Cutibacterium acnes Central Nervous System Catheter Infection Induces Long-Term Changes in the Cerebrospinal Fluid Proteome.

Cutibacterium acnes is the third most common cause of cerebrospinal fluid (CSF) shunt infection and is likely underdiagnosed due to the difficulty in culturing this pathogen. Shunt infections lead to grave neurologic morbidity for patients especially when there is a delay in diagnosis. Currently, the gold standard for identifying CSF shunt infections is microbiologic culture. However, C. acnes infection often results in falsely negative cultures; therefore, new diagnostic methods are needed. To investigate potential CSF biomarkers of C. acnes CSF shunt infection we adapted a rat model of CSF catheter infection to C. acnes. We found elevated levels of interleukin-1ß (IL-1ß), IL-6, chemokine ligand 2, and IL-10 in the CSF and brain tissues of animals implanted with C. acnes-infected catheters compared to sterile controls at day 1 postinfection. This coincided with modest increases in neutrophils in the CSF and, to a greater extent, in the brain tissues of animals with C. acnes infection, which closely mirrors the clinical findings in patients with C. acnes shunt infection. Mass spectrometry revealed that the CSF proteome is altered during C. acnes shunt infection and changes over the course of disease, typified at day 1 postinfection by an acute-phase and pathogen neutralization response evolving to a response consistent with wound resolution at day 28 compared to a sterile catheter placement. Collectively, these results demonstrate that it is possible to distinguish C. acnes infection from sterile postoperative inflammation and that CSF proteins could be useful in a diagnostic strategy for this pathogen that is difficult to diagnose.

Factors and measures predicting external CSF drain-associated ventriculitis: A review and meta-analysis.

OBJECTIVE: To determine the diagnostic value of clinical factors and biochemical or microbiological measures for diagnosing a drain-associated ventriculitis, we summarized the available evidence. METHODS: We performed a systematic review and meta-analysis of studies of patients with external ventricular CSF drains who developed drain-associated ventriculitis by searching MEDLINE, EMBASE, and CENTRAL electronic database. We reported the occurrence of abnormal test results in patients with and without drain-associated ventriculitis. For continuous variables, we recalculated mean values presented in multiple studies. RESULTS: We identified 42 articles published between 1984 and 2018 including 3,035 patients with external CSF drains of whom 697 (23%) developed drain-associated bacterial ventriculitis. Indications for drain placement were subarachnoid, intraventricular or cerebral hemorrhage or hemorrhage not further specified (69%), traumatic brain injury (13%), and obstructive hydrocephalus secondary to a brain tumor (10%). Fever was present in 116 of 162 patients with ventriculitis (72%) compared with 80 of 275 (29%) patients without ventriculitis. The CSF cell count was increased for 74 of 80 patients (93%) with bacterial ventriculitis and 30 of 95 patients (32%) without ventriculitis. CSF culture was positive in 125 of 156 episodes classified as ventriculitis (80%), and CSF Gram stain was positive in 44 of 81 patients (54%). In patients with ventriculitis, PCR on ribosomal RNA was positive on 54 of 78 CSF samples (69%). CONCLUSION: Clinical factors and biochemical and microbiological measures have limited diagnostic value in differentiating between ventriculitis and sterile inflammation in patients with external CSF drains. Prospective well-designed diagnostic accuracy studies in drain-associated ventriculitis are needed.

Antibiotic or silver versus standard ventriculoperitoneal shunts (BASICS): a multicentre, single-blinded, randomised trial and economic evaluation.

BACKGROUND: Insertion of a ventriculoperitoneal shunt for hydrocephalus is one of the commonest neurosurgical procedures worldwide. Infection of the implanted shunt affects up to 15% of these patients, resulting in prolonged hospital treatment, multiple surgeries, and reduced cognition and quality of life. Our aim was to determine the clinical and cost-effectiveness of antibiotic (rifampicin and clindamycin) or silver shunts compared with standard shunts at reducing infection. METHODS: In this parallel, multicentre, single-blind, randomised controlled trial, we included patients with hydrocephalus of any aetiology undergoing insertion of their first ventriculoperitoneal shunt irrespective of age at 21 regional adult and paediatric neurosurgery centres in the UK and Ireland. Patients were randomly assigned (1:1:1 in random permuted blocks of three or six) to receive standard shunts (standard shunt group), antibiotic-impregnated (0·15% clindamycin and 0·054% rifampicin; antibiotic shunt group), or silver-impregnated shunts (silver shunt group) through a randomisation sequence generated by an independent statistician. All patients and investigators who recorded and analysed the data were masked for group assignment, which was only disclosed to the neurosurgical staff at the time of operation. Participants receiving a shunt without evidence of infection at the time of insertion were followed up for at least 6 months and a maximum of 2 years. The primary outcome was time to shunt failure due the infection and was analysed with Fine and Gray survival regression models for competing risk by intention to treat. This trial is registered with ISRCTN 49474281. FINDINGS: Between June 26, 2013, and Oct 9, 2017, we assessed 3505 patients, of whom 1605 aged up to 91 years were randomly assigned to receive either a standard shunt (n=536), an antibiotic-impregnated shunt (n=538), or a silver shunt (n=531). 1594 had a shunt inserted without evidence of infection at the time of insertion (533 in the standard shunt group, 535 in the antibiotic shunt group, and 526 in the silver shunt group) and were followed up for a median of 22 months (IQR 10-24; 53 withdrew from follow-up). 32 (6%) of 533 evaluable patients in the standard shunt group had a shunt revision for infection, compared with 12 (2%) of 535 evaluable patients in the antibiotic shunt group (cause-specific hazard ratio [csHR] 0·38, 97·5% CI 0·18-0·80, p=0·0038) and 31 (6%) of 526 patients in the silver shunt group (0·99, 0·56-1·74, p=0·96). 135 (25%) patients in the standard shunt group, 127 (23%) in the antibiotic shunt group, and 134 (36%) in the silver shunt group had adverse events, which were not life-threatening and were mostly related to valve or catheter function. INTERPRETATION: The BASICS trial provides evidence to support the adoption of antibiotic shunts in UK patients who are having their first ventriculoperitoneal shunt insertion. This practice will benefit patients of all ages by reducing the risk and harm of shunt infection. FUNDING: UK National Institute for Health Research Health Technology Assessment programme.

Standardized Ventriculostomy Protocol without an Occlusive Dressing: Results of an Observational Study in Patients with Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Catheter-related infections are a potentially life-threatening complication of having an external ventricular drain (EVD). Patients with aneurysmal subarachnoid hemorrhage (aSAH) are at increased risk of infection associated with prolonged ventricular drainage, with a reported mean infection rate of 6%. We report the EVD-associated infection rate among patients with aSAH managed with a unique standardized treatment protocol without an occlusive EVD dressing. METHODS: Patients with aSAH admitted from August 2015 through August 2017 were retrospectively analyzed for EVD placement. Cerebrospinal fluid (CSF) samples were obtained twice weekly for culture and routine studies. EVD-associated infection was defined as growth of CSF cultures. RESULTS: During the 2-year study period, 122 patients presented with an aSAH, with 91 (74.6%) having EVD placement. In patients with EVDs, the mean age was 57.9 years (68% women); 88% of aSAHs were Fisher grade III or IV. Mean duration of EVD was 14 days, and 13% of patients required EVD replacement. Endovascular coiling and surgical clipping were performed in 34 (37%) and 53 (58%) patients with EVD, respectively. A total of 347 CSF studies were performed with no EVD-associated infections. There were 3 CSF samples with false-positive Gram stain results but no growth on concurrent or multiple repeat cultures. CONCLUSIONS: Using a standardized protocol for placement and management of EVDs in patients with aSAH is associated with low risk of CSF infection. Our study demonstrates that occlusive EVD dressings are not necessary and that routine CSF sampling in patients with EVD may lead to false-positive findings and unnecessary antibiotic administration.

Identification of Potential Cerebrospinal Fluid Biomarkers To Discriminate between Infection and Sterile Inflammation in a Rat Model of Staphylococcus epidermidis Catheter Infection.

Staphylococcus epidermidis cerebrospinal fluid (CSF) shunt infection is a common complication of hydrocephalus treatment, creating grave neurological consequences for patients, especially when diagnosis is delayed. The current method of diagnosis relies on microbiological culture; however, awaiting culture results may cause treatment delays, or culture may fail to identify infection altogether, so newer methods are needed. To investigate potential CSF biomarkers of S. epidermidis shunt infection, we developed a rat model allowing for serial CSF sampling. We found elevated levels of interleukin-10 (IL-10), IL-1ß, chemokine ligand 2 (CCL2), and CCL3 in the CSF of animals implanted with S. epidermidis-infected catheters compared to sterile controls at day 1 postinfection. Along with increased chemokine and cytokine expression early in infection, neutrophil influx was significantly increased in the CSF of animals with infected catheters, suggesting that coupling leukocyte counts with inflammatory mediators may differentiate infection from sterile inflammation. Mass spectrometry analysis revealed that the CSF proteome in sterile animals was similar to that in infected animals at day 1; however, by day 5 postinfection, there was an increase in the number of differently expressed proteins in the CSF of infected compared to sterile groups. The expansion of the proteome at day 5 postinfection was interesting, as bacterial burdens began to decline by this point, yet the CSF proteome data indicated that the host response remained active, especially with regard to the complement cascade. Collectively, these results provide potential biomarkers to distinguish S. epidermidis infection from sterile postoperative inflammation.

Diagnosis of ventriculostomy-related infection: Is cerebrospinal fluid lactate measurement a useful tool?

OBJECTIVE: To evaluate the value of CSF lactate (LCSF) for the diagnosis of ventriculostomy related infections (VRI), and compare it with other CSF markers. METHODS: Prospective study of neurocritical patients admitted to Maciel Hospital and Clinicas Hospital ICUs in which an external ventricular drain (EVD) was inserted. In patients with clinical suspicion of VRI, a CSF sample was obtained through the EVD for CSF culture and markers analysis (glucose, protein, lactate and leukocytes). We defined proven VRI according to preset criteria as: fever, plus CSF alterations (glucose <50mg/dl or leukocytes >500/µl), plus positive CSF culture. CSF markers were plotted in a receiver operating curve (ROC) to evaluate their diagnostic accuracy. RESULTS: 36 CSF samples were obtained: 14 corresponded to proven VRI and 22 to excluded VRI. Median LCSF was 9.90mmol/L (IQR: 4.7-12) for proven VRI versus 2.95mmol/L (IQR: 2.4-3.6) for excluded VRI (p<0.001). Both LCSF and CSF glucose showed a good diagnostic accuracy for VRI, with an AUC of 0.900 and 0.951 respectively. We found the following diagnostic values for LCSF: sensitivity of 86%, specificity of 86%, PPV of 80%, NPV of 91%, cut-off value of 4mM, positive likehood ratio of 6.1, negative likehood ratio of 0.16, Youden Index of 0.72 and Diagnostic Odds Ratio of 34. CONCLUSIONS: For the studied population, LCSF represents a good marker for VRI. It could be used as a quick and specific test to identify the need for antimicrobial therapy in patients with clinical suspicion of VRI.

Antibiotic-impregnated catheters reduce ventriculoperitoneal shunt infection rate in high-risk newborns and infants.

PURPOSE: The incidence of ventriculoperitoneal (VP) shunt infection accounts for about 5-15%, but it can rise up to 70% in specific high-risk subgroups. Antibiotic-impregnated catheters (AICs) have been designed to reduce shunt infections, but reports on their efficacy are discordant, especially in young children. The aim of this study is to assess, for the first time, the efficacy of AICs in newborns and infants at very high risk for shunt infection. METHODS: We reviewed the medical records of newborns and infants treated with a VP shunt for newly diagnosed hydrocephalus. Patients were divided in two groups: Group A was composed by children who received AICs, whereas Group B included children implanted with standard silicone catheters (non-AICs). We compared the shunt infection rate in both groups, and analyzed differences in specific high-risk subgroups (preterm newborns, children with posthemorrhagic or postinfective hydrocephalus, and children with a previous external ventricular drainage). RESULTS: Forty eight children younger than 1 year old were included in our study. Twenty two patients were implanted with an AIC, whereas 26 patients received a standard silicone catheter. The follow-up was at least 1 year (mean 8 ± 3 years). The overall infection rate decreased from 34% in non-AIC group to 9 % in the AIC group. Moreover, AICs showed to have a protective effect against shunt infections in all the specific high-risk subgroups analyzed. CONCLUSIONS: This study demonstrates for the first time that AICs are effective in reducing VP shunt infection in high-risk pediatric patients younger than 1 year old.

Characteristics of infections associated with external ventricular drains of cerebrospinal fluid.

OBJECTIVES: Manifestations of external ventricular drain (EVD) - associated infections overlap with those of the underlying neurosurgical conditions. We analyzed characteristics of EVD-associated infections. METHODS: We included patients aged ≥18 years with EVD-associated infections from 1997 to 2008, using modified CDC criteria for nosocomial infections. Hospital charts were reviewed retrospectively and the in-hospital outcome was evaluated. RESULTS: Forty-eight patients with EVD-associated infections were included (median age, 52 years, range 20-74 years). The median EVD-indwelling time was 7 days (range, 1-39 days) and EVD-associated infection occurred 6 days after insertion (range, 1-17 days). In 23% of patients, meningitis occurred 1-10 days after EVD removal. Fever >38 °C was present in 79% of patients, but Glasgow Coma Scale (GCS) scores were reduced in only 29%, and headache, vomiting and/or neck stiffness were present in only 31%. The median cerebrospinal fluid (CSF) leukocyte count was higher at onset of EVD-associated infection than at EVD insertion (175 × 10(6)/l versus 46 × 10(6)/l, p = 0.021), but other CSF parameters did not differ significantly. The most commonly implicated organisms were coagulase-negative staphylococci (63%) and Propionibacterium acnes (15%). CONCLUSIONS: Fever and increased CSF leukocytes should raise the suspicion of EVD-associated infection, which may occur up to 10 days after removal of EVD.