Multidrug-resistant Gram-negative infections: the use of colistin

The emergence of nosocomial infections due to multidrug-resistant Gram-negative bacteria led to the revival of ‘forgotten’ antibiotics, such as polymyxins. Colistin, mainly colistimethate sodium (polymyxin E), has been predominantly used. Recent studies suggest that colistin administered as monotherapy or combination therapy is an effective and safe antimicrobial agent for multidrug-resistant Gram-negative bacteria infections. The reported colistin nephrotoxicity is 20% or lower. Although colistin is commonly administered intravenously, it can also be administered via inhalation for pneumonia/ventilator-associated pneumonia treatment or by the intraventricular/intrathecal route for meningitis/ventriculitis treatment. Randomized controlled trials are needed to answer clinical questions such as the appropriate colistin dose, to compare colistin monotherapy with combination therapy, and to determine the exact therapeutic role of aerosolized or intrathecal/intraventricular administration of colistin.     

Intrathecal colistin and sterilization of resistant Pseudomonas aeruginosa shunt infection

OBJECTIVE: To report 2 cases of multidrug-resistant (MDR) Pseudomonas aeruginosa meningitis and ventriculo-peritoneal shunt (VPS) infection successfully sterilized with intrathecal colistin 10 mg/day after development of nephrotoxicity associated with intravenous administration. CASE SUMMARIES: Case 1. A 69-year-old African American woman with a history of subarachnoid hemorrhage and hydrocephalus requiring VPS placement was admitted with VPS infection and meningitis. Cerebrospinal fluid (CSF) cultures revealed MDR P. aeruginosa susceptible only to colistin. Intravenous colistin was initiated but rapidly discontinued due to development of renal dysfunction. Intravenous colistin was the probable cause of the adverse effect. Intrathecal colistin was initiated via an externalized VPS, with subsequent improvement in white blood cell counts in the CSF. Follow-up CSF cultures remained sterile and renal function returned to baseline. Case 2. A 69-year-old white woman with a history of subarachnoid hemorrhage, hydrocephalus, and VPS was transferred from an extended-care facility for management of a VPS infection. CSF cultures revealed MDR P. aeruginosa susceptible only to colistin. Intravenous colistin was initiated but subsequently discontinued due to worsening renal function that, as with the first case, probably correlated with colistin administration and persisted despite dose adjustment. Therapy was changed to intrathecal administration, with subsequent normalization of her CSF white blood cell counts and sterilization of cultures. DISCUSSION: The limited availability of antibiotics for treatment of highly resistant or MDR gram-negative organisms has prompted clinicians to reconsider the use of older drugs. Prior reports have suggested that intravenous colistin is a potential alternative for treating highly resistant gram-negative central nervous system infections, specifically Acinetobacter, but its use is limited by nephrotoxicity. Our experience suggests that intrathecal colistin is a potentially curative intervention for the treatment of severe MDR P. aeruginosa meningitis and VPS infections in patients in whom intravenous colistin is not an option. CONCLUSIONS: Intrathecal use of colistin is a potentially safe, effective, and viable treatment option for MDR P. aeruginosa central nervous system infections when intravenous administration is not feasible.     

Intraventricular vancomycin for treatment of shunt-associated ventriculitis

Twenty episodes of shunt-associated ventriculitis caused by staphylococci or streptococci were treated with intraventricular vancomycin together with removal of the shunt and insertion of an external drain. Systemic antibiotics given concurrently included intravenous vancomycin or flucloxacillin. All the patients responded to therapy although five had re-infections and one had a relapse. Four patients were treated solely with intrathecal vancomycin. We now use intraventricular vancomycin alone for 'blind' treatment of uncomplicated shunt-associated infections when Gram-positive cocci are seen in the ventricular CSF.     

Intraventricular or intrathecal colistin for the treatment of central nervous system infections caused by multidrug-resistant Gram-negative bacteria

Central nervous system infections caused by Gram-negative bacteria susceptible only to colistin are rare but life-threatening and increasing in prevalence. Given the current antibiotic development pipeline it is likely that the paucity of therapeutic options will continue for the next years. Colistin is an amphipathic bactericidal antibiotic which is administered systemically as colistin methanesulfonate (also known as colistimethate sodium). Colistin methanesulfonate is the inactive prodrug, and in cerebrospinal fluid undergoes spontaneous hydrolysis to colistin (the active form with antimicrobial activity). In this review, we describe and evaluate the clinical and experimental data supporting the use of intraventricular (IVT) or intrathecal (IT) colistin against multidrug-resistant Gram-negative infections of the central nervous system, describe the permeability of the blood-brain barrier to colistin, the pharmacokinetics of colistin after IVT administration of colistin methanesulfonate, its anti-endotoxin activity, discuss the opportunity to administer colistin intraventricularly or intrathecally and the dose regimen, and provide recommendations based on the available evidence.     

A multidrug-resistant Acinetobacter baumannii outbreak in intensive care unit: antimicrobial and organizational strategies

Purpose

Multidrug-resistant Acinetobacter baumannii (MRAB) is an emerging cause of intensive care unit (ICU) outbreaks. Patients are the main reservoirs, inducing cross transmission. We describe an MRAB outbreak that occurred in the Prato Hospital ICU in June to August 2009.

Materials and Methods

The ICU consists of 2 separated 4-bed rooms (rooms A and B). The MRAB-positive patients were included in our study. During the outbreak, infection control measures were enhanced; patients and environmental screenings were performed. A 6-month follow-up was carried out.

Results

Four of 26 patients admitted during the outbreak were MRAB positive. All patients were located in room A; no case was detected in room B either in the hospital or during the follow-up. Management included closure to new admissions, reinforcement of infection control measures, patient and environmental screenings, discharge of room B MRAB-negative patients for at least 5 days after the first case identification. All isolates were carbapenems resistant and tigecycline and colistin susceptible. All patients received tigecycline: 2 were successfully treated, 1 died because of preexisting illness, and 1 developed resistance and recovered after colistin therapy.

Conclusions

Enhanced infection control measures and adequate antibiotic strategy limited the outbreak. Tigecycline allowed rapid recovery. Nevertheless, resistance ensued; so colistin remained the only therapeutic option. However, pan-drug resistance has been reported.     

Cerebrospinal fluid tumor necrosis factor-alpha, interleukin-1beta, interleukin-6, and interleukin-8 as diagnostic markers of cerebrospinal fluid infection in neurosurgical patients

OBJECTIVE: To evaluate whether cerebrospinal fluid concentrations of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, or IL-8 may be used as diagnostic markers for the differential diagnosis of aseptic vs. bacterial meningitis and/or ventriculitis in neurosurgical patients. DESIGN: Prospective, observational study. SETTING: University teaching hospital. SUBJECTS: A total of 112 cerebrospinal fluid samples from 14 asymptomatic patients with normal cerebrospinal fluid after neurosurgery, 27 asymptomatic and 19 symptomatic patients with postneurosurgical aseptic meningitis, 32 patients with postneurosurgical cerebrospinal fluid infection, and 20 with severe subarachnoid and/or cerebral hemorrhage. MEASUREMENTS AND MAIN RESULTS: Specific ELISA kits were used to analyze TNF-alpha, IL-1beta, IL-6, and IL-8 concentrations on cerebrospinal fluid samples. Elevations in cerebrospinal fluid concentrations of TNF-alpha, IL-1beta, IL-6, and IL-8 were induced by different diseases or neurosurgical procedures, but cerebrospinal fluid bacterial infection induced the highest concentrations. To discriminate between aseptic cerebrospinal fluid pleocytosis and cerebrospinal fluid infection with a specificity of 95%, cerebrospinal fluid leukocyte count >1700/mL, TNF-alpha >150 pg/mL, and IL-1beta >90 pg/mL showed sensitivities of 51%, 74%, and 90%, respectively. Sufficiently sensitive and specific cutoff points could not be found for cerebrospinal fluid IL-6 or IL-8. CONCLUSION: Cerebrospinal fluid IL-1beta appears to be the best biochemical marker of cerebrospinal fluid infection in neurosurgical patients.     

Treatment of central nervous system infection by vancomycin-resistant enterococcus faecium

Enterococci are uncommon causes of CNS infection. We describe a case of ventriculitis and Ommaya reservoir infection due to vancomycin-resistant Enterococcus faecium successfully treated with the combination of i.v. quinupristin/dalfopristin and i.v. linezolid. The patient deteriorated after receiving three dosages of intraventricular quinupristin/dalfopristin. He recovered after discontinuation of intraventricular quinupristin/dalfopristin.     

Pharmacokinetic model for tobramycin in acinetobacter meningitis

OBJECTIVE: To report a case of acinetobacter meningitis treated with a once-daily intravenous dose of tobramycin and to propose a pharmacokinetic model for the drug disposition. CASE SUMMARY: A 28-year-old man with chronic hydrocephalus was admitted with a diagnosis of intracranial hypertension. Acinetobacter spp. was detected in the cerebrospinal fluid (CSF); it was sensitive to tobramycin, ampicillin/sulbactam, and colistin. Based on the culture report, multiple daily-dose therapy with tobramycin was started. As the infectious symptoms remained, once-daily therapy was recommended; the optimal dose was calculated with nonlinear regression by least-squares analysis and a Bayesian method, using plasma and CSF samples. The infection was resolved, tobramycin therapy was discontinued, and the patient was discharged from the intensive care unit. DISCUSSION: We use once-daily intravenous tobramycin therapy because, although the intrathecal administration of drugs is generally well tolerated, the presence of preservatives may be a source of central nervous system adverse effects. Pharmacokinetic parameters were calculated with plasma and CSF concentration values obtained during the first once-daily dose by using a compartment-effect model which allows fitting of simultaneous plasma and CSF concentrations. The prediction level was determined by the estimation of drug concentrations during the fourth once-daily dose. CSF concentrations of drug were enough to eradicate the clinical signs of infection. CONCLUSIONS: Therapy using once-daily intravenous administration of tobramycin may be an adequate alternative for acinetobacter infections in neurosurgical patients when an intrathecal route is initially not recommended. The development of a compartment-effect model can be useful to predict drug concentrations.     

Intraventricular levels of amikacin after intravenous administration.

Serum and ventricular fluid pharmacokinetic data for amikacin were evaluated prospectively in 10 hydrocephalic children with suspected ventriculitis. After the fourth or fifth intravenous 7.5-mg/kg dose of amikacin given every 8 h, mean peak serum levels were 24.3 +/- 3.2 microgram/ml (achieved at 0.5 h) with a calculated half-life of 2.2 +/- 1.1 h. Mean peak ventricular fluid levels in five patients with bacterial infection were 6.1 +/- 2.0 microgram/ml (achieved at 3 h). In the remaining five patients without bacterial ventriculitis, very low levels (less than or equal to 0.7 microgram/ml) of amikacin were detected. Ventricular fluid pleocytosis was directly correlated and glucose levels were inversely correlated with penetration of amikacin. Systemic therapy with amikacin may be the treatment of choice for children with ventriculitis meningitis caused by bacteria which are highly susceptible to this drug, thereby permitting the avoidance of the potentially hazardous intraventricular route of administration.     

Neuroendoscopic surgery for ventriculitis and hydrocephalus after shunt infection and malfunction: Preliminary report of a new strategy

If not controlled in the early stage, ventriculitis is difficult to treat neurosurgically and can lead to serious sequelae, a long course of treatment, and hospitalization. We report two cases of ventriculitis and progressive hydrocephalus after shunt infection. Both were successfully treated by neuroendoscopic septostomy in combination with thorough intraventricular irrigation through a single burr hole followed by single shunt revision. Although surgical intervention has not been established as a first‐choice treatment for ventriculitis, including early‐stage ventriculitis, prompt neuroendoscopic surgery appears effective for the management of ventriculitis and hydrocephalus after shunt infection. The strategy described in this report might be useful to avoid recurrent shunt infections and malfunctions, simplify a shunt, and reduce the overall duration of hospitalization.     

腰大池持续引流在神经外科中的临床应用体会

目的探讨腰大池持续脑脊液引流在神经外科应用的临床价值。方法回顾性分析2007年1月-2009年9月,12例患者进行了持续腰大池脑脊液引流治疗,其中切口漏8例,术后颅内感染2例,脑室内出血2例。结果持续腰大池脑脊液引流治疗脑脊液漏、颅内感染及脑室内出血的治愈率为91.66%,无颅内感染及脑疝等严重并发症。结论腰大池持续脑脊液引流是一种安全、有效、简单的治疗脑脊液漏、颅内感染及脑室内出血的方法。     

Third-generation cephalosporin resistance among Gram-negative bacilli causing meningitis in neurosurgical patients: significant challenges in ensuring effective antibiotic therapy

OBJECTIVES: The treatment of meningitis caused by Gram-negative bacilli in neurosurgical patients is a major challenge because of the complexity of these patients, the emergence of antibiotic resistance in many of the causative organisms and the restricted choice of antibiotics suitable for use, owing to a failure to achieve high enough concentrations in the CSF. We reviewed the incidence, aetiology, treatment and outcome of all patients with Gram-negative bacillary meningitis (GNBM) in our centre over a 7 year period. METHODS: Beaumont Hospital, Dublin is a 720 bed tertiary referral hospital and contains the national neurosurgical centre for the Republic of Ireland. The case notes and microbiological records of all patients with GNBM between 1998 and 2004 inclusive were reviewed retrospectively. Only patients with positive CSF culture and clinical features compatible with meningitis were included. RESULTS: Forty separate episodes of GNBM involving 34 different patients occurred during the study period. The most common causative organisms were Enterobacter spp. (35%), Escherichia coli (22.5%) and Pseudomonas aeruginosa (15%). Twenty-five per cent of isolates were resistant to third-generation cephalosporins. The median duration of treatment was 19.2 days and a combination of intravenous and intraventricular antibiotics was the most common treatment regimen used. Mortality directly related to GNBM was 2.5%. CONCLUSIONS: Although the mortality directly related to GNBM was low, the emergence of strains resistant to third-generation cephalosporins represents a therapeutic challenge. Treatment with combined intravenous and intraventricular antibiotics is recommended for 2-3 weeks, but more studies are required to determine the optimal management of this difficult condition.     

Central nervous system infections due to Abiotrophia and Granulicatella species: an emerging challenge?

Although Abiotrophia and Granulicatella species, previously referred to as nutritionally variant streptococci, were initially identified over 40 years ago, isolation of these pathogens from the central nervous system (CNS) was first noted only recently. Recognition of CNS involvement with these organisms is of great concern given the association of Abiotrophia/Granulicatella infections with increased morbidity and mortality as well as greater bacteriologic failure and relapse rates. We describe A. defectiva and G. adiacens CNS infections in two patients and review the existing literature of CNS involvement with these bacteria. The clinical presentation and initial cerebrospinal fluid analysis has varied substantially across reported patients. While most infections have been characterized primarily by a localized infection (e.g., abscess), evidence of meningitis has usually also been present. Furthermore, nearly all cases have followed neurosurgical procedures suggesting possible introduction of the organism into the CNS at the time of surgery. Given the significant negative clinical impact of Abiotrophia/Granulicatella infections, elucidation of the emerging epidemiology of CNS infections with these bacteria is warranted.     

Serum procalcitonin monitoring for differential diagnosis of ventriculitis in adult intensive care patients

The objective of our study was to assess the value of serum procalcitonin (PCT) monitoring in the differential diagnosis of ventriculitis in adult intensive care (ICU) patients. We analyzed 15 consecutive patients with ventriculitis in which a ventricular catheter had been inserted and contrasted these data with the observations in 10 patients with community-acquired bacterial meningitis. Cerebrospinal fluid (CSF) and blood samples were collected daily to assess serum PCT, C-reactive protein (CRP) and CSF leukocyte count. PCT levels were normal or slightly elevated in patients with ventriculitis with either positive or negative CSF bacterial culture but elevated in patients with bacterial meningitis. A PCT cut-off value of 1.0 ng/ml or more showed a specificity of 77% and a sensitivity of 68% for ventriculitis with positive CSF bacterial culture. Serum PCT levels reflected more accurately the time phases of disease during therapy. We conclude that the monitoring of serum PCT alone is not helpful for the differential diagnosis of ventriculitis, in contrast to that of bacterial meningitis. The value of PCT as an additional marker with which to assess the efficacy of therapy in ventriculitis is suggested, but requires further assessment.     

Combination therapy with intravenous colistin for management of infections due to multidrug-resistant Gram-negative bacteria in patients without cystic fibrosis

Colistin, an antibiotic almost abandoned for intravenous administration for many years due to its reported toxicity, has been recently reintroduced in clinical practice due to the emergence of multidrug-resistant gram-negative bacteria and the lack of development of new antibiotics to combat them. To assess the safety and effectiveness of intravenous colistin, in combination with other antimicrobial agents, in the treatment of serious infections in patients without cystic fibrosis, a retrospective cohort study in a 450-bed tertiary-care hospital in Athens, Greece, was performed. Patients who were hospitalized from 1 October 2000 to 31 January 2004 and received intravenous colistin for more than 72 h were further analyzed. The primary outcome measure was the in-hospital mortality; secondary end points were the clinical outcome of the infections and the occurrence of colistin toxicity. Fifty patients received intravenous colistin with a median (mean) daily dose of 3 (4.5) million IU for 16.5 (21.3) days for the management of 54 episodes of infections due to multidrug-resistant gram-negative bacteria. The predominant infections were pneumonia (33.3%), bacteremia (27.8%), urinary tract infection (11.1%), and intra-abdominal infection (11.1%). The responsible pathogens were Acinetobacter baumannii (51.9%), Pseudomonas aeruginosa (42.6%), and Klebsiella pneumoniae (3.7%) strains (no pathogen was isolated from one case). In-hospital mortality was 24% (12/50 patients). Clinical response (cure or improvement) of the infection was observed in 66.7% of episodes (36/54). In the studied group, serum creatinine levels were decreased, at the end of colistin treatment, by an average of 0.2 +/- 1.3 mg/dl compared to baseline levels. Deterioration of renal function during colistin therapy was observed in 4/50 patients (8%). Coadministration of other antimicrobial agents with spectrum against gram-negative microorganisms and the absence of a control group constitute the major limitations of this study. The use of intravenous colistin for the treatment of infections due to multidrug-resistant gram-negative bacteria appears to be safe and effective.     

Infectious complications after brain tumor removal: some aspects of their prevention, diagnosis, and treatment

A hundred and fifty-five case histories of neurosurgical patients with the complicated early postoperative period were analyzed. Early postoperative regional pyoinflammatory complications were developed in 21 (4.4%) of 481 patients. There was meningitis in 17 (3.5%) cases, ventriculitis in 2 (0.4%), and wound infection (skin flap suppuration and postoperative wound fistula). Systemic pyoinflammatory complications were observed in 8% of the patients. Among them, there were pyoinflammatory complications in the respiratory system in 30 (6.2%) cases, pyonecrotic cystitis in 5 (1%), and sepsis in 2 (0.4%). Risk factors for regional and systemic complications are shown. Based on the findings, recommendations are given to prevent and treat pyoseptic complications in neurosurgical patients.     

脑积水脑室腹腔分流相关性脑室炎治疗方案的探讨

目的探讨脑积水脑室腹腔分流相关性脑室炎的治疗方法。方法对临床怀疑有脑脊液分流管性感染的患者,先拔除原分流管．同时行脑室外引流术．取脑室内脑脊液行细菌培养和抗生素敏感试验检查。术后,在获得细菌培养结果前．每日经脑室外引流管注入万古霉素25～50mg;在获得细菌培养结果后,确定或调整使用抗生素的种类。在脑室炎治愈后,根据需要最终对脑积水给予合理的治疗。结果11例患者中感染凝固酶阴性或表皮葡萄球菌及金黄色葡萄球菌者共9例,其中1例感染阴沟杆菌、克雷伯杆菌和产气肠杆菌;1例感染链球菌;1例感染牛粪杆菌。药敏试验表明：9例患者感染的球菌对万古霉素均敏感,但其中仅1例对庆大霉素敏感。1例感染链球菌和2例感染杆菌者,均有各自敏感的抗生素。在临床治疗中,万古霉素实际有效者8例;抗生素治疗疗程为16～36d。11例患者全部存活,其中9例神经功能明显改善。结论①脑室内注入抗生素是一种治疗脑室炎可靠而有效的方法。②万古霉素是治疗脑室炎的首选药物,少数患者需要加用或改用其他抗生素。③系统性抗生素治疗的作用尚不能肯定,可在感染表现期辅助使用。④脑室炎的诊断和治疗还涉及很多问题,有待广泛而深入的研究。     

Diffusion of ofloxacin into cerebrospinal fluid of patients with purulent meningitis or ventriculitis.

The penetration of ofloxacin was studied in 22 patients with purulent meningitis or ventriculitis treated with conventional antibiotics. Three successive doses of 200 mg were infused at 12-h intervals during the acute stage of the disease. Ten patients received three additional doses when the meninges were considered to be healed. Cerebrospinal fluid (CSF) was drawn 0.5, 3, 6, or 12 h after the last infusion. Serial plasma and CSF samples were also obtained from patients with ventricular drainage. Concentrations in CSF ranged from 0.96 +/- 0.15 to 1.80 +/- 0.29 microgram/ml, depending on sampling time. The percentage of penetration in ventricular fluid, expressed as the ratio of the CSF area under the curve from 0 to 12 h to the plasma area under the curve from 0 to 12 h, was 73 +/- 6. Ofloxacin readily diffuses into CSF of patients with meningitis or ventriculitis and may be useful for treatment of CSF infections caused by susceptible pathogens.     

The evaluation of safety and efficacy of colistin use in pediatric intensive care unit: Results from two reference hospitals and review of literature

Colistin, an old cationic polypeptide antibiotic, have been reused due to rising incidence of infections caused by multi-drug resistant (MDR) Gram-negative microorganisms and the lack of new antibiotics. Therefore, we evaluated safety and efficacy of colistin in treatment of these infections. This study included 104 critically ill children with a median age of 55,9 months between January 2011 and January 2016. Nephrotoxicity occurred in 11 (10.5%) patients. Nephrotoxicity occurred between the third and seventh day of treatment in 63% of colistin induced nephrotoxicity episodes. The subgroup analysis between the patients who developed nephrotoxicity during colistin treatment and those that did not, showed no significant difference in terms of age, underlying disease, cause for PICU admission and type of infection required colistin treatment, P values were 0.615, 0.762, 0.621, 0.803, respectively. All patients were receiving a concomitant nephrotoxic agent (P = 0,355). The majority of the patients (52%) were having primary or secondary immune deficiency in treatment failure group and the most common cause of PICU admission was sepsis in treatment failure group, P values were 0.007 and 0.045, respectively. Mortality attributed to colistin failure and crude mortality were 14.4% and 29.8%, respectively. In conclusion, colistin may have a role in the treatment of infections caused by multidrug-resistant Gram-negative bacteria in critically ill children. However, the patients have to be followed for side effects throughout colistin treatment, not for only early stage. And the clinicians should be aware of increase in the rate of nephrotoxicity in patients those have been receiving a concomitant nephrotoxic agent.     

Intrathecal amikacin for the treatment of pseudomonal meningitis

OBJECTIVE: To report a case of gram-negative bacillary meningitis (GNBM) secondary to multidrug-resistant Pseudomonas aeruginosa that was treated with intravenous meropenem and intrathecal and intravenous amikacin. CASE SUMMARY: A 76-year-old Arabic woman with previous placement of an extraventricular device developed meningitis secondary to P. aeruginosa as a result of a previous pneumonia. The patient was treated with intravenous meropenem and amikacin, with the addition of intrathecal amikacin, until cerebrospinal cultures remained negative for 18 days. She did not experience any adverse effects as a result of the administration of the intrathecal amikacin. Although the meningitis subsequently resolved, the patient eventually died due to Candida glabrata fungemia. DISCUSSION: Dual therapy is recommended for patients with P. aeruginosa meningitis. In our patient, the increasing resistance to imipenem and resistance to all other potential antibiotics resulted in the use of an alternative administration technique that has not been well documented in recent literature. CONCLUSIONS: In patients who have GNBM due to P. aeruginosa, the combination of intrathecal and intravenous amikacin may be an option for therapy, especially when clinical options are limited by resistance, severity of illness, and location of the infection. More information is required and further study is needed on this topic.