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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).

Serum and ventricular fluid pharmacokinetic data for amikacin were evaluated prospectively in 10 hydrocephalic children with suspected ventriculitis. After the fourth or fifth intravenous 7.5-mg/kg dose of amikacin given every 8 h, mean peak serum levels were 24.3 +/- 3.2 microgram/ml (achieved at 0.5 h) with a calculated half-life of 2.2 +/- 1.1 h. Mean peak ventricular fluid levels in five patients with bacterial infection were 6.1 +/- 2.0 microgram/ml (achieved at 3 h). In the remaining five patients without bacterial ventriculitis, very low levels (less than or equal to 0.7 microgram/ml) of amikacin were detected. Ventricular fluid pleocytosis was directly correlated and glucose levels were inversely correlated with penetration of amikacin. Systemic therapy with amikacin may be the treatment of choice for children with ventriculitis meningitis caused by bacteria which are highly susceptible to this drug, thereby permitting the avoidance of the potentially hazardous intraventricular route of administration.

Six strains of ampicillin-resistant Haemophilus influenzae type b were studied in vitro for synergy between ampicillin and nafcillin. The minimal inhibitory concentrations for these strains with 10(4) colony-forming units per ml were 6.25 to 12.5 microgram of ampicillin per ml and 6.25 to 25 microgram of nafcillin per ml. Studies with these agents demonstrated synergism against all six strains of H. influenzae type b. Most strains were inhibited by 0.78 microgram of nafcillin plus 0.78 microgram of ampicillin per ml. A child with osteomyelitis caused by H. influenzae type b was successfully treated with a combination of ampicillin and nafcillin. These data suggest that further studies assessing the synergistic effect of this drug combination against H. influenzae type b are warranted.

Eight strans of ampicillin-resistant beta-lactamase-producing Haemophilus influenzae type b were studied in vitro for synergy between amoxicillin and clavulanic acid. The minimal inhibitory concentrations for amoxicillin alone were 6.25 to 12.5 microgram/ml, and for clavulanic acid alone they were 12.5 to 25 microgram/ml. However, seven of eight strains were inhibited by a combination of 0.36 microgram of amoxicillin and 0.36 microgram of clavulanic acid per ml. Infant rat models of bacteremia and meningitis were used to test the efficacy of amoxicillin and clavulanic acid alone and in combination upon four strains of ampicillin-resistant H. influenzae. Neither amoxicillin alone (27 animals) nor clavulanic acid alone (20 animals) sterilized the blood or cerebrospinal fluid of the animals. In contrast, 30 of 33 blood cultures and 29 of 33 cerebrospinal fluid cultures were sterile when a combination of the two drugs in the same dosages was used. The observed in vitro and in vivo synergism between amoxicillin and clavulanic acid suggests that the combination may be effective therapy for invasive infections in humans caused by ampicillin-resistant H. influenzae type b.

The presence of the human immunodeficiency virus type 1 (HIV) provirus was assessed in peripheral blood mononuclear cells (PBMCs) from 27 offspring of HIV-infected mothers, 12 of these mothers, and 4 HIV-uninfected mother-infant control pairs. Enzymatic amplification of specific conserved regions of the gag and env genes was performed directly in PBMC lysates using the polymerase chain reaction (PCR) technique. The enzymatically amplified gene products were evaluated using the oligomer hybridization detection procedure. PBMCs from infected infants (as determined by Centers for Disease Control clinical criteria) and from HIV-infected mothers manifested a characteristic HIV oligomer hybridization product. Clinically uninfected seropositive infants with declining HIV antibody titers and infants who became seronegative lacked an enzymatically amplified HIV gene product. These preliminary data indicate that PCR is a valuable diagnostic technique to detect or exclude HIV infection in young infants and children.

In vitro, Haemophilus influenzae strains have two distinct patterns of susceptibility to trimethoprim-sulfamethoxazole (TMP/SMZ); strains with low minimum inhibitory concentration and high minimum bactericidal concentration (tolerant) and those with both low minimum inhibitory concentration and minimum bactericidal concentration (kill-sensitive). Tolerant H. influenzae strains were found to elaborate significantly more type b capsular polysaccharide, a linear polymer of ribosyl ribose phosphate (PRP), than kill-sensitive strains. Tolerant strains became susceptible to killing by TMP/SMZ when type b capsule was physically removed, but reacquired tolerance following growth and reversion to original (mucoid) phenotype. Susceptibility of wild (type a, b, c), isogenic (type b and untypable), and transformed (type b and d) strains indicated that elaboration of type b capsule was associated with TMP/SMZ tolerance. In a second series of studies, virulence of H. influenzae in the infant rat model was correlated with in vitro tolerance. Tolerant strains (13/13) caused systemic disease while none (0/7) of kill-sensitive strains were pathogenic. The efficacy of TMP/SMZ in the treatment of invasive infection was evaluated in rats with established bacteremia and meningitis. TMP/SMZ failed to eradicate H. influenzae b from the blood in 85% (17/20) or from the cerebrospinal fluid in 95% (19/20) of infected animals. Thus, in vitro tolerance correlated with therapeutic failure in vivo.

The efficacy of cefaclor and rifampin in eradicating Haemophilus influenzae type b (HITB) from the nasopharynx of day care center and household contacts of children with HITB meningitis was evaluated. In 38/50 children treated with cefaclor, the carrier state persisted, a failure rate of 76%. Although cefaclor failed to eradicate HITB from many carriers, an appreciable reduction in the intensity of colonization following treatment was noticed. When rifampin was used in 17 children who had failed to respond to cefaclor, persistence of the carrier state with HITB was found in only two children, a failure rate of only 12%. During the study, two episodes of invasive HITB disease were documented to be acquired from sources other than the index cases or from children who were screened, which suggested the need to reevaluate the usually recommended strategy to screen for carriage and to treat only the immediate contacts 6 years of age and younger. Furthermore, the most appropriate agent for eradicating nasopharyngeal carriage of HITB awaits additional studies.

Dog bite wounds of 39 children (ages one to 16 years) were cultured and irrigated. Cultures showed various organisms but were of no predictive value for development of infection. By using a table of random numbers, patients were assigned to either oral penicillin V-K (100,000 U/kg/day every 6 h) or placebo for two days. All patients were seen in follow-up in three to four days and again at seven to 10 days or earlier if signs of inflammation occurred. The mean patient age, location and type of wound, and initial wound care were similar in the two treatment groups. Three of 39 (7.7%) children enrolled in the study developed infection at the bite site, including two of 19 in the penicillin group and one of 20 in the placebo group. In our study, prophylactic penicillin failed to prevent infection in dog bite wounds. Good local care on presentation seems to be the most important factor in determining future infection.

Because of increased aminoglycoside resistance of hospital bacterial isolates, aminoglycoside sensitivity patterns of isolates in a large children's hospital were assessed before and during a 33-month period of almost exclusive amikacin use. There was no significant change in overall resistance rates of gram-negative enteric bacteria to gentamicin (4.8 percent and 4.6 percent), tobramycin (2.5 percent and 3.6 percent), and amikacin (1.2 percent and 1.8 percent) from the pre-amikacin period to the amikacin usage period, respectively. No significant differences were observed for isolates of Escherichia coli, Klebsiella, Serratia, Acinetobacter, and Pseudomonas species. In contrast, significant decreases in gentamicin and tobramycin resistance rates for Enterobacter, Citrobacter, and Pseudomonas aeruginosa and in gentamicin resistance of Proteus were found. Very little change in resistance of staphylococcal isolates was seen during a shorter evaluation period. Pediatric aminoglycoside usage includes therapy of neonatal infections, cystic fibrosis, febrile neutropenic episodes in patients with cancer, abdominal surgery, bacterial endocarditis, and gram-negative central nervous system infections. Amikacin has also been used successfully as single-dose therapy of urinary tract infections, and acceptable cerebrospinal fluid levels of amikacin have been documented in hydrocephalic patients with ventriculitis. In vitro studies of 22 bacterial isolates demonstrated synergy between amikacin and penicillin or newer cephalosporins in 13, an additive effect in seven and indifference in two. No antagonism was found. In addition, in vivo synergy between imipenem and amikacin was found in neutropenic infant rats with P. aeruginosa sepsis using a strain with which no synergy was demonstrable in vitro. Amikacin is effective in pediatric infections and is well tolerated by children. Because excessive or inadequate levels are frequent with usually recommended doses, particularly in neonates and patients with compromised renal function or cystic fibrosis, serum levels should be monitored to minimize risk and to ensure therapeutic levels.

Shunt infections occur in 6-25% of hydrocephalic patients with shunts. Although Staphylococcus epidermidis and Staphylococcus aureus cause the majority of such infections, enteric bacteria account for at least 10-15%. The clinical presentation in most patients is nonspecific. Most investigators agree that the entire infected shunt should be removed before antibiotic therapy is initiated. The choice of an antibiotic should be guided by in vitro susceptibility of the etiologic agent, and the ability of the drug to pass the blood-brain barrier. The efficacy of prophylactic antibiotics in reducing shunt infections is controversial.

The MICs and MBCs for 90% of strains tested (MIC90 and MBC90, respectively) of rifampin for 75 clinical isolates of pathogenic coagulase-negative staphylococci (PCNS) were 0.03 and 0.25 microgram/ml, respectively, while the MIC90 and MBC90 of clindamycin were both greater than 25 micrograms/ml. Although no synergy between rifampicin and clindamycin was found among the 15 strains studied by the checkerboard method, 6 of 12 selected strains showed synergy by the kill-curve method. No antagonism was observed by either method. All 30 strains rapidly developed resistance to rifampin in vitro, and this could be prevented by the simultaneous presence of 1.0 microgram of clindamycin per ml in the 24 methicillin-susceptible PCNS strains. The synergy between rifampin and clindamycin observed in vitro for some strains of PCNS, together with the prevention of emergence of resistance to rifampin by clindamycin, suggests that this antibiotic combination may be useful for the treatment of infections caused by methicillin-susceptible PCNS.

Urinary tract infection in children is usually treated with orally administered antibiotics for 10 to 14 days. Because of the unreliability of patient compliance with prescribed medications and because single-dose aminoglycoside therapy has been shown to be effective in women with cystitis, we assessed the efficacy of single-dose amikacin for treatment of first episodes of Escherichia coli lower urinary tract infection in girls. Upper and lower urinary tract infections were presumptively differentiated by simple criteria such as clinical symptoms, fever, and erythrocyte sedimentation rate. Fifty-four girls (ages 1 to 12 years) with two positive urine cultures (greater than 10(5) CFU/ml E. coli) were assigned by a table of random numbers to receive treatment with either sulfisoxazole 150 mg/kg/day orally for 10 days or a single dose of amikacin 7.5 mg/kg intramuscularly. Six of 23 patients (26%) in the amikacin group and four of 21 (19%) in the sulfisoxazole group had at least one positive urine culture within 40 days after completion of therapy. This difference was not statistically significant (P greater than 0.5). This suggests that a single dose of amikacin is as effective as a 10-day course of sulfisoxazole in the treatment of presumed first lower urinary tract infection in girls. Additional potential advantages of single-dose therapy are fewer side effects and less toxicity, excellent compliance, and reduced potential for selecting resistant organisms.

Enterobacter aerogenes bacteremia associated with the infusion of contaminated admixed intravenous (IV) fluid occurred in seven patients in a pediatric hospital over a five-day period. Clinical illness was characterized by spiking fever in all patients. The temporal clustering of cases allowed for rapid recognition of the problem. The primary control measure was the prompt replacement of the IV fluids, although IV antibiotics were also administered. Hospital pharmacy practices for admixing IV solutions should follow published recommendations to minimize this source of potential contamination of fluids.

Total, cell-free, and cell-bound endotoxin and bacterial density were measured in cerebrospinal fluid (CSF) of 22 children with Hemophilus influenzae meningitis. Also the effect of ceftriaxone on CSF endotoxin levels was investigated in eight patients by reexamining their CSF 2-6 h after the initial dose. Initial CSF bacterial density correlated with initial CSF endotoxin levels (P less than .001). Ceftriaxone induced a marked increase of free endotoxin in CSF, from an initial (mean +/- SE) 0.75 +/- 0.21 to 1.29 +/- 0.23 log10 ng/ml (P less than .01). This increase correlated positively with the number of bacteria killed in the CSF (P less than .01). The increase in free endotoxin was associated with an increase in mean CSF lactate levels from 8.5 to 9.7 units/l (P less than .05) and mean lactate dehydrogenase levels from 102 to 180 mmol/l (P less than .02) and a decrease in mean CSF glucose from 1.17 to 0.46 mmol/l (P less than .05). Initial CSF total endotoxin concentrations correlated both with the Herson-Todd clinical severity score (P less than .001) and with the number of febrile hospital days (P less than .001). These findings suggest that highly bactericidal agents initially lead to release of free endotoxin from gram-negative organisms into CSF, with associated enhanced inflammatory response by the host.

Although all of 14 clinical isolates of Haemophilus influenzae type b strains demonstrated rifampin susceptibility in vitro (minimal inhibitory concentration less than or equal to 0.4 microgram/ml) when an inoculum of 10(4) colony-forming units (CFU) was used, 10 of the 14 strains manifested resistance to this agent when an inoculum of 10(8) CFU was tested. The mutation rate for rifampin resistance ranged from 1 resistant colony per 3.5 x 10(6) CFU to 1 per 4 x 10(7) CFU. The emergence of rifampin-resistant mutants was prevented when trimethoprim was combined with rifampin. This finding suggests that when used alone for prophylaxis of H. influenzae type b nasopharyngeal carriers, rifampin is likely to lead to the emergence of resistant strains.

The pharmacokinetics of chloramphenicol following intravenous and oral administration were studied in 14 infants with Haemophilus influenzae meningitis. Following five days of treatment with intravenous chloramphenicol (100 mg/kg/day every six hours), oral chloramphenicol was substituted at the same dose. Multiple serum levels of chloramphenicol were determined after an intravenous dose on day 4 and after an oral dose on day 10. CSF levels were measured six hours after intravenous or oral chloramphenicol dose on those days (CSF trough). Following intravenous administration, the mean peak serum level of 15.0 micrograms/ml was reached at 45 minutes. In comparison, after oral chloramphenicol in the same dosage, the mean peak serum level of 18.5 micrograms/ml was achieved at two to three hours. The mean serum half-life of the drug (6.5 hours) was significantly longer after oral administration than after intravenous chloramphenicol (4.0 hours) (P less than .001). The increased serum half-life following orally administered chloramphenicol was occasionally associated with drug accumulation. In addition, mean trough CSF levels were somewhat higher when the patient received oral medication (6.6 micrograms/ml) compared to intravenous administration (4.2 micrograms/ml) (P less than .001). For any treatment regimen for H influenzae meningitis that includes a period of oral chloramphenicol therapy the patient should be hospitalized to ensure compliance. Because of the wide range of individual variation in serum half-life that may result in accumulation, periodic monitoring of serum chloramphenicol levels is also recommended.

A modification of the methotrexate radioassay kit (supplied by New England Enzyme Center) enabled determination of trimethoprim levels in 5-microliter serum samples. An excellent correlation between this assay and high-pressure liquid chromatography assay was found. These preliminary results suggest that with this method rapid determination of trimethoprim levels in very small samples (5 to 10 microliters) can be achieved.

Streptococci of Lancefield group C colonize healthy individuals but infrequently cause invasive disease. Eight pediatric cases of infection due to group C streptococci were identified in a retrospective survey of a recent 6-year period at a children's hospital. An additional case of group C meningitis diagnosed in 1975 was included. These nine cases and 22 pediatric cases from the literature are presented to illustrate important points with respect to clinical presentations and complications and to show that these organisms can cause serious, sometimes fatal infection: pneumonitis, sinusitis, septicemia, endocarditis, osteomyelitis, and meningitis. Group C streptococci are described in terms of their biochemical properties, the infections they cause in animals, and their tendency to produce disease in humans. With increasingly frequent serologic grouping of non-group A beta-hemolytic streptococci, recognition of the role of specific non-group A streptococci is likely to increase. The antimicrobial agent of choice for infections due to group C streptococci is penicillin G. The minimum inhibitory and minimum bactericidal concentrations for the organism should be determined since penicillin tolerance may occur and may be responsible for the slow response to penicillin therapy in some cases.

Infants born to women who are asymptomatic hepatitis B surface antigen (HBsAg) carriers frequently acquire hepatitis B virus infection in infancy. The spectrum of disease in such affected infants includes mild transient acute hepatitis B, chronic active hepatitis with or without cirrhosis, chronic persistent hepatitis, chronic asymptomatic HBsAg carriage, and, rarely, fulminant fatal hepatitis B. Recently, the administration of hepatitis B immunoglobulin has been demonstrated to reduce the risk of infantile acquisition of hepatitis B virus; hepatitis B vaccine may also be preventive in this setting. Three young infants, aged 8 to 16 weeks, who died of acute fulminant hepatitis were studied. In each instance, the mother was found, retrospectively, to be asymptomatic but HBsAg positive. One of these mothers was hepatitis B e-antigen-negative but hepatitis B e-antibody positive. All three babies were HBsAg positive; two who were tested for hepatitis B core antibody were positive. These three fatalities serve to dramatize both the importance of HBsAg screening of pregnant women, particularly those with demographic factors that place them at increased risk for HBsAg carriage, as well as the significance of effective immunoprophylaxis for hepatitis B in all offspring of women with HBsAg seropositivity.

Suppurative intracranial complications of respiratory infections are relatively rare in children. These complications occur more often in association with chronic sinusitis and chronic otitis media. Because symptoms and signs of the intracranial complications can be nonspecific, a high index of suspicion by the physician is important for early diagnosis. The routine cerebrospinal fluid examination often does not distinguish between the various complications, and radiologic procedures such as radionuclide brain scan, arteriography and computer-assisted tomographic scan should be used. Computer-assisted tomographic scan is very useful in detecting early complications allowing trial with medical treatment alone. Appropriate selection of antibiotics must be made on the basis of the likely pathogens in the particular setting and the ability of the antibiotic to penetrate the affected area. Appropriate early management of suppurative intracranial complications should result in a favorable outcome.

We evaluated the efficacy of rifampin in eradicating chronic pharyngeal carriage of group A streptococci. Carriers were defined as healthy children whose throat cultures showed persistence of group A streptococci 3 weeks after receiving benzathine penicillin G intramuscularly. Subsequent M and T typing of group A streptococcal isolates and limited serologic studies confirmed that enrolled patients were carriers. Thirty-eight carriers (37 completed the study) were randomly assigned to three groups: group 1 (13 patients) received no treatment; group 2 (10) received benzathine penicillin intramuscularly; group 3 (14) received benzathine penicillin intramuscularly plus rifampin orally (10 mg/kg twice a day for eight doses). Throat cultures were obtained every 3 weeks for at least 9 weeks. Group 2 and 3 patients who still had positive cultures 3 weeks after treatment were crossed to the opposite group. Cultures became negative in 93% (13 of 14) of patients in group 3, compared with 23% in group 1 and 30% in group 2 (P less than 0.001 and P less than 0.01, respectively). Including patients crossed over, the penicillin plus rifampin regimen was effective in 17 (89%) of 19 treatment courses and was significantly superior to no therapy or to penicillin alone (P less than 0.0005 and P less than 0.005, respectively). We conclude that rifampin plus benzathine penicillin intramuscularly is an effective regimen for those selected patients in whom eradication of group A streptococcal carriage is judged to be desirable.

Fifty-four consecutive cases of children with cerebral abscess from 1958 to 1987 are reviewed. Their average age was 6.6 years, ranging from 3 days to 19 years. A wide range of organisms and underlying diseases was encountered. The predominant mode of surgical therapy was craniotomy with resection of the abscess. Aspiration and craniotomy with drainage-evacuation were also employed in our series. No underlying disease was found in 10 (19%) of the children. Cyanotic heart disease (CHD) was present in 13 (24%) of the children. Four children had dental abscesses and 1 had otitis media. Seven (13%) children had abscesses secondary to hydrocephalus/shunt infections. Sinusitis and otitis accounted for 5 cases (9%). Four children (7%) had tuberculomas. One abscess was associated with a nasal dermal sinus and one was congenital. Fourteen (26%) patients had negative cultures. Fourteen (26%) abscesses contained streptococci of various types. Staphylococci were found in only 5 (9%) of the abscesses. The congenital abscess was caused by salmonella. Two abscesses (7%) were fungal. Both of these patients died. Six children (11%) were treated without surgical intervention. Three of them died. Forty-eight children had surgical intervention; 12 underwent aspiration, 14 underwent open evacuation of the abscess, and 22 had abscesses resected. Mortality in the aspiration group was twice that of the evacuation or resection group (17, 7 and 9%), respectively). The factor which correlated best with mortality was the patient's clinical status on admission. The advent of CT scan at our facility improved mortality by facilitating accurate diagnosis and surgical intervention. Overall mortality rates decreased from 31 to 5.7% and surgical mortality fell from 21 to 2.9%.

The seriousness of bacterial meningitis in pediatrics mandates more rapid and accurate diagnostic tests. Of the available tests to detect bacterial antigens, latex particle agglutination appears to be the best because it is simple and highly sensitive. For differentiation between bacterial and aseptic meningitis, serum C-reactive protein levels in excess of 50 mg/liter and cerebrospinal fluid lactate levels higher than 2.2 mmol/ml indicate a bacterial etiology. Available data confirm that one of the newer "third generation" cephalosporins can be used effectively and safely as a single drug for therapy of meningitis caused by the usual spectrum of bacteria, if the achievable cerebrospinal fluid drug levels exceed the minimal inhibitory concentration of the infecting bacteria by at least 10-fold. Use of these agents will obviate the potential toxicity of current antibiotics and may result in considerable cost savings.

Investigation of two infants suggested that peak ventricular fluid levels of chloramphenicol after intravenous administration were achieved after 3 h. The penetration of chloramphenicol into ventricular fluid may be unpredictable. In one patient, the peak ventricular fluid level was 57.5% of the peak serum level, and it was only 22.5% in the other patient. This observation may explain some of the past treatment failures when chloramphenicol was utilized in patients with gram-negative ventriculitis and meningitis.

A retrospective study was performed of 39 children at the Children's Memorial Hospital, Chicago, Illinois, who underwent technetium-99m glucoheptonate (99mTcGH) scintigraphy for evaluation of possible urinary tract infection. Clinical and laboratory criteria classified the children as having pyelonephritis, cystitis, or no urinary tract infection. Of 28 children classified as having pyelonephritis, 24 (86%) children had abnormalities on 99mTcGH scintigraphy. Only 8 of 19 (42%) renal ultrasound scans and 4 of 17 (24%) intravenous pyelography studies performed in these children demonstrated findings consistent with parenchymal disease. Only 9 of 19 (47%) cystograms demonstrated vesicoureteral reflux. Three children who underwent gallium-67 citrate scintigraphy had localization at the sites of focal defects with 99mTcGH scintigraphy. 99mTcGH scintigraphy is a sensitive and specific indicator of renal parenchymal involvement that helps localize urinary tract infection to the kidney.