapy when appropriate. Pbannacokinetic studies. Each dose of nafcillin was infused intravenously during 15 minutes . Serum samples were collected by heel or finger stick Ih, I, 2, and 4 hours after the beginning of the infusion. Serum was stored at -20°C until assayed for nafcillin by the method of Sim on and Yin,13 using a disc diffusion modification of the agar cup method. .The regression line of seru m concentrations, the volume of distribution, and the plasma clearance of nafcillin were determined as previously described," except that plasma clearance rate was corrected for body surface area. A few patients received either intramuscular or peroral doses of nafcillin. Efficacy studies. In children with proved staphylococcal or streptococcal infections, clinical signs and symptoms, repeat cultures, and radiographs were followed to determine the response to nafcillin therapy. The minimal inhibitory and bactericidal concentrations of nafcillin were determined by a tube dilution method
No. of patients
Yes
No
Unable to evaluate"
18 8
9 7
2
7
0
I
6
4
0
2
3
0
0
3
6
3
0
3
3
2 1
0 0 0
0 0 0
29
2
16
3 2
I
-47
*Received concomitant ant ibiotics which may have cured the infection. [One patient had E. coli sepsis during recovery from pneumonia with empyema .
using an inoculum of approximately 10" bacteria per tube in Mueller-Hinton broth . Final nafcillin concentrations were twofold dilutions from 80 to 0.08 ug/rnl. The minimal inhibitory and bactericidal concentrations were the smallest concentrations resulting in inhibition of visible growth and in lack of growth on subculture, respectively, after incubation at 37°C for 24 hours. Serum inhibitory and bactericidal titers were determined by adding an inoculum of approximately 10" colony-forming units of the patient's pathogen to serial twofold dilutions in broth of the patient's serum in a microtiter plate. The inhi bitory titer was the largest dilution of serum which inhibited visible growth after 18 hours incubation at 37 ; the bactericidal titer was the largest dilution of serum from which no bacteria were recovered by subculture to blood agar. Adverse effects. All patients were observed for rashes, liver tenderness, jaundice, phlebitis, or other possible adverse effects of the drug. The complete blood count and differential urinalysis, blood urea nitrogen, and SOOT were determined serially in most patients. QC
RESULTS During the study, 47 episodes of infection in 46 patients were treated with nafcillin (Table I). Patients ranged in age from one to 163 months. Sixteen patients who improved with treatment could not be evaluated regarding nafcillin efficacy because they were given concomitant antibiotic therapy potentially effective against the known
Evaluation of nafcillin
Volume 93 Number 6
1031
Table II. Susceptibility of 18 bacterial isolates to nafcillin MIC (Ilg/ml)
No. of strains
Isolate
0.312 0.16 0.08
9 3 3 1
Staphylococcus aureus S. epidermidis Streptococcus pyogenes Escherichia coli Hemophilus influenzae type b
I
Median
I I
Enterococcus sp.
MBC (Ilg/ml)
Range
Median
:50.08-1.25 0.16-0.312 :50.08-0.312 >80 10 1.25
0.312 0,16 0.08
Range
I
:50.08->5.0 0.16->5,0 :;;0.08-0.312 >80 20 2.5
Table III. Pharmacokinetics of nafcillin in infants and children after intravenous administration of a 37.5 mg/kg dose
Age (mo)
No. of patients
1-12 13-48 49-96 97-164
8 4 6 6 24
All
Serum halflife (hr)t
Serum nafcillin concentration (llg/IIlI)
112'
47.8 ± 43.3 ± 54.7 ± 44.4 ± 48.1 ±
5.611 5.4 9.7 5.2 3.5
I
I
1
27 ± 21.2 ± 20.9 ± 23.4 ± 23.6 ±
4.7 4.5 3.6 2.3 4.8
2
7.5 ± 4.7 ± 5.9 ± 6.5 ± 6.4 ±
I 2.0 1.3
1.6 0.9 0.81
4
1.8 ± 1.4 ± 1.8 ± 2.0 ± 1.8 ±
0.5 0.9 0.5 0.4 0.23
0.75 0.68 0.76 0.81 0.76
± 0.04 0.07 0.08 0.08 0.03
± ± ± ±
Plasma clearance (ml!minll.73 m')t
495 ± 613 ± 613 ± 700 ± 595 ±
75 113 136 43 57
Volume of distribution (ml/kg)§
910 ± 187 850 ± 76 934 ± 225 857 ± 92 893 ± 83
patients 'Hours after a dose. 0.64 by one-way analysis of variance comparing age groups. 0,45 by one-way analysis of variance comparing age groups. §P = 0.98 by one-way analysis of variance comparing age grou ps. IIMean ± SEM.
tP = tP =
or suspected pathogens. Of the remammg 3J patients treated only with nafcillin, bacterial pathogens were isolated before therapy from 15. Staphylococcus aureus was isolated from eight patients, S. epidermidis from three, Streptococcus pyogenes from two patients, and Escherichia coli and Hemophilus infiuenzae type b from one patient each. Clinically, 29 of 31 patients were cured by nafcillin therapy. Pathogenic bacteria were successfully eradicated by nafcillin in 13 of 15 patients. Nafcillin had no effect against E. coli cellulitis in a nephrotic patient and against. H. influenzae type b cellulitis in another patient. Both patients recovered after appropriate antibiotic therapy was given. Susceptibility to nafcillin was determined for 18 bacterial isolates (Table II). Two were resistant to nafcillin; an isolate of E. coli required> 80 /log nafcillin/ml, and an isolate of H. infiuenzae type b had an MIC of 10 p.g nafcillin/ml. The median MIC and MBC were :s: OJ 12p.g nafcillin/ml for 12 strains of staphylococcus. Although two strains were not completely killed by > 5 ug/rnl, infections due to these strains responded clinically to nafcillin therapy as did those due to other staphylococci. Since few data were available on the dosage regimens
ofnafcillin for pediatric patients at the outset of the study, we administered intravenous doses of 25 mg/kg to three patients and 50 mg/kg to two patients. The mean nafcillin concentrations at 30 minutes were 21.8 and 82.8 p.g/ml, respectively. A dose of37.5 mg nafcillin/kg intravenously, which produced a mean serum concentration of 48.1 ug/rnl at 30 minutes, was used in the remainder of the study. Complete pharmacokinetics were evaluated in 24 patients (Table III). There was no effect of age on the concentration-time curves, the serum half-lives, the apparent volumes of distribution or the calculated plasma clearance rates of nafcillin. There was an excellent correlation between the serum inhibitory and bactericidal titers and the nafcillin concentrations (P < 0.001) (Figure). All samples assayed had both inhibitory and bactericidal activity, including some with low concentrations of nafcillin taken after peroral or intramuscular administration. There was no significant difference between the pretreatment and posttreatment values of hemoglobin or blood leukocytes. However, two of 30 patients with serial leukocyte determinations developed a transient neutropenia of < J,500/mm' during therapy and six patients had an eosinophilia of > 400/mm' during therapy. Among 27
1032
Feldman, Nelson, and Stanberry
patients with liver function studies done during therapy, three had mild elevations of SOOT to 53, 59, and 79 units. The SOOT activity was elevated before therapy in three patients but decreased to the normal range during therapy. Urinalyses during and after therapy and renal function were normal in 20 patients who had serial determinations. Parenteral administration of nafcillin was well tolerated; one patient developed phlebitis at the infusion site. No patient had a rash or developed liver tenderness or jaundice.
DISCUSSION Previous studies' have shown that nafcillin is active in vitro against gram-positive cocci and, on a weight basis, nafcillin is more active than methicillin.' Results from this study indicate that nafcillin is effective therapy for systemic infections caused by grampositive cocci in infants and children. These results confirm data from previous investigatorsv-" who successfully treated a variety of systemic infections due to S. aureus or pneumococci, chiefly in adults, with nafcillin. Nafcillin was ineffective in vivo and in vitro against the two gram-negative infections encountered in this study. Although serum concentrations of nafcillin had been reported in neonates and in a small number of infants and children.v- » the data were extremely limited. We arbitrarily chose a range of 40 to 60 ug/rnl as the desirable serum concentration 30 minutes after beginning of the intravenous infusion. We found that serum levels after an intravenous dose of 25 mg/kg were suboptimal by this definition, whereas serum concentrations after a dose of 50 mg/kg were believed to be much higher than was necessary to treat the infection. Our data indicate that a daily dosage of 150 mg/kg/day divided every six hours, which results in serum levels approximately 100 times the MBC of staphylococcal strains at 30 minutes, provides good serum bactericidal activity and is associated with clinical and bacteriologic cures of gram-positive coccal infections. The apparent volume of distribution of nafcillin is much greater than that of other penicillins; this appears to relate to its affinity for the liver. As a result, serum concentrations are lower than with equal doses of other penicillins." Concentrations of nafcillin in bile are from 173 to 1,030 J.lg/ml after a one gram dose given intramuscularly.w Because less than 20% of nafcillin is excreted by the kidneys, it can be given in normal dosage to patients with renal functional impairment. Conversely, if nafcillin were given to a patient with hepatic insufficiert'cy, the pharmacokinetics would have to be studied and appropriate adjustments made in dosage; it would be preferable
The Journal of Pediatrics December 1978
to avoid the use of nafcillin in patients with hepatic disease although the risk has not been evaluated, to our knowledge. Previous reports have implicated nafcillin as a cause of transient neutropenia.o-w In our study, nafcillin was associated with a neutropenia in two and eosinophilia in six of 30 patients. There were minimal elevations of the SOOT levels in a few patients. Possibly because the antibiotic is primarily excreted by the liver, no renal toxicity was observed. There is only one instance of possible nephrotoxicity due to nafcillin in the literature» and that one is poorly documented. Patients receiving nafcillin should be monitored for neutropenia and, although hepatotoxicity has not been reported, it would seem prudent to observe for liver abnormality in patients with pre-existing disease because of the great concentration of nafcillin in the liver. We thank Sharon Shelton, Helen Kusmiesz, and Lula Hinton Iackson for their excellent technical assistance.
REFERENCES Sarff LD, and McCracken GH Jr: Methicillin-associated nephropathy or cystitis, J PEDIATR 90:1031, 1977. 2. Sanjad SA, Haddad 00, and Nassar VH: Nephropathy, an underestimated complication of methicillin therapy, I PED!ATR 84:873, 1974. 3. Feigin RD, Van Reken DE, and Pickering LK: Dosage in methicillin-associated nephropathy, I PEDIATR 85:734, I.
1974.
4. Bracis R, Sanders CV, and Gilbert ON: Methicillin hemorrhagic cystitis, Antimicrob Agents Chemother 12:438, 1977.
5. Yow MD, Taber LH, Barret FF, Mintz AA, Blankinship GR, Clark GE, and Clark 01: A ten-year assessment of methicillin-associated side effects, Pediatrics 58:329, 1976. 6. Schiffer CA, Weinstein HJ, and Wiemik PH: Methicillinassociated thrombocytopenia, Ann Intern Med 85:338, 1976.
7. Klein 10, and Finland M: The new penicillins, N Engl I Med 269:1074, 1973. 8. Klein 10, and Finland M: Nafcillin: Antibacterialaction in vitro and absorption and excretion in normal young men, Am I Med Sci 246:10, 1963. 9. EickhoffTe, Kislak JW, and Finland M: Clinical evaluation of nafcillin in patients with severe staphylococcal disease, N Engl I Med 272:699, 1965. 10. O'Connor WI, Warren GH, Edrada LS, Mandala PS, and RosenmanSB: Serum concentrations of sodium nafcillin in infants during the perinatal period, Antimicrob Agents Chemother 5:220, 1965. 11. O'Connor WI, Warren GH, Mandala PS, Edrada LS, and Rosenman S8: Serum concentrations of nafcillin in newborn infants and children, Antimicrob Agents Chernother 4: 188, 1964. 12. Martin CM, Kushnick TH, Nuccio PA, et al: Controlled,
double-blind efficacy trial of penicillin, methicillin, and nafcillin in 346 adults and children.IT. Comparative clinical efficacy, Antimicrob Agents Chemother 63:290, 1963.
E valuation of nafcilltn
Volt/me 93 Number 6
13. Simon HJ, and Yin EJ: Microbioassay of antimicrobial agents, Appl MicrobioI19:573, 1970. 14. Nelson JO , Shelton S, and Kusmiesz H: Clinical pharmacology of ticarcillin in the newborn infant: Relation to age , gestational age, and weight . J PEDIATR 87:474 , 1975. 15. Kind AC, Tupasi TE, Standiford HC, and Kirb y WMM : Mechanisms responsible for pla sma levels of nafcillin lower th an those of oxacillin , Arch In tern Med 125:685, 1970. 16. Green OR, and Ger aci JE : A not e on the concentration of nafcillin in human bile, Mayo Clin Proc 40:700, 1965.
17. Markowitz SM, Rothkopf M, Holden FO, Stith OM, and Duma RJ : Nafcillin -induced agra n ulocytosis, JAMA 232:1150,1975. 18. Sandberg M, Tuazo n CU, and Sheagren J : Neutropenia probably resulting from nafcill in , JAMA 232: 1152, 1975. 19. Greene OR, and Cohen E: Nafc illin-induced neutropenia in children, Pediatrics 61:94, 1978. 20. Parry MF, Ball WD, Conte JE Jr, and Cohen SN: N afeillin nephritis (letter), JAMA 225:178, J973.
Information for authors
o f the provisions of the Co py right Act of 1976 beca me effective o n Janu ary l. 1978. T here fo re. all manuscript s must be accompanied by the following written statem ent, sign ed by o ne a ut hor: "The undersigned auihor transfers a ll copyright ownersh ip of the manuscript (title of article) 10 T he C. V. Mosby C omp any in the event the work is pub lished , The undersigned aut hor war ran ts that the article is ori ginal. is not under consideration by ano ther j ourn al, and has not been previousl y puhl ished . 1 sign for and accept responsibilit y for releasing this materi al on beh alf of any and all co-authors," Authors will he consulted. when possible. rega rd ing rep ublica tion of their ma terial. MOSI
]033
Clinical and pharmacokinetic evaluation of nafcillin in infants and children Nofcllltn (150 mg/kg/day, divided every six hours) was administered intravenously to 46 patients ranging
from 5 to 163 months of age with suspected or proved bacterial infections. Thirteen of 15 patients with bacteriologically proved infection responded to nafcillin. Two patients with cellulitis due to Escherichia coli or to Hemophilus influenzae type b did not improve with nafcillin therapy. A mean serum nafcilltn
concentration of 48 p.g/ml was observed 30 minutes after a dose of 37.5 mg/kg. The mean serum half-life was 0.76 hours. There was no significant relation between age and serum half-life, volume of distribution, or plasma clearance rate. Two patients developed neutropenia and six other patients developed an eosinophilia> 400/mm 3 while receiving nafcillin. No significant toxic effect of nafcillin on liver or renal function was observed. One patient had phlebitis. There was a significant correlation between nafcillin concentrations and serum inhibitory and bactericidal titers (P
< 0.001). Results from this study indicate
that nafcillin is a safe and effective antibiotic for the treatment of infections due to susceptible bacteria in the dosage tested.
William E. Feldman, M,D., John D. Nelson, M.D.,* and Lawrence R. Stanberry, M.D., Dallas, Texas
METH I CILLIN has been widely used for the treatment of serious infections due to penicillin-resistant Staphylococcus aureus. There is a substantial incidence of adverse reactions associated with methicillin treatment, including nephrotoxicity,':" hemorrhagic cystitis;' neutropenia,' and thrombocytopenia" Nephrotoxicity appears to be more likely to occur in older patients than in infants, in those who receive dosages greater than 200 mg/kg/day, and in those treated for longer than 10 days,'- 3 Because children with staphylococcal pneumonia or osteomyelitis require prolonged antibiotic therapy with large dosage, an alternative penicillinase-resistant penicillin with less toxicity than methicillin would be desirable. Nafcillin (sodium 6-[2-ethoxy-l-naphthamido] penicillinate) is a semi-synthetic, penicillinase-resistant penicillin with a similar spectrum of activity to that of methicillin. Furthermore, it is quantitatively more active than is
From the Department of Pediatrics, The University of Texas Southwestern Medical School at Dallas. Supported by a grant from Wyeth Laboratories. "Reprint address: 5323 Harry Hines Blvd.. Dallas, TX 75235. Reprints available only 10 persons outside the United States.
0022-3476/781121029+05$00.50/0
e
1978 The C. V. Mosby Co.
methicillin against staphylococci.' It is unusual among the penicillins in that only 10% of parenterally administered nafcil1in is excreted in the urine and 90% is excreted in the bile," whereas the reverse is true of other penicillin derivatives. Although the pharmacokinetics and dosage have been defined for adult patients and the drug is currently in general usage, few data are available about efficacy, pharmacokinetics, or toxicity in infants or children.·· ' 2 Abbreviations used MIC: minimal inhibitory concentration MBC: minimal bactericidal concentration SGOT: serum glutamic oxalacetic transaminase
SUBJECTS AND METHODS Subjects. The 46 patients included in this study were admitted to Parkland Memorial Hospital or Children's Medical Center, Dallas, for treatment of suspected or proved staphylococcal infections. Children with a history of penicillin allergy, liver disease, or coagulopathy were excluded from the study. Signed, informed consent to collect serum samples was obtained from the parent or The Journal of P E D [ A T R [ C S Vol. 93, No.6, pp. 1029-1033
1029
1030
The Journal of Pediatrics December 1978
Feldman, Nelson, and Stanberry
80
...
• A
••
Table I. Clinical evaluation of 46 patients tr eated with nafcillin parenterally
• .\
•
A
40
...I
A Vl
z o ;:: «
20
t Clinical diagnosis
•
A
Cellulitis Septicemia] or endocarditis Osteomyelitis or pyarthrosis Meningitis and/or ventriculitis Pneumonia'[ with or without empyema Abscess in skin Lymphadenitis Infected skin laceration
~
ffiu z oL)
[0
8 6 4
•
A
• A
2
• - INHIBITORY
Total
A - BACTERICIDAL
J. 2
.1. 4
I
"8
I
Th SERUM
Clinical improvement
I 32
I
64
I
128
2:.L
256
TI TERS
Figure. Correlation of concentrations of nafcill in in serum (30 minutes after a dose) with serum inhibitory and bactericidal titers. The regression line relating serum concentrations with inhibitory titers is y == 0.257 + O.152X; correlation coefficient r = 0.876, P < 0.00 I. The regression line relating serum concentrationswith bactericidal titers is y "" 0.294 + 0.167X; r == 0.802, P < 0.001.
guardian of each child. Surgical drainage was used as an adjunct to medical therapy when appropriate. Pbannacokinetic studies. Each dose of nafcillin was infused intravenously during 15 minutes . Serum samples were collected by heel or finger stick Ih, I, 2, and 4 hours after the beginning of the infusion. Serum was stored at -20°C until assayed for nafcillin by the method of Sim on and Yin,13 using a disc diffusion modification of the agar cup method. .The regression line of seru m concentrations, the volume of distribution, and the plasma clearance of nafcillin were determined as previously described," except that plasma clearance rate was corrected for body surface area. A few patients received either intramuscular or peroral doses of nafcillin. Efficacy studies. In children with proved staphylococcal or streptococcal infections, clinical signs and symptoms, repeat cultures, and radiographs were followed to determine the response to nafcillin therapy. The minimal inhibitory and bactericidal concentrations of nafcillin were determined by a tube dilution method
No. of patients
Yes
No
Unable to evaluate"
18 8
9 7
2
7
0
I
6
4
0
2
3
0
0
3
6
3
0
3
3
2 1
0 0 0
0 0 0
29
2
16
3 2
I
-47
*Received concomitant ant ibiotics which may have cured the infection. [One patient had E. coli sepsis during recovery from pneumonia with empyema .
using an inoculum of approximately 10" bacteria per tube in Mueller-Hinton broth . Final nafcillin concentrations were twofold dilutions from 80 to 0.08 ug/rnl. The minimal inhibitory and bactericidal concentrations were the smallest concentrations resulting in inhibition of visible growth and in lack of growth on subculture, respectively, after incubation at 37°C for 24 hours. Serum inhibitory and bactericidal titers were determined by adding an inoculum of approximately 10" colony-forming units of the patient's pathogen to serial twofold dilutions in broth of the patient's serum in a microtiter plate. The inhi bitory titer was the largest dilution of serum which inhibited visible growth after 18 hours incubation at 37 ; the bactericidal titer was the largest dilution of serum from which no bacteria were recovered by subculture to blood agar. Adverse effects. All patients were observed for rashes, liver tenderness, jaundice, phlebitis, or other possible adverse effects of the drug. The complete blood count and differential urinalysis, blood urea nitrogen, and SOOT were determined serially in most patients. QC
RESULTS During the study, 47 episodes of infection in 46 patients were treated with nafcillin (Table I). Patients ranged in age from one to 163 months. Sixteen patients who improved with treatment could not be evaluated regarding nafcillin efficacy because they were given concomitant antibiotic therapy potentially effective against the known
Evaluation of nafcillin
Volume 93 Number 6
1031
Table II. Susceptibility of 18 bacterial isolates to nafcillin MIC (Ilg/ml)
No. of strains
Isolate
0.312 0.16 0.08
9 3 3 1
Staphylococcus aureus S. epidermidis Streptococcus pyogenes Escherichia coli Hemophilus influenzae type b
I
Median
I I
Enterococcus sp.
MBC (Ilg/ml)
Range
Median
:50.08-1.25 0.16-0.312 :50.08-0.312 >80 10 1.25
0.312 0,16 0.08
Range
I
:50.08->5.0 0.16->5,0 :;;0.08-0.312 >80 20 2.5
Table III. Pharmacokinetics of nafcillin in infants and children after intravenous administration of a 37.5 mg/kg dose
Age (mo)
No. of patients
1-12 13-48 49-96 97-164
8 4 6 6 24
All
Serum halflife (hr)t
Serum nafcillin concentration (llg/IIlI)
112'
47.8 ± 43.3 ± 54.7 ± 44.4 ± 48.1 ±
5.611 5.4 9.7 5.2 3.5
I
I
1
27 ± 21.2 ± 20.9 ± 23.4 ± 23.6 ±
4.7 4.5 3.6 2.3 4.8
2
7.5 ± 4.7 ± 5.9 ± 6.5 ± 6.4 ±
I 2.0 1.3
1.6 0.9 0.81
4
1.8 ± 1.4 ± 1.8 ± 2.0 ± 1.8 ±
0.5 0.9 0.5 0.4 0.23
0.75 0.68 0.76 0.81 0.76
± 0.04 0.07 0.08 0.08 0.03
± ± ± ±
Plasma clearance (ml!minll.73 m')t
495 ± 613 ± 613 ± 700 ± 595 ±
75 113 136 43 57
Volume of distribution (ml/kg)§
910 ± 187 850 ± 76 934 ± 225 857 ± 92 893 ± 83
patients 'Hours after a dose. 0.64 by one-way analysis of variance comparing age groups. 0,45 by one-way analysis of variance comparing age groups. §P = 0.98 by one-way analysis of variance comparing age grou ps. IIMean ± SEM.
tP = tP =
or suspected pathogens. Of the remammg 3J patients treated only with nafcillin, bacterial pathogens were isolated before therapy from 15. Staphylococcus aureus was isolated from eight patients, S. epidermidis from three, Streptococcus pyogenes from two patients, and Escherichia coli and Hemophilus infiuenzae type b from one patient each. Clinically, 29 of 31 patients were cured by nafcillin therapy. Pathogenic bacteria were successfully eradicated by nafcillin in 13 of 15 patients. Nafcillin had no effect against E. coli cellulitis in a nephrotic patient and against. H. influenzae type b cellulitis in another patient. Both patients recovered after appropriate antibiotic therapy was given. Susceptibility to nafcillin was determined for 18 bacterial isolates (Table II). Two were resistant to nafcillin; an isolate of E. coli required> 80 /log nafcillin/ml, and an isolate of H. infiuenzae type b had an MIC of 10 p.g nafcillin/ml. The median MIC and MBC were :s: OJ 12p.g nafcillin/ml for 12 strains of staphylococcus. Although two strains were not completely killed by > 5 ug/rnl, infections due to these strains responded clinically to nafcillin therapy as did those due to other staphylococci. Since few data were available on the dosage regimens
ofnafcillin for pediatric patients at the outset of the study, we administered intravenous doses of 25 mg/kg to three patients and 50 mg/kg to two patients. The mean nafcillin concentrations at 30 minutes were 21.8 and 82.8 p.g/ml, respectively. A dose of37.5 mg nafcillin/kg intravenously, which produced a mean serum concentration of 48.1 ug/rnl at 30 minutes, was used in the remainder of the study. Complete pharmacokinetics were evaluated in 24 patients (Table III). There was no effect of age on the concentration-time curves, the serum half-lives, the apparent volumes of distribution or the calculated plasma clearance rates of nafcillin. There was an excellent correlation between the serum inhibitory and bactericidal titers and the nafcillin concentrations (P < 0.001) (Figure). All samples assayed had both inhibitory and bactericidal activity, including some with low concentrations of nafcillin taken after peroral or intramuscular administration. There was no significant difference between the pretreatment and posttreatment values of hemoglobin or blood leukocytes. However, two of 30 patients with serial leukocyte determinations developed a transient neutropenia of < J,500/mm' during therapy and six patients had an eosinophilia of > 400/mm' during therapy. Among 27
1032
Feldman, Nelson, and Stanberry
patients with liver function studies done during therapy, three had mild elevations of SOOT to 53, 59, and 79 units. The SOOT activity was elevated before therapy in three patients but decreased to the normal range during therapy. Urinalyses during and after therapy and renal function were normal in 20 patients who had serial determinations. Parenteral administration of nafcillin was well tolerated; one patient developed phlebitis at the infusion site. No patient had a rash or developed liver tenderness or jaundice.
DISCUSSION Previous studies' have shown that nafcillin is active in vitro against gram-positive cocci and, on a weight basis, nafcillin is more active than methicillin.' Results from this study indicate that nafcillin is effective therapy for systemic infections caused by grampositive cocci in infants and children. These results confirm data from previous investigatorsv-" who successfully treated a variety of systemic infections due to S. aureus or pneumococci, chiefly in adults, with nafcillin. Nafcillin was ineffective in vivo and in vitro against the two gram-negative infections encountered in this study. Although serum concentrations of nafcillin had been reported in neonates and in a small number of infants and children.v- » the data were extremely limited. We arbitrarily chose a range of 40 to 60 ug/rnl as the desirable serum concentration 30 minutes after beginning of the intravenous infusion. We found that serum levels after an intravenous dose of 25 mg/kg were suboptimal by this definition, whereas serum concentrations after a dose of 50 mg/kg were believed to be much higher than was necessary to treat the infection. Our data indicate that a daily dosage of 150 mg/kg/day divided every six hours, which results in serum levels approximately 100 times the MBC of staphylococcal strains at 30 minutes, provides good serum bactericidal activity and is associated with clinical and bacteriologic cures of gram-positive coccal infections. The apparent volume of distribution of nafcillin is much greater than that of other penicillins; this appears to relate to its affinity for the liver. As a result, serum concentrations are lower than with equal doses of other penicillins." Concentrations of nafcillin in bile are from 173 to 1,030 J.lg/ml after a one gram dose given intramuscularly.w Because less than 20% of nafcillin is excreted by the kidneys, it can be given in normal dosage to patients with renal functional impairment. Conversely, if nafcillin were given to a patient with hepatic insufficiert'cy, the pharmacokinetics would have to be studied and appropriate adjustments made in dosage; it would be preferable
The Journal of Pediatrics December 1978
to avoid the use of nafcillin in patients with hepatic disease although the risk has not been evaluated, to our knowledge. Previous reports have implicated nafcillin as a cause of transient neutropenia.o-w In our study, nafcillin was associated with a neutropenia in two and eosinophilia in six of 30 patients. There were minimal elevations of the SOOT levels in a few patients. Possibly because the antibiotic is primarily excreted by the liver, no renal toxicity was observed. There is only one instance of possible nephrotoxicity due to nafcillin in the literature» and that one is poorly documented. Patients receiving nafcillin should be monitored for neutropenia and, although hepatotoxicity has not been reported, it would seem prudent to observe for liver abnormality in patients with pre-existing disease because of the great concentration of nafcillin in the liver. We thank Sharon Shelton, Helen Kusmiesz, and Lula Hinton Iackson for their excellent technical assistance.
REFERENCES Sarff LD, and McCracken GH Jr: Methicillin-associated nephropathy or cystitis, J PEDIATR 90:1031, 1977. 2. Sanjad SA, Haddad 00, and Nassar VH: Nephropathy, an underestimated complication of methicillin therapy, I PED!ATR 84:873, 1974. 3. Feigin RD, Van Reken DE, and Pickering LK: Dosage in methicillin-associated nephropathy, I PEDIATR 85:734, I.
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4. Bracis R, Sanders CV, and Gilbert ON: Methicillin hemorrhagic cystitis, Antimicrob Agents Chemother 12:438, 1977.
5. Yow MD, Taber LH, Barret FF, Mintz AA, Blankinship GR, Clark GE, and Clark 01: A ten-year assessment of methicillin-associated side effects, Pediatrics 58:329, 1976. 6. Schiffer CA, Weinstein HJ, and Wiemik PH: Methicillinassociated thrombocytopenia, Ann Intern Med 85:338, 1976.
7. Klein 10, and Finland M: The new penicillins, N Engl I Med 269:1074, 1973. 8. Klein 10, and Finland M: Nafcillin: Antibacterialaction in vitro and absorption and excretion in normal young men, Am I Med Sci 246:10, 1963. 9. EickhoffTe, Kislak JW, and Finland M: Clinical evaluation of nafcillin in patients with severe staphylococcal disease, N Engl I Med 272:699, 1965. 10. O'Connor WI, Warren GH, Edrada LS, Mandala PS, and RosenmanSB: Serum concentrations of sodium nafcillin in infants during the perinatal period, Antimicrob Agents Chemother 5:220, 1965. 11. O'Connor WI, Warren GH, Mandala PS, Edrada LS, and Rosenman S8: Serum concentrations of nafcillin in newborn infants and children, Antimicrob Agents Chernother 4: 188, 1964. 12. Martin CM, Kushnick TH, Nuccio PA, et al: Controlled,
double-blind efficacy trial of penicillin, methicillin, and nafcillin in 346 adults and children.IT. Comparative clinical efficacy, Antimicrob Agents Chemother 63:290, 1963.
E valuation of nafcilltn
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13. Simon HJ, and Yin EJ: Microbioassay of antimicrobial agents, Appl MicrobioI19:573, 1970. 14. Nelson JO , Shelton S, and Kusmiesz H: Clinical pharmacology of ticarcillin in the newborn infant: Relation to age , gestational age, and weight . J PEDIATR 87:474 , 1975. 15. Kind AC, Tupasi TE, Standiford HC, and Kirb y WMM : Mechanisms responsible for pla sma levels of nafcillin lower th an those of oxacillin , Arch In tern Med 125:685, 1970. 16. Green OR, and Ger aci JE : A not e on the concentration of nafcillin in human bile, Mayo Clin Proc 40:700, 1965.
17. Markowitz SM, Rothkopf M, Holden FO, Stith OM, and Duma RJ : Nafcillin -induced agra n ulocytosis, JAMA 232:1150,1975. 18. Sandberg M, Tuazo n CU, and Sheagren J : Neutropenia probably resulting from nafcill in , JAMA 232: 1152, 1975. 19. Greene OR, and Cohen E: Nafc illin-induced neutropenia in children, Pediatrics 61:94, 1978. 20. Parry MF, Ball WD, Conte JE Jr, and Cohen SN: N afeillin nephritis (letter), JAMA 225:178, J973.
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o f the provisions of the Co py right Act of 1976 beca me effective o n Janu ary l. 1978. T here fo re. all manuscript s must be accompanied by the following written statem ent, sign ed by o ne a ut hor: "The undersigned auihor transfers a ll copyright ownersh ip of the manuscript (title of article) 10 T he C. V. Mosby C omp any in the event the work is pub lished , The undersigned aut hor war ran ts that the article is ori ginal. is not under consideration by ano ther j ourn al, and has not been previousl y puhl ished . 1 sign for and accept responsibilit y for releasing this materi al on beh alf of any and all co-authors," Authors will he consulted. when possible. rega rd ing rep ublica tion of their ma terial. MOSI
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