Dosing of Colistin in Special Patient Populations: CNS, Bone, UTIs, Sepsis

Transcription

1 Akropolis Dosing of Colistin in Special Patient Populations: CNS, Bone, UTIs, Sepsis Helen Giamarellou

2 The Erechtheion Temple Colistin in CNS Infections The presence of multi-resistant bacteria and the poor penetration of many drugs through the blood-brain barrier have imposed the use of intrathecal therapies

3 Nosocomial Gram-negative Meningitis Three recent reports document Acinetobacter as the dominant causative microorganism in nosocomial Gram-negative meningitis All cause mortality ranges between 15%-71%, depending on the susceptibility patterns Risk factors include: Neurosurgical procedures, CSF leak, Prolonged use of intravascular devices, Prior treatment with broadspectrum antibiotics, Prior colonisation with Acinetobacter, Prolonged mechanical ventilation and intensive care unit stay Intracranial haemorrhage Lancet Infect Dis 2009; 9: 245 Expert Opin Pharmacother 2010; 11: 779

4 Nosocomial XDR Acinetobacter baumannii strains are usually susceptible only to tigecycline and colistin and rarely to aminoglycosides However, tigecycline and the aminoglycosides do not penetrate the CSF Does colistin penetrate the CSF?

5 The low level (5%) of penetration of Colistin after 2-3 MU IV (trough levels range: μg/ml) suggests that: Inadequate bactericidal colistin concentrations in the CSF after parenteral administration 1 mg CMS = IU

6 CSF colistin concentrations in 5 pts 1 ½ months to 15 years after a dose of IU/kg/day IV were <0.2 μg/ml but increased in the presence of meningitis (0.5 μg/ml or 34% to 67% of concomitant serum levels) Still inadequate levels in the CSF!

7 ot w to b ith e ou co t t pi he ed pe an rm d is dis si tr on ib of ute th d t e o au ot th he or rs Greece 6 patients, 5 with subarachnoid hemorrhage and 1 with head injury XDR A. baumannii sensitive only to colistin and tigecycline were isolated from CSF with simultaneous bacteremia with an identical Acinetobacter strain observed in three patients All patients had an external ventricular drainage (EVD). In five of them the device was replaced during treatment The IVR dose of CST consisted of a loading dose of IU, followed by IU every 24 to 48 hours for a mean of 16.3d IV colistin was concomitantly administrated at a dose of IU q12h The median time of sterilization of the CSF was 2,5 days N All patients were cured Karaiskos I et al. IJAA 2013; 41: 480

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9 A total of 83 episodes in 81 patients were identified (71 cases in adults and 10 in children and neonates) Colistin was administered by the IVT route in 52 and ITH in 22 cases, whilst in 7 cases the exact route was not defined Karaiskos I, et al. IJAA :499

10 The median dose of IVT or ITH colistin was IU with a range of IU to IU in adults The median duration of treatment was 18.5 days, The median time to achieve sterilization of CSF was 4 days Successful outcome: 89% Toxicity manifested as reversible chemical ventriculitis/ meningitis was reported in five cases (6%) whereas other neurological side effects (seizures and cauda equina) in 4 patients (4.8%) Karaiskos I, et al. IJAA :499

11 26/30 episodes 87% Cure Mean dose of colistin MU x 1-9 weeks Meningeal irritation in 4 patients It is obvious that IVR administration of CMS in XDR A. baumannii meningitis offers a unique and successful mode of therapy Falagas M, et al. IJAA 2007; 29: 9

12 Chemical meningeal irritation presents with: o Fever, o Altered mental status, o Elevation of the white blood cell count in CSF o Low glucose concentrations in CSF, Mimicks 100% bacterial meningitis, the only difference being the sterile CSF cultures in case of chemical meningitis! Karaiskos I, et al. IJAA :499

13 Acinetobacter produces biofilm! External Ventricular Drainge should be removed However, the exact time of EVD removal has not been defined It seems that with the first negative CSF culture the EVD should be removed or replaced since relapses are associated with biofilm-producing Acinetobacter strains CMI 2008; 14: 276

14 What is the Appropriate Dose of IVR or ITH Colistin? Antimicrob Agents Chemother 2012; 56:

15 Patient Dose regimen of CMS (mg) Daily dose of CMS (mg) Measured* C trough (μg/ml) /24h C max (μg/ml) /12h /12h /12h /24h /24h /12h /12h /12h * Colistin susceptibility breakpoint is 2 μg/ml Imberti R, et al. AAC 2012; 56: 4416

16 Imberti R, et al. AAC 2012; 56: 4416

17 When CMS was administered at doses of 5.22 mg/day, measured CSF concentrations of colistin were continuously above the MIC of 2 μg/ml (colistin breakpoints), and measured values of trough concentration (C trough ) ranged between 2.0 and 9.7 g/ml Microbiological cure was observed in 8/9 patients Intraventricular administration of CMS at doses of 5.22 mg per day was appropriate, but since external CSF efflux is variable and can influence the clearance of colistin and its concentrations in CSF the daily dose of 10 mg suggested by the Infectious Diseases Society of America may be more prudent Imberti R, et al. AAC 2012; 56: 4416

18 7 pts with gram negative ventriculitis caused by A.baumannii and K.pneumoniae - 3 treated with IV colistin - 4 treated with Combination IV and IVT colistin Control group ( 5pts) with EVD without CNS infection plus IV CMS Dose: 3 MU q8h IV and IU IVT q24h CMS penetration in the absence of inflammation is minimal (CSF/serum ratio:0.07) CSF penetration of IV Colistin in inflammation: 11% CSF/serum only with IV colistin and CSF/serum with both routes: Ratio significantly higher in combination group compared to the control ( ) No evidence of drug accumulation over time Ziaka M, et al. AAC 2013; 57: 1938

19 Karyatides Akropolis Museum Colistin and Bone Infections

20 Difficult-to-treat Gram-negative Bone and Joint Infections: Efficacy and Safety of Prolonged Intravenous Colistin 19 patients with a median age of 54.4 y 14 cases of osteomyelitis and 5 joint infections: 12 with orthopaedic implants Causative pathogens were XDR and MDR Pseudomonas aeruginosa and Enterobacter spp (4 MDR, 13 XDR). Colistin dose was IU/kg/day (divided in 2-3 doses) for a mean of 81 days ( days) Surgical treatment was always performed as necessary Median follow-up was 27.7 weeks (5-59.3) Remission was achieved in 73.7% with 42% failure rate in case of performed orthopaedic devices 4 patients (21.1%) experienced reversible grade 1 acute renal failure Valour et al. IJAA 2013; 41: 197

21 Colistin in UTIs Kore of Chios Akropolis Musuem

22 20% (60%) (<1%) Couet W, et al. Clin Microbiol Infect 2012; 18: 30

23 Microbiologic Clearance Rates 87 cases vs 69 untreated * Polymyxins are not approved by the FDA for the treatment of UTIs *2.25 mg/kg/day Satlin M, et al. AAC 2011; 55: 5893

24 Colistimethate sodium 3.5 mg/kg was dissolved in a 500 ml saline solution administered through a triple intravesical catheter with continuous irrigation over seven days. 10 days post therapy follow-up urine was sterile

25 The Teen of Antikythera Colistin in Pediatrics Experience in 112 children and 28 neonates

26 Falagas et al (7 pts) Celebi et al (15 pts) Josifidis et al (13 pts, 19 courses) Experience from Colistin Administration in Pediatric and Neonatal Patients Mean age 7.2 y 53.2 ± 74.7 m 5 y Colistin daily dose 5mg/kg (monotherapy) (monotherapy) (combianation) Diagnosis Trauma -RTI- Bacteremia VAP, CRBSI, csti RTI, CNS, bacteremia, csti Pathogen A-K-P (XDR) Cure rate Nephrotoxicity 71% 0% A-P (XDR) 73.6% 0% A-K-P-E-S (MDR) 84.3% 0.6% (1 pt) A; Acinetobacter, K; Klebsiella, E; Eschericia coli, S; Stenotrophomonas, P; Pseudomonas

27 Jajoo et al (18 pts) Paksu et al (79 ICU pts) Kang et al (8 pts) Experience from Colistin Administration in Pediatric and Neonatal Patients Mean age 18.8d 30 m 66 d Colistin daily dose (monotherapy) 5.4 ± 0.6 mg/kg/day Inhaled: twice daily (monotheray) A; Acinetobacter, K; Klebsiella, P; Pseudomonas Diagnosis Meningitis, pneumonia sepsis Pathogen A-K-P (XDR) Cure rate Nephrotoxicity 76% 0% VAP A (MDR) 83.9% 2.3% (2 pts) VAP A (XDR) 100% 0%

28 Sounion Colistin in Sepsis and Septic Shock: An Alternative Route of Therapeutic Approach? Polymyxin B-Hemoperfusion

29 Removing the Endotoxin from Blood: Is it Possible? Polymyxin B-Hemoperfusion Polymyxin B has a strong affinity to endotoxin and is able to bind the lipid A portion of endotoxin through ionic and hydrophobic interactions Polymyxin B-immobilized fiber column hemoperfusion (PMX) is a method performed with a clinically applied adsorbent column containing 5 mg of polymyxin B per gram of polystyrene fiber with a priming volume of 135 ml Produced as Toraymyxin 20-R: Toray Industries, Inc, Tokyo, Japan PMX has been used for the treatment of septic shock since 1994 in Japan and since 2002 in Italy Shock 2011; 36: 332 Immunochemistry 1976; 13: 813

30 Clinical Application of Toraymyxin in Endotoxin Removal (Spectral Diagnostics, Torondo, Canada) Extra-corporeal haemoperfusion is done through a cartridge with polymyxin immobilized onto polystyrene fibres. A typical session lasts 2 h and may be repeated after 24 h. Vascular access with a double lumen venous catheter is required Anticoagulation with heparin is commonly used. Blood flow rate is kept between 80 and 120 ml/min. Davies B, Cohen J. Lancet Infect Dis 2011; 11: 65

31 Clinical Experience with Polymyxin-B Columns Japan 1998 Tani et al. Artif Organs 1998;22:1038 The First Pioneer Study Phase 2 trial: 37 control vs 37 with filtration Survival at 2 weeks: 36.4% vs 54% (p<0.05)

32 Until April 2006, 28 publications with 1425 pts, 978 PMX and 447 conventional therapy with sepsis and septic shock: 9 randomized controlled and 7 non-randomized trials 12 pre-post design studies PMX appears to have favorable effects on arterial pressure, dopamine use, PaO 2 /FiO 2 ratio, and mortality (61.5% vs 33.5%). However, publication bias, lack of blinding, high herogenity in patient selection, and suboptimal methodological quality should be considered. These findings support the need for further rigorous study studies of this therapy Crit Care 2007; 11: R47

33 Risk ratio (RR) for death after polymyxin B-immobilized fib fiber column (PMX-F) treatment (920 participants included in meta-analysis). CI, confidence interval Cruz D, et al. Crit Care 2007; 11: R47

34 After removal of Endotoxin by Polymyxin from the blood of patients with sepsis the following were observed: Reduction in various cytokines, i.e., interleukin -6 and interleukin -10 Direct removal of endogenous cannabinoids Anandamide and 2-arachidonoylglycerol may serve as paracrine mediators of hypotension by the activation of cannabinoid receptors in the peripheral vasculature Davies B, Cohen J. Lancet Infect Dis 2011; 11: 65

35 Effects of PMX on Endotoxin Levels In 17 Japanese studies endotoxic was measured with the turbidimetric limulus assay method The pooled estimate showed that endotoxin levels decreased by 21.2 pg/ml (95% CI, 17.5 to 24.9 pg/ml) after PMX, representing a decrease of 33% to 80% from pre-pmx levels. In the European RCT in which endotoxin was measured with the modified LAL assay, endotoxin levels did not change significantly Critical Care 2007; 11: R47

36 JAMA 2009; 301: 2445

37 The EUPHAS Study Prospective, multicenter randomized controlled trial in 64 patients (34 vs 30 pts) with severe sepsis or septic shock post emergency surgery for intrabdominal infections 10 Italian ICU: Dec Dec 2007 Results: Mean arterial blood pressure increased (p=0.001), Vasopressor requirement decreased (p 0.001), SOFA scores improved (p<0.001) Mortality: 32% vs 53% (p=0.026) Cruz D, et al. JAMA 2009; 301: 2445

38 Early Use of Polymyxin B Hemoperfusion in Abdominal Septic Shock Cruz D, et al. JAMA 2009; 301: 2445

39 The trial was stopped early because an interim analysis showed a difference in mortality that led the ethics committee to declare that it would be inappropriate to deprive patients at high risk of mortality of a potentially beneficial therapy! On the other hand, the study has been criticized because the significance of the clinical endpoints is very dependent on the statistical methods used. JAMA 2009; 301: 2245

40 Time to Initiation of Treatment with Polymyxin B Cartridge Hemoperfusion in Septic Shock Patients: The Very Last Study A prospective, open-labeled, multicenter cohort study was performed at intensive care units in Japan. 41 patients received PMX, within 6 h after the diagnosis of septic shock (early group) and 51 patients were treated after 6h (late group) PMX was effective for improvement of hypotension, hypoperfusion, the sequential organ failure assessment score, and pulmonary oxygenation regardless of the timing of its initiation In addition, the early group had a significantly shorter duration of ventilator support and also had a lower catecholamine requirement. Takeyama N, et al. Blood Purif 2012; 33: 252

41 In vitro: Polymyxin B was fully active on Escerichia coli and Acinetobacter calcoaceticus lipopolysaccharide, but was far less active on Neisseria meningitidis (1000 times), Bordetella pertussis, and Salmonella enteritidis lipopolysaccharides. In vivo: The results were confirmed in the rabbit model A large investigation should be done to understand the capacity of polymyxin B to interact with, and efficiently bind and remove, endotoxins dependent on their bacterial origins Lancet Infect Dis 2011; 11: 426

42 Potential Adverse Effects of PMX Thrombocytopenia Clotting of the Device Hypotension during PMX Erythema S.O.S.: Nephrotoxicity and neurotoxicity are theoretically avoided since Polymyxin B is not released into the circulating blood

43 Yes and No! Much More is Required However, it is a Hope!

44 The Newest Approach The results in mice suggest that the use of colistin microspheres may help to maintain a higher colistin concentration in blood for extended time-periods, reducing the levels of endotoxin and cytokines in endotoxin induced sepsis, leading also to decreased toxicity. Nanjo Y, et al. J Infect Chemother 2013, Jan 25 [Epub ahead of print]

45 Colistin Microsphere **(46.1 ± 8.2 μg) ** Nanjo Y, et al. J Infect Chemother 2013, Jan 25 [Epub ahead of print]