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Group B Streptococcus (GBS) is the most common cause of neonatal sepsis and meningitis. Despite antibiotics, GBS in the newborn initiates a cascade of molecular and biological events leading to altered cerebral perfusion, blood-brain barrier disruption, cerebral edema, intracranial hypertension, neurological damage, and even death. Having previously shown that GBS infection impairs cerebral blood flow autoregulation and increases prostaglandin (PG) levels, we examined the regulation of some crucial inflammatory mediators (PGs, nitric oxide (NO), tumor necrosis factor-a) in the brain and cerebral microvessels (MVs) from newborn piglets. Cyclooxygenase (COX), the key enzyme in PG biosynthesis, exists in two isoforms, COX-1 and COX-2. Both may be directly induced by NO in a model of renal inflammation. Besides its neurotransmitter role, NO is a potent vasorelaxant whose production is catalyzed by at least three distinct nitric oxide synthases (NOS) (bNOS, ecNOS, iNOS). Western blot analyses showed that the newborn (4 day old) brain expressed lower levels of COX-1 (8-fold), COX-2 (20-fold), bNOS (12-fold), and ecNOS (5-fold) than in the 1 day old. MV showed approximately equal levels of COX-2, lower levels of COX-1 (4-fold), bNOS (5-fold), and higher levels of ecNOS (20-fold) in comparison to 4-day-old cerebral MV. A 4-day-old brain expressed lower levels of bNOS (5-fold), ecNOS (10-fold), and COX-1 (2-fold) than the 6-week-old pig. COX-2 protein was undetected in a 4-day-old pig brain, but present in great excess in MV. Purified MV showed lower ecNOS (14-fold), COX-1 (2-fold), and about equal levels of bNOS and COX-2 in comparison with MV from 6-week-old pigs. Reverse transcription polymerase chain reaction analyses confirmed these results. Treatment with noo-nitro-L-arginine (LNA), a NOS inhibitor, downregulated COX-1 expression in the newborn brain and both COX-1 and COX-2 cerebral MV expression. GBS infection (10(9) colony-forming units, 0.5 mL intracerebroventricular) of sedated newborn piglets induced the expression of tumor necrosis factor-alpha in the cerebrospinal fluid after 2 hours, upregulated bNOS expression in both brain and MVs, upregulated ecNOS in MVs, and downregulated COX-1, COX-2, and ecNOS in the brain. GBS did not trigger the expression of iNOS. Our data suggest that there is a net deficiency of NOS isoforms in the immature brain and microvasculature of the 4-day-old piglet and that the differences in expression lead to the immature control of NO and PG production, rendering newborns particularly susceptible to neurological damage because of the undeveloped nature of their response mechanisms. Moreover, the GBS-induced cascade deregulates the gene expression of interacting inflammatory mediators and may cause a net vasoconstrictor/vasodilator imbalance, leading to cerebral hypertension and edema in the early stages of infection. Pharmacological manipulations of the inflammatory cascade could lead to novel therapeutic approaches for the treatment of GBS meningitis.

A heightened susceptibility to bacterial infections exists during the neonatal period. Newborn infants frequently are treated with antibiotics for suspected or proven infections. Physicians caring for these infants must familiarize themselves with the proper use of antibiotics in this special age group. This article reviews salient pharmacologic characteristics of newborn infants, emphasizing the marked differences between neonates, especially the small premature infants, and children of other ages. The excretion of antibiotics into breast milk is discussed. The pharmacologic principles of the antibiotics used more commonly in newborn infants, including mechanisms of action and resistance, antibacterial spectra, pharmacokinetics, safety, and indications for use are reviewed. Dosage schedules for use of these antibiotics in newborn infants is presented in tabular form.

The meningeal inflammatory response to a heat-killed mutant unencapsulated strain of type III group B Streptococcus (GBS) was studied in a newborn piglet model. GBS (109 colony-forming unit equivalents) or saline (control) was inoculated intraventricularly. Serial cerebrospinal fluid measurements were done at baseline and over the course of the next 24 h for cytochemical changes and production of tumor necrosis factor (TNF) and prostaglandins. In separate experiments, we defined the time course of early changes during the first 6 h and dose response relationship over a range of inocula 106 to 109 colony-forming unit equivalents. The intraventricular inoculation of the heat-killed unencapsulated GBS induced marked leukocytosis and increased protein by 6 h. These changes were preceded by a several hundredfold increase in TNF (maximum at 2 h) and prostaglandins (maximum at 2–4 h). The early and sharp rise in TNF suggests its pivotal role in initiating the inflammatory cascade. The magnitude of the inflammatory response increased with increasing bacterial dose over the range studied. To study the effect of encapsulation of GBS in the induction of meningeal inflammation, we compared the response to the unencapsulated mutant strain with that to the encapsulated parent strain. The encapsulated strain produced much smaller inflammatory changes, and only with high doses of bacteria. The GBS cell wall appeared to be the primary bacterial product triggering inflammation. Intraventricular injection of the heat-killed unencapsulated GBS with exposed cell wall can serve as a valid model for studying neonatal meningitis.

Group B Streptococcus (GBS) meningitis in the neonate may cause early cerebral hyperemia possibly mediated by NO. We hypothesized that L-Nitroarginine (LNA), a nitric oxide synthase blocker may protect CBF autoregulation at the upper limit in GBS treated piglets. Two groups of sedated piglets (1-5 days old) were studied. The GBS group (n=7) had cerebrointraventricular injection of 0.5 ml heat killed, unencapsulated GBS(109cfu) whereas the GBS + LNA group (n=9) had GBS (109cfu) + 300 mg/kg of LNA. CBF was measured by radioactive microspheres over a range of normotension (MABP range = 50-90 mmHg) and hypertension (MABP range = 90 - 125 mmHg) induced by inflating balloon tipped catheters placed at the descending aorta, at 5 time points: 15 min pre- (baseline) and post injection of GBS with or without LNA and during normo- and hypertension. Using linear regression analysis of CBF (ml/min/100g) vs cerebral perfusion pressure (CPP), the GBS group showed a pressure passive CBF (p=0.0404, r=0.5167). In contrast, the GBS+ LNA group had CBF held constant at CPP 50-125 mmHg (r=0.16, p=0.4). Thus, NO inhibition restores CBF autoregulation at the upper limit and may reduce the amount of cerebral hyperemia in GBS meningitis.Figure

Group B streptococcal (GBS) meningitis impairs cerebral blood flow (CBF) autoregulation in newborn piglets probably via inflammatory mediators in response to GBS. We tested whether TNFα mediates early CBF impairment by GBS in 3 grps of awake sedated newborn piglets (0-5 days). Grp 1 (CTRL), n=8 had normal saline (0.5ml) via the lateral cerebral ventricle (icv), Grp 2(n=7) had heat killed unencapsulated GBS (109 cfu, 0.5ml icv) and Grp 3 had TNFα, 1,000 units icv, 0.5ml). CBF was measured over a range of mean arterial blood pressure (35-125 mmHg) induced by inflating balloon tipped catheters at the aortic root to produce cerebral hypotension or descending aorta for hypertension at 5 time points: 15 min pre (baseline) and post injection of either saline, GBS or TNFα), and during randome hypo-, normo-, and hypertension. RESULTS: 1) Grp 1, CBF and CPP (cerebral perfusion pressure) best fitted a 3rd order polynomial regression (R2=0.57,p=0.008) with constant CBF at 50-90 mmHg CPP. 2) Grp 2, GBS caused direct correlation in CBF and CPP (50-110 mmHg), r=0.52, p

NITRIC OXIDE (NO) MEDIATES CEREBRAL HYPEREMIA IN NEWBORN PIGLETS WITH GROUP B STREPTOCOCCAL (GBS) MENINGITIS. † 1072

Group B Streptococcal (GBS) meningitis impairs cerebral blood flow (CBF) autoregulation in newborn piglets. We determined whether the early impairment could be related to increased prostaglandin (PG) production and if dexamethasone and ibuprofen alter PG production in the early phase (1st 6 hrs) of GBS meningitis. Net cerebrovascular PG production (calculated as total CBF× (sagittal-arterial plasma PG concentration) of 6-keto-PGF1α (stable metabolite of prostacyclin), TXB2(thromboxane B2) and PGE2 were measured in 4 groups of piglets given either 1) saline 0.5 ml intracerebroventrically (icv, control grp, n=9), 2) GBS alone (109 cfu/0.5 ml GBS icv, n=7), or 3) GBS icv plus dexamethasone (DEX) 1 mg/kg intraarterial, ia, n=8) or 4) GBS icv plus ibuprofen (IBU) 30 mg/kg ia,n=7) during periods of normotension (MABP= 50-90 mmHg), hypotension (MABP 90mmHg). MABP was randomly adjusted by balloon tipped catheters in the aortic root and descending aorta. CBF was measured by radioactive microsphere technique and PG's were measured by radioimmunoassay. Results show that within each treatment group there was a decrease in cerebrovascular production of 6 keto-PGF1α, TXB2 and PGE2 (p < 0.05) during hypotension possibly due to relative depletion in tissue oxygen for cyclo-oxygenation of arachidonate. However, between treatment groups (Control, GBS alone, GBS+DEX, and GBS+IBU) PG production did not change with BP adjustments except for increased PGE2 during cerebral hypertension(mean±SD, PGE2=250±25 ng/min/100 g brain tissue) compared to hypotension in GBS alone (PGE2=325±30 ng/min/100 g brain, p< 0.05). Irrespective of MABP, cerebral PG production is highest for PGE2, followed by 6-keto PGF1α with no production of TXB2. Since cerebral PG production is minimally influenced by GBS with or without DEX or IBU over a wide range of cerebral perfusion pressures, we suggest that vasoactive mediators other than PG's may mediate CBF impairment in early meningitis. Thus, treatment directed to PG's may not prevent CBF impairment in neonatal GBS meningitis.