Human papillomavirus infection: the role of vaccination in pediatric patients.

Human papillomavirus (HPV) infection is the most common sexually transmitted infection among adolescents and adults in the United States. Given the prevalence of this infection and its relationship with the development of cervical cancer, HPV vaccine development has been a major public health initiative in the last decade. Despite extensive research in the development of these vaccines, there remain many unanswered questions in academic and public arenas regarding their administration and role in adolescent medicine.

Ganciclovir population pharmacokinetics in neonates following intravenous administration of ganciclovir and oral administration of a liquid valganciclovir formulation.

Cytomegalovirus (CMV) is the most common viral congenital infection, producing both sensorineural hearing loss and mental retardation. Our objective was to assess the population pharmacokinetics of a research-grade oral valganciclovir solution in neonates with symptomatic congenital CMV disease. Twenty-four neonates received 6 weeks of antiviral therapy. Ganciclovir and valganciclovir were measured by liquid chromatography/tandem mass spectroscopy. NONMEM version VI beta was used for population analyses. All profiles were consistent with a one-compartment model. Postnatal age, body surface area, and gender did not improve the model fit after body weight was taken into account. The typical value of clearance (l/h), distribution volume (l), and bioavailability of ganciclovir were 0.146 x body weight (WT)(1.68), 1.15 x WT, and 53.6%, respectively. Although these results cannot be extrapolated to extemporaneously compounded valganciclovir preparations, they provide the foundation on which a commercial-grade valganciclovir oral solution may be a viable option for administration to neonates.

Interaction of primate alveolar macrophages and Legionella pneumophila.

We studied the interaction between Legionella pneumophila, which is principally a pulmonary pathogen, with primate alveolar macrophages (AM), which are the primary pulmonary cellular defense mechanism. For these studies we used L. pneumophila, type I, which were grown in albumin-yeast extract broth, were greater than 80% viable, and were comparable in virulence for guinea pigs to organisms from guinea pig spleen homogenates. For comparison, avirulent agar-passed L. pneumophila, type I, and a strain of Escherichia coli were also used. In the absence of detectable antibody, AM phagocytosed similar numbers of virulent and avirulent Legionella and killed the majority of ingested Legionella in 15-30 min, as determined by two different assays. The virulent and avirulent Legionella appeared to be equally susceptible to the cidal systems of the AM and both were killed more readily than were E. coli under both assay conditions. Phagocytosis of Legionella by AM was associated with a localized respiratory burst, as indicated by nitroblue tetrazolium reduction around ingested organisms. Killing of AM-associated Legionella was inhibited by the hydroxyl radical (OH.) scavenger mannitol (but not by an equiosmolar concentration of sodium sulfate), and by a combination of superoxide dismutase and catalase (but not by either enzyme alone). These findings suggest a contribution by OH., one generated by the metal-catalyzed interaction of superoxide and hydrogen peroxide (Haber-Weiss reaction) in the anti-Legionella activity of AM. The virulent Legionella that survived intracellularly increased in number from 4 X 10(4) at 1 h to 6 X 10(6) at 96 h after infection. In contrast, avirulent Legionella replicated more slowly, increasing in number from 4 X 10(4) to 1 X 10(5) over the same period. Replication of virulent Legionella destroyed the AM monolayers by 120 h, whereas monolayers containing avirulent organisms remained intact. Thus, virulence of Legionella appears not to correlate with its ability to survive early killing by AM, but rather with the ability of the small fraction of surviving organisms to replicate within these cells.

Receptor-mediated ingestion responses by lung macrophages from a canine model of ARDS.

Receptor-mediated ingestion was examined in macrophages derived from a canine model of the adult respiratory distress syndrome (ARDS). The results showed that Fc-mediated ingestion by alveolar macrophages (AM) and macrophages from lung parenchyma (PM) was significantly diminished when compared with their respective controls. Pulsing all the experimental groups with lipopolysaccharide (LPS) for 1 hr in vitro failed to either enhance the response or return the activity to levels achieved by control cells. In parallel studies, an analysis of C3b-mediated ingestion showed that both the experimental AM and PM performed this function only at a magnitude equal to the control cells. Similar responses were observed when an LPS pulse was performed. Although there was a reduction in Fc-mediated ingestion and an apparent restraint of the C3b-mediated ingestion, both AM and PM expressed a significantly enhanced ability to spread. These results suggested that the canine model of ARDS alters at least one select macrophage function that may be important to subsequently protect the host. Such disturbances in the cellular immune response may contribute to the progression of infection and lung pathology associated with this disease process.

Differential induction of macrophage GSIB4-binding activity.

Activated macrophages display a terminal galactopyranosyl group on their membrane surface that binds the lectin Griffonia simplicifolia-IB4 (GSIB4). Using FITC-conjugated GSIB4, we examined the induction and subsequent expression of this corresponding marker on peritoneal macrophages from normal (NMO) and LPS-treated (LPS MO) mice. Although the percentage of fresh LPS MO explants that bound GSIB4 was always higher when compared to the NMO counterparts, marker expression on the latter was readily enhanced by culturing the cells in vitro either alone or with stimuli. Moreover, we found that an increase in this activity was promoted by either nonspecific phagocytosis of latex beads, or gamma-interferon (gamma-IFN) treatment. Further investigation showed that a prerequisite sequence of signal delivery to the macrophages was associated with maximal expression of the GSIB4 binding. When gamma-IFN treatment preceded latex bead ingestion, maximum GSIB4 binding occurred. Data obtained from using short-term (1 hr) and long-term (24 hr) exposure to latex beads showed that metabolic processing of induction signals was required to enhance the response over time. This yielded better GSIB4-binding activity when responses to these pulses were analyzed in freshly explanted macrophages. The overall results of this study demonstrated that macrophage binding of GSIB4 was differentially associated with stimuli induction. Moreover, select signals in the form of soluble mediators, or the mechanical events characteristic of internalization were capable of eliciting an increase in the percentage of macrophages that were positive for binding GSIB4. Thus, the enhanced affinity for binding this lectin may serve as a useful marker to determine the magnitude of macrophage responsiveness when these cells are examined following their exposure to different stimuli.

Fc-gamma receptor-ligand interactions enhance macrophage GSIB4-binding activity.

Activated macrophages have an increased ability to bind the lectin Griffonia simplicifolia-IB4 (GSIB4). Since macrophages readily use the Fc-receptor (FcR) during several immunologic and inflammatory processes, it is important to determine whether interactions with this moiety affect GSIB4-binding ability. Peritoneal macrophages cultured in vitro with Fc fragments of immunoglobulin G (IgG), whole IgG, or heat-aggregated IgG demonstrate an increase in this function. Conversely, treatment of macrophages with (Fab')2 fractions alone has no direct effect on this activity. Although the GSIB4-binding response is minimally expressed by normal macrophages, it is more markedly apparent on macrophages from LPS-treated animals. In both cases, however, pretrypsinization of the cells renders them refractory to IgG-mediated induction of the GSIB4-binding response. Moreover, macrophages cultured independently with IgG subclasses 1, 2a, or 3 demonstrate that the magnitude of their response to this signal is directly associated with the type of subclass used. Although each subclass enhanced the response, in this study interactions with IgG2a produced the best results. Overall, however, the greatest GSIB4-binding activity is generated when FcRs are crosslinked by aggregated IgG rather than simply bound by independent monomeric interactions at the FcRs. This suggests that the event of appropriately interacting with the FcRs amplifies the GSIB4-binding function. Such a mechanism could play a key role in coordinating the humoral, cell-mediated, and innate responses of the immune system.

Timentin therapy for bone, joint, and deep soft tissue infections in children.

Timentin, a combination of clavulanic acid (0.1 g) and ticarcillin (3.0 g), has proved effective in vitro against bacterial pathogens that produce beta-lactamases. The usual etiologic bacteria of osteochondritis of the foot (Pseudomonas species) and osteomyelitis/septic arthritis (Staphylococcus aureus) are commonly resistant to penicillins. To date, we have used Timentin to treat 30 children with bone, joint, and deep soft tissue infections. Timentin was administered intravenously at an average dosage of 207 mg/kg per day for mild to moderate infection and 310 mg/kg per day for bone and joint infections with systemic signs (sepsis). The lower dose was used in 24 patients and the other six patients, who had signs of sepsis, received the higher dose. All patients received Timentin intravenously over 30 minutes every four to six hours for a minimum of five days (mean 6.6 +/- 2.6 days, range five to 14 days). The mean time to defervescence and/or reduction in clinical symptoms was 1.6 +/- 1.3 days (range zero to four days). Osteochondritis due to P. aeruginosa was diagnosed in six patients, and septic bursitis, osteomyelitis, or septic arthritis due to S. aureus (13 patients) or Staphylococcus species and group A streptococci (four patients) was diagnosed in 17 patients. All isolates were susceptible to Timentin in vitro by disk-diffusion analysis. All patients showed a response to therapy with Timentin, with or without surgical intervention. All patients had clinical and microbiologic cures; no adverse reactions or side effects were observed. There have been no clinical or microbiologic relapses to date. Timentin may prove to be useful in specific bone and joint infections in children.

Tularemia in adults and children: a changing presentation.

Tularemia, a febrile zoonosis with six clinical types, recently has been shown to occur at an increased incidence in children compared with previous reports. Ulceroglandular and glandular tularemia are still the most common types, but pneumonic tularemia has increased in incidence. However, with these changes, an overall decline in mortality has been observed. Children exhibit fever, pharyngitis, hepatosplenomegaly, and constitutional symptoms more often than affected adults. The complication of late lymph node suppuration is found in half of the tularemia patients with lymphadenopathy. A high index of clinical suspicion and a good medical history and physical examination confirmed by specific serologic studies are the critical factors in the successful diagnosis of tularemia in children.

Management of Pseudomonas osteochondritis complicating puncture wounds of the foot.

Pseudomonas osteochondritis following puncture wounds of the foot is described in 13 children. All children had received at least one oral antibiotic and local wound therapy before admission; none had improved on these modalities. Pseudomonas aeruginosa was isolated alone from seven patients and with one or more other organisms from six patients. Initial administration of parenteral antibiotics active against Pseudomonas for one to 14 days did not result in clinical improvement. Eradication of Pseudomonas osteochondritis occurred in each patient only after thorough surgical debridement and curettage of all infected tissue. Following thorough surgical debridement, anti-Pseudomonas antibiotic therapy was continued for five to 14 days (10.8 +/- 2.7 days). The successful treatment of Pseudomonas osteochondritis should include adequate surgical debridement of all infected tissue; following thorough debridement, only one to two weeks of anti-Pseudomonas antibiotic therapy appears to be necessary.

Recurrent bacterial meningitis: coronal thin-section cranial computed tomography to delineate anatomic defects.

Three patients with histories of recurrent bacterial meningitis were previously examined with skull and sinus radiographs, routine cranial computed tomography, intrathecal radioisotope tracer studies, and immunologic evaluation. None of these studies were diagnostic. Pneumococcal vaccine and prophylactic penicillin therapy were ineffective in preventing recurrent episodes in two cases. Thin-section (2-mm) direct coronal computed cranial tomography demonstrated anatomic defects in all three patients. The use of metrizamide cisternography was not necessary to diagnose the defects. All patients had basiethmoidal encephaloceles which were repaired surgically. Direct coronal computed tomography offers a relatively easy noninvasive method for delineating anatomic abnormalities in patients with recurrent meningitis.

Apparent meningococcemia: clinical features of disease due to Haemophilus influenzae and Neisseria meningitidis.

To determine the etiology of apparent meningococcemia, all cases of sepsis with coagulopathy, purpura, and/or adrenal hemorrhage (Waterhouse-Friderichsen syndrome) with and without shock occurring over a 12-year period were reviewed. A total of 42 cases were identified; 30 cases were caused by Neisseria meningitidis and 12 cases were caused by Haemophilus influenzae. Compared with patients with disease caused by H influenzae, patients with meningococcal disease were older, more often male, more often contracted the disease in winter-spring, and had a longer duration of antecedent symptoms; however, none of these differences was statistically significant. All patients were febrile (greater than 38 degrees C) and appeared toxic. Similar proportions in each group had shock and disseminated intravascular coagulopathy at the time of admission. Ten of 12 patients with H influenzae infection compared with 15/30 (P less than .05) with meningococcal infection were lethargic or comatose at the time of admission. Nine of 12 patients with H influenzae infection died compared with 5/30 with meningococcal disease (P less than .005); the mean time from onset of symptoms to death with H influenzae infection (20.7 +/- 11.4 [SE] hours) was significantly shorter (P less than .05) than with meningococcal infection (120 +/- 74.4 hours). Children with clinical signs of sepsis and with purpura, petechiae, or coagulopathy may have N meningitidis or H influenzae as etiologic agents. Initial antibiotic therapy should be directed against these pathogens.

Cefotaxime dosage in infants and children. Pharmacokinetic and clinical rationale for an extended dosage interval.

Cefotaxime is a third generation cephalosporin antimicrobial agent which has received wide acceptance as a first-line antibiotic for many infections in neonates, infants and children. With an average elimination half-life of about 1 h, cefotaxime is not considered to be a 'long half-life cephalosporin' like ceftriaxone. For this reason, currently accepted dosage regimens for cefotaxime in infants and children employ a dosage of 50 mg/kg every 6 h. Re-examination of the paediatric pharmacokinetic data for cefotaxime and use of simple multiple-dose pharmacokinetic simulation of alternative dosage regimens was performed. From this analysis, regimens administering 75 mg/kg of the drug every 8 h or every 12 h were projected to produce serum cefotaxime concentrations adequate to effectively kill many of the common pathogens against which the drug is currently indicated for use in children. The clinical utility of these alternative dosage regimens was supported by a review of the medical literature and examination of the clinical results from studies in neonates, infants and children where cefotaxime was administered in 2 to 3 divided doses daily. It would appear, therefore, that increasing the cefotaxime dosage to 75 mg/kg administered at 8 h intervals would result in less frequent drug administration which would not be expected to compromise safety and efficacy. Alternative dosage regimens for cefotaxime merit further consideration and clinical evaluation before they become commonly used in paediatric therapeutics.

Cefotaxime treatment of gram-negative enteric meningitis in infants and children.

18 infants and children (1 week to 3 months of age) were treated with cefotaxime 200 mg/kg/day for Gram-negative enteric bacillary meningitis. 17 of these patients (94.4%) survived, with a complication rate of 23.5% (4/17 patients). The follow-up cerebrospinal fluid cultures at 24 hours were sterile in all patients. Cefotaxime was safe and effective in treating Gram-negative enteric bacillary meningitis in infants and children and should be considered as a potential drug of choice in Gram-negative neonatal meningitis due to susceptible organisms.

Lymphocyte subpopulations of blood and alveolar lavage in blastomycosis.

Patients with blastomycosis were found to have differing lymphocyte populations depending on the extent of disease manifestations and whether or not therapy had been started. Patients with recovering pulmonary blastomycosis who had been receiving antifungal treatment for at least four weeks had lymphocyte subpopulations no different from control donors. Patients with treated extrapulmonary blastomycosis had similar T helper (TH) to T suppressor (TS) ratios compared to recovering pulmonary patients and control subjects; this ratio gives a false impression because extrapulmonary blastomycosis patients had a reduced absolute number of lymphocytes with either marker. In bronchoalveolar lavage fluid, pulmonary blastomycosis patients who were clinically improved while receiving antifungal therapy had fewer TH cells and a greater number of lymphocytes with the TS marker than did control subjects. Patients with pulmonary blastomycosis prior to therapy had a smaller TH/S ratio than the other groups in peripheral blood primarily due to a reduction in the circulating TH fraction in both absolute numbers of cells and in the percentage of total T lymphocytes. Pulmonary blastomycosis patients re-evaluated after at least four weeks of antifungal therapy had TH/S ratios that were similar to normal persons. This increase in TH lymphocytes corresponded to clinical improvement and in a temporal correlation to that described for the development of specific immunity in this illness.

Judicious use of antibiotics for common pediatric respiratory infections.

BACKGROUND: Antibiotic resistance among common respiratory infection-producing bacteria such as Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis has become a major global public health problem. The use of antibiotics, whether or not medically justified for a particular illness, contributes to the development of resistant bacteria. To help to contain the proliferation of drug-resistant bacteria, members of the CDC and the American Academy of Pediatrics (AAP) recently published principles for the judicious use of antibiotics in common pediatric respiratory infections including the common cold, otitis media, sinusitis and tonsillopharyngitis. This article reviews the CDC/AAP principles for management of these illnesses and describes results of clinical practice studies in which efforts to improve the judicious use of antibiotics were undertaken. CONCLUSIONS: The success of the CDC/AAP principles in containing the increase in antimicrobial resistance depends upon their being practiced. Results of clinical practice studies indicate that judicious use of antimicrobial therapy in pediatric respiratory infections can be realized through education and persistence. More widespread educational and behavior modification efforts are necessary to reduce unnecessary prescription of antibiotics and to curtail the still burgeoning problem of bacterial resistance.

Timentin therapy for Staphylococcus aureus infections in children: results of a multicenter trial.

Multicenter trials of ticarcillin/potassium clavulanate (Timentin) for bone, joint, skin and soft tissue infections in children were performed from 1983 to 1986. Fifty children with culture-confirmed Staphylococcus aureus infections were identified. Sixteen children (ages 6.2 +/- 3.9 years) with bone and joint infections received Timentin for 8.7 +/- 2.4 days with 11 of 16 cures, 5 of 16 improved, 11 of 11 bacteriologic cures and 3.9 +/- 3.5 days of fever. Thirty-two children (ages 5.7 +/- 3.5 years) with skin and soft tissue infections received Timentin for 5.3 +/- 1.6 days with 22 of 32 cures, 10 of 32 improved, 32 of 32 bacteriologic cures and 1.4 +/- 1.3 days of fever. Three patients had S. aureus bacteremia; all were clinical and bacteriologic cures. All S. aureus isolates were susceptible to Timentin, 18 of 23 isolates tested produced beta-lactamase and 21 of 44 isolates tested were resistant to ticarcillin. The purpose of this report is to describe the clinical efficacy of Timentin in treating these types of S. aureus infections in children.

Intensive short course chemotherapy for tuberculous meningitis.

This nonrandomized, open clinical investigation of tuberculous meningitis evaluated 53 children with Stage I (n = 8), Stage II (n = 29) and Stage III (n = 16) disease. The overall mortality was 20.8% (11 of 53) with a rate of sequelae of 35.7% (15 of 42) in survivors reflecting the advanced stages of children at diagnosis. Various combinations of standard antituberculous drugs including isoniazid, rifampin, pyrazinamide, streptomycin and ethambutol were given. Three treatment durations used during various time periods were evaluated: 12, 9 and 6 months with only the 6-month regimen receiving pyrazinamide (PZA). This prospective evaluation demonstrated that: (1) severe disease at presentation is highly associated with early mortality (P less than 0.05), regardless of drug regimen; and (2) intensive short course chemotherapy (6 months) with PZA, regardless of stage of disease at presentation, is more efficacious than longer course therapy (9 or 12 months) without PZA in preventing total negative outcomes and sequelae (P less than 0.05). This study demonstrates that a 6-month regimen containing PZA can be used in treating children with tuberculous meningitis.

Epidemiology of acute respiratory infections in young children from Thailand.

A prospective evaluation of the epidemiology and presentations of acute respiratory infections in children younger than 5 years of age admitted to Children's Hospital Bangkok (1988 to 1989) was supported by the World Health Organization. There were 226 patients with the inclusion criteria: 1 to 5 years of age; duration of illness less than 2 weeks; no prior antibiotic therapy; and low socioeconomic status. The disease categories included: croup, 19 cases; bronchiolitis, 60 cases; and pneumonia, 147 cases. Pathogens isolated were: respiratory syncytial virus (40); parainfluenza III (1); influenza B (1); and adenovirus (1); bacterial infections were proved in 23 cases. No significant differences in clinical features between bacterial and viral pneumonia were found. Interstitial radiographic patterns were more common in viral pneumonia whereas alveolar patterns were more common in bacterial pneumonia. However, 91% of mixed radiographic patterns (interstitial and alveolar) in chest films were from viral pneumonia.

Septic shock in children: bacterial etiologies and temporal relationships.

In a retrospective analysis of 2110 admissions to the pediatric intensive care unit, 564 cases of septic shock were identified (26.7% of the total admissions). Septic shock was defined in patients with: (1) clinical evidence of sepsis; (2) fever (greater than 38.3 degrees C) or hypothermia (less than 35.6 degrees C); (3) tachycardia; (4) tachypnea; and (5) inadequate organ perfusion. Inadequate perfusion was defined as hypotension or evidence of peripheral hypoperfusion (poor capillary refill or cyanosis with hypoxemia, oliguria, acidosis or altered mentation). Inotropic support was required to maintain an adequate blood pressure and perfusion in 268 of 564 patients (47.5%). Septic shock with confirmed bacterial infection occurred in 143 patients (143 of 564, 25.2%); these cases were caused by Haemophilus influenzae, type b (59 of 143, 41.3%), Neisseria meningitidis (26 of 143, 18.2%) and Streptococcus pneumoniae (16 of 143, 11.2%). Eight of 564 (1.4%) cases of septic shock were not clinically apparent on initial evaluation and were diagnosed within 24 hours after admission to the hospital. We conclude that septic shock occurs more frequently in children than previously appreciated and may develop after admission to the hospital.

Cefpodoxime pharmacokinetics in children: effect of food.

BACKGROUND: Cefpodoxime, an oral third generation cephalosporin antibiotic, is used for the treatment of acute upper respiratory tract infection caused by susceptible bacteria in children 5 months to 12 years of age. We report the results of a randomized two-way crossover study designed to characterize the disposition of a single dose (10 mg/kg) of cefpodoxime proxetil oral suspension in children, under fed and fasted conditions. METHODS: Seventeen children (8.4 months to 12.2 years old, seven female) participated in this study. Each subject received a single 10-mg/kg dose of cefpodoxime proxetil oral suspension, after a predose fast and again coadministered with food. Repeated blood samples (n=10) were obtained during 12 h postdose and cefpodoxime was quantified from plasma by high performance liquid chromatography. Plasma concentration vs. time data were curve fit for each subject with a nonlinear weighted least squares algorithm, and pharmacokinetic parameters were determined from the polyexponential estimates. RESULTS: Cefpodoxime disposition was best characterized using a one-compartment open model with first order absorption. The area under the plasma concentration vs. time curve, Cmax and Ke were not significantly different between fed and fasted conditions. However, Tmax was significantly prolonged (fed=2.79+/-1.10 h vs. fasted=1.93+/-0.54 h) and Ka was significantly smaller (fed=0.42+/-0.14 h(-1) vs. fasted=0.81+/-0.72 h(-1)) in the fed state. CONCLUSIONS: Administration of cefpodoxime in the presence of food affected the rate but not the extent of absorption. Cefpodoxime proxetil oral suspension can be administered without regard to meals in children 6 months to 12 years of age.