Empiric treatment of healthcare-associated central nervous system infections in Denmark: do we need carbapenems?

BACKGROUND: Carbapenems are widely used for empiric treatment of healthcare-associated central nervous system (CNS) infections. We investigated the feasibility of a carbapenem-sparing strategy, utilising a third-generation cephalosporin (ceftriaxone or cefotaxime) (combined with vancomycin) for the empirical treatment of healthcare-associated CNS infections in Eastern Denmark. METHODS: The departments of neurosurgery and neuro-intensive care at Copenhagen University Hospital Rigshospitalet. First, we analysed local microbiological data (1st January 2020-31st August 2022) to identify microorganisms non-susceptible to third-generation cephalosporin. Subsequently, we assessed all carbapenem prescriptions over a three-month period for their indication and justification. RESULTS: In total, 25,247 bacterial cultures were identified, of which 2,563 CNS-related, were included in the analysis. The positivity rate was 10.5% (n = 257/2439) for cerebrospinal-fluid samples and 75.8% (n = 95/124) for brain parenchyma. CNS samples from five individual patients revealed bacteria non-susceptible to third generation cephalosporins (Enterobacter spp. (n = 3), Pseudomonas spp. (n = 2), Klebsiella spp. (n = 2), Citrobacter freundii (n = 1)). All five patients had been hospitalised for ≥10days at the time-point of antibiotic therapy. Out of 11,626 sets of blood cultures, a total of 10 individual patients had Gram-negative blood-stream infections with resistance to ceftriaxone and piperacillin/tazobactam. 140 days-of-therapy (32%) with carbapenem in 18 patients (36%) were definitively or possibly indicated according to guidelines, none were indicated for healthcare-associated CNS-infections. CONCLUSION: An empiric treatment strategy relying on a third-generation cephalosporin appears suitable for healthcare-associated CNS infections at our tertiary hospital, serving a population of 2.6 million. However, in patients with prolonged hospitalization (≥10 days), immunosuppression, prior broad-spectrum antibiotic use, or history of resistant Gram-negative bacteria, empirical prescription of carbapenem may be needed.

The pharmacokinetics/pharmacodynamics of ceftazidime/avibactam for central nervous system infections caused by carbapenem-resistant Gram-negatives: a prospective study.

OBJECTIVES: To describe the pharmacokinetics/pharmacodynamics (PK/PD) of ceftazidime/avibactam in critically ill patients with CNS infections. METHODS: A prospective study of critically ill patients with CNS infections who were treated with ceftazidime/avibactam and the steady-state concentration (Css) of ceftazidime/avibactam in serum and/or CSF was conducted between August 2020 and May 2023. The relationship between PK/PD goal achievement, microbial eradication and the clinical efficacy of ceftazidime/avibactam was evaluated. RESULTS: Seven patients were finally included. The ceftazidime/avibactam target attainment in plasma was optimal for three, quasi-optimal for one and suboptimal for three. In three patients with CSF drug concentrations measured, ceftazidime/avibactam target attainment in CSF was 100% (3/3), which was optimal. The AUCCSF/serum values were 0.59, 0.44 and 0.35 for ceftazidime and 0.57, 0.53 and 0.51 for avibactam. Of the seven patients, 100% (7/7) were treated effectively, 71.4% (5/7) achieved microbiological eradication, 85.7% (6/7) survived and 14.3% (1/7) did not survive. CONCLUSIONS: The limited clinical data suggest that ceftazidime/avibactam is effective in the treatment of CNS infections caused by MDR Gram-negative bacilli (MDR-GNB), can achieve the ideal drug concentration of CSF, and has good blood-brain barrier penetration.

Innovative and potential treatments for fungal central nervous system infections.

Fungal infections of the central nervous system (FI-CNS) are a problematic and important medical challenge considering that those most affected are immunocompromised. Individuals with systemic cryptococcosis (67-84%), candidiasis (3-64%), blastomycosis (40%), coccidioidomycosis (25%), histoplasmosis (5-20%), mucormycosis (12%), and aspergillosis (4-6%) are highly susceptible to develop CNS involvement, which often results in high mortality (15-100%) depending on the mycosis and the affected immunosuppressed population. Current antifungal drugs are limited, prone to resistance, present host toxicity, and show reduced brain penetration, making FI-CNS very difficult to treat. Given these limitations and the rise in FI-CNS, there is a need for innovative strategies for therapeutic development and treatments to manage FI-CNS in at-risk populations. Here, we discuss standards of care, antifungal drug candidates, and novel molecular targets in the blood-brain barrier, which is a protective structure that regulates movement of particles in and out of the brain, to prevent and combat FI-CNS.

Clinical and microbiological characteristics of carbapenem-resistant Enterobacteriaceae causing post-operative central nervous system infections in China.

OBJECTIVES: Postoperative central nervous system infections (PCNSIs) caused by carbapenem-resistant Enterobacteriaceae (CRE) frequently result in unfavourable outcomes. However, CRE PCNSIs have not been well described from a clinical and microbiological perspective. METHODS: A total of 254 PCNSIs cases were included (January 2017 through June 2020), and clinical features were compared based on pathogenic classification. Cox regression analysis was performed to assess risk factors for mortality. Antibiotic susceptibility testing and whole genome sequencing were conducted on CRE isolates preserved. MLST, cgMLST, resistance genes and virulence genes were further analysed. RESULTS: Among 254 PCNSI cases, 15.4% were caused by Enterobacteriaceae including 28 cases by CRE. The 28-day mortality rates for CRE, CSE and non-Enterobacteriaceae PCNSIs were 50.0%, 27.3%, and 7.4%, respectively. 42.9% (12/28) of the CRE PCNSIs patients achieved clinical cure, with 25.0% achieved microbiological clearance. ST11-KL64 carrying blaKPC-2 was dominant in CRE (17/23, 73.9%), and the 28-day mortality rate of its infection was 58.5%. Most CRKP carried rampA/rampA2 genes (17/23, 73.9%). CONCLUSION: ST11-KL64 CRKP carrying blaKPC-2 dominated among CRE PCNSIs. Targeted anti-infective combination therapy based on ceftazidime/avibactam or amikacin, combined with intrathecal administration of amikacin, was found to be effective. These findings render a new insight into the clinical and microbiological landscape of CRE PCNSIs.

Plasma and Cerebrospinal Fluid Population Pharmacokinetics of Vancomycin in Patients with External Ventricular Drain.

Vancomycin is a commonly used antibacterial agent in patients with primary central nervous system (CNS) infection. This study aims to examine predictors of vancomycin penetration into cerebrospinal fluid (CSF) in patients with external ventricular drainage and the feasibility of CSF sampling from the distal drainage port for therapeutic drug monitoring. Fourteen adult patients (9 with primary CNS infection) were treated with vancomycin intravenously. The vancomycin concentrations in blood and CSF (from proximal [CSF_P] and distal [CSF_D] drainage ports) were evaluated by population pharmacokinetics. Model-based simulations were conducted to compare various infusion modes. A three-compartment model with first-order elimination best described the vancomycin data. Estimated parameters included clearance (CL, 4.53 L/h), central compartment volume (Vc, 24.0 L), apparent CSF compartment volume (VCSF, 0.445 L), and clearance between central and CSF compartments (QCSF, 0.00322 L/h and 0.00135 L/h for patients with and without primary CNS infection, respectively). Creatinine clearance was a significant covariate on vancomycin CL. CSF protein was the primary covariate to explain the variability of QCSF. There was no detectable difference between the data for sampling from the proximal and the distal port. Intermittent infusion and continuous infusion with a loading dose reached the CSF target concentration faster than continuous infusion only. All infusion schedules reached similar CSF trough concentrations. Beyond adjusting doses according to renal function, starting treatment with a loading dose in patients with primary CSF infection is recommended. Occasionally, very high and possibly toxic doses would be required to achieve adequate CSF concentrations, which calls for more investigation of direct intraventricular administration of vancomycin. (This study has been registered at ClinicalTrials.gov under registration no. NCT04426383).

Microbiologic and Clinical Description of Postoperative Central Nervous System Infection After Endoscopic Endonasal Surgery.

BACKGROUND: Consensus guidelines for antibiotic prophylaxis in endoscopic endonasal surgery (EES) have not been developed. The study objective was to define the microbiologic and clinical characteristics of post-EES central nervous system (CNS) infections. METHODS: This was a single-center retrospective study of patients >18 years of age who underwent EES between January 2010 and July 2021 at a high-volume skull base center. Patients with confirmed CNS infection within 30 days of EES were included. During the study period, the standard prophylaxis regimen was ceftriaxone 2 g every 12 hours for 48 hours. For patients with a documented penicillin allergy, vancomycin plus aztreonam was recommended. RESULTS: In total, 2440 EES procedures were performed on 2005 patients; the CNS infection rate was 1.8% (37/2005). CNS infections were more common among patients with a history of previous EES (6.5%; 20/307) compared with those who did not (1%; 17/1698; P < 0.001). The median time from EES to CNS infection was 12 (6-19) days. Thirty-two percent (12/37) of CNS infections were polymicrobic, which was more common among patients without previous EES (52.9%; 9/17) compared with those with previous EES (15%; 3/20; P = 0.03). Across all cases, Staphylococcus aureus (n = 10) and Pseudomonas aeruginosa (n = 8) were commonly isolated pathogens. Among those with confirmed methicillin-resistant Staphylococcus aureus (MRSA) nares colonization before EES, 75% (3/4) developed MRSA CNS infections compared with 6.1% (2/33) of noncolonized patients (P = 0.005). CONCLUSIONS: CNS infection after EES is rare and causative pathogens vary. Further studies are needed to identify the impact of MRSA nares screening on antimicrobial prophylaxis before EES.

Ceftazidime-avibactam-based combination therapy for hospital-acquired central nervous system infections caused by carbapenem-resistant Klebsiella pneumoniae.

OBJECTIVES: Klebsiella pneumoniae (K. pneumoniae) is one of the most common bacteria in the hospital-acquired central nervous system (CNS) infections. Central nervous system infections caused by carbapenem-resistant K. pneumoniae (CRKP) are associated with significant mortality rates and high hospital costs due to limited antibiotic treatment options. This retrospective study aimed to evaluate the clinical efficacy of ceftazidime-avibactam (CZA) for the treatment of CNS infections caused by CRKP. METHODS: Twenty-one patients with hospital-acquired CNS infections caused by CRKP who received treatment with CZA for ≥ 72 hours were enrolled. The primary outcome was to assess the clinical and microbiology efficacy of CZA for the treatment of CNS infections caused by CRKP. RESULTS: A high burden of comorbidity was discovered in 20 of 21 patients (95.2%). Most patients had a history of craniocerebral surgery and 17 (81.0%) of the patients were in the intensive care unit with a median APACHE II score of 16 (IQR 9-20) and SOFA score of 6 (IQR 3-7). Eighteen cases were treated by CZA-based combination therapies, while the remaining three cases were treated with CZA alone. At the end of the treatment, the overall clinical efficacy was 76.2% (16 of 21) with a bacterial clearance rate of 81.0% (17 of 21) and all-cause mortality of 23.8% (five of 21). CONCLUSION: This study showed that CZA-based combination therapy is an effective treatment option for CNS infections caused by CRKP.

Cefazolin in the treatment of central nervous system infections: A narrative review and recommendation.

Infections of the central nervous system (CNS) are complex to treat and associated with significant morbidity and mortality. Historically, antistaphylococcal penicillins such as nafcillin were recommended for the treatment of methicillin-susceptible staphylococcal CNS infections. However, the use of antistaphylococcal penicillins presents challenges, such as frequent dosing administration and adverse events with protracted use. This narrative reviews available clinical and pharmacokinetic/pharmacodynamic (PK/PD) data for cefazolin in CNS infections and produces a recommendation for use. Based on the limited available evidence analyzed, dose optimized cefazolin is likely a safe and effective alternative to antistaphylococcal penicillins for a variety of CNS infections due to methicillin-susceptible Staphylococcus aureus. Given the site of infection and wide therapeutic index of cefazolin, practitioners may consider dosing cefazolin regimens of 2 g IV every 6 h or a continuous infusion of 8-10 g daily instead of 2 g IV every 8 h to optimize PK/PD properties.

Impact of Penicillin Allergy-Based Alternative Antibiotics on the Risk of Postoperative Central Nervous System Infection: A Retrospective Cohort Study.

BACKGROUND: Central nervous system (CNS) infection is one of the most serious complications after neurosurgery. This study aimed to analyze the effect of penicillin allergy (PA) and alternative prophylactic antibiotics on risk of postoperative CNS infection in patients undergoing neurosurgery. METHODS: Data of patients who underwent neurosurgical procedures from January 2015 to December 2021 were analyzed retrospectively. Patients with PA were compared with patients without PA in a 1:1 ratio. A multivariate logistic regression model was used to examine whether PA was a risk factor for postoperative CNS infection. RESULTS: Overall, 15,049 eligible neurosurgical records were reviewed, from which 578 surgical records of 556 patients with PA were matched to 578 records of 570 patients without PA. Patients with PA showed significantly lower probability to receive prophylactic cephalosporins (55.9% vs. 98.8%, P < 0.01), but significantly higher probability to receive clindamycin (41.86% vs. 1.03%, P < 0.01), than patients without PA. Multivariate analysis revealed that patients with PA were more likely to experience postoperative CNS infection than patients without PA (odds ratio = 2.03; 95% confidence interval, 1.15-3.56; P = 0.014). The incidence of postoperative CNS infection returned to a level comparable to that in general population when patients with suspected PA received prophylactic cephalosporins. CONCLUSIONS: PA is associated with higher risk of postoperative CNS infection in patients undergoing neurosurgery. This may be attributed to the use of alternative prophylactic antibiotics other than cephalosporins, especially clindamycin.

[Central nervous system infections and targeted therapies: what to consider]. / Infections du système nerveux central et thérapies ciblées : à quoi faut-il penser ?

The development of targeted therapies has revolutionized the approach to immunosuppression in several medical specialties. While the prescriber of these therapies is familiar with these agents, both the general internist and the infectious disease specialist must deal with the consequences of these products. Encephalitis, for which prompt and appropriate management is paramount, is a challenge in the patient undergoing immunomodulatory therapies because of its atypical presentation, the involvement of particular germs and the potential brain toxicity of some immunomodulatory treatments. This article outlines the mechanisms of action of some targeted therapies and reviews the associated brain infections.

Le développement des thérapies ciblées a révolutionné l'approche de l'immunosuppression dans plusieurs spécialités médicales. Si le prescripteur de ces thérapies est familiarisé avec ces agents, l'interniste généraliste et l'infectiologue doivent tous deux faire face aux conséquences de ces produits. Les encéphalites, dont la prise en charge rapide et adéquate est primordiale, représentent un défi chez le patient soumis aux thérapies immunomodulatrices, en raison de leur présentation atypique, de l'implication de germes particuliers et de la toxicité cérébrale potentielle de certains traitements immunomodulateurs. Cet article expose les mécanismes d'action de certaines thérapies ciblées et passe en revue les infections de l'encéphale qui y sont associées.

Application of therapeutic drug monitoring to the treatment of bacterial central nervous system infection: a scoping review.

BACKGROUND: Bacterial central nervous system (CNS) infection is challenging to treat and carries high risk of recurrence, morbidity, and mortality. Low CNS penetration of antibiotics may contribute to poor clinical outcomes from bacterial CNS infections. The current application of therapeutic drug monitoring (TDM) to management of bacterial CNS infection was reviewed. METHODS: Studies were included if they described adults treated for a suspected/confirmed bacterial CNS infection and had antibiotic drug concentration(s) determined that affected individual treatment. RESULTS: One-hundred-and-thirty-six citations were retrieved. Seventeen manuscripts were included describing management of 68 patients. TDM for vancomycin (58/68) and the beta-lactams (29/68) was most common. Timing of clinical sampling varied widely between studies and across different antibiotics. Methods for setting individual PK-PD targets, determining parameters and making treatment changes varied widely and were sometimes unclear. DISCUSSION: Despite increasing observational data showing low CNS penetration of various antibiotics, there are few clinical studies describing practical implementation of TDM in management of CNS infection. Lack of consensus around clinically relevant CSF PK-PD targets and protocols for dose-adjustment may contribute. Standardised investigation of TDM as a tool to improve treatment is required, especially as innovative drug concentration-sensing and PK-PD modelling technologies are emerging. Data generated at different centres offering TDM should be open access and aggregated to enrich understanding and optimize application.

Management of Extensive Central Nervous System Cladophialophora bantiana Infection in a 9-Year-Old Child.

BACKGROUND: Pediatric central nervous system (CNS) phaeohyphomycosis is a rare invasive fungal infection associated with high mortality. METHODS: We describe a child with progressive neurologic symptoms whose ultimate diagnosis was Cladophialophora bantiana -associated CNS phaeohyphomycosis. We discuss her clinical presentation, medical and surgical management and review the current literature. RESULTS: A 9-year-old female presented with acute onset of headaches, ophthalmoplegia and ataxia. Initial infectious work-up was negative, including serial fungal cerebrospinal fluid cultures. Over 2 months, she experienced progressive cognitive and motor declines, and imaging revealed worsening meningitis, ventriculitis and cerebritis. Ultimately, Cladophialophora was detected by plasma metagenomic next-generation sequencing (mNGS). Fourth ventricle fluid sampling confirmed the diagnosis of C. bantiana infection. Given the extent of her disease, complete surgical resection was not feasible. She required multiple surgical debridement procedures and prolonged antifungal therapy, including the instillation of intraventricular amphotericin B. With aggressive surgical and medical management, despite her continued neurologic deficits, she remains alive 3 years after her initial diagnosis. To our knowledge, this is one of a few published pediatric cases of CNS phaeohyphomycosis and the first with the causative pathogen identified by plasma mNGS. CONCLUSION: CNS phaeohyphomycosis is a serious, life-threatening infection. The preferred management includes a combination of surgical resection and antifungal therapy. In cases complicated by refractory ventriculitis, intraventricular antifungal therapy can be considered as adjuvant therapy. Direct sampling of the CNS for pathogen identification and susceptibility testing is the gold standard for diagnosis; however, the use of plasma mNGS may expedite the diagnosis.

Application of Nano-based Drug Loading Systems in the Treatment of Neurological Infections: An Updated Review.

Infection of the central nervous system (CNS) is a global healthcare concern with high rates of death and disease. CNS infections mainly include meningitis, encephalitis, and brain abscesses. Bacteria, viruses, fungi, protozoa, and parasites are the most common causes of neuroinfections. There are many types of medications used in the treatment of CNS infections, but drug delivery through the blood-brain barrier (BBB) is a major challenge to overcome. The BBB is a specialized multicellular barrier separating the neural tissue from the peripheral blood circulation. Unique characteristics of the BBB allow it to tightly control the movement of ions and molecules. Thus, there is a critical need to deal with these conditions with the aim of improving novel antimicrobial agents. Researchers are still struggling to find effective drugs to treat CNS infections. Nanoparticle (NP)-mediated drug delivery has been considered a profound substitute to solve this problem because NPs can be tailored to facilitate drug transport across the BBB. NPs are colloidal systems with a size range of 1-1000 nm, which can be used to encapsulate therapeutics, improve drug transport across the BBB, and target specific brain areas in CNS infections. A wide variety of NPs has been displayed for the CNS delivery of therapeutics, especially when their surfaces are coated with targeting moieties. This study aimed to review the available literature on the application of NPs in CNS infections.

Intravenous plus intraventricular tigecycline-amikacin therapy for the treatment of carbapenem-resistant Klebsiella pneumoniae ventriculitis: A case report.

RATIONALE: Central nervous system infections (CNSIs) are one of the most serious complications after neurosurgery, especially carbapenem-resistant bacterial meningitis. Owing to the poor blood-brain barrier permeability of most antibiotics, the treatment of CNSIs by intraventricular (IVT) administration is becoming a hot topic in clinical research. Currently, the treatment of CNSIs caused by carbapenem-resistant Klebsiella pneumoniae is mainly based on intraventricular injection of an antibiotic combined with one or more other systemic intravenous (IV) antibiotics, whereas there are few case reports of intraventricular injection of 2 antibiotics. PATIENT CONCERNS: A 57-year-old man with an open craniocerebral injury presented with dyspnea, high fever, and seizures associated with surgery. DIAGNOSIS: Intracranial infection caused by carbapenem-resistant K. pneumoniae was diagnosed. INTERVENTIONS: On the advice of a clinical pharmacist, the patient was given tigecycline (100 mg IV + 3 mg IVT q12h) combined with amikacin (0.8 g IV + 30 mg IVT qd) antiinfective therapy. Ultimately, the pathogens in the cerebrospinal fluid were eradicated after 7 days, and the CNSIs were completely cured after 14 days. OUTCOMES: The patient recovered and was discharged from the hospital without adverse reactions. LESSONS: A series of in vitro and in vivo synergy tests of carbapenem-resistant K. pneumoniae showed that tigecycline combined with aminoglycosides had good synergistic effects and effectively suppressed bacterial resistance selection. Intravenous plus intraventricular tigecycline-amikacin seems to be a safe and effective treatment option for carbapenem-resistant K. pneumoniae CNSIs.

Pearls & Oy-sters: Diagnosis and Subtyping of Listeria Ventriculitis in an Immunocompetent Host.

Listeria monocytogenes is a Gram-positive food-borne pathogen that causes gastrointestinal symptoms and CNS infection in susceptible hosts. Two lineages of Listeria cause the majority of neurolisteriosis in humans. In this report, we discuss a case of a 23-year-old previously healthy woman who presented with acute-onset rapidly progressive altered mental status after eating undercooked meats at a local restaurant. Given her age and lack of comorbidities, bacterial meningitis was suspected, and she was treated with ceftriaxone, vancomycin, and steroids. MRI of the brain was consistent with meningitis and ventriculitis; CSF analysis also suggested bacterial meningitis. Despite mechanical ventilation, pressors, and ventricular drain placement, she quickly decompensated and died 12 hours after arrival. CSF culture later returned positive for Listeria monocytogenes We used whole-genome sequencing and near-source comparison to identify the Listeria subtype that led to her unexpected presentation. The results suggest that her CSF isolate was consistent with a lineage II Listeria serotype, which is known to exhibit greater genetic variation than the more commonly isolated lineage I serotypes. We conclude the discussion with diagnostic and treatment approaches to neurolisteriosis. In susceptible hosts, namely immunocompromised, pregnant, neonatal, or elderly patients, Listeria infection may result in CNS invasion, causing meningoencephalitis and, rarely, ventriculitis and rhombencephalitis. Although neurolisteriosis most commonly affects individuals with known risk factors, CNS infection is nevertheless possible in otherwise healthy young patients. Suspicion should be raised in patients with an exposure history who do not improve with empiric antibiotics.

How we deal with Staphylococcus aureus (MSSA, MRSA) central nervous system infections.

Among central nervous system (CNS) infections (e.g., meningitis, brain abscess, ventriculitis, transverse myelitis), those caused by Staphylococcus aureus (SA) are particularly challenging both in management and treatment, with poor clinical outcomes and long hospital stay. It has been estimated that SA is responsible for around 1%-7% of meningitis (up to 19% in healthcare-associated meningitis). Recent neurosurgical procedures and immunocompromisation are major risk factors for SA CNS infections. Hand hygiene, surveillance nasal swabs and perioperative prophylaxis are crucial points for effective SA infections prevention. In case of SA-CNS infections, pending microbiological results, anti-methicillin-resistant SA (MRSA) antibiotic, with good CNS penetration, should be included, with prompt de-escalation as soon as MRSA is ruled out. Consultation with an expert in antimicrobial therapy is recommended as well as prompt source control when feasible. In this narrative review, we reviewed current literature to provide practical suggestions on diagnosis, prevention, management, and treatment of SA CNS infections.

Early Surgical Intervention with Antibiotic Treatment for Congenital Dermal Sinus with Central Nervous System Infection: A Retrospective Study of 20 Cases.

OBJECTIVE: To investigate the efficacy of surgical intervention with antibiotic treatment for congenital dermal sinus (CDS) with central nervous system infection. METHODS: Clinical data of 20 patients with CDS and central nervous system infection were retrospectively analyzed. All patients received early surgical treatment combined with postoperative antibiotic therapy after the diagnosis was confirmed. The infection control effect was evaluated according to the clinical symptoms, laboratory examination results, and improvement of neurological function. RESULTS: All 20 patients were treated with complete resection of the CDS and postoperative antibiotic therapy. No severe surgical complications occurred. Patients were followed for 3-81 months with a median follow-up time of 37.5 months. Postoperative infection was effectively controlled with no recurrence. Neurological dysfunction and related symptoms improved to varying extents after treatment, and the Spina Bifida Neurological Scale score at the final follow-up significantly increased. CONCLUSIONS: Patients with CDS and central nervous system infection should receive surgical management at an early stage with antibiotic treatment. This treatment algorithm was effective for control infection and protection of neurological function.

Clinical and Financial Impact of a Diagnostic Stewardship Program for Children with Suspected Central Nervous System Infection.

OBJECTIVE: To investigate the optimal implementation and clinical and financial impacts of the FilmArray Meningitis Encephalitis Panel (MEP) multiplex polymerase chain reaction testing of cerebrospinal fluid (CSF) in children with suspected central nervous system infection. STUDY DESIGN: A pre-post quasiexperimental cohort study to investigate the impact of implementing MEP using a rapid CSF diagnostic stewardship program was conducted at Children's Hospital Colorado (CHCO). MEP was implemented with electronic medical record indication selection to guide testing to children meeting approved use criteria: infants <2 months, immunocompromised, encephalitis, and ≥5 white blood cells/µL of CSF. Positive results were communicated with antimicrobial stewardship real-time decision support. All cases with CSF obtained by lumbar puncture sent to the CHCO microbiology laboratory meeting any of the 4 aforementioned criteria were included with preimplementation controls (2015-2016) compared with postimplementation cases (2017-2018). Primary outcome was time-to-optimal antimicrobials compared using log-rank test with Kaplan-Meier analysis. RESULTS: Time-to-optimal antimicrobials decreased from 28 hours among 1124 preimplementation controls to 18 hours (P < .0001) among 1127 postimplementation cases (72% with MEP testing conducted). Postimplementation, time-to-positive CSF results was faster (4.8 vs 9.6 hours, P < .0001), intravenous antimicrobial duration was shorter (24 vs 36 hours, P = .004), with infectious neurologic diagnoses more frequently identified (15% vs 10%, P = .03). There were no differences in time-to-effective antimicrobials, hospital admissions, antimicrobial starts, or length of stay. Costs of microbiologic testing increased, but total hospital costs were unchanged. CONCLUSIONS: Implementation of MEP with a rapid central nervous system diagnostic stewardship program improved antimicrobial use with faster results shortening empiric therapy. Routine MEP testing for high-yield indications enables antimicrobial optimization with unchanged overall costs.