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Background For treatment of ventriculitis, vancomycin and meropenem are frequently used as empiric treatment but cerebrospinal fluid (CSF) penetration is highly variable and may result in subtherapeutic concentrations. Fosfo ‑ mycin has been suggested for combination antibiotic therapy, but data are sparse, so far. Therefore, we studied CSF penetration of fosfomycin in ventriculitis. Methods Adult patients receiving a continuous infusion of fosfomycin (1 g/h) for the treatment of ventriculitis were included. Routine therapeutic drug monitoring ( TDM) of fosfomycin in serum and CSF was performed with subse‑ quent dose adaptions. Demographic and routine laboratory data including serum and CSF concentrations for fosfo‑ mycin were collected. Antibiotic CSF penetration ratio as well as basic pharmacokinetic parameters were investigated. Results Seventeen patients with 43 CSF/serum pairs were included. Median fosfomycin serum concentration was 200 [159–289] mg/L and the CSF concentration 99 [66–144] mg/L. Considering only the first measurements in each patient before a possible dose adaption, serum and CSF concentrations were 209 [163–438] mg/L and 104 [65– 269] mg/L. Median CSF penetration was 46 [36–59]% resulting in 98% of CSF levels above the susceptibility break‑ point of 32 mg/L. Conclusion Penetration of fosfomycin into the CSF is high, reliably leading to appropriate concentrations for the treatment of gram positive and negative bacteria. Moreover, continuous administration of fosfomycin appears to be a reasonable approach for antibiotic combination therapy in patients suffering from ventriculitis. Further studies are needed to evaluate the impact on outcome parameters. Keywords Critical Care (D003422), Drug Monitoring (D016903), Pharmacokinetics (D010599), Fosfomycin (D005578), Cerebral Ventriculitis (D058565) *Correspondence: Jörn Grensemann j.grensemann@uke.de Full list of author information is available at the end of the article © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. König et al. Ann Clin Microbiol Antimicrob (2023) 22:29 Page 2 of 7 Background Methods In acute hydrocephalus, external ventricular drains Study design and population (EVD) are often used as temporary devices for the This analysis was reported to the Ethics Committee of the therapeutic diversion of cerebrospinal fluid (CSF). As Hamburg Chamber of Physicians (Reference: WF-028/20, a percutaneously placed catheter, EVDs are prone to February 11, 2020). Due to the non-interventional nature bacterial colonization that can lead to ventriculitis, of this study and anonymous recording of data, written requiring antibiotic therapy [1]. As opposed to menin- informed consent was waived. gitis, little meningeal inflammatory exists in ventricu - Patients included were diagnosed with ventriculitis and litis, resulting in only little antibiotic penetration into treated with fosfomycin by continuous infusion as com- the CSF [2]. Therefore, despite high-dose antibiotic bination therapy with meropenem and vancomycin as therapy subtherapeutic CSF levels may be present. To initial empiric therapy. TDM measurements were per- prevent from subtherapeutic concentrations a routine formed in regular intervals during EVD diagnostics from therapeutic drug monitoring (TDM) from the cerebro- serum and CSF. Antibiotic dosages were adjusted accord- spinal fluid (CSF) has been established in our institu - ing to TDM results from serum and CSF samples. More- tion to adjust antibiotic therapy accordingly [3]. This is over, antibiotic regimens were deescalated, adjusted, or only possible within certain limits as toxicity may occur discontinued after species identification or at the discre - at high serum levels, mandating the measurement of tion of the treating physician. serum concentrations, as well. Diagnosis of ventriculitis was generally applied accord- As initial empirical therapy, meropenem and vanco- ing to the CDC/NHSN surveillance definition [12]. Since mycin are indicated [4] but current data shows variable clinical criteria like meningeal or cranial nerve signs could and often low penetration into the CSF [5]. Therefore, not be obtained in some patients due to sedation, impaired combination antibiotic therapy has been suggested to consciousness or interfering neurological deficits, a suspi - overcome this problem [4]. Fosfomycin exerts a broad- cion for ventriculitis and subsequent treatment indication spectrum bactericidal activity covering both gram posi- was solely based on pathological CSF parameters such as tive and negative bacteria including Staphylococcus spp. increased leucocytes, elevated protein, decreased absolute and Pseudomonas spp. As recently discussed [6] fosfo- glucose or decreased CSF/serum glucose ratio also if no mycin also shows biofilm activity against Staphylococ - growth was seen in the CSF culture in these cases. cus spp. which makes it suitable for the treatment of device associated central nervous system (CNS) infec- Data collection tions. Therefore, the local antibiotic therapy standard Demographic and clinical data were obtained from the for EVD associated ventriculitis includes adding fos- patients’ electronic records (Integrated Care Manager fomycin where timely removal or replacement of EVD ICM, version 10.1, Drägerwerk AG, Lübeck, Germany, is not possible. Fosfomycin is eliminated renally and and Soarian Clinicals 4.01 SP08, Cerner Health Services, shows a half-life of approximately 2 h in adults with Idstein, Germany). We recorded data on antibiotic serum normal renal function. With a small volume of distri- and CSF concentrations. Renal function was determined bution (V ), small molecular size and almost no pro- by the estimated glomerular filtration rate (eGFR) calcu - tein-binding fosfomycin is distributing widely into all lated according to the Chronic Kidney Disease Epidemi- body compartments. Preliminary results have shown ology Collaboration (CKD-EPI) [13]. Moreover, clinical that fosfomycin penetrates well into the CSF even in routine data such as CSF parameters as well as micro- the absence of meningeal inflammation [2 , 7, 8]. Even biological results from CSF and blood cultures were though, current data show that fosfomycin exhibits obtained. As fosfomycin is available as a disodium salt, time-dependent bactericidal activity it is most often serum sodium levels were collected from the blood gas used as intermittent infusion. Assuming that fosfomy- analysis (BGA), as well. The Simplified Acute Physiology cin pharmacokinetics are relatively similar to merope- Score II (SAPS II) [14] was recorded as a measure of dis- nem, where continuous infusion lead to more sufficient ease severity. Outcome was assessed at discharge accord- CSF levels [3, 9], this administration type was adopted ing to the Glasgow Outcome Scale (GOS), which consists for fosfomycin. Moreover, this approach has been used of the five categories death (1), persistent vegetative state previously in CNS infections with fosfomycin being (2), severe (3), moderate (4) and low disability (5) [15]. administered by continuous infusion (24 g/24 h) [10, 11]. As this approach has not been systematically stud- Drug administration ied, we aimed to investigate fosfomycin CSF concentra- Fosfomycin (Infectopharm, Heppenheim, Germany) was tions attained in neurocritical care patients with device reconstituted with water and used with a final concentra - (EVD) associated ventriculitis. tion of 100 mg/mL. It was administered by continuous König et al. Ann Clin Microbiol Antimicrob (2023) 22:29 Page 3 of 7 intravenous infusion (CI) with an initial dose of 1 g/h. calculated by linear or non-linear regression methods Considering a potential disequilibrium effect in CSF included in Prism 9 (GraphPad Software, San Diego, CA, two times the minimal inhibitory concentration (MIC) USA). was targeted. Regarding the general European Commit- tee on Antimicrobial Susceptibility Testing (EUCAST) breakpoint for susceptibility (32 mg/L) 64 mg/L was tar- Results geted. For Pseudomonas spp. and Enterococcus spp., a Between January 2020 and October 2021, 43 pairs of target concentration above 128 mg/L was aimed for. This serum and CSF concentrations of fosfomycin were represented a pragmatic approach adapted from the pub- obtained from 17 patients treated for device associated lished wild-type MIC distributions although neither an ventriculitis. An overview on patient characteristics is epidemiological cut-off value (ECOFF) nor a breakpoint given in Table 1. has been defined in these cases by the EUCAST, yet [16]. The patients showed a regular body composition (body Fosfomycin exposure in serum and CSF was optimized mass index 27 ± 5 kg/m ) and a preserved renal function by adapting the infusion rate taking into account a pen- with a mean estimated GFR of 110 ± 32 ml/min/1.73m . etration rate of approximately 30% [17]. Fosfomycin dosing was started with 24 g/24 h and adapted to a mean fosfomycin dosing regimen of Bioanalytical method 20 g/24 h during the course of the therapy. Fosfomycin serum samples were collected and cen- The mean fosfomycin clearance was 4.2 ± 2.2 L/h and trifuged (5000 rpm, 10 min, 20 °C), subsequently. The correlated best with the CKD-EPI eGFR values with a serum supernatant and CSF samples were stored at dry coefficient of correlation R = 0.63 (see Fig. 1). ice until being further processed. Serum samples were The median attained serum concentration of fosfomy - analyzed by LC–MS/MS according to the procedure cin was 200 [159–289] mg/L and the median CSF concen- described by Martens-Lobenhoffer et al. [18]. CSF sam - tration 99 [66–144] mg/L (Table 2). When considering ples were prepared and analyzed in a similar manner. only the first measurements before a possible dose adap - Calibration ranges were 15–750 mg/L in serum as well as tion, the median serum and CSF concentrations were in CSF. Coefficients of variation for serum samples were 209 [163–438] mg/L and 104 [65–269] mg/L, respec- 6.0% at 15 mg/L and 4.0% at 750 mg/L, respectively, with tively. The median area under the curve (AUC) was 4800 accuracies of 10.9% to − 0.2%. The corresponding coeffi - [3816–7152] in serum and 2381 [1585–3456] mg*h/L in cients of variation in CSF were 5.6–3.6%, with accuracies CSF, respectively. The time course of fosfomycin serum of − 13.9–9.7%. The lower limits of quantification were and CSF levels are presented in supplement Fig. 1. set to the lower end of the calibration range of 15 mg/L The CSF penetration for fosfomycin was 46 [36–59]% for both matrices. Samples with concentrations above with an R of 0.65 (Fig. 2). Penetration ratio per GOS the upper limit of quantification (750 mg/L) were diluted group is presented in supplement Table 1. with blank serum (or water in case of CSF samples) and All CSF values but one were above the EUCAST break- were re-analyzed. point of 32 mg/L (98%) and 13 CSF values (30%) were above 128 mg/L. In total, 98% of the observed CSF con- Statistics centrations were above the MIC of 32 mg/L for suscep- Data management, non- compartmental calculations tible isolates (see Fig. 3). When targeting Pseudomonas for fosfomycin clearance (CL) and area under the curve species with an ECOFF of 128 mg/L 30% of the analyzed (AUC) were performed by using Microsoft Excel 365 CSF specimens achieved this concentration. The corre - (Microsoft Corp., Redmond, WA, USA). CL (Eq. 1) and sponding AUC/MIC ratio in CSF for an MIC of 32 mg/L AUC (Eq. 2) were calculated as follows: was 74 [50–108]. Most patients received fosfomycin as a part of a com- CL L h bination therapy including meropenem and/or vanco- fosfomycin dose mg 24h mycin. Two patients were deescalated to fosfomycin monotherapy due to infections with Staphylococcus epi- fosfomycin concentration in serum mg L ∗ 24 h dermidis. Microbiological results are shown in Table 3. (1) Within the cohort, serum sodium concentrations fosfomycin dose mg 24h mg h ranged between 124 to 167 mmol/L with a mean value AUC = (2) CL L h of 142 mmol/L. Hypernatremia was already present in 47% (n = 8) of the patients prior to fosfomycin treatment Visualization, statistical evaluation as well as deter- start with a mean sodium value of 153 mmol/L in this mination of coefficients of correlation (R ) were either subgroup. >P/ König et al. Ann Clin Microbiol Antimicrob (2023) 22:29 Page 4 of 7 Table 1 Patient characteristics Age [years] 57 ± 12 Gender Male: 59% Female: 41% Body height [cm] 175 ± 7 Weight [kg] 84 ± 20 BMI [kg/m ] 27 ± 5 Creatinine [mg/dL] 0.64 ± 0.36 eGFR CKD‑EPI [ml/min/1.73m ] 110 ± 32 Serum sodium [mmol/L] 142 ± 8 GOS GOS 1: 2 (12%) GOS 2: 1 (6%) GOS 3: 11 (65%) GOS 4: 0 (0%) GOS 5: 3 (17%) Underlying disease Aneurysmal subarachnoid hemorrhage: 8 (47%) Neoplasia: 4 (23%) Intracerebral hemorrhage: 3 (18%) Ventricular‑peritoneal shunt infection: 2 (12%) LOS [days] 25 [21–52] Inflammation markers on day 1 of fosfomycin treatment CSF glucose [mg/dL] 530 [442–650] CSF cell count [× 10 /L] 582 [162–2562] CSF protein level [mg/dL] 1163 [802‑ 2393] CSF lactate [mmol/L] 5 ± 2 CSF IL‑6 [pg/mL] 1782 [61–13229] SAPS II 36 [29–60] White blood count in serum [x 10 /L] 9.4 ± 5.4 C‑reactive protein [mg/L] 67 [27–99] Data are shown as the mean ± standard deviation or median with interquartile range [IQR] BMI body mass index, eGFR estimated glomerular filtration rate, CSF cerebrospinal fluid, CKD-EPI chronic kidney disease epidemiology collaboration, IL-6 interleukin 6, SAPS II simplified acute physiology score II, GOS glasgow outcome scale, LOS length of stay Table 2 Fosfomycin general pharmacokinetics 犈犆 犆 5 犆 犏犊 Fosfomycin [g/24 h] 20 ± 6 Fosfomycin therapy [d] 13 ± 9 犇犋 犆 Fosfomycin CL [L/h] 4.2 ± 2.2 Fosfomycin serum level [mg/L] first measurement 209 [163–438] 犇犆 犆 Fosfomycin CSF level [mg/L] first measurement 104 [65–269] Fosfomycin serum level [mg/L]—all samples 200 [159–289] 犋犆 Fosfomycin CSF level [mg/L]—all samples 99 [66–144] Fosfomycin penetration rate [%] 46 [36–59] Fosfomycin AUC in serum [mg*h/L] 4800 [3816–7152] 犆犋 犆犇 犆犆 犇犋 犆犈 犆犆 Fosfomycin AUC in CSF [mg*h/L] 2381 [1586–3456] AUC/MIC (32 mg/L) ratio in serum 150 [119–224] &. ,H* )5 >P/ P @ AUC/MIC (32 mg/L) ratio in CSF 74 [50–108] Fig. 1 Fosfomycin clearance vs. CKD‑EPI eGFR. CKD-EPI chronic kidney disease epidemiology equation, CL clearance, eGFR estimated Data are shown as the mean ± standard deviation or median with interquartile glomerular filtration rate, R ‑ coefficient of correlation range [IQR] AUC area under the curve, CL clearance, CSF cerebrospinal fluid, MIC minimal inhibitory concentration &/ PLQ@ LQ犇犍犉P (3 ' 犌犈 > PJ/ IRVIRP\FLQ König et al. Ann Clin Microbiol Antimicrob (2023) 22:29 Page 5 of 7 Table 3 Microbiological results of CSF cultures 犋犆 犆 犈 5 犆 犌犋 犉犊 Pathogens Staphylococcus epidermidis 犊犆 犆 (n = 5) other coagulase negative 犉犆 犆 Staphylococci (n = 5) Staphylococcus aureus (n = 1) 犈犆 犆 Enterobacter cloacae (n = 4) Klebsiella pneumoniae (n = 1) 犇犆 犆 Citrobacter koseri (n = 1) no pathogens isolated (n = 4) 犆犈 犆犆 犊犆 犆犌 犆犆 犎犆 犆犇 犆犆 犆 More than one pathogen was detected in four patients Fig. 2 Fosfomycin concentrations in serum and cerebrospinal fluid. CSF cerebrospinal fluid, MIC minimal inhibitory concentration, light inflammation is often not present [19]. Therefore, inter - grey shaded areas depict concentrations within targeted range of 32 mittent infusions might insufficiently attain appropriate to 128 mg/L of fosfomycin plasma-CSF-equilibration resulting in lower penetration ratios. To date, no method allows for a quantification of meningeal inflammation and therefore approximations 犇犆 犆 regarding drug CSF penetration ratios often remain uncer- tain. This problem was thought to be overcome by admin - istering fosfomycin as a continuous infusion (CI), thereby permanently increasing the diffusion gradient towards 犍犋 the CSF accompanied by routine TDM of serum und CSF samples. To the best of our knowledge, this is the first study ana - 犋犆 lyzing the penetration whilst using fosfomycin by a CI regimen. Application of fosfomycin by CI or prolonged infusion has been studied by in-vitro and in-vivo analy- ses [20] and was performed successfully in case studies 犈犋 before [21–23]. This is also in concordance with in-vitro data showing pharmacodynamic indexes such as either time-dependent pharmacodynamics for species such as Staphylococcus aureus or Enterococcus spec. [24] or AUC/MIC dependency for Pseudomonas aeruginosa or Escherichia coli [25–27]. With the chosen dosing regimen PJ/ P PJ/ fosfomycin (d1 24 g/d) penetration into the CSF was reli- 犉犈 犈犎 犌犊 ably reaching CSF concentrations well above the defined EUCAST breakpoint of 32 mg/L for susceptible bacteria such as Staphylococcus aureus. The AUC/MIC ratio for an IR ) MIC of 32 mg/L was 74 for CSF specimens. This is in con - Fig. 3 Percent fosfomycin concentrations in CSF above a given cordance with in-vitro data showing bacteriostasis at mean target. CSF cerebrospinal fluid. Black bars depict values not achieving AUC/MIC ratios of 22.7 and a 1-log kill for 83.3 when tar- a given threshold geting the group of Enterobacterales [25]. Unfortunately, MICs of the identified isolates were not reported by the local laboratory and therefore, no MIC guided dose adap- Discussion tion could be performed. In general, the achieved mean As opposed to meningitis, reaching sufficient bactericidal AUC of 4800 [3816–7152] mg*h/L in serum was higher concentrations in ventriculitis may be difficult. Diffusion of than in a previous study reporting 4411 mg*h/L in healthy anti-infectives into the CNS is dependent on different fac - volunteers receiving a CI of 1 g/h [28]. tors such as their lipophilicity, protein binding and molec- Because our cohort included one patient with renal ular size [19]. Moreover, meningeal inflammation leads to insufficiency (eGFR < 50 mL/min/1.73m ), increased the opening of tight junctions allowing for the penetration AUC and serum concentrations (> 400 mg/L) using the of drugs into the CSF whereas in ventriculitis meningeal initial standard fosfomycin dose were seen. LQ &6 )> RP\FLQLQ&6 VI VHUXP>PJ/ IRVIRP\FLQLQ König et al. Ann Clin Microbiol Antimicrob (2023) 22:29 Page 6 of 7 The penetration ratio of 46% in our cohort is within susceptible gram negative and positive pathogens. Future the range of 30–60% as reported earlier by Silica et al. studies are needed to systematically investigate fosfomy- [11] who used intermittent infusion regimens with up cin treatment in infections of the central nervous system to 16 g/d in patients with meningitis. Pfausler et al. con- regarding efficacy and patient outcome. ducted lower CSF concentrations of 62 ± 32 mg/L when using 8 g fosfomycin 8 hourly in patients with ventriculi- Abbreviations tis [17]. This translated into a penetration ratio of approx - AUC Ar ea under the curve imately 25% when compared to serum. However, higher CRP C‑reactive protein CSF Cerebrospinal fluid CSF concentrations as required for MIC > 64 mg/L which ECOFF Epidemiolog ical cut‑ off values are often present in Pseudomonales or other non-fer- EUCAST European Committee on Antimicrobial Susceptibility Testing menting bacteria could not be attained in all specimens EVD Ex ternal ventricular drain GFR Glomerular filtration rate of our cohort, even though 24 g/d by continuous infusion GOS Glasgow outcome scale was used empirically. LC–MS/MS Liquid chromatography‑tandem mass spectrometry More recently, CSF protein levels could be associated MIC Minimal inhibitory concentration SAPS II Simplified acute physiology score II with an improved CSF penetration ratio of meropenem TDM Therapeutic drug monitoring in patients with ventriculitis [3], whereas in our cohort no such association with variables such as GOS or other Supplementary Information laboratory parameters could be identified for fosfomycin. The online version contains supplementary material available at https:// doi. Fosfomycin CI was generally well tolerated as it was org/ 10. 1186/ s12941‑ 023‑ 00572‑4. infused via a central line. In cases where increased serum sodium levels occurred during treatment, hypernatremia Additional file 1: Additional Figure and Table; Figure 1: Fosfomycin concentration in serum and CSF over time, Table 1: Fosfomycin concen‑ was already present prior to fosfomycin start. This is in tration in CSF and penetration ratio per GOS concordance with Putensen et al. who also found a mod- erate incidence for hypernatremia of 14.3% [29]. Besides, Acknowledgements none of the treated patients had to discontinue fosfomy- Not applicable. cin treatment due to adverse events. Author contributions Our study has certain limitations. We performed an CK designed the study, wrote the manuscript, and interpreted the data. JML analysis from clinically obtained samples that were col- analyzed the samples and helped to interpret the data. PC helped to acquire lected at irregular time intervals from patients with ven- the data, helped to write the manuscript, and to interpret the data. SK and MW helped with the interpretation and revised the manuscript. SMBB helped triculitis presenting different underlying pathologies. to design the study, to analyze the samples, and to interpret the data. JG However, our data therefore represents “real-world” con- designed the study, wrote the manuscript, acquired and interpreted the data, ditions from a mixed cohort of patients. Moreover, there and acquired the funding. All authors read and approved the final manuscript. is currently no guideline regarding required antibiotic Funding CSF concentrations for the treatment of ventriculitis. Open Access funding enabled and organized by Projekt DEAL. This study was u Th s, we suggest that concentrations one to two times kindly supported by Infectopharm (Heppenheim, Germany). the MIC of the targeted pathogen are sufficient as inflam - Availability of data and materials mation occurs within the CSF and the surrounding tis- The dataset used and/or analyzed during the current study are available from sue. On the other hand, tissue concentrations obtained the corresponding author on reasonable request. by microdialysis as reported for meropenem can exceed the CSF concentrations by a factor of three [30]. Hence, Declarations if targeting either CSF concentrations representing a Ethics approval and consent to participate multiple of the MIC or if lower targets could also be This analysis was reported to the Ethics Committee of the Hamburg Chamber sufficient for successful treatment remains a matter of of Physicians (Reference: WF‑028/20, February 11, 2020). Due to the non‑ interventional nature of this study and anonymous recording of data, written debate. To clarify, further studies are needed to under- informed consent was waived. stand the pathophysiology of ventriculitis and to deter- mine the antibiotic targets to optimize patient outcome. Consent for publication Not applicable. Conclusion Competing interests CK received a research grant from the DAMP foundation and lecture fees from Fosfomycin administration by continuous infusion is Shionogi. JML has no conflicts of interest. MW has no conflicts of interest. PC a feasible way in patients with ventriculitis resulting in has no conflicts of interest. SK received research support from Ambu, Daiichi appropriate drug concentrations in CSF. Our patient Sankyo, ETView Ltd, Fisher & Paykel, Pfizer, and Xenios, lecture fees from Astra, C.R. Bard, Baxter, Biotest, Cytosorbents, Daiichi Sankyo, Fresenius, Gilead, Mit‑ cohort showed a high fosfomycin CSF penetration subishi Tanabe Pharma, MSD, Pfizer, Philips, and Zoll, and consultant fees from rate of 46%, making it a potential treatment option for König et al. Ann Clin Microbiol Antimicrob (2023) 22:29 Page 7 of 7 Bayer, Fresenius, Gilead, MSD and Pfizer. SMBB has no conflicts of interest. JG 15. Jennett B, Bond M. Assessment of outcome after severe brain damage. Lancet. has received research support from Adroit Surgical, Ambu, ETView, Infectop‑ 1975;1(7905):480–4. https:// doi. org/ 10. 1016/ s01406736(75)‑ 928305‑ . harm, and Pfizer, and received consultant and lecture fees from Drägerwerk, 16. European Committee on Antimicrobial Susceptibility Testing: fosfomycin Fresenius Medical, GE Healthcare, and Smith Medical, and holds shares from ECOFF. https:// mic. eucast. org/ searc h/? search% 5Bmet hod% 5D= mic& search% AstraZeneca, Bayer, Gilead, and Pfizer.5Bant ibiot ic% 5D= 100& search% 5Bspe cies% 5D=1&‑ search% 5Bdisk_ conte nt% 5D=1&‑ search% 5Blim it% 5D= 50 (2021). Accessed 2021 02 19. Author details 17. Pfausler B, Spiss H, Dittrich P, Zeitlinger M, Schmutzhard E, Joukhadar C. Department of Intensive Care Medicine, University Medical Center Hamburg‑ Concentrations of fosfomycin in the cerebrospinal fluid of neurointensive care Eppendorf, Martinistraße 52, 20246 Hamburg, Germany. 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Annals of Clinical Microbiology and Antimicrobials – Springer Journals
Published: Apr 24, 2023
Keywords: Critical Care (D003422); Drug Monitoring (D016903); Pharmacokinetics (D010599); Fosfomycin (D005578); Cerebral Ventriculitis (D058565)
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