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 -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 < 0.001).The infection rate in hydrocephalic patients with shunts ranges from 6 to 25% (12, 13). Staphylococcus epidermidis and S. aureus account for the majority of such infections. The semisynthetic penicillins represent the drugs of choice for treatment of penicillin-resistant staphylococci. One imnportant factor in evaluating the potential efficacy of a drug for treatment of ventriculitis is its ability to penetrate into the central nervous system and cerebrospinal fluid (CSF). Very low CSF concentrations of methicillin are encountered in meningitis in either experimental animals or humans (1, 9). In contrast, nafcillin levels in the CSF of patients with staphylococcal meningitis are significant, exceeding minimal bactericidal concentrations for the infecting organism (6, 10). Although the data on nafcillin levels in CSF are limited, it seems to be the drug of choice for staphylococcal meningitis (4,8). Kane (6) reported a case of staphylococcal meningitis in which the level of nafcillin in lumbar CSF (58 ,Lg/ml) was markedly different from the level in ventricular fluid (9.8 ug/ml) obtained simultaneously, even though both fluids had the same degree of pleocytosis. This observation suggests that the pharmacokinetics of nafcillin may be different in ventricular fluid than in lumbar CSF.This report describes ventricular fluid nafcillin levels after intravenous administration in a group of hydrocephalic children with and without shunt infection. MATERLALS AND METHODSFourteen hydrocephalic children 3 weeks to 8.5 years of age with suspected ventriculoperitoneal shunt infections were studied. Informed consent was obtained from parents in each instance. In keeping with the standard neurosurgical practice in our institution, the shunt was removed from each patient, and extraventricular drainage was instituted. After placement of the extraventricular drainage catheter, administration of intravenous nafcillin (50 mg/kg every 6 h) was started. Each dose was infused over a 30-to 40-min period. Blood and ventricular fluid samples were obtained at 5 and 30 min and 1, 2, 3, and 6 h after infusion of the fifth or sixth dose of nafcillin. The extraventricular drainage catheter was clamped for 3 to 4 h after completion of the infusion. Ventricular fluid was obtained from the extraventricular drainage catheter as follows: 1.5 ml of ventricular fluid was aspirated and discarded; another 0.5 ...

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A previous report(1) from this laboratory has shown that strains of Staphylococcus aureus grown in the presence of subinhibitory concentrations of benzylpenicillin or nafcillin produced a marked accumulation of polysaccharide component within the staphylococcal cell. It was also found that treatment with nafcillin rendered the normally lysozyme-resistant S. aureus susceptible to partial lysis by lysozyme, and that concomitant addition of trypsin resulted in further dissolution of the cell bdies (2). Although the precise cytologic action of subinhibitory levels of penicillin on the integrity of the cell wall of S. aureus is unknown, evidence supported the hypothesis that relatively low concentrations interfered with normal utilization of the polysaccharide by preventing its incorporation into the bacterial cell wall( 1,Z). We also suggested that the accumulation of polysaccharide within the cell might be closely correlated with ability of lysozyme and trypsin to penetrate the cell wall. More recent observations made with subinhibitory concentrations of semisynthetic penicillins nafcillin, oxacillin, and cloxacillin (3) have suggested quantitative differences in their ability to disorganize the cell wall structure of S. aureus.The experimental design reported here was predicated on an initial assumption that changes in the integrity of the cell wall induced by a particular penicillin may fairly accurately reflect the antibacterial activity of that penicillin. Thus it is conceivable that impairment of the cell wall of S. aureus by subinhibitory levels of a penicillin may be correlated with the lytic behavior following treatment with lysozyme and trypsin. If this concept is substantiated, a model system for evaluation of the antibiotic activity of the penicillins could be developed in which pretreatment folIowed by Iytic response would be utilized as a determinative method. As far as ascertained, no studies have been reported that quantitate penicillin activity as a function of the ability to influence enzymic lysis of cells.We attempted in the present study (a) to determine the possible effects of subinhibitory concentrations of nafcillin, oxacillin, and cloxacillin on the enzymic lysis of a number of penicillin-sensitive and penicillin-resistant isolates of S. aweus and (b) to correlate differences in susceptibility to lysis and sensitivity to penicillins. Since lysozyme is present in secretions and certain cells of man and animals, the study may contribute toward a better understanding of the differences observed between the therapeutic action of nafcillin and the isoxazole penicillins in experimental infections in mice(4).Materials and methods. Clinical isolates of S. aureus were obtained from several sources. Minimal inhibitory concentrations (MIC) were determined in brain heart infusion (BHI) by the tube serial dilution technic of Knox ( 5). Benzylpenicillin, nafcillin, oxacillin, and cloxacillin were procured from commercial sources. Stock solutions (1 mg/ml) were prepared in distilled water, sterilized by pas...

The ovine chronotropic response t o i n j e c t i o n of catecholamines i s reported to increase during gestation, exhibit denervation s u p e r s e n s i t i v i t y , but i s s i m i l a r to the adult a f t e r b i r t h . This study examined the developmental changes i n the h e a r t r a t e response t o beta adrenergic stimulation with IS. Dose response s t u d i e s were carried out i n chronically c a t h e t e r i z e d , sheep --5 near-term f e t u s e s , 4 newborn, and 5 pregnant adults. IS was infused f o r 15-30 min u n t i l a steady s t a t e response was obtained f o r each dosage of the s e r i e s . Results a r e shown below.ISOPROTERENOL DOSE % CHANCE HEART RATE (meankSEM) (ug/kg/min) 69.858.7 These s t u d i e s indicate t h a t the ovine chronotropic response t o beta adrenergic stimulation increases not only during gestat i o n but from the newborn period t o adulthood. This may repres e n t a maturational increase in cardiac beta receptor number, a f f i n i t y or responsiveness. ONTOGENY OF 8-ADRENERGIC RECEPTORS IN MAMMALIAN378 LUNG. J.A. WhjJ_s_e_tt, Dept. Peds. Cincinnati, 0.The ontogeny o f 6-adrenergic receptors (BAR) i n lung was described i n the r a b b i t , r a t , sheep and guinea pig. Developmental increases i n binding capacity were demonstrated i g a l l species, f o r examp e, r a b b i t lung membrane bound ( -) - 3[ HI-di hydroalprenolol , [ HIDHA t o a single class o f sites, was stereoselective, r e v e r s i b l e and saturable; KD 1.78~0.30 nM. Binding a t a l l ages was i n h i b i t e d by agonists i n the order o f potency: I s o > Epi=Norepi c h a r a c t e r i s t i c o f a 8lAR subtype. Studies w i t h metoprolol (0 ) and z i n t e r o l (8 selective) revealed 60% 81-and 4h% 8 adrenergic suitypes a t a l l ages. Bmax increased 11.5 f o l % from day 25 o f gestation t o adulthood, increasing during the l a t t e r days o f gestation and the e a r l y neonatal period, from 3 7~1 0 fmolemg-1 p r o t e i n t o 4 2 5~5 1 i n the adult, mkSD. Gpp(NH)p decreased agonist a f f i n i t y more e f f e c t i v e l y i n adult than i n f e t a l lung and we hypothesize t h a t a "coupling" defect e x i s t s i n f e t a l lung BAR. The s e n s i t i v i t y o f adenylate cyclase a c t i v i t y t o catecholami ne was maximal i n adult r a b b i t lung increasing w i t h age from 23% a t day 25 gestation t o 255% stimulation i n the adult. Pulmonary BAR numbers a t term gestation were higher i n animals which are r e l a t i v e l y more mature a t b i r t h (guinea p i g and sheep) as compared t o less mature ( r a b b i t and r a t ) . I n conclusion, padrenergic receptors appear t o be a sensitive i n d i c a t o r of pulmonary maturation and the increase i n BAR during development i n mammalian lung and supports the r o l e of padrenergic receptors i n the regulation o f pulmonary function. PHARMACOKINETICS OF PIPERACILLIN I N INFANTS AND CHILD- 379REN. Chris B. Wilson, Terry I..Stull, Kent Opheim,Jcff Koup, Lee Adelman, Arnold L; Smith. Univ. of Wash. :Sch. of ~e d . ...