Measures of Longitudinal Immune Dysfunction and Risk of AIDS and Non-AIDS Defining Malignancies in Antiretroviral-Treated People With Human Immunodeficiency Virus.

BACKGROUND: Human immunodeficiency virus (HIV) infection leads to chronic immune activation/inflammation that can persist in virally suppressed persons on fully active antiretroviral therapy (ART) and increase risk of malignancies. The prognostic role of low CD4:CD8 ratio and elevated CD8 cell counts on the risk of cancer remains unclear. METHODS: We investigated the association of CD4:CD8 ratio on the hazard of non-AIDS defining malignancy (NADM), AIDS-defining malignancy (ADM) and most frequent group of cancers in ART-treated people with HIV (PWH) with a CD4 and CD8 cell counts and viral load measurements at baseline. We developed Cox proportional hazard models with adjustment for known confounders of cancer risk and time-dependent cumulative and lagged exposures of CD4:CD8 ratio to account for time-evolving risk factors and avoid reverse causality. RESULTS: CD4:CD8 ratios below 0.5, compared to above 1.0, were independently associated with a 12-month time-lagged higher risk of ADM and infection-related malignancies (adjusted hazard ratio 2.61 [95% confidence interval {CI }1.10-6.19] and 2.03 [95% CI 1.24-3.33], respectively). CD4 cell counts below 350 cells/µL were associated with an increased risk of NADMs and ADMs, as did infection, smoking, and body mass index-related malignancies. CONCLUSIONS: In ART-treated PWH low CD4:CD8 ratios were associated with ADM and infection-related cancers independently from CD4 and CD8 cell counts and may alert clinicians for cancer screening and prevention of NADM.

Expanded Multivariable Models to Assist Patient Selection for Long-Acting Cabotegravir + Rilpivirine Treatment: Clinical Utility of a Combination of Patient, Drug Concentration, and Viral Factors Associated With Virologic Failure.

BACKGROUND: Previously reported post hoc multivariable analyses exploring predictors of confirmed virologic failure (CVF) with cabotegravir + rilpivirine long-acting (CAB + RPV LA) were expanded to include data beyond week 48, additional covariates, and additional participants. METHODS: Pooled data from 1651 participants were used to explore dosing regimen (every 4 or every 8 weeks), demographic, viral, and pharmacokinetic covariates as potential predictors of CVF. Prior dosing regimen experience was accounted for using 2 populations. Two models were conducted in each population-baseline factor analyses exploring factors known at baseline and multivariable analyses exploring baseline factors plus postbaseline model-predicted CAB/RPV trough concentrations (4 and 44 weeks postinjection). Retained factors were evaluated to understand their contribution to CVF (alone or in combination). RESULTS: Overall, 1.4% (n = 23/1651) of participants had CVF through 152 weeks. The presence of RPV resistance-associated mutations, human immunodeficiency virus-1 subtype A6/A1, and body mass index ≥30 kg/m2 were associated with an increased risk of CVF (P < .05 adjusted incidence rate ratio), with participants with ≥2 of these baseline factors having a higher risk of CVF. Lower model-predicted CAB/RPV troughs were additional factors retained for multivariable analyses. CONCLUSIONS: The presence of ≥2 baseline factors (RPV resistance-associated mutations, A6/A1 subtype, and/or body mass index ≥30 kg/m2) was associated with increased CVF risk, consistent with prior analyses. Inclusion of initial model-predicted CAB/RPV trough concentrations (≤first quartile) did not improve the prediction of CVF beyond the presence of a combination of ≥2 baseline factors, reinforcing the clinical utility of the baseline factors in the appropriate use of CAB + RPV LA.

Study APV20002: Safety and Efficacy Results Through Week 684 for Pediatric Participants Living With HIV-1 Treated With Ritonavir-Boosted Fosamprenavir Oral Solution-Based Antiretroviral Therapy.

APV20002 was a multicenter, international, open-label study that began in 2003 investigating the pharmacokinetics, efficacy, and safety of ritonavir-boosted fosamprenavir (FPV/r) oral solution (OS) in combination with nucleoside reverse transcriptase inhibitor-based antiretroviral therapy (ART) in participants living with HIV-1 aged 4 weeks to <2 years with a primary endpoint at Week 48 (48W). Participants in APV20002 could continue in the study post-48W until FPV OS was locally available in their countries. Children were required to discontinue after reaching >39 kg or if FPV OS had no clinical benefit. Fifty-nine participants were enrolled; 5/59 received a single FPV OS visit for pharmacokinetic determinations. Most (38/54; 70%) were antiretroviral-experienced; 39/59 participants had >48 weeks on treatment, 4/39 of whom discontinued after 48 weeks due to an adverse event (AE). At 48W, 88% of participants had HIV-1 RNA <400 copies/mL by Observed analysis; the proportion with HIV-1 RNA <400 copies/mL remained high (84%-100%) through Week 684. The median CD4+ cell count was 1235 cells/mm3 [n=51] at baseline, 1690 cells/mm3 (n=41) at Week 48, and 1280 cells/mm3 (n=21) at Week 180. From baseline to Week 684, 54/59 (92%) participants had ≥1 treatment-emergent AE regardless of causality; 42/59 (71%) had a treatment-emergent grade 2-4 AE, predominantly maximum toxicity: grade 2; 21/59 (36%) and 21/59 (36%) had severe or grade 3/4 AEs. From baseline to Week 684, 14/54 (26%) participants met virologic failure (VF) criteria, 9/14 before 48W. HIV from 1/9 VFs through 48W developed treatment-emergent reduced susceptibility to FPV and 1/9 to lamivudine/emtricitabine. Post-48W, 4/5 participants with VF had phenotype results; all were still susceptible to all study drugs at VF. In conclusion, FPV OS-based ART was efficacious and generally well tolerated in this long-running pediatric study through 684 weeks of treatment, with a safety profile consistent with experience in adults and older children.

Implementation of long-acting cabotegravir and rilpivirine: primary results from the perspective of staff study participants in the Cabotegravir And Rilpivirine Implementation Study in European Locations.

INTRODUCTION: Cabotegravir plus rilpivirine (CAB + RPV) is the first complete long-acting (LA) regimen recommended for maintaining HIV-1 virological suppression. Cabotegravir And Rilpivirine Implementation Study in European Locations (CARISEL) is an implementation-effectiveness study examining the implementation of CAB+RPV LA administered every 2 months (Q2M) in European HIV centres. We present staff study participant (SSP) perspectives on the administration of CAB+RPV LA over 12 months. METHODS: Eighteen clinics were randomized to one of two implementation support packages: standard arm (Arm-S) or enhanced arm (Arm-E). Arm-S included video injection training and provider/patient toolkits. Additionally, Arm-E included skilled wrap-around team meetings, face-to-face injection training and continuous quality improvement (CQI) calls. SSPs completed surveys on the acceptability, appropriateness and feasibility of CAB+RPV LA as an intervention and its implementation into their clinics, as well as barriers and facilitators to implementation. All surveys were completed at Month (M)1 (baseline), M5 and M12; data collection was completed by February 2022. Qualitative data were obtained from semi-structured interviews at M1, M5 and M12. The primary objective was assessed via formal statistical comparisons between study arms of the Acceptability of Implementation Measure, Implementation Appropriateness Measure and Feasibility of Implementation Measure surveys (1-5 Likert scale ranging from 1 = "completely disagree" to 5 = "completely agree"). Equivalent measures anchored to CAB+RPV LA as a therapy were also assessed. RESULTS: Seventy SSPs completed surveys and interviews at M1, 68 at M5 and 62 at M12. Mean acceptability/appropriateness/feasibility scores were ≥3.8 (out of 5) at M12 for implementation- and intervention-based measures. An analysis of covariance showed no significant differences between study arms for these outcomes. Although barriers were noted, most SSPs were not overly concerned that these would impact implementation; concern about these anticipated barriers also decreased over time. At M12, 90.3% (n = 56/62) of SSPs held a positive opinion about CAB+RPV LA implementation. Qualitative interviews and CQI calls highlighted three top practices that supported implementation: implementation planning; education about CAB+RPV LA clinical efficacy; and education around administering injections and managing pain/discomfort after injections. CONCLUSIONS: CARISEL demonstrated that CAB+RPV LA dosed Q2M was successfully implemented across a range of European locations, with SSPs finding implementation highly acceptable, appropriate and feasible. GOV NUMBER: NCT04399551.

Efficacy, safety, and tolerability of switching to long-acting cabotegravir plus rilpivirine versus continuing fixed-dose bictegravir, emtricitabine, and tenofovir alafenamide in virologically suppressed adults with HIV, 12-month results (SOLAR): a randomised, open-label, phase 3b, non-inferiority trial.

BACKGROUND: Cabotegravir plus rilpivirine is the only approved complete long-acting regimen for the maintenance of HIV-1 virological suppression dosed every 2 months. The SOLAR study aimed to compare long-acting cabotegravir plus rilpivirine every 2 months with continued once-daily bictegravir, emtricitabine, and tenofovir alafenamide for the maintenance of HIV-1 virological suppression in adults living with HIV. METHODS: SOLAR is a randomised, open-label, multicentre, phase 3b, non-inferiority study. The study was done in 118 centres across 14 countries. Participants with HIV-1 RNA less than 50 copies per mL were randomly assigned (2:1), stratified by sex at birth and BMI, to either long-acting cabotegravir (600 mg) plus rilpivirine (900 mg) dosed intramuscularly every 2 months or to continue daily oral bictegravir (50 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg). Participants randomly assigned to long-acting therapy had a choice to receive cabotegravir (30 mg) plus rilpivirine (25 mg) once daily as an optional oral lead-in for approximately 1 month. The primary efficacy endpoint was the proportion of participants with virological non-response (HIV-1 RNA ≥50 copies per mL; the US Food and Drug Administration snapshot algorithm, 4% non-inferiority margin; modified intention-to-treat exposed population) at month 11 (long-acting start with injections group) and month 12 (long-acting with oral lead-in group and bictegravir, emtricitabine, and tenofovir alafenamide group). The study is registered with ClinicalTrials.gov, NCT04542070, and is ongoing. FINDINGS: 837 participants were screened between Nov 9, 2020, and May 31, 2021, and 687 were randomly assigned to switch treatment or continue existing treatment. Of 670 participants (modified intention-to-treat exposed population), 447 (67%) switched to long-acting therapy (274 [61%] of 447 start with injections; 173 [39%] of 447 with oral lead-in) and 223 (33%) continued bictegravir, emtricitabine, and tenofovir alafenamide. Baseline characteristics were similar; median age was 37 years (range 18-74), 118 (18%) of 670 were female sex at birth, 207 (31%) of 670 were non-White, and median BMI was 25·9 kg/m2 (IQR 23·3-29·5). At month 11-12, long-acting cabotegravir plus rilpivirine showed non-inferior efficacy versus bictegravir, emtricitabine, and tenofovir alafenamide (HIV-1 RNA ≥50 copies per mL, five [1%] of 447 vs one [<1%] of 223), with an adjusted treatment difference of 0·7 (95% CI -0·7 to 2·0). Excluding injection site reactions, adverse events and serious adverse events were similar between groups. No treatment-related deaths occurred. More long-acting group participants had adverse events leading to withdrawal (25 [6%] of 454 vs two [1%] of 227). Injection site reactions were reported by 316 (70%) of 454 long-acting participants; most (98%) were grade 1 or 2. INTERPRETATION: These data support the use of long-acting cabotegravir plus rilpivirine dosed every 2 months as a complete antiretroviral regimen that has similar efficacy to a commonly used integrase strand transfer inhibitor-based first-line regimen, while addressing unmet psychosocial issues associated with daily oral treatment. FUNDING: ViiV Healthcare.

Meningitis in preterm neonates: importance of cerebrospinal fluid parameters.

Cerebrospinal fluid parameters are of great importance in diagnosing meningitis, but normal values for preterm neonates are based on small, single-center studies. We sought to determine current values for preterm neonate cerebrospinal fluid parameters and assess the association of cerebrospinal fluid parameters with culture proven meningitis. We performed a cohort study of the first lumbar puncture from 4632 neonates < 34 weeks' gestation performed in the years 1997 to 2004 at 150 neonatal intensive care units managed by the Pediatrix Medical Group. We identified 95 cases of meningitis from the 4632 lumbar punctures. The area under the receiver operating characteristic curves for white blood cell count, glucose, and protein were 0.80, 0.63, and 0.72, respectively, for prediction of culture-proven meningitis. Cerebrospinal fluid parameters used to diagnose meningitis in the absence of dependable cerebrospinal fluid cultures are unreliable. Caution should be employed when interpreting cerebrospinal fluid parameters in the premature neonate.

Postconception age and other risk factors associated with mortality following Gram-negative rod bacteremia.

BACKGROUND: Neonatal nosocomial Gram-negative rod bacteremia (GNR-b) is considered ominous. DESIGN: Multi-center cohort study of premature infants (N=6172) who had a blood culture after day of life 3 and whose birthweight was < or =1250 g. RESULTS: A total of 437 neonates developed GNR-b; most commonly with Klebsiella (122/437; 28%), Enterobacter (97/437; 22%), Escherichia coli (90/437; 21%), Pseudomonas (63/437; 14%), and Serratia (49/437; 11%). Neonates infected with Pseudomonas were more likely to die (21/63; 33%) than infants infected with other GNR (50/374; 13%). In multivariable logistic regression, infection with Pseudomonas, mechanical ventilation, and race were associated with subsequent mortality. Postconception age (PCA) was most strongly associated with mortality. Using neonates with >34 weeks PCA at the time of the first blood culture as the reference category, mortality was higher in neonates <26 weeks PCA (odds ratio (OR)=9.21; 95% confidence interval (CI)=2.79, 30.44), and in neonates 26 to 28 weeks PCA (OR=3.94; 95% CI=1.29, 12.03). CONCLUSIONS: Among premature infants, much of the mortality experienced in GNR-b is due to infection with Pseudomonas rather than enteric GNR. Race, the need for mechanical ventilation, and younger PCA when the blood culture was obtained were also strongly associated with mortality.

Mortality following blood culture in premature infants: increased with Gram-negative bacteremia and candidemia, but not Gram-positive bacteremia.

OBJECTIVE: To describe survival following nosocomial bloodstream infections and quantify excess mortality associated with positive blood culture. STUDY DESIGN: Multicenter cohort study of premature infants. RESULTS: First blood culture was negative for 4648/5497 (78%) of the neonates--390/4648 (8%) died prior to discharge. Mortality prior to discharge was 19% in the 161 infants with Gram-negative rod (GNR) bacteremia, 8% in the 854 neonates with coagulase negative staphylococcus (CONS), 6% in the 169 infants infected with other Gram-positive bacteria (GP-o), and 26% in the 115 neonates with candidemia. The excess 7-day mortality was 0% for Gram-positive organisms and 83% for GNR bacteremia and candidemia. Using negative blood culture as referent, GNR [hazard ratio (HR)=2.61] and candidemia (HR=2.27) were associated with increased mortality; CONS (HR=1.08) and GP-o (HR=0.97) were not. CONCLUSIONS: Nosocomial GNR bacteremia and candidemia were associated with increased mortality but Gram-positive bacteremia was not.

Pharmacokinetics, safety and antiviral activity of fosamprenavir/ritonavir-containing regimens in HIV-infected children aged 4 weeks to 2 years-48-week study data.

BACKGROUND: Pharmacokinetics, safety and antiviral activity of fosamprenavir (FPV) with ritonavir (RTV) twice daily were evaluated in HIV-1-infected infants and children 4 weeks to <2 years over 48 weeks. METHODS: Results from intensive pharmacokinetic sampling of subjects enrolled in single dose visits was used to determine individualized dosing for the first 6-10 subjects in each of 2 cohorts (4 weeks to <6 months, 6 months to <2 years); steady state pharmacokinetic data were then used to select the dosage regimen for the remaining subjects recruited to the cohort. Intensive pharmacokinetic sampling was performed at week 2 or 8; predose samples were collected every 4-12 weeks thereafter. Safety and plasma HIV-1 RNA were monitored every 4-12 weeks. RESULTS: Fifty-nine subjects received study medication. FPV 45 mg/kg boosted with RTV 7 to 10 mg/kg BID achieved average plasma amprenavir area under curve(0-τ) values 26% to 28% lower and Cmax similar to historical adult data for FPV/RTV 700/100 mg BID; amprenavir Cτ values were lower in the subjects <6 months of age. At week 48, 35 of 54 (65%) subjects had achieved plasma HIV-1 RNA <400 copies/mL and 33 of 54 (61%) had plasma HIV-1 RNA values <50 copies/mL. The most common adverse events were diarrhea, upper respiratory tract infection, gastroenteritis and otitis media. CONCLUSIONS: Final FPV/RTV dosing regimens achieved plasma amprenavir exposures comparable with those from regimens approved in adults, with the exception of trough exposures in the <6-month-old infants. The FPV/RTV regimens led to viral suppression in 61% of patients and were generally well tolerated.

Pharmacokinetics and 48-week safety and antiviral activity of fosamprenavir-containing regimens in HIV-infected 2- to 18-year-old children.

BACKGROUND: Pharmacokinetics, safety and antiviral activity of twice-daily fosamprenavir with or without ritonavir were evaluated in 2- to 18-year-old protease inhibitor-naïve and -experienced HIV-1-infected children. METHODS: Serial pharmacokinetic samples were collected at week 2 and predose samples every 4-12 weeks. Safety and plasma HIV-1 RNA were monitored every 4-12 weeks. RESULTS: Twenty protease inhibitor-naïve 2- to <6-year-old subjects received antiretroviral treatment including unboosted fosamprenavir twice-daily, whereas 89 protease inhibitor-naïve and -experienced 2- to 18-year-old subjects received fosamprenavir/ritonavir-containing therapy twice-daily. Median fosamprenavir exposure was 891 days (range 15-1805 days), with 88% exposed >48 weeks. Twice-daily doses of fosamprenavir/ritonavir 23/3 mg/kg in 2- to <6-year olds, 18/3 mg/kg in ≥6-year olds and 700/100 mg in adolescents achieved plasma amprenavir exposures comparable with or higher than 700/100 mg twice-daily in adults while fosamprenavir 30 mg/kg twice-daily in 2- to <6-year olds led to exposures higher than 1400 mg twice-daily in adults. The proportion of subjects with HIV-1 RNA <400 copies/mL at week 48 was 60% for fosamprenavir and 53-74% for fosamprenavir/ritonavir (intent-to-treat [exposed], snapshot analysis). Median increases in absolute and relative (percentage) CD4 counts from baseline to week 48 occurred in both the fosamprenavir (340 cells/mm; 8%) and fosamprenavir/ritonavir group (190 cells/mm; 8%). The most common adverse events were vomiting, cough, and diarrhea; 18 subjects experienced serious adverse events, including 9 with suspected abacavir hypersensitivity. CONCLUSIONS: Fosamprenavir regimens administered to HIV-1-infected children aged 2-18 years were generally well-tolerated and provided sustained antiviral activity over 48 weeks, with plasma amprenavir exposures comparable with or higher than adults.

Modeling and analysis of Gleason score 8-10 prostate cancers in the REDUCE study.

OBJECTIVE: To explore explanations for the numerical imbalance of biopsy-detected Gleason 8-10 prostate cancers (PCa) diagnosed in years 3-4 in the dutasteride and placebo groups of the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) study. METHODS: REDUCE was a 4-year, randomized, double-blind, placebo-controlled trial of dutasteride (0.5 mg/d) vs placebo for PCa risk reduction. We modeled the incidence of Gleason 8-10 cancer and used logistic regression analysis to evaluate the effects of baseline predictors of PCa, as well as post-baseline prostate volume at the time of biopsy, on PCa diagnosis. We compared needle biopsy Gleason scores with corresponding surgery Gleason scores. All statistical tests conducted were 2-sided. RESULTS: Had there been a scheduled biopsy occurring only at year 4, we estimated a similar incidence of Gleason 8-10 PCa in the dutasteride (n = 45) and placebo (n = 46) groups. Two biopsy Gleason 7 cancers in the placebo group (n = 150) were upgraded to Gleason 8-10 cancer on prostatectomy, and no patients in the dutasteride group (n = 111) were upgraded. Logistic regression analysis demonstrated the effect of prostate volume on Gleason 8-10 cancer diagnosis. CONCLUSION: Although modeling of REDUCE data showed a similar incidence of Gleason 8-10 cancer in the dutasteride and placebo groups at year 4, an association between dutasteride and Gleason 8-10 cancer cannot be definitely excluded. It is likely that several biases, notably study design and prostate size at the time of biopsy, contributed to the numerical imbalance in Gleason 8-10 cancers observed between the treatment groups in years 3-4.

Group B streptococcal meningitis: cerebrospinal fluid parameters in the era of intrapartum antibiotic prophylaxis.

OBJECTIVE: Describe cerebrospinal fluid parameters in infants with culture-proven Group B streptococcal meningitis in the era of intrapartum antibiotic prophylaxis. STUDY DESIGN: Cohort study of the first lumbar puncture from 13,495 infants cared for at 150 neonatal intensive care units. We compared cerebrospinal fluid parameters [white blood cell count, red blood cell count, glucose, and protein], demographics, and outcomes between infants with and without Group B streptococcal meningitis. RESULTS: We identified 46 infants with Group B streptococcal meningitis. The median cerebrospinal fluid white blood cell count was 271 cells/mm(3) for infants with Group B streptococcal meningitis and 6 cells/mm(3) for infants without meningitis (p=0.0001). Of the infants with Group B streptococcal meningitis, 9/46 (20%) had negative blood cultures. Meningitis complicated 22/145 (15%) of episodes of early-onset Group B streptococcal sepsis and 13/23 (57%) of episodes of late-onset Group B streptococcal sepsis. CONCLUSIONS: Group B streptococcal meningitis occurs in the presence of negative blood cultures. In hospitalized infants who undergo a lumbar puncture, Group B streptococcal sepsis is frequently complicated by GBS meningitis.

Preliminary safety and efficacy data of brecanavir, a novel HIV-1 protease inhibitor: 24 week data from study HPR10006.

BACKGROUND: Brecanavir, a novel protease inhibitor (PI), has sub-nM in vitro antiviral activity against multi-PI-resistant HIV-1 and in vitro is >100-fold more potent than previously marketed PIs and approx. 10-fold more potent than the recently marketed PI, darunavir. METHODS: HPR10006 is an open label, single-arm, descriptive 48 week study, with 8 and 24 week interim analyses. Thirty-one HIV-1-infected patients were enrolled and received brecanavir/ritonavir 300 mg/100 mg twice daily, with two nucleoside reverse transcriptase inhibitors, based on history and genotype. RESULTS: At baseline, 25/31 had PI-sensitive virus and 6/31 had PI-resistant virus (median of two primary PI and five secondary PI mutations). Median baseline HIV-1 RNA was 5.0 and 4.2 log(10) copies/mL, respectively. Four patients discontinued prior to Week 24. At Week 24, 77% (24/31) had HIV-1 RNA <50 copies/mL regardless of screening genotype, including 5/6 patients with PI-resistant virus (6/6 had HIV-1 RNA <400 copies/mL). Brecanavir/ritonavir was well tolerated with no serious adverse events or clinically concerning changes in laboratory parameters. Of 31 patients, 10 (32%) experienced drug-related Grade 2-4 adverse events [most frequent events were fatigue (13%), dyspepsia (10%) and nausea (10%)]. Baseline isolate brecanavir IC(50) values for all patients ranged from 0.1 to 0.2 nM. Median plasma trough concentration at Week 4 was 150 ng/mL. Correcting the IC(50) (0.2 nM) value for protein binding (6-fold increase in vitro with 50% human serum) gives a corrected inhibitory quotient of 180. CONCLUSIONS: Brecanavir/ritonavir was well tolerated and showed potent antiviral activity in HIV-1-infected patients harbouring both PI-sensitive and PI-resistant virus, following 24 weeks of dosing.

Neonatal meningitis: what is the correlation among cerebrospinal fluid cultures, blood cultures, and cerebrospinal fluid parameters?

BACKGROUND: Meningitis is a substantial cause of morbidity and mortality in neonates. Clinicians frequently use the presence of positive blood cultures to determine whether neonates should undergo lumbar puncture. Abnormal cerebrospinal fluid (CSF) parameters are often used to predict neonatal meningitis and determine length and type of antibiotic therapy in neonates with a positive blood culture and negative CSF culture. METHODS: We evaluated the first lumbar puncture of 9111 neonates at > or =34 weeks' estimated gestational age from 150 NICUs, managed by the Pediatrix Medical Group, Inc. CSF culture results were compared with results of blood cultures and CSF parameters (white blood cells [WBCs], glucose, and protein) to establish the concordance of these values in culture-proven meningitis. CSF cultures positive for coagulase-negative staphylococci and other probable contaminants, as well as fungal and viral pathogens, were excluded from analyses. RESULTS: Meningitis was confirmed by culture in 95 (1.0%) neonates. Of the 95 patients with meningitis, 92 had a documented blood culture. Only 57 (62%) of 92 patients had a concomitant-positive blood culture; 35 (38%) of 92 had a negative blood culture. In neonates with both positive blood and CSF cultures, the organisms isolated were discordant in 2 (3.5%) of 57 cases. In each case, the CSF pathogen required different antimicrobial therapy than the blood pathogen. For culture-proven meningitis, CSF WBC counts of >0 cells per mm3 had sensitivity at 97% and specificity at 11%. CSF WBC counts of >21 cells per mm3 had sensitivity at 79% and specificity at 81%. Culture-proven meningitis was not diagnosed accurately by CSF glucose or by protein. CONCLUSIONS: Neonatal meningitis frequently occurs in the absence of bacteremia and in the presence of normal CSF parameters. No single CSF value can reliably exclude the presence of meningitis in neonates. The CSF culture is critical to establishing the diagnosis of neonatal meningitis.