Pharmacodynamics of trimethoprim-sulfamethoxazole in Listeria meningitis: a case report

Infections in the cerebrospinal fluid (CSF) occur in an area of impaired host defenses; therefore, bactericidal antibiotics that reach adequate concentrations in the CSF are necessary for treatment. Measurements of antibiotic penetration into the CSF include CSF inhibitory and bactericidal titers, the absolute antibiotic concentration in the CSF, and the CSF: serum concentration ratio. We present the case of a patient with Listeria monocytogenes meningitis who failed to respond clinically to standard therapy, and whose organism demonstrated tolerance to Ampicillin (MBC: MIC = 258:1) that successfully responded to trimethoprim-sulfamethoxazole (TMP-SMX). The CSF peak bactericidal titer to TMP-SMX was 1:8, corresponding to that reported as necessary for successful outcome in patients with meningitis. The CSF peak: MBC ratios for TMP and SMX were less than 3:1 and equal to 3:1, respectively. These individual ratios are lower than those suggested for successful treatment of meningitis; however, the recommended ratios were established using single agents and did not account for synergistic activity with a drug combination such as TMP-SMX. The failure of standard therapy in this patient underscores the importance of MIC/MBC testing when tolerance is suspected or when CSF penetration of antibiotics is relatively poor. In addition, measurements of CSF inhibitory and bactericidal titers, which incorporate the antibiotic concentration in the CSF, susceptibility of the infecting microorganism, and host defense factors, may be useful in monitoring patients with meningitis.     

Simvastatin attenuates leukocyte recruitment in experimental bacterial meningitis

Statins exert multiple effects besides lowering the serum cholesterol level, which might be beneficial for patients with sepsis and infections. We designed this study to assess the therapeutic potential of simvastatin in an established animal model of pneumococcal meningitis, a disease characterized by high morbidity and mortality despite effective antibiotic treatment. 24 h after injection of live pneumococci into the cisterna magna of mice, animals were clinically evaluated, cerebrospinal fluid (CSF) leukocyte counts and intracranial pressure were determined, and brains were removed for assessment of bacterial titer and blood–brain barrier breakdown. The following experimental groups were investigated: (I) no infection and treatment with vehicle; (II) infection and treatment with vehicle; infection and treatment with (III) 20 mg/kg or (IV) 40 mg/kg simvastatin s.c. 18 h before and just prior to infection. Treatment with simvastatin dose-dependently decreased CSF leukocyte counts, a marker for CNS inflammation. In addition, hypothermia was completely abolished in the 40 mg/kg simvastatin group. In contrast, a neurological clinical score, and intracranial complications like increase in intracranial pressure and blood–brain barrier breakdown were not altered by the treatment. In conclusion, simvastatin attenuates CNS leukocyte recruitment and systemic complications of experimental pneumococcal meningitis.     

Therapy of community-acquired acute bacterial meningitis: the clock is running

Despite antibiotic therapy and supportive intensive medical care, bacterial meningitis remains a disease with high mortality and morbidity. Rapid recognition of symptoms is crucial to direct physicians quickly towards appropriate diagnostic measures and, initially, empiric antibiotic therapy. It has become evident that time from arrival at the hospital to application of the first dose of antibiotics is a crucial independent factor that influences outcome. Here, we review the clinical and laboratory presentation of community-acquired bacterial meningitis and the antibiotic regiments that are currently recommended for its treatment; future therapeutic options are also discussed. Finally, suggestions for the approach to a patient with suspected bacterial meningitis are presented.     

A 61-year-old man with bloody purulent cerebrospinal fluid

Staphylococcus aureus meningitis (SAM) is a relatively uncommon but serious disease, accounting for only 1%–9% of cases of bacterial meningitis. In this report, we described a 61-year-old man, whose appearance of CSF was bloody and purulent. CSF test showed extremely elevated WBC count and protein quantification. Bacterial culture demonstrated SAM. Complications included septic shock, acute respiratory failure, and renal failure. Empiric antibiotic treatment was not effective for him. Therefore, we prescribed up to five types of antibiotics. We found that the clinical symptoms, CSF indicators, inflammatory markers, respiratory and renal function got better. The nerve function comparatively recovered well after 6 months of follow-up.     

Treatment of bacterial meningitis: an update

Introduction: The introduction of protein conjugate vaccines for Haemophilus influenzae type b (Hib), Streptococcus pneumoniae (S. pneumoniae) and Neisseria meningitidis (N. menigitidis) has changed the epidemiology of bacterial meningitis. Bacterial meningitis continues to be an important cause of mortality and morbidity, and our incomplete knowledge of its pathogenesis and emergence of antimicrobial resistant bacteria contribute to such mortality and morbidity. An early empiric antibiotic treatment is critical for the management of patients with bacterial meningitis.

Areas covered: This article gives an overview on optimal treatment strategies of bacterial meningitis, along with considerations of new insights on epidemiology, clinical and laboratory findings supportive of bacterial meningitis, chemoprophylaxis, selection of initial antimicrobial agents for suspected bacterial meningitis, antimicrobial resistance and utility of new antibiotics, status on anti-inflammatory agents and adjunctive therapy, and pathogenesis of bacterial meningitis.

Expert opinion: Prompt treatment of bacterial meningitis with an appropriate antibiotic is essential. Optimal antimicrobial treatment of bacterial meningitis requires bactericidal agents able to penetrate the blood–brain barrier (BBB), with efficacy in cerebrospinal fluid (CSF). Several new antibiotics have been introduced for the treatment of meningitis caused by resistant bacteria, but their use in human studies has been limited. More complete understanding of the microbial and host interactions that are involved in the pathogenesis of bacterial meningitis and associated neurologic sequelae is likely to help in developing new strategies for the prevention and therapy of bacterial meningitis.     

Treatment options for the pharmacological therapy of neonatal meningitis.

Neonatal bacterial meningitis has a relatively low incidence in developed countries, but continues to cause morbidity and mortality despite advances in antimicrobial therapy. Bacterial pathogens commonly associated with neonatal meningitis include Group B streptococci, Escherichia coli K1 and other coliforms, Listeria monocytogenes and staphylococci. As it can be difficult to differentiate meningitis from septicaemia in neonates, empirical antibiotic therapy should be effective for both. Selection of an empirical antibiotic regimen should be based on: (a) bacterial prevalence and susceptibility; (b) drug characteristics; (c) postnatal age at the onset of disease; and (d) patient-specific factors. A penicillin in combination with an aminoglycoside or cefotaxime is commonly used in empirical therapies. The increased risk of staphylococcal infection in older neonates requires consideration of an antistaphylococcal antibiotic in the empirical therapy regimen. Once a causative organism has been identified, antimicrobial therapy should be directed towards that pathogen. Duration of therapy remains empirical, but should be at least 7 days for documented bacterial meningitis. Viral meningitis continues to have a high mortality despite the availability of antiviral agents. Adjunctive therapies may further reduce the morbidity and mortality of meningitis. While most of these therapeutic options have not been investigated in neonates, they may prove to be of benefit in the future. Anti-inflammatory agents, such as glucocorticoids, nonsteroidal anti-inflammatory agents and immunoglobulin, may modulate the inflammatory response of a meningeal infection. Other possible therapies in neonatal meningitis include cerebral blood flow modulators and disease prevention with maternal vaccines and perinatal antibiotics. Practical aspects of drug therapy such as route of administration and serum drug concentration monitoring can improve both drug therapy and patient outcome. While antibiotics have greatly improved the treatment outcome of neonatal meningitis, it is clear that additional intervention will be required to increase cure rates and reduce sequelae.     

Cerebrospinal fluid pharmacokinetics of cefpodoxime proxetil in piglets

Cefpodoxime is an oral third-generation cephalosporin used for the treatment of acute upper-respiratory tract infections caused by susceptible bacteria in children. Although not indicated for the treatment of bacterial meningitis, it is used to treat other infections produced by organisms associated with meningitis and may obscure the result of cerebrospinal fluid (CSF) cultures in children who develop meningitis while receiving oral antibiotics if sufficient concentrations are achieved in the CSF. This study evaluated the disposition of cefpodoxime and penetration into CSF in piglets. Fifteen Landacre-Camborough cross piglets (10-20 days old) received cefpodoxime proxetil oral suspension (10 mg/kg). Repeated plasma and CSF samples were collected over 24 hours for quantitation of cefpodoxime by HPLC. Pharmacokinetic analysis was performed on both plasma and CSF data. The plasma concentration versus time data for cefpodoxime were best characterized using a one-compartment model with first-order absorption. The mean (+/- SD) pharmacokinetic parameters for Cmax, tmax, and AUC0-infinity were 23.3 +/- 12.9 mg/L, 3.9 +/- 1.4 h, and 237 +/- 129 mg/L.h, respectively. CSF/plasma ratios for AUC0-infinity demonstrated a mean cefpodoxime penetration of approximately 5%. CSF penetration of cefpodoxime was evident following a single oral dose of cefpodoxime proxetil suspension. Despite the small percentage of total cefpodoxime dose distributing into the CSF, the resultant concentrations approached or exceeded the MIC90 for many bacterial pathogens considered susceptible to cefpodoxime. Accordingly, clinicians should use caution in the interpretation of CSF cultures in patients who develop clinical signs and symptoms consistent with meningitis and who have been previously treated with cefpodoxime.     

Arrêt de la valorisation humanitaire des médicaments non utilisés : enjeux et perspectives

Since the 1970s, drugs unused by French households have been collected for humanitarian aid. In 1993, the Cyclamed^® system was created by pharmacists in order to manage and collect unused drugs. However, experience has shown that in developing countries unused drugs caused more problems than they solved, including: poorly adapted to the needs of the population, poor quality of the collected medicines, interferences with local pharmaceutical policies, misappropriation… As recommended by the World Health Organisation, most of the humanitarian organizations stopped unused drug donations. In France this practice has been forbidden since the 1st of January 2009. Associations that still desire to send unused drugs to developing countries must develop other approaches, such as essential generic medicines or emergency health kits.     

Clinical evaluation of cefotiam in the cerebrospinal fluid of patients with ruptured cerebral aneurysms in the acute stage

The treatment of the patients with ruptured cerebral aneurysm in acute stage is performed by direct neck clipping and cisternal drainages for preventing vasospasm. The cisternal drainage is carried out for 1 to 2 weeks' duration. The cisternal drainage has higher risk for bacterial infections in the cerebrospinal fluid (CSF). In this paper, penetration characteristics of cefotiam (CTM) in CSF were studied. CTM concentrations in CSF were measured at 1, 3 and 6 hours after intravenous drip infusion of CTM (2 g). CTM concentration in cisternal CSF was higher than that of ventricular CSF. The peak concentration in CSF was higher than 0.78 micrograms/ml and obtained at 3 hours after intravenous drip infusion. Our data suggest that CTM is a useful cephalosporin for treatment of meningitis (Staphylococcus aureus, Streptococcus pneumoniae et al.). Apart from meningitis, the higher concentration of CTM in CSF was obtained in the cases with the vasospasm. The result may support that the breakdown of blood brain barrier is induced by the peroxidative substance from the cisternal subarachnoid clots which has the vasospastic activity.     

隐球菌性脑膜炎患者真菌培养结果分析及潜在意义

目的探讨真菌培养结果对隐球菌性脑膜炎诊疗的意义。方法回顾性分析了隐球菌患者的脑脊液培养结果及印度墨汁染色结果,将两者对照研究。结果 45例隐球菌性脑膜炎患者首次脑脊液培养结果43例阳性,虽然高于印度墨汁染色38例阳性的结果,但差异无统计学意义（χ2=1.975,P=0.157）;治疗中期脑脊液培养结果30例为阳性,和印度墨汁染色的结果比较未见差异（χ2=1.661,P=0.195）;首次脑脊液培养结果显示26例患者对氟康唑耐药而未见对两性霉素B耐药者（χ2=33.804,P=0.000）;治疗末期脑脊液培养的结果先于印度墨汁染色转阴,10例印度墨汁染色持续阳性患者,脑脊液培养转阴患者停药后未见复发[P（1≤X）=0.002]。结论脑脊液培养对指导隐球菌脑膜炎患者抗真菌药物的使用有重要的价值,需高度重视;培养结果可能更适合作为停药的指标之一。     

Emerging drugs for acute bacterial meningitis

The management of acute bacterial meningitis is based on early antibiotic treatment to prevent unfavorable outcome (death and permanent sequelae). β-Lactam antibiotics, particularly third-generation cephalosporins, are effective against most agents of community-acquired acute bacterial meningitis. Resistance to β-lactams evolves, particularly in Streptococcus pneumoniae, that may lead to treatment failure. Evaluation of other antibiotics such as fourth-generation cephalosporin, new penems and quinolones is warranted. Adjunctive therapy aims to reduce tissue injuries provoked by the inflammatory response. The use of dexamethasone is still a matter of debate, but seems to be helpful under conditions of rapid etiological diagnosis and prompt management. Other drugs that neutralize bacterial factors or host mechanisms involved in induction of inflammatory response are under development.     

脑脊液降钙素原测定在颅脑外伤术后患者中的临床应用研究

目的探讨脑脊液降钙素原测定在早期诊断脑外伤术后患者颅内感染及指导抗生素使用的价值。方法选取40例颅脑外伤术后脑脊液细菌培养阳性的患者作为研究组,40例颅脑外伤术后脑脊液细菌培养阴性的患者作为对照组,分析两组患者的脑脊液PCT水平及血清PCT水平的分布,并对革兰染色阴性及阳性菌的脑脊液PCT水平及治疗前后脑脊液PCT、血清PCT、脑脊液培养进行比较。结果研究组患者的脑脊液PCT及血清PCT均明显高于对照组患者,P〈0．05;研究组患者于抗生素治疗1周后,体温正常后复查,脑脊液PCT明显高于血清PCT和脑脊液培养阳性结果,P〈0．05。结论脑脊液PCT检测则更为快捷、准确、方便,对颅脑外伤术后颅内感染的早期诊断更具临床意义;脑脊液PCT检测价值高于血清PCT检测和脑脊液细菌培养,可作为协助判断脑外伤术后患者颅内感染的指标,更能指导抗生素的使用。     

Treatment of E. coli meningitis with cefmetazole. Report of two cases with favorable response and determination of the concentrations in CSF (author's transl)]

Two patients with purulent meningitis, of which causative organism was presumed to be E. coli, were treated with intravenous administration of cefmetazole, 300 approximately 400 mg/kg/day in 4 approximately 6 divided doses, and the following conclusions were obtained. 1) Clinical response was favorable and a complete cure was obtained without sequelae in both patients. There were no adverse reactions noted except for a mild and transient eosinophilia (12%) in one case. 2) Of two strains of E. coli recovered from CSF, one was sensitive to ampicillin, cefazolin and cefmetazole, among which cefmetazole had the highest bacterial activity. Although another strain was sensitive to cefmetazole, it showed resistance to cefazolin (greater than 12.5 microgram/ml) and to ampicillin (greater than 100 microgram/ml). 3) Concentrations of cefmetazole in CSF following 1 approximately 2 hours of its intravenous administration were either equal to or higher than those of ampicillin, which was given to the same patient for a short period of time. The concentrations in CSF were higher than 3.1 microgram/ml on each occasion except for in some specimens during the convalescent phase and exceeded well the MIC of the causative organism. 4) Based on the above results, cefmetazole is considered to be a potent antibiotic in the treatment of E. coli meningitis. Although further studies are needed as to the dosage, an intravenous administration at 4-hour interval appears to be warranted based on the studies that the half-life of the drug is short in CSF in animal experiments.     

Cefotaxime and ceftriaxone cerebrospinal fluid levels during treatment of bacterial meningitis in children

Cefotaxime (CTX) and ceftriaxone (CRO) were compared for cerebrospinal fluid (CSF) penetration and antimicrobial efficacy in cases of bacterial meningitis in children. This was a comparative study of CRO (100mg/kg once daily) and CTX (50 mg/kg 6 hourly) in the treatment of children with bacterial meningitis. The aetiological agents included Streptococcus pneumoniae (SPn), Haemophilus influenzae type b (Hib) and Neisseria meningitidis (NMen). Minimum inhibitory concentrations (MICs) were measured. In 33 patients from whom a second CSF specimen was obtained, CSF was cultured and assayed for antibiotic concentration. Median MICs of CTX and CRO for SPn, Hib and NMen were 0.01 and 0.01 microg/mL, 0.004 and 0.002 microg/mL and 0.008 and 0.004 microg/mL, respectively. All 33 repeat lumbar puncture specimens were sterile. The lowest CSF level recorded (0.45 microg/mL for CTX) was 45 times the MIC (0.01 microg/mL). The highest levels (24-35 microg/mL for CRO) were up to 8750 times the MIC of the patient's causative organism. A wide range of CSF levels for both antibiotics was observed. Levels varied with post-dose interval and duration of illness. On the basis of these findings, clinicians should be reassured that repeat lumbar puncture is not recommended for the causative organisms in this study (i.e., for Hib, NMen and penicillin/cefotaxime/ceftriaxone fully-susceptible SPn).     

Bacterial meningitis associated with infliximab

We report an episode of bacterial meningitis in a 45 year-old woman, who was treated with infliximab for Wegener’s granulomatosis. This patient presented with the classic clinical presentation of acute meningitis: the triad of fever, neck stiffness, and an altered mental state that appeared 6 months after the infliximab initiation. A computed tomographic (CT) scan of the head showed cerebral edema and Streptococcus peumoniae was isolated from blood and CSF cultures. Prompt diagnosis and early treatment improved the outcome of this patient.     

Aseptic meningitis after intraventricular administration of gentamicin

Infection of the central nervous system (CNS) is a major cause of morbidity in patients with cerebrospinal fluid (CSF) shunts. Intraventricular administration of gentamicin, in combination with systemic antibiotics and shunt removal, may be beneficial in treating these infections. A young child was treated successfully for a ventriculoperitoneal shunt infection while receiving systemic nafcillin and intraventricular gentamicin. During treatment she developed CNS toxicity resembling aseptic meningitis. Based on CSF gentamicin levels and differential white blood cell counts, it was suspected that gentamicin was causing meningeal inflammation. Discontinuation of the drug relieved her symptoms. Rebound CSF leukocytosis associated with lymphocyte increase, despite a negative CSF culture, can indicate aseptic meningitis when drugs are administered intraventricularly. Clinicians should evaluate CSF cell count differentials before concluding treatment failure when administering antibiotics intraventricularly for meningitis.     

Réévaluation de la colistine

Colistin (polymyxin E) designates two different drugs, colistin sulfate, an oral digestive decontaminant, and colismethate sodium (CMS) intended for intravenous, intrathecal/intraventricular, or inhaled therapy. Colistin interferes with bacterial membranes creating cytoplasmic leaks lethal to bacteria through interactions with membrane proteins and phospholipids (including LPS). This mechanism of action confers bactericidal activity to colistin on frequently multiresistant pathogens such as Acinetobacter spp., P. aeruginosa, and Klebsiella spp. It also leads to specific resistance mechanisms, which arise from modifications in bacterial membrane proteins. New methods applied to pharmacokinetic studies of colistin take into account the in-solution and plasmatic hydrolysis of CMS, the inactive prodrug, into active compounds among which colistin. These studies show that current therapeutic regimens may be optimized. Colistin being a concentration dependent bactericidal antibiotic, the area under the curve (AUC)/MIC was proven the best PK/PD parameter associated with in vivo efficacy, opening new perspectives in alternate dosing regimens. Nephrotoxicity occurs at a rate comparable to aminoglycosides and neurotoxicity is more often benign; both being reversible upon discontinuation of therapy. In multiresistant Gram negative, mostly A. baumanii or P. aeruginosa, nosocomial infections as well as in chronic P. aeruginosa infections and exacerbations in cystic fibrosis patients, the efficacy of colistin has been demonstrated within the limitations inherent to studies of an antibiotic which can only be used after determination of susceptibility in severe infections nonetheless requiring urgent adequate therapy. Further clarifications are required concerning the added benefit of combination with antibiotics considered as synergistic such as rifampicin and carbapenems.     

Handiness and acceptability of the new Abak bottle in chronically treated patients. A cross-sectional, retrospective and multicentre study

Background

Difficulty of use of eyedrops is a factor associated with poor patient compliance that reduces treatment efficacy. The aim of this study was to evaluate the handiness and global acceptability of the new Abak^® timolol bottle (multidose preservative-free eyedrops) in comparison with that of other administration systems (classical multidose eyedrops or single-doses) in patients treated for glaucoma or ocular hypertension.

Methods

Cross-sectional, retrospective and multicentre study involving 41 ophthalmologists in France. Selected patients were those who had been treated with the new Abak^® bottle since at least two months, as a replacement for other beta-blocker eyedrops. Handiness and acceptability of the new Abak^® bottle in comparison with other delivery systems were evaluated using a questionnaire filled by the investigator.

Results

Almost all the patients were unanimous regarding the handiness of the new Abak^® bottle: easy to open for 96.5% of them, easy to handle for 96.0%, and easy to get drops for 91.1%. For all these criteria and in a general manner, patients preferred the new Abak^® bottle in comparison with the previous eyedrop container. These results were confirmed in the oldest patients.

Conclusion

The new Abak^® bottle had a greater acceptability compared to preserved multidose eyedrops or to single-doses. Its handiness and the absence of preservative which may improve local tolerance are in favor of a greater compliance in chronically treated patients.     

Bacteriological efficacy of nafcillin and vancomycin alone or combined with rifampicin or amikacin in experimental meningitis due to methicillin-susceptible or -resistant Staphylococcus aureus

The pharmacokinetics and bacteriological efficacy of nafcillin (NFPC), vancomycin (VCM), amikacin (AMK) and rifampicin (RFP) alone and in VCM combinations were evaluated in the experimental rabbit meningitis caused by methicillin-susceptible Staphylococcus aureus (MSSA) or methicillin-resistant Staphylococcus aureus (MRSA). The mean concentrations of NFPC, VCM, AMK and RFP in cerebrospinal fluid (CSF) with MSSA meningitis exceeded the minimal bactericidal concentrations of MSSA during 8 hours therapy period. The mean CSF penetration rates of the 4 drugs during therapy were from 1% to 26% which are comparable to those observed in humans with meningitis. The median CSF bactericidal titers of RFP, VCM plus RFP, AMK, VCM plus AMK regimens were larger than 1:8 during therapy of MSSA meningitis study. In experimental MRSA meningitis, RFP and VCM plus RFP achieved titers greater than 1: 16 during therapy and at 24 hours. No statistically significant reduction in the CSF bacterial colony count was obtained with any of the antibiotic regimens in MSSA meningitis. By contrast, in 8 hours MRSA meningitis model, significant reductions in the number of MRSA were observed in animals treated for 8 hours with VCM plus RFP (P less than 0.01), RFP (P less than 0.05), and NFPC plus RFP (P less than 0.01).     

Clinical experience with cefuzonam in bacterial infection of children

Clinical studies were performed on cefuzonam (L-105, CZON), a new cephem antibiotic, as follows. Cerebrospinal fluid (CSF) and serum concentrations. CSF and serum concentrations of CZON were measured in 1 case of septic arthritis without meningitis. One hour after 50 mg/kg intravenous bolus injection, the CSF and serum concentrations were 0.10 and 18.1 micrograms/ml, respectively, and CSF to serum concentration ratio was 0.55%. Clinical efficacy CZON was administered to 15 patients in doses ranging 54.5 approximately 212.4 mg/kg/day (94.1 mg/kg/day on average) t.i.d. or q.i.d. for 4 approximately 12 days (6.5 days on average). Of those patients, 9 were with pneumonia, one each was with bronchitis, with tonsillitis, with septic arthritis, with septicemia, with purulent meningitis and with urinary tract infection. The overall efficacy rate was 100%, i.e., efficacy was excellent in 12, good in 3. Bacteriological efficacy was excellent, i.e., 8 of 8 strains were eradicated. Side effects were observed in 2 cases, i.e., one case with loose stool and another with eruption. Laboratory abnormalities to the drug were not observed during the treatment. The above results suggested that CZON would be a useful antibiotic for treating pediatric bacterial infections.