Low thoracic muscle radiation attenuation is associated with postoperative pneumonia following partial hepatectomy for colorectal metastasis.

BACKGROUND: Low skeletal muscle radiation attenuation (SM-RA) is indicative of myosteatosis and diminished muscle function. It is predictive of poor outcome following oncological surgery in several cancer types. Postoperative pneumonia is a known risk factor for increased postoperative mortality. We hypothesized that low SM-RA of the respiratory muscles at the 4th thoracic-vertebra (T4) is associated with postoperative pneumonia following liver surgery. METHODS: Postoperative pneumonia was identified using prospective infection control data. Computed tomography body composition analysis was performed at the L3-and T4 level to determine SM-RA. Body composition variables were corrected for confounders and related to postoperative pneumonia and admission time by multivariable logistic regression. RESULTS: Body composition analysis of 180 patients was performed. Twenty-one patients developed postoperative pneumonia (11.6%). Multivariable analysis showed that low T4 SM-RA as well as low L3 SM-RA were significantly associated with postoperative pneumonia (OR 3.65, 95% CI 1.41-9.49, p < 0.01) and (OR 3.22, 95% CI 1.20-8.61, p = 0.02, respectively). CONCLUSION: Low SM-RA at either the L3-or T4-level is associated with a higher risk of postoperative pneumonia following CLRM resection.

Appearance of vanD-positive Enterococcus faecium in a tertiary hospital in the Netherlands: prevalence of vanC and vanD in hospitalized patients.

Vancomycin-resistant enterococci (VRE) can rapidly spread through hospitals. Therefore, our hospital employs a screening program whereby rectal swabs are screened for the presence of vanA and vanB, and only PCR-positive broths are cultured on VRE selection agar. Early November 2016, a clinical vanA-/vanB-negative VRE isolate was detected in a vanA/vanB-screening-negative patient, giving the possibility that an undetected VRE might be spreading within our hospital. Whole-genome-sequencing of the isolate showed that resistance was vanD-mediated and core genome multilocus sequence typing showed it was a rare type: ST17/CT154. To determine the prevalence of vanA/B/C/D-carrying enterococci, we designed a real-time PCR for vanC1/2/3 and vanD and screened rectal swabs from 360 patients. vanD was found in 27.8% of the patients, yet culture demonstrated only E. faecium from vanA-positive broths and E. gallinarum from vanC1-positive broths. No vanD-positive VRE were found, limiting the possibility of nosocomial spread of this VRE. Moreover, the high prevalence of non-VRE vanD in rectal swabs makes it unfeasible to include the vanD PCR in our VRE screening. However, having validated the vanC1/2/3 and vanD PCRs allows us to rapidly check future vanA/B-negative VRE for the presence of vanC and vanD genes.

Improving peak concentrations of a single dose regime of gentamicin in patients with sepsis in the emergency department.

OBJECTIVE: To achieve an optimal effect in patients with sepsis at the emergency department (ED), the gentamicin peak-concentration should be sufficiently high (i.e. peak-concentration/MIC ≥8-10). ICU patients with sepsis often need higher gentamicin doses to achieve sufficiently high peak-concentrations. The aim of this study is to investigate which dose is needed to reach adequate peak-concentrations in patients presenting with sepsis at the ED. METHODS: Patients with sepsis at the ED were included from August 2015 until February 2017. Peak-concentrations were measured in blood 30 minutes after the first gentamicin dose. The study consisted of three phases. In the first phase, peak-concentrations were measured after a standard dose of 5mg/kg. In the second phase, a simulation ((peak-concentration/actual dose) × simulated dose) was performed to determine which dose was needed to reach adequate gentamicin peak-concentrations of ≥16mg/L. In the third phase, peak-concentrations were measured for the best simulated dose. RESULTS: In phase one, of 86 patients who received a dose of 5mg/kg, 34 (39.5%) patients did not reach the target peak-concentration of ≥16mg/L, and 73 (84.9%) did not reach ≥20mg/L. In phase two, the simulation showed that with a dose of 7mg/kg 83 (96.5%) patients would reach peak-concentrations ≥16mg/L, and 67 (77.9%) of ≥20mg/L. In phase three, 53 patients received a dose of 7mg/kg, of whom 45 (84.9%) reached peak-concentrations of ≥16mg/L, and 31 (58.5%) of ≥20mg/L. CONCLUSION: Patients with sepsis at the ED need higher doses of gentamicin. A dose of 7mg/kg is needed to achieve adequate peak-concentrations in the majority of patients.

Impact of chemotherapy-associated liver injury on tumour regression grade and survival in patients with colorectal liver metastases.

BACKGROUND: An inverse relation between chemotherapy-associated liver injury (CALI) and tumour response to chemotherapy has been reported. The aim was to validate these findings, and further investigate the impact of CALI on survival in patients who underwent partial hepatectomy for colorectal liver metastases (CRLM). METHODS: Patients who received neoadjuvant chemotherapy and underwent partial hepatectomy for CRLM between 2008 and 2014 were included. Liver and tumour specimens were histologically examined for CALI (steatosis, steatohepatitis, sinusoidal dilatation [SD], nodular regeneration) and tumour regression grade (TRG). TRG 1-2 was defined as complete tumour response. RESULTS: 166 consecutive patients were included with a median survival of 30 and 44 months for recurrence-free and overall survival, respectively. Grade 2-3 SD was found in 44 (27%) and TRG 1-2 was observed in 33 (20%) patients. Of studied CALI, only grade 2-3 SD was associated with increased TRG 3-5 (odds ratio 3.99, 95% CI 1.17-13.65, p = 0.027). CALI was not significantly related to survival. TRG 1-2 was associated with prolonged recurrence-free (hazard ratio 0.47, 95% CI 0.25-0.89, p = 0.020) and overall survival (hazard ratio 0.35, 95% CI 0.18-0.68, p = 0.002). CONCLUSION: CALI was not directly related to survival. CALI was, however, associated with diminished complete tumour response, and diminished complete tumour response, in turn, was associated with decreased survival.

Confirmation of high specificity of an automated enzyme immunoassay test for serological diagnosis of syphilis: retrospective evaluation versus results after implementation.

BACKGROUND: The optimal algorithm for serological syphilis screening is still a matter of debate. We have previously evaluated the performance of the Bioelisa Syphilis 3.0, using a selection of archived sera, and in this study compare these results with the Bioelisa results after clinical implementation. METHODS: All Bioelisa Syphilis 3.0 results obtained since clinical implementation were analyzed. Bioelisa-positive or borderline samples were retested using Treponema pallidum particle agglutination, rapid plasma reagin test, fluorescent treponemal antibody-absorption test, and/or immunoblot. On sera sent in together with cerebrospinal fluid, occasionally both the T. pallidum particle agglutination and Bioelisa were performed. RESULTS: The Bioelisa was performed on 14,622 sera. Bioelisa-positive samples, which were not retested by the previously described assays, were withdrawn from the database (n = 36). In 1.3% of the samples (187/14,586), the Bioelisa was positive or borderline and, ultimately, 115 sera were considered true positive (prevalence 0.8%). The specificity of the Bioelisa was 99.5%. CONCLUSIONS: Based on the results of all performed diagnostic assays, the specificity of the Bioelisa of 99.5% is very consistent with that found in the initial study (100%; 95% confidence interval was 98.0%-100%). Interpreting (positive) test results is difficult in the absence of a gold standard, especially when the disease prevalence is low. Results should be viewed in the light of the patients' characteristics.

Microbiology of surgical site infections after gastrointestinal surgery in the south region of The Netherlands.

AIM: To give an overview of the microbiology of blood and wound samples from surgical site infections (SSIs) after gastrointestinal surgery, as well as the antimicrobial susceptibility of the microorganisms involved, and to discuss the appropriateness of the prophylactic antibiotics administered. MATERIALS & METHODS: During a 3.5-year study period, wound swabs and blood samples of patients with an SSI were taken in the first 48 h after surgery until 30 days thereafter. RESULTS: Most pathogens were isolated from wound swabs. Escherichia coli (25%) and Pseudomonas aeruginosa (10%) were the most frequently found microorganisms. Both microorganisms showed a slight tendency towards a decrease in susceptibility for the tested antibiotics, although after correction, this was not significant. CONCLUSION: The comparison between wound swabs taken in the first 48 h after a surgical procedure and swabs in the 30 days thereafter provides important information concerning the microbiology of SSIs and the development of antibiotic resistance of the causative agents over time.

Aspergillosis due to voriconazole highly resistant Aspergillus fumigatus and recovery of genetically related resistant isolates from domiciles.

BACKGROUND: Azole resistance is an emerging problem in Aspergillus fumigatus and complicates the management of patients with Aspergillus-related diseases. Selection of azole resistance may occur through exposure to azole fungicides in the environment. In the Netherlands a surveillance network was used to investigate the epidemiology of resistance selection in A. fumigatus. METHODS: Clinical A. fumigatus isolates were screened for azole resistance in 8 university hospitals using azole agar dilution plates. Patient information was collected using an online questionnaire and azole-resistant A. fumigatus isolates were analyzed using gene sequencing, susceptibility testing, and genotyping. Air sampling was performed to investigate the presence of resistant isolates in hospitals and domiciles. RESULTS: Between December 2009 and January 2011, 1315 A. fumigatus isolates from 921 patients were screened. A new cyp51A-mediated resistance mechanism (TR46/Y121F/T289A) was observed in 21 azole-resistant isolates from 15 patients in 6 hospitals. TR46/Y121F/T289A isolates were highly resistant to voriconazole (minimum inhibitory concentration ≥16 mg/L). Eight patients presented with invasive aspergillosis due to TR46/Y121F/T289A, and treatment failed in all 5 patients receiving primary therapy with voriconazole. TR46/Y121F/T289A Aspergillus fumigatus was recovered from 6 of 10 sampled environmental sites. CONCLUSIONS: We describe the emergence and geographical migration of a voriconazole highly resistant A. fumigatus that was associated with voriconazole treatment failure in patients with invasive aspergillosis. Recovery of TR46/Y121F/T289A from the environment suggests an environmental route of resistance selection. Exposure of A. fumigatus to azole fungicides may facilitate the emergence of new resistance mechanisms over time, thereby compromising the use of azoles in the management of Aspergillus-related diseases.

Influence of temperature, medium, and storage duration on Chlamydia trachomatis DNA detection by PCR.

We validated the use of stored samples for Chlamydia trachomatis research. C. trachomatis DNA was detected by real-time PCR in clinical (urine and self-taken vaginal swabs) and spiked samples using six different media, five different time points (up to 2 years), and four different temperature conditions. C. trachomatis was detected in all 423 samples, and no clinically relevant degradation impact was detected.

Clinical implications of azole resistance in Aspergillus fumigatus, The Netherlands, 2007-2009.

The prevalence and spread of azole resistance in clinical Aspergillus fumigatus isolates in the Netherlands are currently unknown. Therefore, we performed a prospective nationwide multicenter surveillance study to determine the effects of resistance on patient management strategies and public health. From June 2007 through January 2009, all clinical Aspergillus spp. isolates were screened for itraconazole resistance. In total, 2,062 isolates from 1,385 patients were screened; the prevalence of itraconazole resistance in A. fumigatus in our patient cohort was 5.3% (range 0.8%-9.5%). Patients with a hematologic or oncologic disease were more likely to harbor an azole-resistant isolate than were other patient groups (p<0.05). Most patients (64.0%) from whom a resistant isolate was identified were azole naive, and the case-fatality rate of patients with azole-resistant invasive aspergillosis was 88.0%. Our study found that multiazole resistance in A. fumigatus is widespread in the Netherlands and is associated with a high death rate for patients with invasive aspergillosis.

Eradication of carriage with methicillin-resistant Staphylococcus aureus: determinants of treatment failure.

BACKGROUND: Using data from an observational study in which the effectiveness of a guideline for eradication of methicillin-resistant Staphylococcus aureus (MRSA) carriage was evaluated, we identified variables that were associated with treatment failure. METHODS: A multivariate logistic regression model was performed with subgroup analyses for uncomplicated and complicated MRSA carriage (the latter including MRSA infection, skin lesions, foreign-body material, mupirocin resistance and/or exclusive extranasal carriage) and for those treated according to the guideline (i.e. mupirocin nasal ointment and chlorhexidine soap solution for uncomplicated carriage, in combination with two oral antibiotics for complicated carriage). RESULTS: Six hundred and thirteen MRSA carriers were included, of whom 333 (54%) had complicated carriage; 327 of 530 patients (62%) with known complexity of carriage were treated according to the guideline with an absolute increase in treatment success of 20% (95% confidence interval 12%-28%). Among those with uncomplicated carriage, guideline adherence [adjusted odds ratio (OR(a)) 7.4 (1.7-31.7)], chronic pulmonary disease [OR(a) 44 (2.9-668)], throat carriage [OR(a) 2.9 (1.4-6.1)], perineal carriage [OR(a) 2.2 (1.1-4.4)] and carriage among household contacts [OR(a) 5.6 (1.2-26)] were associated with treatment failure. Among those with complicated carriage, guideline adherence was associated with treatment success [OR(a) 0.2 (0.1-0.3)], whereas throat carriage [OR(a) 4.4 (2.3-8.3)] and dependence in activities of daily living [OR(a) 3.6 (1.4-8.9)] were associated with failure. CONCLUSIONS: Guideline adherence, especially among those with complicated MRSA carriage, was associated with treatment success. Adding patients with extranasal carriage or dependence in daily self-care activities to the definition of complicated carriage, and treating them likewise, may further increase treatment success.

Eradication of carriage with methicillin-resistant Staphylococcus aureus: effectiveness of a national guideline.

BACKGROUND: We evaluated the effectiveness of eradication of methicillin-resistant Staphylococcus aureus (MRSA) carriage in the Netherlands after the introduction of a guideline in 2006. The guideline distinguishes complicated (defined as the presence of MRSA infection, skin lesions, foreign-body material, mupirocin resistance and/or exclusive extranasal carriage) and uncomplicated carriage (not meeting criteria for complicated carriage). Mupirocin nasal ointment and chlorhexidine soap solution are recommended for uncomplicated carriers and the same treatment in combination with two oral antibiotics for complicated carriage. METHODS: A prospective cohort study was performed in 18 Dutch centres from 1 October 2006 until 1 October 2008. RESULTS: Six hundred and thirteen MRSA carriers underwent one or more decolonization treatments during the study period, mostly after hospital discharge. Decolonization was achieved in 367 (60%) patients with one eradication attempt and ultimately 493 (80%) patients were decolonized, with a median time until decolonization of 10 days (interquartile range 7-43 days). Three hundred and twenty-seven (62%) carriers were treated according to the guideline, which was associated with an absolute increase in treatment success of 20% [from 45% (91/203) to 65% (214/327)]. CONCLUSIONS: Sixty percent of MRSA carriers were successfully decolonized after the first eradication attempt and 62% were treated according to the guideline, which was associated with an increased treatment success.

Evaluation of one-sample testing of self-obtained vaginal swabs and first catch urine samples separately and in combination for the detection of Chlamydia trachomatis by two amplified DNA assays in women visiting a sexually transmitted disease clinic.

This study evaluates the performance of self-obtained vaginal swabs (SVS)/first-catch urine (FCU) combination samples in comparison to testing FCU or SVS alone. The Chlamydia trachomatis detection rate for the SVS, FCU, and SVS/FCU combination were 94%, 90%, and 94%, respectively. Self-obtained vaginal swabs are therefore the specimen of choice for Chlamydia trachomatis Nucleic Acid Amplification Tests in females.

Alarmingly poor performance in Chlamydia trachomatis point-of-care testing.

BACKGROUND: Infection by Chlamydia trachomatis (CT) is the most prevalent sexually transmitted infection (STI) world wide. The most frequently used diagnostic test for CT is a nucleic acid amplification test (NAAT), which is highly sensitive and specific. To further shorten time delay until diagnosis has been made, in order to prevent CT spread, the use of point-of-care (POC) tests may be the way forward. OBJECTIVES: The diagnostic performance of three POC tests, Handilab-C, Biorapid CHLAMYDIA Ag test and QuickVue Chlamydia test, was evaluated and compared with NAAT. METHODS: All women, above the age of 16 years, attending for a consultation at an STI clinic between September 2007 and April 2008, were asked to participate. Women were asked to complete a short questionnaire and to collect six self-taken vaginal swabs (SVS). SVS 2 was used for NAAT and SVS 3 to 5 were randomised for the different POC tests. SVS 1 and 6 were used for determining quantitative CT load to validate the use of successive SVS. All POC tests were performed without knowledge of NAAT results. NAAT was used as the 'gold standard'. RESULTS: 772 women were included. CT prevalence was 11% in our population. Sensitivities of the Biorapid CHLAMYDIA Ag test, QuickVue Chlamydia and Handilab-C test were 17%, 27% and 12%, respectively. CONCLUSIONS: The evaluated POC tests, owing to their very low sensitivities, are not ready for widespread use. These results underline the need for good-quality assurance of POC tests, especially in view of the increased availability of these tests on the internet.

[Does ultraclean air in the operating room provide greater safety?]. / Brengt ultraschone lucht op de OK meer veiligheid?

The Dutch quality control plan for climatisation of the operating room (OR), which was published in 2005, describes the management and maintenance of the air conditioning system. This management plan proposes a standard for air quality in class 1 ORs. This has been adopted by the Dutch Orthopaedic Society, but not by other surgical societies. The British study which underlies the proposed norm for air quality in class 1 ORs, a study on the infection preventive effect of ultraclean air, dates from 1982 and is inadequately controlled for prophylactic use of antibiotics. Antibiotic prophylaxis in itself already reduces the number of surgical site infections.-More recent studies fail to show an infection preventive effect of ultraclean air in the OR. The Dutch Working Party for Infection Prevention (WIP) ought to take the initiative, together with the medical Scientific Societies and the Society of Infection Prevention and Control in the health care setting (VHIG), to establish enforceable norms for microbiological air quality and to set criteria as to which types of operations are allowed to be performed in which class of OR.

Cross-border dissemination of methicillin-resistant Staphylococcus aureus, Euregio Meuse-Rhin region.

Because the prevalence of methicillin-resistant Staphylococcus aureus (MRSA) differs among the 3 countries forming the Euregio Meuse-Rhin (EMR) region (Belgium, Germany, and the Netherlands), cross-border healthcare requires information about the spread of MRSA in the EMR. We investigated the emergence, dissemination, and diversity of MRSA clones in the EMR by using several typing methods. MRSA associated with clonal complexes 5, 8, 30, and 45 was disseminated throughout the EMR. Dutch isolates, mainly associated with sequence types (ST) ST5-MRSA-II, ST5-MRSA-IV, ST8-MRSA-IV, and ST45-MSRA-IV had a more diverse genetic background than the isolates from Belgium and Germany, associated with ST45-MRSA-IV and ST5-MRSA-II, respectively. MRSA associated with pigs (ST398-MRSA-IV/V) was found in the Dutch area of the EMR. Five percent of the MRSA isolates harbored Panton-Valentine leukocidin and were classified as community-associated MRSA associated with ST1, 8, 30, 80, and 89.

Molecular characterization of Staphylococcus aureus bloodstream isolates collected in a Dutch University Hospital between 1999 and 2006.

We observed that, between 1999 and 2006, up to 50% of the methicillin-susceptible Staphylococcus aureus (MSSA) bloodstream isolates in our hospital had a genetic background common to endemic methicillin-resistant S. aureus clones (clonal complex 5 [CC5], CC8, CC22, CC30, and CC45). Furthermore, several successful MSSA lineages, such as CC7 and CC15, were observed.

Protein binding of flucloxacillin in neonates.

The isoxazolyl penicillins, including flucloxacillin, have the highest levels of plasma protein binding among the semisynthetic penicillins. Because only the free fraction of the penicillin is pharmacologically active, it would be useful to measure both protein-bound and free flucloxacillin to determine its protein binding. Until now, flucloxacillin protein binding in newborn infants has been investigated in only two studies with relatively small populations. In the present study, flucloxacillin protein binding was investigated in 56 (preterm) infants aged 3 to 87 days (gestational age, 25-41 weeks). Surplus plasma samples from routine gentamicin assays of each infant were collected and combined to obtain a sufficiently large sample for analysis. Free flucloxacillin was separated from protein-bound flucloxacillin using ultrafiltration. Reversed-phase high-performance liquid chromatography with ultraviolet detection was used to measure free flucloxacillin concentrations in ultrafiltrate and total flucloxacillin concentrations in pooled plasma. Flucloxacillin protein binding was 74.5% +/- 13.1% (mean +/- standard deviation) with a high variability among the infants (34.3% to 89.7%). High Pearson correlations were found between protein binding and the covariates-plasma albumin concentration (r = 0.804, P < 0.001, n = 18) and plasma creatinine concentration (r = -0.601, P < 0.001, n = 45). Statistically significant but less striking correlations were found between protein binding and gestational age, postconceptional age, body weight, and triglyceride concentration. Because of the high variability of protein binding among infants, it is difficult to devise a flucloxacillin dosage regimen effective for all infants. Individualized dosing, based on free flucloxacillin concentrations, might help to optimize treatment of late-onset neonatal sepsis, but practical obstacles will probably prevent analysis of free flucloxacillin concentrations in newborn infants on a routine basis.

Pharmacokinetics of intravenous rifampicin (rifampin) in neonates.

Few reports have addressed neonatal rifampicin plasma concentrations and data on neonatal rifampicin pharmacokinetics are completely lacking. Therefore, plasma concentrations of rifampicin and its main metabolite 25-O-desacetylrifampicin (DES) were measured in 123 surplus plasma samples from routine vancomycin monitoring in 21 neonates using reversed-phase HPLC. Rifampicin peak and trough plasma concentrations were 4.66 +/- 1.47 mg/L and 0.21 +/- 0.20 mg/L, respectively, after a dose of 8.5 +/- 2.1 (mean +/- SD) mg/kg per day. A significant linear relationship between rifampicin dose and peak plasma concentrations was found, but inter-patient variability was high. Pharmacokinetic parameters of rifampicin were calculated according to a one-compartment open model with iterative two-stage Bayesian fitting (MW\PHARM 3.60, Mediware, The Netherlands). First-order elimination constant, volume of distribution corrected for weight, total body clearance corrected for weight (CL/W), and elimination half-life were 0.16 +/- 0.06 h(-1), 1.84 +/- 0.59 L/kg, 0.28 +/- 0.11 Lkg(-1) h(-1), and 4.9 +/- 1.7 h, respectively. A high Pearson correlation was found between CL/W rifampicin and the covariates plasma creatinine and CL/W gentamicin of a preceding gentamicin treatment course, r = 0.728 (n = 17) and r = 0.837 (n = 12), respectively. DES was detected in each plasma sample. Therefore, rifampicin seems to be eliminated by both renal and metabolic pathways in neonates. In 8 study patients, plasma concentrations of rifampicin and DES were measured again after two weeks of therapy. CL/W rifampicin was significantly higher (67 +/- 50%). The authors suggest maintaining the current dose regimen of 10 mg/kg once a day. Because of the large inter-patient variability in rifampicin plasma concentrations and CL/W increase during therapy, the authors suggest monitoring rifampicin peak and trough plasma concentrations to avoid low plasma concentrations. More research is needed to determine well-founded dosing guidelines.

Population pharmacokinetics and dosing of flucloxacillin in preterm and term neonates.

In total 235 flucloxacillin total (free+protein bound) plasma concentrations were determined in 55 neonates (gestational age 26 to 42 weeks, postnatal age 0 to 44 days) with reversed-phase HPLC in surplus plasma samples from routine gentamicin assays. Population pharmacokinetic parameters were calculated according to an one compartment open model with iterative two-stage Bayesian fitting (MWPHARM 3.50, Mediware, The Netherlands). Mean clearance corrected for weight was 0.18+/-0.10 L kgh and volume of distribution corrected for weight was 0.54+/-0.17 L/kg. Pearson correlations between the individual pharmacokinetic parameters and covariates, like gestational age, plasma creatinine, and gentamicin clearance, were low and therefore not relevant for use in clinical practice. Total plasma concentrations above 200 mg/L were considered toxic and T>MIC (time above minimum inhibitory free plasma concentration) of more than 40% was considered effective. Protein binding was assumed to be 86.3% in all neonates, based on literature. The current dosage regimen, 25 or 50 mg/kg every 8 or 12 hours, did not result in effective plasma concentrations for the treatment of Staphylococcus aureus in 17 (31%) of the 55 neonates. Therefore, the authors suggest an initial dose of 25 mg/kg/4 h for all neonates, irrespective of their age, based on the breakpoint MIC value of flucloxacillin for Staphylococcus aureus (2.0 mg/L). After isolation of the causative agent of infection, flucloxacillin administration ought to be reconsidered based on the expected susceptibility pattern of the isolate. When oxacillin sensitive coagulase negative staphylococci are isolated, the initial dose should be reduced to 10 mg/kg/6 h, based on the breakpoint MIC value of 0.25 mg/L. Simulation with these new dosage regimens indicated that satisfactory plasma concentrations were reached in 52 of the 55 neonates. However, the regimens need prospective verification. Moreover, the exact role of neonatal protein binding needs to be further investigated.