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Background Knowledge regarding CNS pharmacokinetics of moxifloxacin is limited, with unknown consequences for patients with meningitis caused by bacteria resistant to beta-lactams or caused by TB. Objective (i) To develop a novel porcine model for continuous investigation of moxifloxacin concentrations within brain extracellular fluid (ECF), CSF and plasma using microdialysis, and (ii) to compare these findings to the pharmacokinetic/pharmacodynamic (PK/PD) target against TB. Methods Six female pigs received an intravenous single dose of moxifloxacin (6 mg/kg) similar to the current oral treatment against TB. Subsequently, moxifloxacin concentrations were determined by microdialysis within five compartments: brain ECF (cortical and subcortical) and CSF (ventricular, cisternal and lumbar) for the following 8 hours. Data were compared to simultaneously obtained plasma samples. Chemical analysis was performed by high pressure liquid chromatography with mass spectrometry. The applied PK/PD target was defined as a maximum drug concentration (C max):MIC ratio >8. Results We present a novel porcine model for continuous in vivo CNS pharmacokinetics for moxifloxacin. C max and AUC0–8h within brain ECF were significantly lower compared to plasma and lumbar CSF, but insignificantly different compared to ventricular and cisternal CSF. Unbound C max:MIC ratio across all investigated compartments ranged from 1.9 to 4.3. Conclusion A single dose of weight-adjusted moxifloxacin administered intravenously did not achieve adequate target site concentrations within the uninflamed porcine brain ECF and CSF to reach the applied TB CNS target. [ABSTRACT FROM AUTHOR]

This is the thirteenth chapter of the guideline “Calculated initial parenteral treatment of bacterial infections in adults – update 2018” in the 2 updated version. The German guideline by the Paul-Ehrlich-Gesellschaft für Chemotherapie e.V. (PEG) has been translated to address an international audience.Bacterial meningitis is a life-threatening infectious disease with high mortality and disability rates requiring prompt initiation of antimicrobial treatment to lower these rates.

Background: Despite established antiviral therapy for herpes simplex (HSV), varicella zoster (VZV) and cytomegalovirus (CMV) encephalitis, outcome remains poor., Objectives: To assess pharmacokinetic (PK) and -dynamic (PD) data of antiviral drugs in the central nervous system (CNS) to optimize treatment of Herpesviridae encephalitis., Sources: PUBMED search 1950 to September 2024, terms 1. "encephalitis" and ("HSV" or "VZV" or "CMV") or 2. cerebrospinal and ["(val)acyclovir" or "(val)ganciclovir" or "foscarnet" or "cidofovir"]., Content: Antivirals against herpes viruses apparently act in a time-dependent manner. To suppress viral replication, drug concentration in the extracellular space at the site of the infection should be kept above the concentrations active in cell cultures for 24h per day. Most data reflect delayed drug entry into lumbar cerebrospinal fluid (CSF). Ratios of the areas of the concentration/time curves (AUC) in CSF and serum (AUC CSF /AUC S ) of acyclovir, ganciclovir and foscarnet are 0.15-0.3 in the absence of meningeal inflammation and increase in severe meningoencephalitis. Elimination half-lives (t 1/2β ) are longer in CSF than in plasma. CSF concentrations are rough approximations of drug concentrations in the cerebral extracellular fluid (ECF). Lumbar CSF concentrations usually are higher than ventricular or cisternal CSF concentrations tending to overestimate cerebral ECF concentrations. Provided the availability of adequate measurements in individual CNS compartments - antiviral concentrations and efficacy may be predicted by future PK/PD modeling. Probenecid holds potential to reduce efflux of antiviral drugs from the CNS., Implications: The long t 1/2β of antiviral drugs in CSF suggest relatively uniform steady state CSF levels at dosing intervals ≤12h and accumulation after repeated dosing. Probenecid is of unproven utility. To rapidly attain effective concentrations in the infected tissue, physiologically based pharmacokinetic (PBPK) and PK/PD modeling may be helpful. Until reliable PK/PD data are available, doubling the first dose should be considered., Competing Interests: Conflicts Of Interest The authors have no financial interests in the drugs discussed in this review. We did not receive support from institutions or companies mentioned in the manuscript., (Copyright © 2024 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Hyponatremia is the most frequent electrolyte imbalance in geriatric medicine. Causes of hyponatremia were retrospectively analyzed in all in-patients treated in 2016 (N = 2267, 1564 women, 703 men, mean age ± standard deviation 81.9 ± 7.6 years). Any form of hyponatremia on admission, during the stay or on discharge was noted in 308 patients (13.6%, 231 women, 77 men; mean age ± standard deviation 83.1 ± 7.3 years, p = 0.009 vs. age of all patients). Women had a higher probability of developing hyponatremia compared to men (p = 0.019), 131 patients were hypovolemic, and dyspnea as an indicator of hypervolemia was noted in 71 patients.Only 12 patients suffering from hyponatremia (3.9%) did not receive any of the potentially sodium-lowering drugs assessed (diuretics, angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists, antidepressants, neuroleptics, nonsteroidal antirheumatics, carbamazepine, oxcarbazepine). The median number of drugs per patient potentially lowering the plasma sodium level was 3 and the maximum number was 7.Hypovolemic hyponatremia and the syndrome of inadequate antidiuretic hormone secretion were the most important causes of hyponatremia. Adverse drug effects were the main origins of both conditions. In patients with hyponatremia the drug load influencing plasma sodium level should be minimized, thiazide diuretics should be avoided and older individuals should receive a diet with sufficient salt content., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Background: Poliomyelitis is an infectious disease of the peripheral motor neurons, which predominantly affects children and causes residual palsies. Because of the oral poliomyelitis vaccination started in Germany in 1960 and 1962 and the following rapid decline of the incidence of this infection, the postpolio syndrome in Germany is a disease of older people., Methods: Since 2008, we have offered a poliomyelitis outpatient consultation at the Center of Geriatrics, Protestant Hospital Göttingen-Weende and have treated 33 patients., Results: The spectrum of persistent deficits after poliomyelitis ranges from palsy of single extremities to severe disability with (temporary) ventilator dependence. Many patients suffer from scoliosis or shortening of limbs of different degrees, which promotes degenerative diseases of the spinal cord and joints with secondary myelopathy, injury of spinal nerve roots or peripheral nerves or respiratory failure. The postpolio syndrome is characterized by an increase of the functional deficits after decades of compensation. The palsies of 2 of the 33 patients were not caused by poliomyelitis but by myelomeningocele and schizencephaly, respectively., Conclusion: The motor deficits acquired in childhood enable the majority of the patients to successfully master their lives. Because of the limited compensatory capacities of postpolio patients, even small increases in the severity of the palsy can cause a severe decline of the functional status and an impairment of the ability to live an independent life. In a substantial proportion of patients with the diagnosis poliomyelitis the symptoms are caused by other diseases., (© 2023. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Background: Gum arabic, a polysaccharide exudate from Acacia senegal (L.) Willdenow trees, has already been used by African native people in natural medicine., Methods: Using whole-blood samples from young (20-35 years) and older (>80 years) healthy volunteers (each group n = 10), the effect of an aqueous solution of GA on phagocytosis of Escherichia coli was examined with a gentamicin protection assay. Whole-blood samples of each volunteer were stimulated with GA and as a control with CpG oligodeoxynucleotides (Toll-like receptor -9 agonists) for 2 h, then co-incubated with E. coli for 30 min and thereafter treated with gentamicin for up to 240 min to kill extracellular bacteria. Then, whole-blood cells were lysed with distilled water, and colony-forming units were counted by quantitative plating. Cytokine enzyme-linked immunosorbent assay for the detection of TNF-α and IL-6 was performed using the blood supernatant., Results: The GA concentration tested (20 mg/mL) did not affect the viability of eukaryotic cells. Phagocytosis of E. coli by whole-blood leukocytes derived from young ( p = 0.008) and older ( p = 0.004) healthy volunteers was increased by 120.8% (young) and 39.2% (old) after stimulation with GA. In contrast, CpG only stimulated the bacterial phagocytosis by cells derived from young volunteers ( p = 0.004). Stimulation of whole blood with GA increased the intracellular killing of E. coli in young ( p = 0.045) and older volunteers ( p = 0.008) and induced a TNF-α release in whole blood collected from older volunteers but not from younger ones ( p = 0.008)., Conclusions: These data encourage the isolation of active compounds of GA and the initiation of clinical trials addressing the preventive effect of GA on bacterial infections.

Introduction: Streptococcus pneumoniae is the most common cause of bacterial meningitis and meningoencephalitis in humans. The bacterium produces numerous virulence determinants, among them hydrogen peroxide (H2O2) and pneumolysin (Ply), which contribute to bacterial cytotoxicity. Microglia, the resident phagocytes in the brain, are distinct from other macrophages, and we thus compared their susceptibility to pneumococcal toxicity and their ability to phagocytose pneumococci with those of bone marrow-derived macrophages (BMDM)., Methods: Microglia and BMDM were co-incubated with S. pneumoniae D39 to analyze survival of phagocytes by fluorescence microscopy, bacterial growth by quantitative plating, and phagocytosis by an antibiotic protection assay. Ply was detected by hemolysis assay and Western blot analysis., Results: We found that microglia were killed during pneumococcal infection with a wild-type and an isogenic ply-deficient mutant, whereas viability of BMDM was not affected by pneumococci. Treatment with recombinant Ply showed a dose-dependent cytotoxic effect on microglia and BMDM. However, high concentrations of recombinant Ply were required and under the chosen experimental conditions, Ply was not detectable in the supernatant during infection of microglia. Inactivation of H2O2 by exogenously added catalase abolished its cytotoxic effect. Consequently, infection of microglia with pneumococci deficient for the pyruvate oxidase SpxB, primarily producing H2O2, resulted in reduced killing of microglia., Conclusion: Taken together, in the absence of Ply, H2O2 caused cell death in primary phagocytes in concentrations produced by pneumococci., (The Author(s). Published by S. Karger AG, Basel.)

Objectives: Many patients receive benzodiazepines or Z-drugs during hospitalisation due to sleeping problems. In a pilot study, we aimed to find out whether, and to what degree, a multi-faceted intervention can reduce the use of these drugs, especially in older patients and those without a psychiatric or neurological disorder. The results of this pilot study should inform the design of a randomised controlled trial (RCT)., Methods: In a quasi-experimental design, we implemented the intervention in a German hospital with the support of the hospital director, medical and nursing staff and employee representatives. We compared prescription data for sleep-inducing drugs before and after the intervention by Fisher's exact test and used odds ratios (ORs) with their 95% CIs as a measure of effect size., Results: The data from 960 patients aged ≥65 years before intervention and 1049 patients after intervention were analysed. Before intervention, 483 (50.3%) of the patients received sleep-inducing drugs at some time during their hospital stay. After the intervention, 381 (36.3%) patients received a sleep-inducing drug, resulting in an OR of 0.56 (95% CI 0.47 to 0.68) (p<0.001). The reduction was particularly pronounced in patients without a psychiatric or neurological disorder (from 45.0% to 28.8%). In particular, the consumption of benzodiazepines declined from 24.3% to 8.5% (OR 0.31; 95% CI 0.23 to 0.4) (p<0.001)., Conclusions: A multi-faceted intervention to change the practice of the use of sleep-inducing drugs in one hospital was successful in terms of drug reduction, particularly for benzodiazepines. The intervention was effective especially for target persons-that is, those without a psychiatric or neurological disease. Awareness of the magnitude of the change and the role of important stakeholders could help researchers and hospital staff to design a large RCT, including control hospitals, to evaluate the success of a multi-faceted intervention on a scientifically sound basis., Competing Interests: Competing interests: None declared., (© European Association of Hospital Pharmacists 2024. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ.)

Nosocomial central nervous system (CNS) infections with carbapenem- and colistin-resistant Gram-negative and vancomycin-resistant Gram-positive bacteria are an increasing therapeutic challenge. Here, we review pharmacokinetic and pharmacodynamic data and clinical experiences with new antibiotics administered intravenously for the treatment of CNS infections by multi-resistant bacteria. Cefiderocol, a new siderophore extended-spectrum cephalosporin, pharmacokinetically behaves similar to established cephalosporins and at high doses will probably be a valuable addition in our therapeutic armamentarium for CNS infections. The new glycopeptides dalbavancin, telavancin, and oritavancin are highly bound to plasma proteins. Although effective in animal models of meningitis, it is unlikely that they reach effective cerebrospinal fluid (CSF) concentrations after intravenous administration alone. The β-lactam/β-lactamase inhibitor combinations have the principal problem that both compounds must achieve adequate CSF concentrations. In the commercially available combinations, the dose of the β-lactamase inhibitor tends to be too low to achieve adequate CSF concentrations. The oxazolidinone tedizolid has a broader spectrum but a less suitable pharmacokinetic profile than linezolid. The halogenated tetracycline eravacycline does not reach CSF concentrations sufficient to treat colistin-resistant Gram-negative bacteria with usual intravenous dosing. Generally, treatment of CNS infections should be intravenous, whenever possible, to avoid adverse effects of intraventricular therapy (IVT). An additional IVT can overcome the limited penetration of many new antibiotics into CSF. It should be considered for patients in which the CNS infection responds poorly to systemic antimicrobial therapy alone.

Introduction: Patients suffering from a Clostridioides difficile infection have a higher overall mortality than patients with similar comorbidities., Methods: Whole blood samples of 15 patients with C. difficile enteritis and 15 control patients matched for age and sex were used to analyze the capacity of blood phagocytes to internalize and kill encapsulated Escherichia (E.) coli. The median age of C. difficile patients and control patients was 81 and 82 years, respectively. Blood samples were co-incubated with E. coli for 15 or 30 min. After 15 min of co-incubation, extracellular bacteria were killed by gentamicin for 15-45 min. Then eukaryotic cells were lysed with distilled water, and the number of intracellular bacteria per ml whole blood was determined by quantitative plating on agar plates. Both groups were compared by Mann-Whitney U test., Results: After 15 or 30 min of co-incubation, blood phagocytes from patients with C. difficile enteritis showed a reduced density of phagocytosed or adherent bacteria in comparison to blood phagocytes from control patients (15 min: p = 0.046, 30 min: p = 0.005). The density of intracellular bacteria decreased less rapidly over time in the blood from C. difficile patients (median Δlog CFU/mL × h [25th/75th percentile] -0.893 [-1.893/-0.554] vs. -1.483 [-2.509/-1.028]; p = 0.02). In line with these results, the percentage of intracellularly killed bacteria was decreased in phagocytes from C. difficile-infected patients compared to controls (median intracellular killing rate 64.3% for blood phagocytes from C. difficile patients vs. 81.9% for blood phagocytes from control patients within 30 min of co-incubation, p = 0.048)., Conclusion: Blood phagocytes from patients with C. difficile enteritis exhibited a reduced capacity to phagocytose and kill bacteria in comparison to blood phagocytes from age- and sex-matched control patients. Patients with C. difficile infection may have a higher disposition to develop infectious diseases than age- and sex-matched control patients., (© 2024 S. Karger AG, Basel.)