HIV incidence in the Estonian population in 2013 determined using the HIV-1 limiting antigen avidity assay.

OBJECTIVES: Estonia has one the highest number of new HIV diagnoses in the European Union, mainly among injecting drug users and heterosexuals. Little is known of HIV incidence, which is crucial for limiting the epidemic. Using a recent HIV infection testing algorithm (RITA) assay, we aimed to estimate HIV incidence in 2013. METHODS: All individuals aged ≥18 years newly-diagnosed with HIV in Estonia January- December 2013, except blood donors and those undergoing antenatal screening, were included. Demographic and clinical data were obtained from the Estonian Health Board and the Estonian HIV-positive patient database. Serum samples were tested for recent infection using the LAg-avidity EIA assay. HIV incidence was estimated based on previously published methods. RESULTS: Of 69,115 tested subjects, 286 (0.41%) were newly-diagnosed with HIV with median age of 33 years (IQR: 28-42) and 65% male. Self-reported routes of HIV transmission were mostly heterosexual contact (n = 157, 53%) and injecting drug use (n = 62, 21%); 64 (22%) were with unknown risk group. Eighty two (36%) were assigned recent, resulting in estimated HIV incidence of 0.06%, corresponding to 642 new infections in 2013 among the non-screened population. Incidence was highest (1.48%) among people who inject drugs. CONCLUSIONS: These high HIV incidence estimates in Estonia call for urgent action of renewed targeted public health promotion and HIV testing campaigns.

EAN consensus review on prevention, diagnosis and management of tick-borne encephalitis.

BACKGROUND AND PURPOSE: Tick-borne encephalitis (TBE) is an infection of the central nervous system (CNS) caused by tick-borne encephalitis virus (TBEV) and transmitted by ticks, with a variety of clinical manifestations. The incidence of TBE in Europe is increasing due to an extended season of the infection and the enlargement of endemic areas. Our objectives are to provide recommendations on the prevention, diagnosis and management of TBE, based on evidence or consensus decisions. METHODS: For systematic evaluation, the literature was searched from 1970 to 2015 (including early online publications of 2016), and recommendations were based on evidence or consensus decisions of the Task Force when evidence-based data were not available. RECOMMENDATIONS: Vaccination against TBE is recommended for all age groups above 1 year in highly endemic areas (≥5 cases/100 000/year), but also for individuals at risk in areas with a lower incidence. Travellers to endemic areas should be vaccinated if their visits will include extensive outdoor activities. Post-exposure prophylaxis after a tick bite is not recommended. A case of TBE is defined by the presence of clinical signs of meningitis, meningoencephalitis or meningoencephalomyelitis with cerebrospinal fluid (CSF) pleocytosis (>5 × 106 cells/l) and the presence of specific TBEV serum immunoglobulin M (IgM) and IgG antibodies, CSF IgM antibodies or TBEV IgG seroconversion. TBEV-specific polymerase chain reaction in blood is diagnostic in the first viremic phase but it is not sensitive in the second phase of TBE with clinical manifestations of CNS inflammation. Lumbar puncture should be performed in all patients with suspected CNS infection unless there are contraindications. Imaging of the brain and spinal cord has a low sensitivity and a low specificity, but it is useful for differential diagnosis. No effective antiviral or immunomodulating therapy is available for TBE; therefore the treatment is symptomatic. Patients with a potentially life threatening meningoencephalitis or meningoencephalomyelitis should be admitted to an intensive care unit. In the case of brain oedema, analgosedation should be deepened; osmotherapy and corticosteroids are not routinely recommended. If intracranial pressure is increased, therapeutic hypothermia or decompressive craniectomy might be considered. Seizures should be treated as any other symptomatic epileptic seizures. CONCLUSIONS: Tick-borne encephalitis is a viral CNS infection that may result in long-term neurological sequelae. Since its incidence in Europe is increasing due to broadening of endemic areas and prolongation of the tick activity season, the health burden of TBE is enlarging. There is no effective antiviral treatment for TBE, but the disease may be effectively prevented by vaccination.

An observational study of blood concentrations and kinetics of methyl- and propyl-parabens in neonates.

PURPOSE: Systemic exposure to parabens in the neonatal population, in particular propyl-parabens (PPB), remains a concern. Blood concentrations and kinetics of methyl-parabens (MPB) and PPB were therefore determined in neonates receiving medicines containing these excipients. METHODS: A multi-centre, non-interventional, observational study of excipient-kinetics in neonates. 'Dried Blood Spot' samples were collected opportunistically at the same time as routine samples and the observations modelled using a non-linear mixed effects approach. RESULTS: A total of 841 blood MPB and PPB concentration data were available for evaluation from 181 pre- and term-neonates. Quantifiable blood concentrations of MPB and PPB were observed in 99% and 49% of patients, and 55% and 25% of all concentrations were above limit of detection (10 ng/ml), respectively. Only MPB data was amenable to modelling. Oral bioavailability was influenced by type of formulation and disposition was best described by a two compartment model with clearance (CL) influenced by post natal age (PNA); CL PNA<21 days 0.57 versus CL PNA>21 days 0.88 L/h. CONCLUSIONS: Daily repeated administration of parabens containing medicines can result in prolonged systemic exposure to the parent compound in neonates. Animal toxicology studies of PPB that specifically address the neonatal period are required before a permitted daily exposure for this age group can be established.

Risk assessment of neonatal excipient exposure: lessons from food safety and other areas.

Newborn babies can require significant amounts of medication containing excipients intended to improve the drug formulation. Most medicines given to neonates have been developed for adults or older children and contain excipients thought to be safe in these age groups. Many excipients have been used widely in neonates without obvious adverse effects. Some excipients may be toxic in high amounts in which case they need careful risk assessment. Alternatively, it is conceivable that ill-founded fears about excipients mean that potentially useful medicines are not made available to newborn babies. Choices about excipient exposure can occur at several stages throughout the lifecycle of a medicine, from product development through to clinical use. Making these choices requires a scalable approach to analysing the overall risk. In this contribution we examine these issues.

Five-year prospective surveillance of nosocomial bloodstream infections in an Estonian paediatric intensive care unit.

BACKGROUND: Few studies provide rates of nosocomial bloodstream infections (BSIs) in mixed neonatal and paediatric intensive care units (PICUs). AIM: To determine the rate, pathogens and outcome of BSIs in an Estonian PICU. METHODS: Data were collected prospectively from 1st January 2004 to 31st December 2008 in the PICU of Tartu University Hospital. The definition criteria of the US Centers for Disease Control and Prevention were applied for the diagnosis of laboratory-confirmed BSI. FINDINGS: A total of 126 episodes of BSI were identified in 89 patients (74 neonates, eight infants, seven patients aged >1 year). Among neonates 42 (57%) had birth weight <1000 g. The overall incidence of BSI was 9.2 per 100 admissions, incidence density 12.8 per 1000 patient-days. Primary BSI was diagnosed in 92 episodes. Central line (CL)-associated BSI incidence density for neonates was 8.6 per 1000 CL-days with the highest incidence (27.4) among neonates with extremely low birth weight. The most common pathogens were coagulase-negative staphylococci (43%) and Serratia marcescens (14%). Resistance to meticillin was detected in four out of seven S. aureus isolates (all were part of an outbreak) and 23% of Enterobacteriaceae were extended spectrum beta-lactamase (ESBL)-producing strains. Overall case-fatality rate was 10%. CONCLUSION: We observed higher rates of BSIs in our mixed PICU than reported previously. High levels of antimicrobial resistance were detected. Future research should focus on the effects of infection control measures to prevent outbreaks and to decrease incidence of CL-associated BSI.

Mucosal surveillance cultures in predicting Gram-negative late-onset sepsis in neonatal intensive care units.

This study aimed to examine the spectrum and time course of gut and nasopharyngeal colonization with Gram-negative micro-organisms, and to define the value of surveillance cultures in predicting late-onset sepsis in neonates admitted to neonatal intensive care units. Nasopharyngeal and rectal swabs were collected on admission and twice weekly thereafter in 278 neonates admitted within the first 72 h of life with risk factors of early-onset sepsis. Sterile body fluid cultures were obtained on admission and subsequently as clinically indicated. Approximately half of the rectal (693/1250, 55%) and nasopharyngeal (558/1153, 48%) samples but only 6% (32/555) of the sterile fluid samples in 26 patients were culture positive for Gram-negative organisms. In total, 2108 invasive and mucosal culture pairs were analysed. The overall sensitivity, specificity, and positive and negative predictive values of a mucosal sample to predict late-onset sepsis were 27%, 66%, 4% and 94%, respectively. Patients with pre-existing colonization with Klebsiella pneumoniae (P = 0.011), Klebsiella oxytoca (P = 0.002), Escherichia coli (P = 0.003), Stenotrophomonas spp. (P = 0.003) and Pseudomonas spp. (P ≤ 0.001) were more likely to develop late-onset sepsis. No such association was found for Acinetobacter baumannii, Serratia spp. or Enterobacter cloacae. In conclusion, routine mucosal cultures are inefficient for the prediction of Gram-negative late-onset sepsis in neonatal intensive care units. However, targeted screening for specific organisms in an outbreak (e.g. Klebsiella spp., E. coli, Stenotrophomonas spp. and Pseudomonas spp.) may offer an opportunity to improve infection control measures and enable timely initiation of appropriate antibiotic therapy.

Impact of empiric antibiotic regimen on bowel colonization in neonates with suspected early onset sepsis.

The purpose of this study was to compare the impact of ampicillin and penicillin used for empiric treatment of early onset sepsis (EOS) on initial gut colonization by aerobic and facultative anaerobic microorganisms. A cluster-randomized, two-center, switch-over study was conducted in two paediatric intensive care units in Estonia and included 276 neonates. Rectal swabs were collected twice a week until discharge or day 60. Colonizing microbes were identified on species level and tested for ampicillin resistance (AR). The number of patients colonized with Gram negative microorganisms and Candida spp was similar in both treatment arms but ampicillin resulted in longer colonization duration (CD) of K. pneumonia (p = 0.012), AR Serratia spp (p = 0.012) and Candida spp (p = 0.02) and penicillin in that of AR Acinetobacter spp (p = 0.001). As for Gram positive microorganisms penicillin treatment was associated with a greater number of colonized patients and higher CD of Enterococcus spp and S. aureus but lower ones of S. haemolyticus and S. hominis. Influence of ampicillin and penicillin on initial gut colonization is somewhat different but these differences are of low clinical relevance and should not be a limiting step when choosing between these two antibiotics for the empiric treatment of EOS.

Comparison of ampicillin plus gentamicin vs. penicillin plus gentamicin in empiric treatment of neonates at risk of early onset sepsis.

AIM: We aimed to compare the clinical efficacy of ampicillin (AMP) vs. penicillin (PEN) both combined with gentamicin in the empirical treatment of neonates at risk of early onset neonatal sepsis (EOS). METHODS: We performed an open label cluster randomized equivalence study in both Estonian neonatal intensive care units, including neonates with suspected EOS, aged less than 72 h. Primary end-point was clinical failure rate, expressed by need for change of antibiotic regimen within 72 h and/or 7-day all cause mortality. Bowel colonization was followed with biweekly perineal swab cultures. RESULTS: Incidence of proven EOS was 4.9%. Among neonates receiving AMP (n = 142) or PEN (n = 141) change of antibiotic regimen within 72 h (10/142 vs. 10/141; OR 1.02; 95% CI 0.40-2.59), 7-day mortality (11/142 vs. 14/141; OR 0.76; 95% CI 0.33-1.75) and over-all treatment failure (20/142 vs. 20/141; OR 1.01; 95% CI 0.52-1.97) occurred at similar rates. The only differences in gut colonization were lower number of patients colonised with enterococci, S. aureus and AMP resistant Acinetobacter spp. in AMP and lower number of those with S. haemolyticus and S. hominis in PEN arm. CONCLUSIONS: AMP and PEN combined with gentamicin have similar effectiveness in the empiric treatment of suspected neonatal EOS.

Antimicrobial susceptibility and serogroup/serotype distribution of nasopharyngeal isolates of Streptococcus pneumoniae in healthy Estonian children in 1999-2003.

This study determined nasopharyngeal (NP) carriage rates of Streptococcus pneumoniae among healthy Estonian children, aged 1-7 years, and characterised the serotype/serogroup distribution and antibiotic susceptibility rates. NP swabs were collected from 685 previously healthy children attending 29 day care centres during the winters of 1999-2000 and 2003. The NP carriage rate of S. pneumoniae was 44%. Rates of penicillin and erythromycin non-susceptibility were low (both 6%), but high (67%) rates of co-trimoxazole resistance were found. Among the pneumococcal serotypes identified, 64% were included in or cross-reacted with the licensed heptavalent pneumococcal vaccine.

Immunogenicity and safety of a combined hepatitis A and B vaccine administered concomitantly with either a measles-mumps-rubella or a diphtheria-tetanus-acellular pertussis-inactivated poliomyelitis vaccine mixed with a Haemophilus influenzae type b conjugate vaccine in infants aged 12-18 months.

Two studies were undertaken to investigate the concomitant administration of combined hepatitis A/B vaccine with a diphtheria-tetanus-acellular pertussis-inactivated poliomyelitis vaccine mixed with Haemophilus influenzae vaccine (DTPa-IPV/Hib), or with a measles-mumps-rubella vaccine (MMR), during the second year of life. On completion of the vaccination course, all subjects were seropositive or seroprotected against all antigens except for one subject who was seronegative for anti-PT. Seropositivity and seroprotection rates for all other antibodies were comparable to reference values for each vaccine component, indicating that the immunogenicity of MMR, DTPa-IPV/Hib and combined hepatitis A/B vaccines is not impaired by co-administration. All vaccines were well tolerated.

Factors influencing the anti-inflammatory effect of dexamethasone therapy in experimental pneumococcal meningitis.

Dexamethasone (DXM) interferes with the production of tumour necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1) and can thereby diminish the secondary inflammatory response that follows initiation of antibacterial therapy. A beneficial effect on the outcome of Haemophilus meningitis in children has been proven, but until recently the effect of DXM therapy in pneumococcal meningitis was uncertain. The aim of the present study was to evaluate factors that might influence the modulatory effect of DXM on the antibiotic-induced inflammatory response in a rabbit model of pneumococcal meningitis. DXM (1 mg/kg) was given intravenously 30 min before or 1 h after administration of a pneumococcal cell wall extract, or the first dose of ampicillin. In meningitis induced by cell wall extract, DXM therapy prevented the increase in cerebrospinal fluid (CSF) leucocyte and lactate concentrations, but only if given 30 min before the cell wall extract. In meningitis caused by live organisms, initiation of ampicillin therapy resulted in an increase in CSF TNF-alpha and lactate concentrations only in animals with initial CSF bacterial concentrations > or =5.6 log10 cfu/mL. In those animals, DXM therapy prevented significant elevations in CSF TNF-alpha [median change -184 pg/mL, -114 pg/mL versus +683 pg/mL with DXM (30 min before or 1 h after ampicillin) versus controls (no DXM), respectively, P=0.02] and lactate concentrations [median change -10.6 mmol/L, -1.5 mmol/L versus +14.3 mmol/L with DXM (30 min before or 1 h after ampicillin) versus controls (no DXM), respectively, P=0.01]. These effects were independent of the timing of DXM administration. In this model of experimental pneumococcal meningitis, an antibiotic-induced secondary inflammatory response in the CSF was demonstrated only in animals with high initial CSF bacterial concentrations (> or =5.6 log10 cfu/mL). These effects were modulated by DXM therapy whether it was given 30 min before or 1 h after the first dose of ampicillin.

Pharmacokinetics and pharmacodynamics of cephalosporins in cerebrospinal fluid.

Largely because of their low lipophilicity, cephalosporins poorly penetrate through the blood-brain barrier, achieving relatively low cerebrospinal fluid (CSF) concentrations. However, the minimum bactericidal concentrations (MBCs) of the extended spectrum cephalosporins for common meningeal pathogens are generally low; thus, therapeutic CSF drug concentrations several-fold greater than the MBC can be achieved with currently recommended dosage regimens. However, the effectiveness of cephalosporin therapy is unreliable in patients with meningitis caused by highly penicillin-resistant pneumococci. As in other body sites, the bactericidal activity of cephalosporins in CSF predominantly depends on the time their concentrations exceed the MBC of infecting organisms (t>MBC). Experimental studies show that, for maximal efficacy, t>MBC values greater than 90% of the dosage interval are required in meningitis. Such values are usually achieved in humans with currently recommended dosage regimens because the half-lives of cephalosporins are 2- to 3-fold longer in CSF than in serum. Several advanced generation cephalosporins have shown equal efficacy in clinical trials, but only cefotaxime, ceftriaxone and ceftazidime are currently approved for the treatment of patients with bacterial meningitis.

Buffy coat PCR for diagnosis of experimental pneumococcal pneumonia.

An immunocompetent murine model of pneumococcal pneumonia and bacteremia was used to evaluate a PCR assay based on amplification of the pneumolysin gene. Mice were treated with trovafloxacin to determine the decline in sensitivity of PCR as lung bacterial concentrations decreased and blood cultures became sterile. Forty-three mice were studied for up to 120 h after start of antibiotic treatment. PCR of buffy coat specimens was more sensitive than PCR of plasma. Only 21% of animals had a positive blood culture, whereas 77% of PCR buffy coat assays were positive. After 48 h of therapy all blood culture specimens were sterile, whereas buffy coat PCR was positive in 57.8% of specimens. PCR of buffy coat specimens was negative in all mice colonized nasally with Streptococcus pneumoniae and in rabbits with Escherichia coli bacteremia. Our results demonstrate that our PCR technique using buffy coat specimens is highly specific for invasive pneumococcal disease and remains positive in the majority of animals for at least 48 h after start of antibiotic therapy.

Efficacy of gatifloxacin in experimental Escherichia coli meningitis.

The effectiveness of gatifloxacin therapy (15 mg/kg every 5 h [q5h]) was compared with that of meropenem (75 mg/kg q5h) and cefotaxime (75 mg/kg q5h) therapy in experimental meningitis caused by a beta-lactamase-producing strain of Escherichia coli. Gatifloxacin therapy was more rapidly bactericidal than cefotaxime but similar to meropenem therapy (bacterial killing rates at 5 h, 0.83 +/- 0.26, 0. 46 +/- 0.3, and 0.73 +/- 0.17 CFU/ml/h, respectively; P = 0.03 for gatifloxacin versus cefotaxime). At 10 h, seven of eight animals treated with gatifloxacin had <10 CFU/ml in their cerebrospinal fluid, compared with one of seven treated with cefotaxime therapy (P = 0.01). Gatifloxacin was at least as effective as currently available antibiotics in this model of E. coli meningitis.

Pharmacodynamics of trovafloxacin in a mouse model of cephalosporin-resistant Streptococcus pneumoniae pneumonia.

Trovafloxacin is a potentially useful agent for treatment of infections caused by cephalosporin-resistant Streptococcus pneumoniae. We studied the effectiveness of trovafloxacin therapy and examined the correlation between pharmacodynamic indices in serum and lung, and bacterial killing. Immunocompetent Balb/c mice were infected by intranasal inoculation of a cephalosporin-resistant S. pneumoniae isolate (MIC of ceftriaxone and trovafloxacin 2 and 0.06 mg/L, respectively). Trovafloxacin 10-30 mg/kg/day in one or three divided doses was started 15 h after infection. Serum and lung drug concentrations were measured at multiple time points for 24 h. Serum concentrations peaked at 30-60 min and lung concentrations approximately 30 min later. The serum T1/2 was approximately 9 h and lung T1/2 varied from 5 to 9 h. Lung AUC and Cmax values were 2-3 times greater than those in serum. At the start of therapy lung bacterial concentrations were 8.4 +/- 0.3 log10 cfu/mL and 24 h later had decreased by 3.5 +/- 0.2, 4.0 +/- 0.2, 0.8 +/- 0.3 and 1.0 +/- 1.2 log10 cfu/mL with 30 mg/kg x 1, 10 mg/kg x 3, 10 mg/kg x 1 and 3.3 mg/kg x 3 regimens, respectively. Although the larger dosages were more effective (P < 0.001) the differences between divided and single dosage regimens were not significant. Trovafloxacin serum AUC/MIC ratio correlated best with bacterial killing in the lungs over 24 h. Trovafloxacin is likely to be useful in the treatment of cephalosporin-resistant S. pneumoniae pneumonia.

Pharmacodynamics of trovafloxacin in experimental pneumococcal meningitis: basis for dosage selection in children with meningitis.

Trovafloxacin is a recently approved fluoroquinolone with excellent activity against gram-positive and gram-negative organisms that offers a potential alternative for treatment of beta-lactam-resistant pneumococcal meningitis. Using the rabbit meningitis model, we sought to characterize the pharmacodynamic properties of trovafloxacin in the cerebrospinal fluid (CSF). Animals were given single doses of trovafloxacin of 10, 15, 20 or 30 mg/kg; 1 h after Infusion mean CSF concentrations were 0.59+/-0.18, 0.74+/-0.14, 1.12+/-0.12 and 1.07+/-0.35 mg/L, respectively. The bacterial killing rate Increased with increasing dosages of trovafloxacin, indicating that its activity is concentration dependent. All three pharmacodynamic Indices (area under the concentration curve (AUC)/MBC, peak concentration (Cmax)/MBC, and time above MBC (T > MBC)) correlated with bacterial killing; however, AUC/MBC correlated best (r = 0.71). In a second experiment we found comparable bacterial killing with multiple doses of trovafloxacin given either every serum half-life or every two serum half-lives. In both experiments bacterial regrowth occurred when the concentration of trovafloxacin in CSF fell below the MBC. These data have been used in formulating an appropriate regimen for trovafloxacin treatment of bacterial meningitis in children.

Pharmacodynamics of vancomycin for the treatment of experimental penicillin- and cephalosporin-resistant pneumococcal meningitis.

With the emergence of beta-lactam antibiotic resistance among strains of Streptococcus pneumoniae, vancomycin has assumed an important role in the treatment of bacterial meningitis. Using the rabbit meningitis model, we evaluated the pharmacokinetics and pharmacodynamics of vancomycin in this setting. Animals were given 80 mg/kg of body weight daily in two or four divided doses to determine the penetration and activity of vancomycin in cerebrospinal fluid (CSF); each regimen was administered with and without dexamethasone. Mean peak (2 h) concentrations in CSF that were four- to eightfold higher than the minimum bactericidal concentration (MBC; 0.5 microgram/ml) for the pathogen were adequate for bacterial clearance. In both groups concentrations in CSF remained higher than the MBC for greater than 80% of the respective dosing intervals, and the penetration of vancomycin into CSF was 20%. Mean concentrations in CSF at 24 to 36 h of therapy were lower than those achieved during the first 12 h, consistent with a decline in the level of antibiotic entry into CSF as inflammation wanes. Rates of bacterial clearance were similar for the two regimens, and for all animals cultures of CSF were sterile by 36 h. The coadministration of dexamethasone significantly reduced the penetration of vancomycin into CSF by 29% and significantly lowered the rate of bacterial clearance during the first 6 h in animals receiving 20-mg/kg doses of vancomycin. For animals receiving 40-mg/kg doses, therapeutic peak concentrations in CSF were obtained even with steroid use, suggesting that the effect of steroids may be circumvented by the use of larger daily doses of vancomycin.

Safety and immunogenicity of combined Dtpa-IPV vaccine for primary and booster vaccination.

This study evaluated the safety and immunogenicity of combined diphtheria, tetanus, acellular pertussis, inactivated poliomyelitis vaccine (DTPa-IPV) given as primary immunization at ages 3, 4.5 and 6 months and a booster dose between the ages of 18 and 27 months to healthy children. The acellular pertussis tricomponent vaccine contains pertussis toxoid (PT), filamentous haemaglutinin (FHA) and 69 kDa outer membrane protein (PRN). Serum immune responses to the administered antigens were measured before and after the primary and the booster vaccination series. The safety of the vaccine was evaluated based on diary cards completed by parents within 4 d following each vaccination. A total of 237 and 150 children completed the primary and booster vaccination series, respectively. A total of 483 (66.5%) and 111 (74%) local and 317 (43.7%) and 98 (65.3%) general adverse events were reported after 726 doses of the primary series and 150 of the booster doses, respectively. Compared with primary vaccination, the incidence of all adverse symptoms was greater after the booster dose and a previous severe reaction was a risk factor for a severe reaction after the booster dose (OR = 5.11). All but 1 child, who failed to have antibodies to diphtheria toxoid after the booster dose, responded to all administered antigens with antibody titres greater than the assay cut-off points. The combined DTPa-IPV used for primary and booster immunization induced good immunity, but was associated with large local reactions in 21.3% of children after the booster dose.

Antibiotic pharmacodynamics in cerebrospinal fluid.

The CSF half-lives of lipophilic agents, such as quinolones, are similar to those in serum and peak concentrations in CSF are achieved relatively quickly. In contrast, the pharmacokinetics of hydrophilic agents (beta-lactams and vancomycin) in CSF often differ from those in serum. In particular, the half-lives of these agents in CSF tend to be extended, and the time to achieve peak concentrations in CSF is delayed. Hydrophilic antibiotics, such as beta-lactams, penetrate poorly through the BBB, but CSF penetration is significantly increased in the presence of inflammation. In contrast, lipophilic antibiotics, such as quinolones, enter the CSF more efficiently and their penetration is not inflammation dependent. The pharmacodynamic properties of antibiotics in CSF are generally similar to those in other body sites; beta-lactam agents and vancomycin are time-dependent, whereas the quinolones and aminoglycosides are concentration-dependent. However, a notable difference from infections in other sites is that quinolones have a short PAE in CSF and need to continually exceed the MBC for maximal effectiveness. Thus, in CSF, quinolones demonstrate features of both concentration-dependency and time-dependency, evidence that the AUC/MBC is an important predictor of effectiveness. With the exception of quinolones, many antibiotics appear to have prolonged sub-MIC effects and longer half-lives in CSF than in serum, suggesting that dosing intervals longer than those used traditionally would be effective in meningitis. However, this requires clinical verification.