New Antibiotics for the Treatment of Nosocomial Central Nervous System Infections.

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 ß-lactam/ß-lactamase inhibitor combinations have the principal problem that both compounds must achieve adequate CSF concentrations. In the commercially available combinations, the dose of the ß-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.

[Congenital malformations of the brain misinterpreted as sequelae of poliomyelitis]. / Angeborene Fehlbildungen des Gehirns als Folgezustände der Poliomyelitis verkannt.

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.

Ceftriaxone-induced neutropenia successfully overcome by a switch to penicillin G in Cardiobacterium hominis endocarditis.

Leukopenia, including agranulocytosis, is a severe complication of treatment with all ß-lactam antibiotics. Its incidence increases with age. Cardiobacterium hominis endocarditis after implantation of an aortic valve bio-prosthesis in a 77-year-old woman was treated with ceftriaxone 2 g/day plus gentamicin 160 mg/day intravenously. On Day 25 of treatment, blood leukocytes had decreased to 1800/µl (neutrophils 370/µl). Antibiotic therapy was switched to penicillin G 20 million international units (IU)/day. Thereafter, blood leukocytes including neutrophils normalized suggesting that penicillin G was less bone marrow-toxic than ceftriaxone. High-dose ciprofloxacin, the alternative to penicillin G, was avoided because of the risk of cognitive and behavioral side effects. The present case suggests that with close laboratory monitoring a ß-lactam with differing side chains should not be considered contraindicated after ß-lactam antibiotic-induced neutropenia.

Serological testing for syphilis in the differential diagnosis of cognitive decline and polyneuropathy in geriatric patients.

BACKGROUND: In the 19th century, neurosyphilis was the most frequent cause of dementia in Western Europe. Now dementia caused by syphilis has become rare in Germany. We studied whether routine testing of patients with cognitive abnormalities or neuropathy for antibodies against Treponema pallidum has therapeutic consequences in geriatric patients. METHODS: A Treponema pallidum electrochemiluminescence immunoassay (TP-ECLIA) is routinely performed in all in-patients treated at our institution with cognitve decline or neuropathy and no or insufficient previous diagnostic workup. Patients with a positive TP-ECLIA treated from October 2015 to January 2022 (76 months) were retrospectively evaluated. In cases of positive TP-ECLIA, further specific laboratory investigations were performed to assess whether antibiotic therapy was indicated. RESULTS: In 42 of 4116 patients (1.0%), TP-ECLIA detected antibodies directed against Treponema in serum. Specifity of these antibodies was ensured by immunoblot in 22 patients (11 × positiv, 11 × borderline values). Treponema-specific IgM was detectable in the serum of one patient, in 3 patients the Rapid Plasma Reagin (RPR) test, a modified Venereal Disease Research Laboratory test (VDRL), in serum was positiv. CSF analysis was performed in 10 patients. One patient had CSF pleocytosis. In 2 other patients, the Treponema-specific IgG antibody index was elevated. 5 patients received antibiotic therapy (4 × ceftriaxone 2 g/d i.v., 1 × doxycycline 300 mg/d p.o.). CONCLUSION: In approx. 1‰ of patients with previously undiagnosed or not sufficiently diagnosed cognitive decline or neuropathy, the diagnostic workup for active syphilis resulted in a course of antibiotic treatment.

Reduced Clostridioides difficile infections in hospitalised older people through multiple quality improvement strategies.

OBJECTIVES: To reduce infections with Clostridioides difficile (CDI) in geriatric patients by interventions easily implementable in standard clinical care. METHODS: Prevalence and incidence of CDI between January 2015 and February 2020 were analysed (n = 25,311 patients). Pre-intervention status was assessed from April 2016 to March 2017 (n = 4,922). Between May 2017 and August 2019, a monocentric interventional crossover study (n = 4,655) was conducted including standard care and three interventions: (A) sporicidal cleaning of hospital wards, (B) probiotics and (C) improvement in personal hygiene for CDI patients. This was followed by a multicentric comparison of the interventional bundle (A + B + C) between September 2019 and February 2020 (n = 2,593) with the pre-intervention phase. In 98 CDI cases and matched controls individual risk factors for the development of CDI were compared. RESULTS: Time series analyses of CDI cases revealed a reduction in the prevalence of CDI in all three participating centres prior to the multicentric intervention phase. In the monocentric phase, no effect of individual interventions on CDI prevalence was identified. However, an aggregated analysis of CDI cases comparing the pre-intervention and the multicentric phase revealed a significant reduction in CDI prevalence. Risk factors for the development of CDI included use of antibiotics, anticoagulants, previous stay in long-term care facilities, prior hospital admissions, cardiac and renal failure, malnutrition and anaemia. CONCLUSIONS: The observed reduction in CDI may be attributed to heightened awareness of the study objectives and specific staff training. Individual interventions did not appear to reduce CDI prevalence. A further randomised trial would be necessary to confirm whether the bundle of interventions is truly effective.

Central nervous system infections and antimicrobial resistance: an evolving challenge.

PURPOSE OF REVIEW: Antimicrobial resistance is an increasing threat to patients also in nosocomial central nervous system (CNS) infections. The present review focusses on optimizing intravenous treatment in order to achieve sufficient concentrations of antibiotics in the different compartments of the CNS when the causative pathogens have reduced sensitivity to antibiotics or/and the impairment of the blood-cerebrospinal fluid (CSF) and blood-brain barrier is mild. RECENT FINDINGS: Experience has been gathered with treatment protocols for several established antibiotics using increased doses or continuous instead of intermittent intravenous therapy. Continuous infusion in general does not increase the average CSF concentrations (or the area under the concentration-time curve in CSF) compared to equal daily doses administered by short-term infusion. In some cases, it is postulated that it can reduce toxicity caused by high peak plasma concentrations. In case reports, new ß-lactam/ß-lactamase inhibitor combinations were shown to be effective treatments of CNS infections. SUMMARY: Several antibiotics with a low to moderate toxicity (in particular, ß-lactam antibiotics, fosfomycin, trimethoprim-sulfamethoxazole, rifampicin, vancomycin) can be administered at increased doses compared to traditional dosing with low or tolerable adverse effects. Intrathecal administration of antibiotics is only indicated, when multiresistant pathogens cannot be eliminated by systemic therapy. Intravenous should always accompany intrathecal treatment.

Sepsis-associated encephalopathy and septic encephalitis: an update.

INTRODUCTION: Sepsis-associated encephalopathy (SAE) and septic encephalitis (SE) are associated with increased mortality, long-term cognitive impairment, and focal neurological deficits. AREAS COVERED: The PUBMED database was searched 2016-2020. The clinical manifestation of SAE is delirium, SE additionally is characterized by focal neurological symptoms. SAE is caused by inflammation with endothelial/microglial activation, increase of permeability of the blood-brain-barrier, hypoxia, imbalance of neurotransmitters, glial activation, axonal, and neuronal loss. Septic-embolic (SEE) and septic-metastatic encephalitis (SME) are characterized by focal ischemia (SEE) and small abscesses (SME). The continuum between SAE, SME, and SEE is documented by imaging techniques and autopsies. The backbone of treatment is rapid optimum antibiotic therapy. Experimental approaches focus on modulation of inflammation, stabilization of the blood-brain barrier, and restoration of membrane/mitochondrial function. EXPERT OPINION: The most promising diagnostic approaches are new imaging techniques. The most important measure to fight delirium remains establishment of daily structure and adequate sensory stimuli. Dexmedetomidine and melatonin appear to reduce the frequency of delirium, their efficacy in SAE and SE remains to be established. Drugs already licensed for other indications or available as food supplements which may be effective in SAE are statins, L-DOPA/benserazide, ß-hydroxybutyrate, palmitoylethanolamide, and tetracyclines or other bactericidal non-lytic antibiotics.

Intrathecal Antibacterial and Antifungal Therapies.

Intrathecal administration of anti-infectives is indicated in central nervous system infections by multiresistant pathogens when drugs that can reach adequate cerebrospinal fluid (CSF) concentrations by systemic therapy are not available. Antibiotics that readily pass the blood-brain and blood-CSF barriers and/or that have low toxicity allowing an increase in the daily dosage should not be used for intrathecal therapy. Intrathecal therapy is accompanied by systemic treatment. Antibacterials indispensable for intrathecal therapy include aminoglycosides, colistin, daptomycin, tigecycline, and vancomycin. Limited experience suggests the utility of the antifungals amphotericin B and caspofungin. Intraventricular administration ensures distribution throughout the CSF compartment, whereas intralumbar dosing often fails to attain adequate antibiotic concentrations in the ventricles. The individual dose is determined by the estimated size of the CSF space and by the estimated clearance from CSF. For moderately lipophilic anti-infectives with a molecular weight above approximately 1,000 g/mol, as well as for hydrophilic drugs with a molecular weight above approximately 400 g/mol, one daily dose is normally adequate. The ventricular drain should be clamped for 15 to 120 min to facilitate the distribution of the anti-infective in the CSF space. Therapeutic drug monitoring of the trough levels is necessary only in cases of therapeutic failure.

[Challenges in diagnostics for intestinal tuberculosis - Pitfalls of a forgotten infectious disease: case series and literature review]. / Herausforderungen in der Diagnostik der Darmtuberkulose ­ Pitfalls einer vergessenen infektiösen Erkrankung: Eine Fallserie und Literaturübersicht.

Intestinal tuberculosis is an infectious disease of the extrapulmonary manifestation with the Mycobacteria tuberculosis complex. In developed countries, this disease is rarely seen. The clinical features are heterogeneous and unspecific. Furthermore, intestinal tuberculosis poses diagnostic challenges. Regarding intestinal tuberculosis the Ziehl-Neelsen staining for acid-fast bacillus, PCR examination and culture methods show only poor sensitivity and specificity. In this case series, we present three patients suffering from intestinal tuberculosis, who were diagnosed and treated successfully. Furthermore, we review the literature about the pitfalls of the diagnostic approaches and the treatment options of intestinal tuberculosis.

Transmission Risk on a Neonatal Intensive Care Unit: Escherichia coli versus Klebsiella pneumoniae.

Isolation precautions required for neonatal intensive care units are part of a bundle with the aim to prevent transmission, colonization, and infection with multidrug-resistant gram-negative pathogens as neonates face an increased risk of mortality and morbidity in case of infection. The following short report describes a transmission of 3MDRGN Klebsiella pneumoniae on a neonatal intensive care unit in a university hospital in Germany. This transmission occurred even though intensified infection control measures were in place, which impressively shows the importance of surveillance, outbreak management, and awareness of contributing factors regarding outbreak situations.

Pharmacokinetics and pharmacodynamics of antibiotics in central nervous system infections.

PURPOSE OF REVIEW: The barriers surrounding the central nervous system (CNS) together with the emergence of multiresistant pathogens pose a therapeutic challenge for the effective treatment of CNS infections. RECENT FINDINGS: In addition to vancomycin, colistin and aminoglycosides, classically used for intrathecal injection, drug concentrations in cerebrospinal fluid after intrathecal injection of daptomycin and tigecyclin were recently studied. SUMMARY: The entry of antiinfectives into the CNS compartments is determined by the physicochemical properties of the drug and by conditions in the host. The most important drug properties are lipophilicity at a neutral pH, molecular mass and drug binding to serum proteins. In clinical practice, active transport is of importance only for some drugs. In recent years, intrathecal injection of antiinfectives in addition to systemic therapy has regained attention as a means to achieve high cerebrospinal fluid concentrations. The classification of antibacterials and antifungals into time-dependent and concentration-dependent compounds is also valid for the CNS compartments.

Detection of Bacteria Colonizing Titanium Spinal Implants in Children.

BACKGROUND: Bacterial colonization of spinal implants may cause severe complications in patients with early-onset scoliosis. Correct diagnosis and detection of microbiologic formation is crucial to prevent delayed infections caused by bacterial colonization. The purposes of this study were to estimate the rate and risk factors of colonization of vertical expandable prosthetic titanium rib (VEPTR) implants in children and to compare the different methods for detecting microbiologic formation on the spinal implants. METHODS: We evaluated prospectively a group of 42 children with spinal deformities with an overall of 95 lengthening surgeries and applied different methods to detect potential bacterial colonization of VEPTR implants: swab of the implant, swab with culture of tissue, analysis of the removed lock, polymerase chain reaction (PCR), and confocal microscopy. Potential risk factors were evaluated. RESULTS: Of 42 patients, 17 (40%) were rated positive for bacterial colonization with Propionibacterium acnes and coagulase-negative staphylococci being the most commonly found bacteria. Risk factors for colonization were increasing age, body height, and weight. The swab with culture of removed tissue yielded most positive results, whereas direct microscopy and PCR were the least sensitive detection methods. Furthermore, commonly used infectious blood parameters were inconclusive. CONCLUSIONS: Although the impact of bacterial colonized implants on the health of the patients is not fully elucidated, clinicians aim for prevention of microbiologic formation on implanted devices. Therefore, reliable, inexpensive, and easy to apply diagnostic tools are indispensable to detect colonization. Based on our data, the swab together with tissue culture has the potential to become the method of choice for future diagnosis.

Monitoring microevolution of OXA-48-producing Klebsiella pneumoniae ST147 in a hospital setting by SMRT sequencing.

Objectives: Carbapenemase-producing Klebsiella pneumoniae pose an increasing risk for healthcare facilities worldwide. A continuous monitoring of ST distribution and its association with resistance and virulence genes is required for early detection of successful K. pneumoniae lineages. In this study, we used WGS to characterize MDR blaOXA-48-positive K. pneumoniae isolated from inpatients at the University Medical Center Göttingen, Germany, between March 2013 and August 2014. Methods: Closed genomes for 16 isolates of carbapenemase-producing K. pneumoniae were generated by single molecule real-time technology using the PacBio RSII platform. Results: Eight of the 16 isolates showed identical XbaI macrorestriction patterns and shared the same MLST, ST147. The eight ST147 isolates differed by only 1-25 SNPs of their core genome, indicating a clonal origin. Most of the eight ST147 isolates carried four plasmids with sizes of 246.8, 96.1, 63.6 and 61.0 kb and a novel linear plasmid prophage, named pKO2, of 54.6 kb. The blaOXA-48 gene was located on a 63.6 kb IncL plasmid and is part of composite transposon Tn1999.2. The ST147 isolates expressed the yersinabactin system as a major virulence factor. The comparative whole-genome analysis revealed several rearrangements of mobile genetic elements and losses of chromosomal and plasmidic regions in the ST147 isolates. Conclusions: Single molecule real-time sequencing allowed monitoring of the genetic and epigenetic microevolution of MDR OXA-48-producing K. pneumoniae and revealed in addition to SNPs, complex rearrangements of genetic elements.

Bacterial and histopathological findings in deep head and neck infections: a retrospective analysis.

OBJECTIVES: Deep neck infections are among the most dangerous acute diseases in the head and neck region. This analysis gives an overview of the bacterial and histopathologic findings of deep neck infections. STUDY DESIGN: From January 2002 to December 2012, 63 patients were diagnosed with and treated for deep neck infections at the University Medical Center Göttingen. Bacterial and histopathologic examinations were made, and the occurrence of bacterial pathogens and histopathologic findings were analyzed. RESULTS: The most commonly isolated aerobic gram-positive pathogen was Streptococcus viridans (26.7%); Staphylococcus epidermidis and Staphylococcus aureus were each found in 16.7% of infections. The most commonly isolated aerobic gram-negative pathogens were Escherichia coli, Klebsiella oxytoca, and Haemophilus influenzae. In 1.6% of patients, a malignant cancer was detected. CONCLUSION: For clear diagnosis and effective therapy, a bacteriologic investigation of deep neck infections is essential because of the heterogeneous spectrum of the detected bacteria. In contrast to Asia, where Klebsiella pneumoniae is the most common pathogen, in South Lower Saxony, Germany, we discovered a dominating spectrum of aerobic gram-positive cocci. Biopsy obtained from an abscess cavity for histologic examination should always be part of the diagnostic process in order to exclude a malignant process.

Infections in the differential diagnosis of Bell's palsy: a plea for performing CSF analysis.

PURPOSE: Peripheral facial nerve palsy (FP) is the most common single nerve affection. Most cases are idiopathic, but a relevant fraction is caused by potentially treatable aetiologies including infections. Not all current diagnosis and treatment guidelines recommend routine cerebrospinal fluid (CSF) analysis in the diagnostic workup of this symptom. In this study, we evaluated frequency of aetiologies and relevance of CSF analysis in an interdisciplinary cohort. METHODS: We retrospectively analysed all cases of newly diagnosed FP treated at a German university medical centre in a 3-year period. Diagnostic certainty was classified for infectious aetiologies according to clinical and CSF parameters. RESULTS: 380 patients with FP were identified, 63 children and 317 adults. Idiopathic Bell´s palsy was predominant in 61 %. 25 % of FP was attributed to infections, and other causes were identified in 14 %. Clinical presentation alone was not conclusive for infectious aetiology, in almost half of patients with infection-attributed FP the reported symptoms or clinical signs did not differ from common symptoms of idiopathic Bell`s palsy. Determination of C-reactive protein or white blood cell count was not helpful in the identification of infectious causes, and radiological imaging was performed in a high proportion of adult patients without conclusive results. Nuchal rigidity was found only in 7 % of patients with CSF pleocytosis. The predominant infectious agents were Borrelia burgdorferi, VZV and HSV, and in most of these cases diagnosis relied on the findings of CSF analysis. CONCLUSIONS: This study outlines the importance of careful differential diagnosis to identify infectious causes of facial nerve palsy. The high incidence and frequent unspecific clinical presentation of infectious FP underlines the importance of including CSF analysis in the diagnostic routine workup of FP.

Septic encephalopathy and septic encephalitis‬‬.

INTRODUCTION: During the last two decades, septic encephalopathy (SE) was recognized as a clinically relevant problem with a high prevalence in patients at admission and during their hospital stay. SE is a condition associated with increased mortality and morbidity such as long-term cognitive impairment. Areas covered: This review illustrates the pathophysiology of sepsis-associated encephalopathy and encephalitis involving blood-brain-barrier dysfunction and neuroinflammation caused by endothelial and microglial activation by endogenous or pathogen-derived compounds, hypoxia by impaired microvascular regulation and septic shock as well as imbalance of neurotransmitters. The continuum between septic-embolic and septic-metastatic encephalitis and SE is underlined by histological findings. The options of technical examinations and biomarkers to diagnose SE are discussed together with established therapeutic options as well as current experimental approaches. Expert commentary: An outlook for clinicians is provided including promising diagnostic approaches by means of new imaging techniques. Clinical trials with drugs already established for other indications such as statins, erythropoietin and minocycline are warranted in the future.

Early pneumonia and timing of antibiotic therapy in patients after nontraumatic out-of-hospital cardiac arrest.

BACKGROUND: While early pneumonia is common in patients after out-of-hospital cardiac arrest (OHCA), little is known about the impact of pneumonia and the optimal timing of antibiotic therapy after OHCA. METHODS: We conducted a 5-year retrospective cohort study, including patients who suffered from OHCA and were treated with therapeutic hypothermia. ICU treatment was strictly standardized with defined treatment goals and procedures. Medical records, chest radiographic images and microbiological findings were reviewed. RESULTS: Within the study period, 442 patients were admitted to our medical ICU after successfully resuscitated cardiac arrest. Of those, 174 patients fulfilled all inclusion and no exclusion criteria and were included into final analysis. Pneumonia within the first week could be confirmed in 39 patients (22.4%) and was confirmed or probable in 100 patients (57.5%), without a difference between survivors and non-survivors (37.8% vs. 23.1% confirmed pneumonia, p = 0.125). In patients with confirmed pneumonia a tracheotomy was performed more frequently (28.2 vs. 12.6%, p = 0.026) compared to patients without confirmed pneumonia. Importantly, patients with confirmed pneumonia had a longer ICU- (14.0 [8.5-20.0] vs. 8.0 [5.0-14.0] days, p < 0.001) and hospital stay (23.0 [11.5-29.0] vs. 15.0 [6.5-25.0] days, p = 0.016). A positive end expiratory pressure (PEEP) > =10.5 mbar on day 1 of the hospital stay was identified as early predictor of confirmed pneumonia (odds ratio 2.898, p = 0.006). No other reliable predictor could be identified. Median time to antibiotic therapy was 8.7 [5.4-22.8] hours, without a difference between patients with or without confirmed pneumonia (p = 0.381) and without a difference between survivors and non-survivors (p = 0.264). Patients receiving antibiotics within 12 hours after admission had a shorter ICU- (8.0 [4.0-14.0] vs. 10.5 [6.0-16.0] vs. 13.5 [8.0-20.0] days, p = 0.004) and hospital-stay (14.0 [6.0-25.0] vs. 16.5 [11.0-27.0] vs. 21.0 [17.0-28.0] days, p = 0.007) compared to patients receiving antibiotics after 12 to 36 or more than 36 hours, respectively. CONCLUSIONS: Early pneumonia may extend length of ICU- and hospital-stay after OHCA and its occurrence is difficult to predict. A delayed initiation of antibiotic therapy in OHCA patients may increase the duration of the ICU- and hospital-stay.

Bacterial meningitis: an update of new treatment options.

The outcome of bacterial meningitis critically depends on the rapid initiation of bactericidal antibiotic therapy and adequate management of septic shock. In community-acquired meningitis, the choice of an optimum initial empirical antibiotic regimen depends on the regional resistance patterns. Pathogens resistant to antibacterials prevail in nosocomial bacterial meningitis. Dexamethasone is recommended as adjunctive therapy for community-acquired meningitis in developed countries. In comatose patients, aggressive measures to lower intracranial pressure <20 mmHg (in particular, external ventriculostomy, osmotherapy and temporary hyperventilation) were effective in a case-control study. Although many experimental approaches were protective in animal models, none of them has been proven effective in patients. Antibiotics, which are bactericidal but do not lyse bacteria, and inhibitors of matrix metalloproteinases or complement factor C5 appear the most promising therapeutic options. At present, vaccination is the most efficient method to reduce disease burden. Palmitoylethanolamide appears promising to enhance the resistance of the brain to infections.