Treatment Of Central Nervous System Infections Research Articles

Utilizing Ceftazidime/Avibactam Therapeutic Drug Monitoring in the Treatment of Neurosurgical Meningitis Caused by Difficult-to-Treat Resistant Pseudomonas aeruginosa and KPC-Producing Enterobacterales.

Central nervous system (CNS) infections caused by Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacterales and difficult-to-treat resistant (DTR) Pseudomonas aeruginosa represent a formidable clinical challenge. Antimicrobial regimens that efficiently penetrate the cerebrospinal fluid (CSF) and achieve sufficient concentrations associated with microbiologic and clinical cure are limited. We evaluated therapy with ceftazidime-avibactam (CAZ-AVI) in order to guide precise dosing in the treatment of CNS infections. Therapeutic drug monitoring (TDM) was performed in 3 patients with health care-associated ventriculitis and meningitis (HAVM) using CAZ-AVI 2.5 g infused intravenously every 8 hours as standard and extended infusion. Simultaneous CSF and plasma samples were obtained throughout the dosing interval in each patient. Concentrations of CAZ and AVI were determined by liquid chromatography/mass spectrometry. Bacterial identification revealed KPC-producing Klebsiella pneumoniae (KPC-Kp), DTR Pseudomonas aeruginosa, and KPC-producing Enterobacter cloacae (KPC-Ent.c). All isolates were resistant to carbapenems. The minimum inhibitory concentrations (MICs) of CAZ-AVI were 0.25/4, 4/4, and 0.25/4 μg/mL, respectively. CAZ and AVI concentrations were determined in CSF samples ranging from 29.0 to 15.0 µg/mL (CAZ component) and 4.20 to 0.92 µg/mL (AVI component), respectively. AVI achieved concentrations ≥1 µg/mL in 11 out of 12 CSF samples collected throughout the dosing interval. Clinical and microbiologic cure were attained in all patients. Postinfusion concentrations of CAZ-AVI were measured in plasma and CSF samples obtained from 3 patients with complicated CNS infections caused by antimicrobial-resistant isolates. The measured concentrations revealed that standard CAZ and AVI exposures sufficiently attained values correlating to 50% fT > MIC, which are associated with efficient bacterial killing.

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.

Nanoparticles and nanoformulated drugs as promising delivery system in treatment of microbial-induced CNS infection: a systematic review of literature.

Central nervous system (CNS) infection is a global health problem with high rate of mortality and associated morbidities. Viruses, bacteria, fungi, and protozoa parasites are the main cause of CNS infection. Various medications are currently used for treatment of brain infections, but most of them do not have enough efficiency because the majority of conventional drugs cannot pass the blood-brain barrier (BBB) to combat the pathogens. Nanotechnology has provided promising approaches to solve this issue, since nanoparticles (NPs) can facilitate the drugs entrance through the BBB. Herein, we systematically reviewed all available literature to provide evidences for practicality of NPs in treatment of CNS infection. A systematic literature search was performed on January 29, 2021, in Web of Science, PubMed, Scopus, Science Direct, Embase, Ovid, and Google Scholar using "CNS infections" and "NPs/nanoformulation" including all their equivalent terms as keyword. Due to lack of human studies, no strict inclusion criteria were defined, and all relevant documents were included. After several steps of article selection, a total of 29 documents were collected and used for data synthesis. The results showed that drug-loaded NPs is fairly safe and can be a promising approach in developing anti-infective agents for treatment of CNS infection, since nanoformulated drugs could act up to tenfold more efficient that drug alone. Findings of this review indicate the importance of NPs and nanoformulation of drugs to enhance the efficiency of treatment and warrant the safety of treatment in human studies; however, clinical trials are required to confirm such efficiency and safety in clinical practice.

The Use of Adjunctive Steroids in Central Nervous Infections.

Central nervous system (CNS) infections continue to be associated with significant neurological morbidity and mortality despite various existing therapies. Adjunctive steroid therapy has been employed clinically to reduce inflammation in the treatment of CNS infections across various causative pathogens. Steroid therapy can potentially improve clinical outcomes including reducing mortality rates, provide no significant benefit, or cause worsened outcomes, based on the causative agent of infection. The data on benefits or harms of adjunctive steroid therapy is not consistent in outcome or density through CNS infections, and varies based on the disease diagnosis and pathogen. We summarize the existing literature on the effects of adjunctive steroid therapy on outcome for a number of CNS infections, including bacterial meningitis, herpes simplex virus, West Nile virus, tuberculosis meningitis, cryptococcal meningitis, Angiostrongylus cantonensis, neurocysticercosis, autoimmune encephalitis, toxoplasmosis, and bacterial brain abscess. We describe that while steroid therapy is beneficial and supported in pathogens such as pneumococcal meningitis and tuberculosis, for other diseases, like Listeria monocytogenes and Cryptococcus neoformans they are associated with worse outcomes. We highlight areas of consistent and proven findings and those which need more evidence for supported beneficial clinical use of adjunctive steroid therapy.

Effect of subinhibitory concentrations of ampicillin on Listeria monocytogenes

Listeria monocytogenes is an important cause of meningoencephalitis associated with high mortality. The treatment of choice for listeriosis is ampicillin alone or in combination with gentamicin or penicillin G. However, only low ampicillin concentrations are recorded in the central nervous system (CNS). In this study, we analysed the effect of subinhibitory concentrations of ampicillin on the morphology, growth and survival of L. monocytogenes. The non-inhibitory concentration (NIC), the minimum inhibitory concentration (MIC) and the MIC/NIC ratio were determined. Gram and Live/Dead staining showed aggregates of L. monocytogenes cells when grown at subinhibitory concentrations of ampicillin, with >90% of viable cells. The L. monocytogenes strains tested showed an intermediate heteroresistance to ampicillin, characterised by a MIC/NIC ratio of 4. Our results seem to indicate that both intermediate heteroresistance and the formation of aggregates could play a role in the clinical failure of ampicillin in the treatment of CNS infections caused by L. monocytogenes. However, more studies are necessary to elucidate this question.

Effect of subinhibitory concentrations of ampicillin on Listeria monocytogenes

Listeria monocytogenes is an important cause of meningoencephalitis associated with high mortality. The treatment of choice for listeriosis is ampicillin alone or in combination with gentamicin or penicillin G. However, only low ampicillin concentrations are recorded in the central nervous system (CNS). In this study, we analysed the effect of subinhibitory concentrations of ampicillin on the morphology, growth and survival of L. monocytogenes. The non-inhibitory concentration (NIC), the minimum inhibitory concentration (MIC) and the MIC/NIC ratio were determined. Gram and Live/Dead staining showed aggregates of L. monocytogenes cells when grown at subinhibitory concentrations of ampicillin, with >90% of viable cells. The L. monocytogenes strains tested showed an intermediate heteroresistance to ampicillin, characterised by a MIC/NIC ratio of 4. Our results seem to indicate that both intermediate heteroresistance and the formation of aggregates could play a role in the clinical failure of ampicillin in the treatment of CNS infections caused by L. monocytogenes. However, more studies are necessary to elucidate this question.

Viral infections of the central nervous system in Qatar: epidemiology, pathogenesis and clinical outcomes.

Virus-induced diseases of the central nervous system (CNS) represent a significant burden to human health worldwide. They are common causes of morbidities and mortality. There are no previous epidiomologic studies about viral CNS infections done in Qatar or in the Gulf region. We conducted this study to determine the etiology, clinical and epidimiological characteristics, and outcome of viral central nerveous system infection in patients across a larger national healthcare system. We retrospectively evaluated all cerebrospinal fluid findings from January 2011 - March 2015 at any of the 7 hospitals in the Hamad Medical Corporation healthcare system. We included those with an abnormal CSF finding in our study. We excluded those with missing medical records, those with no clinical evidence of CNS infection or proven bacterial CNS infection. Based on pre-defined clinical and CSF (lab, culture, PCR) criteria, persons with abnormal CSF and CNS clinical findings were classified as having meningitis, meningoencephalitis, encephalitis or myelitis. We reviewed the laboratory results to determine the proportion of persons with confirmed viral etiology. Among 7690 patients with available CSF results, 550 cases met the case definition criteria for viral CNS infection (meningitis 75%; meningoencephalitis 16%; encephalitis 9%; myelitis 0.4%). Two-thirds (65%) were male and 50% were between 16-60 years old. Persons from Southeast Asia (India, Pakistan, Bangladesh, Nepal, and Sri Lanka) accounted for 39.6 of all infections. A definitive virologic etiologic agent was found in 38%, among whom enterovirus was the most common (44.3%) followed by Epstein-Barr virus (31%) and varicella zoster virus (12.4%). The clinical outcome was overall good, only 2 cases died and the rest discharged to home. Ninety-eight per cent were admitted to medical ward (mean stay 7.8±6.4 days) and 2 % to an intensive care unit. (mean stay 2.7±5.4 days). Among those with confirmed viral etiology, 83.8% received ceftriaxone, 38% received vancomycin and 38% received at least one other antibiotic. Viral etiology is not uncommon among those evaluated for CNS infection in Qatar, and is most commonly seen in Southeast Asian immigrants. Clinical outcomes are generally excellent in this group of patients. Antibiotics are overly used even when a viral etiology is confirmed. There is a need for clinician education regarding etiology and treatment of CNS infections.

Viral Infections of the Central Nervous System in Qatar: Epidemiology, Pathogenesis and Clinical Outcomes

BackgroundViral central nervous system (CNS) infections are common causes of morbidity and mortality globally. There are no existing data about viral CNS infections in Gulf Cooperation Council countries. We conducted this study to determine the etiology, clinical and epidimiological characteristics, and outcomes of viral central nerveous system infection in patients in Qatar.MethodsWe retrospectively evaluated all cerebrospinal fluid findings from January 2011–March 2015 at any of the 7 hospitals in the Hamad Medical Corporation. We included those with an abnormal CSF findings and excluded those with missing medical records, no clinical evidence of CNS infection and those with proven bacterial infection. Based on pre-defined clinical and CSF (lab, culture, PCR) criteria, patients were classified as having meningitis, meningoencephalitis, encephalitis or myelitis. We reviewed the laboratory results to determine the proportion of persons with confirmed viral etiology.ResultsAmong 7690 patients with available CSF results, 550 cases met the case definition criteria for viral CNS infection (meningitis 75%; meningoencephalitis 16%; encephalitis 9%; myelitis 0.4%). Two-thirds (65%) were male and 50% were between 16-60 years old. The most common presenting signs and symptoms are listed in the table. Persons of Southeast Asian origin accounted for 39.6% of all infections. A definitive virologic etiologic agent was found in 38%, with enterovirus being the most common (44.3%) followed by Epstein–Barr virus (31%) and varicella-zoster virus (12.4%). The clinical outcome was overall good, only 2 cases died and the rest were discharged to home. Among those with confirmed viral etiology, 83.8% received ceftriaxone (mean duration 7.3 ± 5.2 days), 38% received vancomycin (mean duration 2.7 ± 5.4 days) and 38% received at least one other antibiotic.ConclusionViral etiology is common among those evaluated for CNS infection in Qatar, and is most commonly seen in Southeast Asian immigrants. Clinical outcomes are generally excellent in this group of patients. Antibiotics are overly used even when a viral etiology is confirmed. There is a need for clinician education regarding etiology and treatment of CNS infections.Disclosures A. Butt, Merck: Investigator, Grant recipient

Opioid‐Induced Alterations of TLR4 Protein Expression in a Human Microglial Cell Line

Opioids are recognized to modulate immune function; however, the exact mechanisms for altered immune responses continue to be elusive. The current research investigates the role of toll-like receptor 4 (TLR4) protein expression in response to opioids in central nervous system (CNS) immunomodulation. Human CHME-5 microglia were treated with morphine, methadone, oxycodone, or buprenorphrine at the concentrations of 3-33 µM either alone or with a single dose of 100 ng/mL of lipopolysaccharide (LPS). Morphine at 10 µM upregulated TLR4 protein expression in the presence of LPS. The most pronounced effect occurred with methadone, which at 3 µM and 10 µM also upregulated TLR4 protein expression; however, methadone with LPS at all concentrations had the opposite effect (p<0.05). 33 µM oxycodone + LPS, 10 µM buprenorphrine + LPS, and 33 µM buprenorphrine alone also downregulated TLR4 protein expression (p<0.05). As opioid use increases the likelihood for opportunistic infection, these changes in TLR4 expression may be a contributing factor in the development and treatment of CNS infection and neurodegeneration. This work was supported by OCAST Oklahoma Health Research Program HR 10-31 (CWS) and NIH grant NS 062664 (RLD).

Higher mortality and impaired elimination of bacteria in aged mice after intracerebral infection with E. coli are associated with an age-related decline of microglia and macrophage functions.

Incidence and mortality of bacterial meningitis are strongly increased in aged compared to younger adults demanding new strategies to improve prevention and therapy of bacterial central nervous system (CNS) infections the elderly. Here, we established a geriatric mouse model for an intracerebral E. coli infection which reflects the clinical situation in aged patients: After intracerebral challenge with E. coli K1, aged mice showed a higher mortality, a faster development of clinical symptoms, and a more pronounced weight loss. Elimination of bacteria and systemic inflammatory response were impaired in aged mice, however, the number of infiltrating leukocytes and microglial cells in the CNS of aged and young mice did not differ substantially. In vitro, primary microglial cells and peritoneal macrophages from aged mice phagocytosed less E. coli and released less NO and cyto-/chemokines compared to cells from young mice both without activation and after stimulation by agonists of TLR 2, 4, and 9. Our results suggest that the age-related decline of microglia and macrophage functions plays an essential role for the higher susceptibility of aged mice to intracerebral infections. Strategies to improve the phagocytic potential of aged microglial cells and macrophages appear promising for prevention and treatment of CNS infections in elderly patients.

Enhanced activity of linezolid against Staphylococcus aureus in cerebrospinal fluid

Linezolid is considered for treatment of central nervous system (CNS) infections caused by multidrug-resistant Gram-positive bacteria. Therefore, the influence of cerebrospinal fluid (CSF) on the antimicrobial activity of linezolid was evaluated in vitro. Time-kill curves were conducted in CSF and Mueller-Hinton broth (MHB) using Staphylococcus aureus (ATCC 29213) and Staphylococcus epidermidis (ATCC 12228) strains. In CSF lower linezolid concentrations were needed against S. aureus (1× MIC) and S. epidermidis (0.5× MIC) to achieve bacteriostasis than in MHB (4× MIC for both strains). Good activity of linezolid in CSF supports performance of clinical trials evaluating its potential for treatment of CNS infections.

Cure of Listeria monocytogenes Meningitis after Early Transition to Oral Therapy

Due to its lethality, Listeria monocytogenes infection of the central nervous system (CNS) typically is treated parenterally. We describe a case of L. monocytogenes meningitis cured with trimethoprim-sulfamethoxazole (TMP-SMX) utilizing early oral therapy on an outpatient basis. A 64-year-old woman was hospitalized with an acute onset of fever and personality change. She had a history of hypertension and rheumatoid arthritis controlled with weekly methotrexate without recent exposure to corticosteroids or tumor necrosis factor-alpha antagonists. Ten days before the current illness, she experienced a 3-day, self-limited episode of fever, vomiting, and diarrhea. The day of admission, her family noted the abrupt onset of bizarre behavior. She began attempting to rearrange furniture and shouting obscenities, which progressed into incoherent speech. After witnessing a fall without head strike, her family brought her to the hospital. At the time of admission, she was confused. Her temperature was 39.3°C. She had nuchal rigidity and photophobia without focal neurological findings. The peripheral leukocyte count was 15,600 cells/mm3 (79% neutrophils, 5% bands, and 14% lymphocytes). A noncontrast computed tomography (CT) examination of the head was unremarkable. Cerebrospinal fluid (CSF) contained 545 leukocytes/mm3 (77% neutrophils), a protein level of 209 mg/dl, and a glucose level of 62 mg/dl (serum glucose, 128 mg/dl). Gram stain showed few leukocytes but no organisms. After obtaining a history of oro-labial swelling following penicillin, the patient was given intravenous vancomycin, moxifloxacin, and TMP-SMX (15 mg/kg of body weight TMP daily in four divided doses). Dexamethasone and acyclovir were also administered for the first 48 h. After L. monocytogenes was isolated from the CSF, treatment was continued with TMP-SMX alone. Within 4 days she was afebrile, alert, and oriented and no longer had nuchal rigidity. In face of the rapid clinical response and with the availability of reliable family members to ensure adherence, the patient was discharged on hospital day 5 on oral TMP-SMX (three single-strength tablets every 6 h) to complete 3 weeks of treatment. She was completely well at an office visit 1 week after completing therapy and by phone interview 6 weeks after completion. No controlled trials exist to establish a drug of choice, mode of delivery, or optimal duration of therapy for CNS listeriosis. Ampicillin is the preferred and most widely used agent; many authorities recommend the addition of an aminoglycoside to ampicillin for at least the first week in treatment of CNS infection (4). For patients with penicillin hypersensitivity, TMP-SMX is the treatment of choice. Comparable levels of TMP-SMX are attained in the CSF with oral and intravenous administration (1). There have been several reported cases of L. monocytogenes meningitis treated successfully with oral TMP-SMX or TMP alone (Table ​(Table1).1). Together with this report, they suggest that oral TMP-SMX can be an efficacious and inexpensive therapeutic option for patients who demonstrate rapid clinical response to intravenous therapy and in whom good adherence is expected. TABLE 1. Cases of L. monocytogenes meningitis treated with oral TMP-SMX

Posaconazole therapy for systemic coccidioidomycosis in a chimpanzee (Pan troglodytes): a case report

Systemic coccidioidomycosis was diagnosed in a 4-year-old male chimpanzee (Pan troglodytes) with ascites and failure to thrive. Physical examination, laboratory and radiological studies, and exploratory laparotomy showed signs of systemic fungal infection that included penetration into the central nervous system (CNS). Serum and cerebrospinal fluid (CSF) titres, along with ascites cytology findings, confirmed the presence of Coccidioides immitis. However, the organism could not be cultured from the CSF. Treatment with fluconazole 10 mg kg(-1) daily for 6 months was not associated with clinical improvement. Subsequent treatment with posaconazole 50 mg kg(-1) daily for approximately 24 months resulted in negative serum titres and improved clinical status. Illness not directly related to the C. immitis infection caused the chimpanzee's deterioration and eventual killing. Histological examination performed during necropsy provided no evidence of coccidioidomycosis; however, a positive C. immitis serum antibody titre was noted. The successful suppression of coccidioidomycosis observed in this chimpanzee suggests that posaconazole may have a role in the treatment of CNS infections caused by susceptible fungi.

Blood-brain Barrier Drug Discovery for Central Nervous System Infections

Central nervous system (CNS) infections are formidable diseases with high rates of morbidity and mortality. Since the majority of antimicrobial agents discovered so far do not cross the blood-brain barrier (BBB), the treatment of CNS infections is a major challenge issue. The development of drugs to treat those diseases requires consideration of achievable brain concentrations by targeting the following question. How can the chemistry and biology of the BBB, and infectomics be exploited for the development of drugs against CNS infections? To date drug targeting approaches, such as chemistry-based, biology-based, and infectomics-based, have been implicated in the development of drugs for treatment of CNS infections. The chemistry-based strategies rely on lipid-mediated BBB drug transport as substances that readily permeate the BBB. These usually include small molecular weight of lipophilic or hydrophobic molecules. The biology-based strategies depend on endogenous BBB transport systems, including carrier-mediated transport (CMT), active efflux transport (AET), and receptor-mediated transport (RMT). These transporters play important roles in the influxes and/or effluxes of drugs including antimicrobial agents in brain capillary endothelial cells that form the BBB. Both microbial and host signatures of infectomes, which can be dissected by infectomics, provide invaluable fountains in the search for novel antimicrobial therapies. Key markers associated with the mechanisms of neuronal injury may be identified, and thus, provide important targets for the prevention and treatment of CNS infections. This review focuses on the major BBB drug targeting strategies in the development of therapeutics for CNS infections. A combination of these strategies will ultimately lead to improved treatments.

Antimicrobial therapy for infections of the central nervous system

A variety of physiologic characteristics of the central nervous system (CNS) and pharmacologic characteristics of the antimicrobial agents can influence the effectiveness of therapy in the treatment of CNS infections. The cerebral spinal fluid (CSF) is a large, unique extravascular compartment that is supplied by a nonporous capillary bed. The capillary bed does not allow for the ready diffusion of hydrophilic compounds in the abscence of inflammed meninges. These compounds include the aminoglycosides, β-lactam antimicrobials, and vancomycin. Compounds that are more lipophilic, such as metronidazole, enter the CSF much more readity. The entry of β-lactam agents is facilitated by a transport system. Penetration of the CSF by vancomycin is poor in the absence of meningeal inflammation, raising concern regarding the adjunctive use of cortiosteroids. Methods of circumventing the poor penetration of these agents in patients with meningitis include the use of higher doses and, occasionally, clirect instillation of vancomycin and the aminoglycosides into the intraventricular fluid.

Use of Antimicrobial Agents to Treat Central Nervous System Infection

When dealing with infections of the central nervous system (CNS), the clinician is often faced with a daunting diagnostic and therapeutic challenge. The clinical presentation can vary from an insidious course that allows time for a full diagnostic examination to fulminant catastrophic events that require immediate therapeutic intervention. Fortunately, a thorough clinical evaluation combined with current laboratory and imaging techniques often allows for a prompt provisional diagnosis of infection. Clinical experience and scientific investigation have laid the basis for rational empiric antimicrobial therapy of CNS infection. The role of antibiotics in the treatment of CNS infections is reviewed and updated, emphasizing current rationale for empiric therapy as well as the proper use of specific antibiotics for specific pathogens.