Lisa M. Dunkle

Prospective evaluation of treatment of Hemophilus influenzae meningitis

Fifty children with Hemophilus influenzae meningitis have been enrolled in a prospective study. Patients were randomly assigned chloramphenicol or ampicillin treatment; there were no significant differences between groups in other respects. Countercurrent immunoelectrophoresis proved to be a valuable tool for rapid diagnosis of the causative agent even in pretreated patients. Increasing quantities of capsular polyribosephosphate antigen detected in the initial cerebrospinal fluid correlated significantly (r=0.62419; p less than 0.01) with early and late sequelae of meningitis. None of the patients died. Severe and persistent neurologic or intellectual deficits were noted in four (8%) of the children, and an additional 14 (28%) had IQ scores between 70 and 90. The presence of bactericidal antibody in serum was not protective. Anti-PRP antibody generally was not present in acute serum specimens and irrespective of the quantity of antigenic stimulus provided by the disease was nondetectable in 21 of 24 children less than 17 months of age following recovery.

Eradication of epidemic methicillin-gentamicin-resistant staphylococcus aureus in an intensive care nursery

A methicillin-resistant strain of Staphylococcus aureus (phage type 47,54,75,83A) became epidemic in our 50 bed level III nursery, with a colonization rate of 70 percent and an infection rate of more than 25 percent. This prevalence and the appearance of gentamicin resistance necessitated epidemic control measures. Standard measures included separate housing for infants in whom colonization had occurred and infants in whom it had not, low nurse to patient ratios, and cohorting of all personnel. Use of all antibiotics was curtailed by the requirement of infectious disease consultation. Gentamicin was available only on order of the Director. The colonization rate fell from 55 percent to 25.4 percent, the first-week colonization rate from 31 percent to 0 percent, and the infection rate from 29.3 percent to 15.9 percent over eight weeks. The mean duration of antibiotic therapy decreased from 12.21 to 9.05 days per treated patient; however, the frequency of gentamicin usage and the proportion of gentamicin resistance were unchanged. Nurse to patient ratios were modified to allow increased admissions, but cohorting was continued for 12 weeks until all infants in whom colonization had occurred were discharged. With the elimination of the reservoir, no further colonization occurred and antibiotic resistance did not reappear. Standard infection control measures can eliminate epidemics of multiple antibiotic-resistant Staph. aureus, and control of antibiotic usage may present re-emergence of resistant strains.

A single-dose study to assess the penetration of stavudine into human cerebrospinal fluid in adults

Penetration of stavudine into the cerebrospinal fluid (CSF) was studied in healthy humans. In this open, randomized study, a single oral dose of 40 mg of stavudine was given to 12 fasting volunteers > or = 18 years of age. Subjects were divided into three groups based on the time of CSF sampling (i.e., 0.75-1.25, 2-3, or 4-5 hours after dosing). Blood samples were collected over an 8-hour period after dosing and included a sample simultaneous with CSF collection to permit an estimate of CSF : plasma ratios. Stavudine concentrations in plasma and CSF were determined by a validated high-performance liquid chromatography method. Repeated measurements of vital signs, physical examination, and clinical laboratory tests indicated that the stavudine dose was well tolerated. CSF levels were not detected 0.75 to 1.25 hours after dosing. Thereafter, levels were detected in the CSF of five subjects; the mean concentration was 61 ng/ml. The mean CSF: plasma ratio increased with time, from 0.16 at 2 to 3 hours postdose in one subject to 0.40 at 4 to 5 hours postdose in four subjects. In conclusion, the mean stavudine concentration of 61 ng/ml achieved in the CSF of five subjects exceeds the ED50 of clinical isolates of HIV (230 nM, 52 ng/ml).

Food-induced reduction in bioavailability of didanosine.

The effect of food on the pharmacokinetics of didanosine was evaluated in an open two‐way crossover study in eight male subjects who tested seropositive for the human immunodeficiency virus. Each subject received a single 375 mg oral dose of didanosine in a chewable tablet form with or without food. Serial blood samples and the total urinary output during 12 hours were collected and assayed for intact didanosine by validated HPLC methods. The mean (SD) values for the peak concentration (Cmax) of didanosine in plasma were 2789 (1032) ng/ml and 1291 (536) ng/ml and for the area under the plasma concentration‐time curves (AUC0‐∞) were 3902 (1316) and 2083 (922) hr · ng/ml, and the urinary excretion (%UR) accounted for 21% and 11% of dose as intact didanosine when didanosine was given under fasting conditions and with food, respectively. The values of Cmax, AUC0‐∞, and %UR were significantly lower for subjects who received didanosine with food compared with those observed for the fasted subjects. The time to reach Cmax, mean residence time, elimination half‐life, and renal clearance remained essentially the same between the two treatments. The results from this study indicated that the rates of absorption and elimination were not affected by the presence of food; however, the extent of absorption, as indicated by AUC0‐∞ and %UR, was reduced significantly in the presence of food. It is recommended that didanosine be administered under fasting conditions.

Cefotaxime therapy of neonatal gram-negative bacillary meningitis.

Seven neonates were treated with cefotaxime during eight episodes of Gram-negative bacillary meningitis and sepsis. The causative organisms were Escherichia coli in six cases and Klebsiella pneumoniae and Enterobacter sakazakii in one each. After identification of the pathogen cefotaxime was used alone in six instances. Two patients with brain abscesses received adjunctive therapy with another antibiotic. The sterility of cerebrospinal fluid was documented after a mean of 3.3 days of therapy. Mean cerebrospinal fluid bactericidal titer was 1:64. All patients recovered with good neurologic outcome. Cefotaxime in a dosage of 150 mg/kg/day divided every 6 hours intravenously seems safe and effective therapy for neonatal Gram-negative bacillary meningitis.

Relation of peripheral neuropathy to HIV treatment in four randomized clinical trials including didanosine.

Peripheral neuropathy has been recognized as a dose-limiting adverse effect in Phase I studies of didanosine (ddI) therapy for HIV infection. To study the effect of the currently recommended lower dose of ddI, the databases of 4 randomized, controlled trials were used to assess the frequency of dose-limiting peripheral neuropathy during treatment with ddI 500 or 750 mg/d, compared with zidovudine (ZDV) monotherapy or combination therapy with ddI/ZDV or zalcitabine/ZDV. No between-group differences in risk factors for neuropathy (eg, infectious and metabolic factors, malignancy, concurrent medications) were observed in the individual trials, and the presence of these risk factors appeared to have no increased treatment effect on the occurrence of neuropathy. No significant between-group differences were observed in the individual studies with regard to the incidence or time to onset of peripheral neuropathy. Analysis of the combined results by treatment regimen showed no significant difference in the incidence of neuropathy between recipients of ddI 500 mg/d, ddI 750 mg/d, or ZDV and no significant difference in the cumulative dose received until the onset of neuropathy between the ddI 500- and 750-mg regimens. Entry CD4+ cell counts were significantly predictive of neuropathy, with each 100-cell/microL decrement associated with a 17% increase in risk (P = 0.002); a CD4+ cell count of <50 cells/microL was highly predictive of neuropathy (P = 0.0001). In summary, the risk for peripheral neuropathy was not increased by treatment with ddI versus comparator regimens or by treatment with ddI at the dosages used in studies conducted more recently than the Phase I trials. Peripheral neuropathy seems more likely to be associated with advanced HIV infection and lower CD4+ cell counts (particularly counts <50 cells/microL) than with ddI therapy at the currently recommended dose.

Didanosine Compared with Continued Zidovudine Therapy for HIV-Infected Patients with 200 to 500 CD4 Cells/mm3: A Double-Blind, Randomized, Controlled Trial

Zidovudine (3-azido-3-deoxythymidine) has been shown in placebo-controlled studies [1, 2] to prolong survival in patients with the acquired immunodeficiency syndrome (AIDS), to delay the development of AIDS in those with AIDS-related complex, and to delay the development of AIDS and AIDS-related complex in patients with asymptomatic human immunodeficiency virus (HIV) infection. The duration of the clinical benefit afforded by zidovudine monotherapy, however, appears to be limited [3-6]. The underlying mechanism or mechanisms responsible for disease progression during zidovudine therapy must still be definitively established. However, current evidence suggests that the development of viral resistance to zidovudine is at least partly responsible for the short duration of benefit [7, 8]. Didanosine (2,3-dideoxyinosine) is a newer nucleoside analog that has been shown to be effective in vitro against HIV [9]. Didanosine has in vitro activity against viral isolates that have high-level resistance to zidovudine [10]. Early clinical trials showed that didanosine can have a persistent beneficial effect on surrogate markers of HIV infection, such as CD4 counts, p24 antigen levels, and constitutional symptoms [11-14]. The investigators who did these studies found that peripheral neuropathy and pancreatitis were the dose-limiting toxicities of didanosine. More recently, controlled studies have shown that a switch to didanosine can improve clinical outcome in persons with advanced HIV disease who have received zidovudine [15, 16]. More specifically, Kahn and colleagues [15] showed such a benefit in patients with AIDS or AIDS-related complex who were clinically stable while receiving zidovudine and who had CD4 counts of 300 cells/mm3 or less and in asymptomatic HIV-infected patients with CD4 counts of 200 cells/mm3 or less. Spruance and coworkers [16] showed a similar benefit in patients with CD4 counts of 300 cells/mm3 or less and signs of clinical deterioration while receiving zidovudine therapy. No clinical data are available on the role of didanosine in stable patients in earlier stages of HIV disease who have received zidovudine. We therefore specifically compared the safety and efficacy of didanosine with that of continued zidovudine therapy in clinically stable HIV-infected persons who had CD4 counts between 200 and 500 cells/mm3 and had received zidovudine for at least 6 months. We hypothesized that a change to a second effective antiretroviral agent before the anticipated development of high-level resistance to zidovudine would prevent resistance and consequently delay the progression of HIV disease. Methods Study Design Randomization was stratified by the study center and by the CD4 cell count at study enrollment (more than or less than 300 cells/mm3). Successfully screened patients were randomly assigned using computer-generated random numbers. Randomization was done at a central location to ensure that patients, research personnel, and pharmacists remained blinded to the treatment allocation. All study participants provided informed consent. The study protocol and informed consent were approved by the review boards of the participating institutions and by the Canadian HIV Trials Network (CTN), with which our study is registered as protocol CTN-002. Patients Eligible study participants were male and nonpregnant female patients 12 years of age or older. Other entry criteria were the following: 1) HIV infection documented by enzyme-linked immunosorbent assay; 2) two sequential prerandomization CD4 counts between 200 and 500 cells/mm3 obtained at least 72 hours apart within 30 days of randomization, with the most recent measurement done within 14 days of randomization; 3) zidovudine therapy received for at least 6 months before randomization at a dose of at least 500 mg/d for the month immediately preceding study entry; 4) zidovudine therapy at 500 mg/d or greater for at least 21 of the previous 26 weeks; 5) a Karnofsky performance status of greater than 60 at study entry; 6) a hemoglobin level greater than 85 g/L or a hematocrit greater than 0.25 (in the absence of blood transfusion in the preceding 2 weeks); 7) a neutrophil count greater than 0.75 109/L; 8) a platelet count greater than 50 109/L; 9) serum aminotransferase and alkaline phosphatase levels greater than five times the upper limit of normal; 10) a serum creatinine level greater than 1.5 times the upper limit of normal; 11) a serum uric acid level less than 530 mol/L; and 12) a serum amylase level less than 2.1 times the upper limit of normal. The following are the normal values for chemical variables: aspartate aminotransferase, as high as 0.67 kat/L; alkaline phosphatase, 0.58 to 1.75 kat/L; creatinine, 40 to 120 mol/L; and amylase, 0.50 to 1.83 kat/L. Study participants were required to take adequate birth control measures during the study. The following were the exclusion criteria: 1) the presence of an uncontrolled AIDS-defining illness; 2) known or suspected pulmonary Kaposi sarcoma or Kaposi sarcoma requiring systemic cytotoxic chemotherapy; 3) grade II or greater dementia; 4) active substance abuse; 5) antiretroviral therapy other than zidovudine; 6) any use of biological-response modifiers or corticosteroids within 30 days of entry or therapy with ribavirin within 90 days of entry; 7) previous participation in studies involving didanosine or zalcitabine; 8) grade II or greater neurologic, allergic, or renal toxicities; 9) any history of pancreatitis, intractable diarrhea, or malabsorption; 10) unexplained seizures within the previous 6 months or need for anticonvulsant agents; 11] treatment with neurotoxic drugs within 30 days of entry; and 12) past or current heart disease or requirement for cardiac medication. All study participants were encouraged to use prophylaxis for Pneumocystis carinii infection according to contemporary guidelines [17]. The use of megestrol acetate, foscarnet, aspirin, acetaminophen, nonsteroidal anti-inflammatory agents, oral acidifying agents, and oral acyclovir was discouraged. Treatment of opportunistic infections was permitted. In patients developing serious symptoms or laboratory abnormalities, study medications were withheld until the symptoms or laboratory abnormalities resolved; at this point, patients were encouraged to resume the study medication, according to a prespecified dose-reduction scheme. Treatment Regimens Zidovudine (Retrovir, Burroughs-Wellcome, Research Triangle Park, North Carolina) was provided in 100-mg capsules to be taken at a dosage of 600 mg/d divided into at least three daily doses. Didanosine (Videx, Bristol-Myers Squibb, Princeton, New Jersey) was provided in sachets containing 5.2 g of citrate-phosphate buffer and sucrose adjusted to yield a final net weight of 20 g. The contents of one sachet were to be dissolved in water and swallowed. Didanosine dosage was adjusted for weight: Patients weighing at least 60 kg received 500 mg/d in two divided doses; patients weighing less than 60 kg received 334 mg/d in two divided doses. The didanosine formulation was changed in October 1991 from 500- and 334-mg/d sachet formulations to 400- and 200-mg/d tablet formulations. Study participants were instructed to chew the didanosine tablets thoroughly either together or in rapid succession and then to rinse with approximately 120 mL of room-temperature drinking water, which was also to be swallowed. Alternatively, the two tablets were to be crushed and thoroughly dispersed in at least 120 mL of drinking water; this solution was to be drunk immediately, followed by approximately 120 mL of drinking water. Study participants were instructed to always take didanosine on an empty stomach, at least 2 hours after and 1 hour before meals. To maintain the double-blind nature of the protocol, patients assigned to receive didanosine were given identical zidovudine placebo, and those assigned to receive zidovudine were given identical didanosine placebo. Follow-up After completion of the baseline evaluation, patients were seen at biweekly intervals for the first 2 months and monthly thereafter. A safety profile, including a symptom-targeted questionnaire, hematologic assessment, and chemistry panel were done at each visit. The CD4 count and viral resistance studies were done at baseline; at weeks 2, 8, and 12; and every 3 months thereafter. Formal follow-up of this cohort, as per the study protocol, was completed on 12 October 1992. Long-term, off-protocol, follow-up information on survival, AIDS-defining illnesses, and CD4 lymphocyte counts was compiled on one occasion using standardized data collection forms in December 1993. This allowed us to collect additional follow-up information on all patients after study completion and information on the complete study period for patients who dropped out of the study. Study End Points The primary clinical end point was the occurrence of a new, previously undiagnosed AIDS-defining event (according to the revised 1987 criteria of the Centers for Disease Control and Prevention) or death [18]. Clinical end points were reviewed by study monitors at each clinical site and were confirmed in a blinded manner by the clinical end points committee. Didanosine was licensed by the Food and Drug Administration in the United States and by the Health Protection Branch in North America in the fall of 1991. At that time, didanosine became the standard therapy in Canada for persons with zidovudine intolerance or disease progression despite zidovudine therapy. Thus, in late 1991, while the study remained blinded and before any data were analyzed, a 33% decline in CD4 counts from baseline was added as a primary study end point to maintain consistency with prevailing clinical practice. Sensitivity Testing Samples for testing sensitivity to the study drugs were obtained from 102 of 120 patients (85%) enrolled at five clinical sites who were preselected on the basis of logistic issues. For

Safety and antiretroviral effects of combined didanosine and stavudine therapy in HIV-infected individuals with CD4 counts of 200 to 500 cells/mm3.

The safety and antiretroviral effects of didanosine and stavudine in combination were evaluated in 86 people infected with HIV with CD4 counts between 200 and 500 cells/mm3 who had received <7 days of prior nucleoside analogue antiretroviral treatment. Patients were randomized to receive blinded treatments with one of five weight-adjusted, twice-daily regimens of didanosine and stavudine (100 + 10 mg, 100 + 20 mg, 100 + 40 mg, 200 + 20 mg, and 200 + 40 mg) for up to 1 year. Dosages were adjusted appropriately for patients weighing <60 kg and reduced in response to adverse effects. No clear dose-related differences among treatment groups were detected with regard to suppression of plasma HIV RNA level or reduction in infectious titers in peripheral blood mononuclear cells (PBMCs), improvement in CD4 count, or adverse effects. However, trends toward greater decreases in viral load and increases in CD4 count were detected when treatment groups containing the full recommended dosage of one or both agents (high-dose subgroup; arms 3, 4, and 5) were compared with the groups receiving lower dosages. At 28 weeks the mean log 10 HIV RNA decrease was 1.12 (n = 52) and at 52 weeks it was 0.97 (n = 32). Combination therapy was well tolerated, with no apparent dose-related adverse effects. Peripheral neuropathy occurred in 2 of 86 (2.3%) of patients. Didanosine and stavudine together appear to be a good nucleoside analogue foundation for aggressive triple- or quadruple-drug therapy. Full therapeutic doses of each of these two agents should be used to achieve optimal suppression of HIV replication.

Determination of Dosing Guidelines for Stavudine (2′,3′-Didehydro-3′-Deoxythymidine) in Children with Human Immunodeficiency Virus Infection

ABSTRACT The results of the development of dosing guidelines for stavudine in human immunodeficiency virus (HIV)-infected children are summarized. Included in the integrated analyses were 21 and 33 HIV-infected pediatric and adult patients, respectively, from three phase I-II studies. Data for 21 children and 18 adults who received intravenous doses of 0.125 to 2 and 0.5 to 1 mg/kg of body weight, respectively, were used for the determination of dosing guidelines; exposure data for 16 children and 15 adults who received oral doses of 1 to 2 and 0.5 to 1 mg/kg/day, respectively, were used to validate the dosing recommendations for children. Significant relationships were observed between total body clearance (in milliliters per minute) in children and adults combined and demographic parameters of age, body weight, and body surface area (R2 = 0.77 to 0.80;P = 0.0001). Models of approximated pediatric dose based on clearance values and direct adult exposure yielded a stavudine dosage of 2 mg/kg/day for children of ≤30 kg of body weight and 1 mg/kg/day (adult dose) for children of >30 kg of body weight.

Significance of Neutrophils in Cerebrospinal Fluid Samples Processed by Cytocentrifugation

We reviewed medical records of 155 pediatric patients whose cerebrospinal fluid (CSF) sam ples contained an increased proportion of neutrophils when processed by cytocentrifugation, despite normal CSF total white blood cell count. It was determined that these CSF findings occurred more commonly in patients with bacteremia, peripheral leukocytosis, and increased numbers of red blood cells in the CSF. Pulmonary infiltrates in infants and otitis media in children were also significantly associated. Cytocentrifugation allows the identification of neutrophils in the CSF, even in the absence of central nervous system infection. Infants and children with more than 10 per cent neutrophils in CSF require evaluations for focal and bacteremic infections.