510487
research-article2013
AOPXXX10.1177/1060028013510487Annals of PharmacotherapyNevrekar et al
Case Report
Dual Intraventricular Plus Systemic Antibiotic Therapy for the Treatment of Klebsiella pneumoniae Carbapenemase– Producing Klebsiella pneumoniae Ventriculitis
Annals of Pharmacotherapy XX(X) 1–5 © The Author(s) 2013 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028013510487 aop.sagepub.com
Sonia Nevrekar, PharmD, BCPS1, Kathleen C. Cunningham, PharmD2, Kasey M. Greathouse, PharmD, BCPS3, and Nicholas G. Panos, PharmD, BCPS4
Abstract Objective: To report a case of Klebsiella pneumoniae carbapenemase (KPC)-producing K pneumoniae ventriculitis successfully treated with dual intraventricular plus systemic antibiotic therapy. Case Summary: A 43-year-old woman with a ventriculoperitoneal shunt was transferred from a nursing home with fever, altered mental status, and leukocytosis. She was found to have KPC-producing K pneumoniae ventriculitis. Combination intraventricular antibiotic therapy with colistin and gentamicin plus systemic colistin and amikacin led to the resolution of infection. Discussion: Utilization of intraventricular or intrathecal antibiotics has been described in the literature for multidrug resistant (MDR) Gram-negative central nervous system (CNS) infections; however, none of the cases were caused by a KPC-producing organism. Given the pathogenicity and limited treatment options for this resistant organism, we utilized intraventricular colistin 10 mg and intraventricular gentamicin 10 mg in combination with systemic colistin and amikacin. An extensive literature search revealed several case reports and case series of documented MDR Acinetobacter baumanii CNS infections successfully treated with intraventricular colistin or aminoglycoside therapy with good tolerability. Additionally, recent pharmacokinetic analyses suggest improved cerebrospinal fluid (CSF) concentrations with direct CNS antimicrobial administration in combination with systemic therapy. Although our patient’s cerebral spinal fluid cultures were cleared with dual intraventricular plus systemic therapy, she continued to deteriorate clinically because of her comorbid conditions and required hospice admission. Conclusions: This describes the first reported case of KPC-producing K pneumoniae ventriculitis microbiologically cured based on negative blood and CSF cultures with a combination of intraventricular and systemic therapy. Keywords ventriculitis, intraventricular antimicrobials, Klebsiella pneumoniae carbapenemase (KPC) Received August 20, 2013; revised October 7, 2013; accepted October 7, 2013
Introduction Central nervous system (CNS) infections (ventriculitis, abscesses, and meningitis) caused by Gram-negative bacteria are difficult to treat because of limited CNS penetration of many antimicrobials, which often results in inadequate drug concentrations at the site of infection.1,2 This challenge is even further complicated by the emergence of multidrug resistant (MDR) Gram-negative bacteria, specifically Acinetobacter baumanii, Pseudomonas aeruginosa, Escherichia coli, or Klebsiella pneumoniae, which have the capability of becoming resistant to extended-spectrum β-lactams, aminoglycosides, monobactams, and carbapenems. Carbapenemase-resistant
Enterobacteriaceae, including Klebsiella pneumoniae carbapenemase (KPC)-producing strains are an additional problem since they are able to efficiently hydrolyze penicillins, 1
Alexian Brothers Medical Center, Elk Grove Village, IL, USA University of Wisconsin Hospital and Clinics, Madison, WI, USA 3 Northwestern Memorial Hospital, Chicago, IL, USA 4 Rush University Medical Center, Chicago, IL, USA 2
Corresponding Author: Nicholas G. Panos, PharmD, BCPS, Neuroscience Intensive Care, Department of Pharmacy, Rush University Medical Center, 1653 W Congress Parkway, Chicago, IL 60612, USA. Email: [email protected]
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Annals of Pharmacotherapy XX(X)
cephalosporins, and carbapenems.3 Treatment of these serious infections caused by MDR Gram-negative organisms is often difficult because there are few antibiotics that retain susceptibility and are able to attain therapeutic concentrations in the cerebrospinal fluid (CSF). These infections often require unique combinations of intraventricular and systemic antibiotic therapy with broad-spectrum agents to achieve microbiological and clinical resolution of the infection. Treatment of these infections is usually limited to polymixins such as colistin, aminoglycosides, and/or tigecycline with variable clinical success. Due to pharmacokinetic data suggesting poor CSF penetration of colistin and aminoglycosides when administered intravenously, many clinicians have resorted to utilizing intrathecal or intraventricular (IVT) administration of these antimicrobials to treat patients with MDR CNS infections to acheive higher concentrations at the site of infection.1,4-6 We report the case of a patient with a KPC-Klebsiella pneumoniae ventriculitis who attained microbiological eradication with combination IVT antimicrobial therapy consisting of colistin and gentamicin plus systemic antimicrobials.
Case A 43-year-old woman with a past medical history of a right internal carotid artery stroke complicated by hemorrhagic conversion and hydrocephalus requiring a hemicraniectomy and ventriculoperitoneal shunt (VPS) placement in 2010 presented to an outside hospital. She was admitted from a skilled nursing facility, with increased right-sided gaze deviation, aphasia, fever, and tachycardia. She was found to have an elevated white blood cell count to 21.5 × 109/L, with concern for pneumonia and left-foot ulceration. After a computed tomography (CT) scan of the head revealed hydrocephalus and increased right ventricle size, the patient was transferred to our facility for management of a suspected ventriculitis. On admission to our facility, the patient was started on vancomycin 15 mg/kg intravenous piggy back (IVPB) every 12 hours (goal trough of 15-20 µg/mL) and cefepime 2 g IVPB every 8 hours. On hospital day 2, the VPS was removed, and an extraventricular drain (EVD) was placed. CSF analysis and cultures from the outside hospital ruled out a ventriculitis, and the antibiotics were discontinued. The patient was then placed on cefazolin 1 g IVPB every 8 hours for EVD prophylaxis, per neurosurgery team preference. On hospital day 4, cefepime 2 g IVPB every 12 hours and vancomycin 15 mg/kg every 12 hours were restarted because of fever, leukocytosis, neurological exam changes, and right upper-extremity tenderness thought to be either a hematoma or abscess. A right upper-extremity ultrasound with aspiration of the fluid collection was done to rule out an abscess and CSF cell counts and cultures were obtained to rule out ventriculitis. On hospital day 11, after the cultures from right upper-extremity fluid aspiration and CSF
returned with no growth, all antibiotics were discontinued and cefazolin 1 g IVPB every 8 hours was restarted for EVD prophylaxis, per neurosurgery team preference. Because of continued clinical signs of ventriculitis, vancomycin and cefepime were restarted on hospital day 15, with a targeted length of therapy of 2 weeks. On hospital day 26, a new VPS was placed after it was determined that there was no further concern for CNS infection since daily CSF cultures remained negative. Unfortunately, 3 days after the VPS was placed, the patient suddenly began to have projectile vomiting and became febrile and hypotensive with neurological exam changes. The patient was pan cultured (including CSF), and a CT scan of the head, chest, abdomen, and pelvis were performed to determine the cause of the patient’s sudden change in clinical exam. In addition, vancomycin and cefepime were discontinued, and meropenem 1 g IVPB every 12 hours (renally adjusted as a result of acute kidney injury from distributive shock) and linezolid 600 mg IVPB every 12 hours were started. The patient also received a dose of tobramycin 7 mg/kg IVPB; however, it was not continued. Over the course of the next 3 days, cultures from the urine grew Candida glabrata and C tropicalis. A CT scan of the abdomen and pelvis showed what appeared to be a chronic bilateral hip synovitis not related to the acute infectious process. Based on these findings, the patient was continued on meropenem and linezolid for ventriculitis and started on liposomal amphotericin B 1 mg/kg IVPB every 24 hours which was changed to fluconazole 400 mg IVPB every 24 hours to complete a 14 day course for complicated cystitis from the Candida species found in the urine. The patient’s condition improved over the next 10 days. On hospital day 41, because of new onset of abdominal tenderness and transependymal edema that was noted on head CT, there was concern for an abdominal pseudocyst. An abdominal CT was performed, which was suspicious for an infected pseudocyst. The VPS was externalized, and cultures were obtained from both the CSF and the VPS abdominal incision site. Preliminary Gram stain from the cultures on hospital day 41 showed Gram-negative rods from both culture sites. On hospital day 42, the VPS was removed, a new EVD was placed, and antibiotics were broadened to colistimethate sodium 2.5 mg/kg IVPB every 12 hours, colistimethate sodium 10 mg IVT daily, cefepime 2 g IVPB every 8 hours, and gentamicin 7 mg/kg IVPB every 24 hours; meropenem was discontinued. On hospital day 45, the CSF culture from hospital day 41 grew KPC K pneumoniae sensitive only to gentamicin, colistin, and tigecycline, based on the modified Hodge test (Table 1). The patient’s fever curve had continued to show an upward trend; therefore, the infectious diseases service recommended adding IVT gentamicin 10 mg daily to the antibiotic regimen on hospital day 45. Because the compatibility of colistimethate sodium and gentamicin in solution together is unknown, the administration of the IVT agents
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Nevrekar et al Table 1. Microbiological Sensitivity of Klebsiella pneumoniae. MIC (µg/mL): Susceptibility Interpretation Drug Amikacin Amoxicillin/Clavulanate Aztreonam Cefazolin Cefepime Cefoxitin Ceftriaxone Colistin Ertapenem Gentamicin Imipenem Levofloxacin Piperacillin/Tazobactam Ticarcillin/K Clavulanate Tigecycline Tobramycin Trimethoprim/Sulfonamide
Hospital Day 41; Source: CSF
Hospital Day 41; Source: Abdominal Wound
Hospital Day 47; Source: CSF
>32: Resistant — >16: Resistant — >16: Resistant — >32: Resistant 0.50: Susceptible >4: Resistant ≤4: Susceptible >8: Resistant — >64: Resistant >64: Resistant 2.00: Susceptible >8: Resistant >2/38: Resistant
>32: Resistant >16/8: Resistant >16: Resistant >16: Resistant >16: Resistant >16: Resistant >32: Resistant 0.50: Susceptible >4: Resistant ≤4: Susceptible >8: Resistant >4: Resistant >64: Resistant >64: Resistant 2.00: Susceptible >8: Resistant >2/38: Resistant
32: Intermediate >16/8: Resistant >16: Resistant — >16: Resistant — >32: Resistant 0.25: Susceptible >4: Resistant ≤4: Susceptible >8: Resistant — >64: Resistant >64: Resistant 2.00: Susceptible >8: Resistant >2/38: Resistant
Abbreviations: MIC, minimum inhibitory concentration; CSF, cerebrospinal fluid.
by neurosurgery was separated by 12 hours to prevent a potential chemical and physical incompatibility within the CSF. On hospital day 46, the abdominal incision site culture from hospital day 41 reported KPC K pneumoniae sensitive only to gentamicin, colistin, and tigecycline and MDR P aeruginosa sensitive only to amikacin and piperacillintazobactam. Antibiotics were changed to tigecycline 100 mg IVPB once, then 50 mg IVPB every 12 hours; amikacin 15 mg/kg IVPB every 24 hours; and continuation of the IVT gentamicin and colistimethate sodium. After 4 days of dual IVT therapy, the IVT colistimethate sodium was discontinued on hospital day 48 because the isolate was susceptible to gentamicin. All subsequent CSF cultures from hospital day 49 were negative. The patient continued to receive IVT gentamicin for a total of 21 days after the first negative CSF culture on hospital day 49. The systemic amikacin was renally adjusted after pharmacokinetic analysis and continued for 14 days for the treatment of the MDR P aeruginosa. In addition, the systemic tigecycline was given for a total of 21 days for the treatment of the KPC K pneumoniae together with the IVT gentamicin. After the course of antibiotics, the patient was cured from her infections. CSF cultures drawn 3 days after the completion of the IVPB tigecycline and IVT gentamicin confirmed cure of the ventriculitis. In addition, a CT scan confirmed resolution of the abdominal abscess prior to the placement of a VPS, which was scheduled at a later date. Despite successful treatment of the patient’s MDR infections, the patient’s family opted to initiate comfort measures because of the poor prognosis
related to her previous ischemic stroke and potential for further infectious complications after placing a new VPS. The patient was transferred to hospice care on hospital day 79.
Discussion Ventriculitis is a major cause of morbidity and mortality in patients with ventricular shunts and EVDs.1 Because MDR pathogens are often the cause of ventriculitis, clinicians are forced to resort to unique modes of antimicrobial delivery due to variable drug penetration across the blood-brain barrier and into the CSF, as well as lack of susceptibility data. The major challenge of treating ventriculitis caused by KPC-producing Enterobacteriaceae is the ability to maintain adequate and consistent concentrations of the antimicrobials within the CSF without causing adverse effects. To overcome these issues, IVT antibiotics are often utilized to treat ventriculitis because they can be directly administered through an EVD and achieve higher CSF concentrations compared with antimicrobials administered intravenously. A recent retrospective study by Wang et al7 found a 73.3% cure rate when IVT colistin, gentamicin, or amikacin monotherapy was utilized for postneurosurgical Gram-negative bacillary meningitis or ventriculitis. In addition, the mean period to sterilize the CSF after appropriate IVT antibiotic treatment was 6.6 days, and there were no associated adverse events.7 Colistin is a rapidly bactericidal, concentration-dependent antimicrobial agent that binds to and disrupts cell
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Annals of Pharmacotherapy XX(X)
membrane phospholipids of Gram-negative bacteria causing cell lysis.8 Colistin is commonly administered as colistin methanesulfonate (CMS), which is converted to active colistin by hydrolysis of methanesulfonate radicals. Despite the risk of renal and neurological toxicity, the use of colistin for the treatment of MDR organisms is becoming more common because of increasing resistance to preferred antimicrobial agents. Unfortunately, colistin and CMS have poor CSF penetration in the presence and absence of inflamed meninges. Intravenous colistin only attains 25% of serum concentrations in the CSF.5,6 A pharmacokinetic analysis of colistin penetration into the CSF in humans showed a CSF to serum concentration ratio of 0.051:0.057.6 Attaining an effective AUC/MIC (area under curve/minimum inhibitory concentration) in the CSF using intravenous colistin is difficult with the current US Clinical and Laboratory Standards Institute susceptibility MIC breakpoint of 2 µg/mL for K pneumoniae. Because of poor agar diffusion characteristics of colistin and limited predictive accuracy of the disk diffusion test, colistin susceptibility is measured utilizing Etest strips at our institution with the European Committee on Antimicrobial Susceptibility testing (EUCAST) breakpoints of 2 µg/mL (S), 4 µg/mL (I), and 8 µg/mL (R) for Enterobacteriaceae.9 The Infectious Diseases Society of America (IDSA) clinical practice guidelines for bacterial meningitis support the use of IVT antimicrobials for the treatment of difficultto-eradicate or MDR CSF infections despite none of the agents being US Food and Drug Administration approved for this indication.1 The recommended empirical dosages of gentamicin and colistin based on case reports and series are 1 to 8 mg and 10 mg daily, respectively, with dose and interval adjustments based on the ability to achieve adequate concentrations. A recent study by Imberti et al8 found that IVT-administered CMS at doses of ≥5.22 mg/d resulted in CSF concentrations of colistin continuously above the MIC of 2 µg/mL, and measured values of trough concentrations ranged between 2.0 and 9.7 µg/mL. The researchers did not observe neurotoxicity with the intraventricular administration of CMS, but the patients were mechanically ventilated and sedated, which may have limited their ability to determine the presence of an adverse drug effect. Therefore, because of variable clearance of colistin from the CSF and the wide range of recommended IDSA doses of IVT colistin, this study supported our decision to utilize high-dose IVT colistin of 10 mg daily. A retrospective study reported that combination therapy with IVT gentamicin and systemic anti-infectives resulted in higher cure rates and lower rates of relapse than intravenous therapy alone.10 These study results were supported by that of Ziaka et al,11 who found that the maximum steadystate concentration of colistin (Cmax) in the CSF was statistically higher in patients who received a combination of intravenous and intraventricular therapy and remained
above the MIC at all time points compared than in those who received intravenous therapy alone. By combining intraventricular and systemic therapy, our patient was able to achieve sustained microbiological cure after the completion of therapy. Our patient’s KPC Klebsiella pneumoniae isolate showed susceptibility to colistin and gentamicin, with a MIC of less than 0.5 and 4 µg/mL, respectively. Because her CSF cultures remained positive after 3 days of IVT colistin 10 mg daily, as monotherapy, the infectious diseases service added IVT gentamicin 10 mg daily separated from IVT colistin by 12 hours to minimize the risk of an adverse drug event. Our patient received dual IVT therapy for 4 days, followed by IVT gentamicin plus systemic tigecycline therapy for 21 days from the first negative CSF culture. There are several cases reported in the literature where MDR A baumanii CNS infections have been successfully treated with IVT colistin or combinations of IVT and IV agents.1,4,5 Patel et al2 published a case report of a patient with MDR A baumanii, coagulase-negative Staphylococcus spp, and methicillin-resistant Staphylococcus aureus ventriculitis who was successfully treated with prolonged IVT tobramycin and colistin and systemic rifampin and colisitin. This is the first reported case of a KPC-producing K pneumoniae successfully treated with dual IVT-administered antibiotics in combination with systemic therapy. Although the use of the combination therapy and source control resulted in favorable microbiological outcomes, the patient’s family decided to place her in hospice because of her poor prognosis after her initial ischemic stroke and high risk for reinfection if a new VPS were to be placed. As MDR infections, such as KPCs, become more common, future studies using combination IVT antimicrobial therapy for bacterial ventriculitis are needed to further support the use of this treatment modality. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
References 1. Tunkel AR, Hartman BJ, Kaplan SL, et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis. 2004;29:1267-1284. 2. Patel JA, Pacheco SM, Postelnick M, et al. Prolonged triple therapy for persistent multidrug-resistant Acinetobacter baumanii ventriculitis. Am J Health Syst Pharm. 2011;68:15271531.
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Nevrekar et al 3. Tumbarello M, Viale P, Viscoli C, et al. Predictors of mortality in bloodstream infections caused by Klebsiella pneumoniae carbapenemase–producing K. pneumoniae: importance of combination therapy. Clin Infect Dis. 2012;55:943-950. 4. Lopez-Alvarez B, Martin-Laez R, Farinas MC, et al. Multidrug-resistant Acinetobacter baumanii ventriculitis: successful treatment with intraventricular colisitin. Acta Neurochir (Wien). 2009;151:1465-1472. 5. Kasiakou SK, Rafailidis PI, Liaropouos K, et al. Cure of posttraumatic recurrent multiresistant Gram-negative rod meningitis with intraventricular colistin. J Infect. 2005;50:348-352. 6. Markantonis SL, Markou N, Fousteri M, et al. Penetration of colistin into cerebrospinal fluid. Antimicrob Agents Chemother. 2009;53:4907-4910. 7. Wang JH, Lin PC, Chou CH, et al. Intraventricular antimicrobial therapy in postneurosurgical Gram-negative bacillary meningitis or ventriculitis: a hospital-based retrospective study. J Microbiol Immunol Infect. 2012;12:00204-00206.
8. Imberti R, Cusato M, Accetta G, et al. Pharmacokinetics of colistin in cerebrospinal fluid after intraventricular administration of colistin methanesulfonate. Antimicrob Agents Chemother. 2012;56:4416-4421. 9. Galani I, Kontopidou F, Souli M, et al. Colistin susceptibility testing by Etest and disk diffusion methods. Int J Antimicrob Agents. 2008;31:434-439. 10. Tangden T, Enblad P, Ullberg M, et al. Neurosurgical Gram-negative bacillary ventriculitis and meningitis: a retrospective study evaluating the efficacy of intraventricular gentamicin therapy in 31 consecutive cases. Clin Infect Dis. 2011;11:1310-1316. 11. Ziaka M, Markantonis SL, Fousteri M, et al. Combined intravenous and intraventricular administration for colistin methanesulfonate in critically ill patients with central nervous system infection. Antimicrob Agents Chemother. 2013;57:1938-1940.
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research-article2013
AOPXXX10.1177/1060028013510487Annals of PharmacotherapyNevrekar et al
Case Report
Dual Intraventricular Plus Systemic Antibiotic Therapy for the Treatment of Klebsiella pneumoniae Carbapenemase– Producing Klebsiella pneumoniae Ventriculitis
Annals of Pharmacotherapy XX(X) 1–5 © The Author(s) 2013 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028013510487 aop.sagepub.com
Sonia Nevrekar, PharmD, BCPS1, Kathleen C. Cunningham, PharmD2, Kasey M. Greathouse, PharmD, BCPS3, and Nicholas G. Panos, PharmD, BCPS4
Abstract Objective: To report a case of Klebsiella pneumoniae carbapenemase (KPC)-producing K pneumoniae ventriculitis successfully treated with dual intraventricular plus systemic antibiotic therapy. Case Summary: A 43-year-old woman with a ventriculoperitoneal shunt was transferred from a nursing home with fever, altered mental status, and leukocytosis. She was found to have KPC-producing K pneumoniae ventriculitis. Combination intraventricular antibiotic therapy with colistin and gentamicin plus systemic colistin and amikacin led to the resolution of infection. Discussion: Utilization of intraventricular or intrathecal antibiotics has been described in the literature for multidrug resistant (MDR) Gram-negative central nervous system (CNS) infections; however, none of the cases were caused by a KPC-producing organism. Given the pathogenicity and limited treatment options for this resistant organism, we utilized intraventricular colistin 10 mg and intraventricular gentamicin 10 mg in combination with systemic colistin and amikacin. An extensive literature search revealed several case reports and case series of documented MDR Acinetobacter baumanii CNS infections successfully treated with intraventricular colistin or aminoglycoside therapy with good tolerability. Additionally, recent pharmacokinetic analyses suggest improved cerebrospinal fluid (CSF) concentrations with direct CNS antimicrobial administration in combination with systemic therapy. Although our patient’s cerebral spinal fluid cultures were cleared with dual intraventricular plus systemic therapy, she continued to deteriorate clinically because of her comorbid conditions and required hospice admission. Conclusions: This describes the first reported case of KPC-producing K pneumoniae ventriculitis microbiologically cured based on negative blood and CSF cultures with a combination of intraventricular and systemic therapy. Keywords ventriculitis, intraventricular antimicrobials, Klebsiella pneumoniae carbapenemase (KPC) Received August 20, 2013; revised October 7, 2013; accepted October 7, 2013
Introduction Central nervous system (CNS) infections (ventriculitis, abscesses, and meningitis) caused by Gram-negative bacteria are difficult to treat because of limited CNS penetration of many antimicrobials, which often results in inadequate drug concentrations at the site of infection.1,2 This challenge is even further complicated by the emergence of multidrug resistant (MDR) Gram-negative bacteria, specifically Acinetobacter baumanii, Pseudomonas aeruginosa, Escherichia coli, or Klebsiella pneumoniae, which have the capability of becoming resistant to extended-spectrum β-lactams, aminoglycosides, monobactams, and carbapenems. Carbapenemase-resistant
Enterobacteriaceae, including Klebsiella pneumoniae carbapenemase (KPC)-producing strains are an additional problem since they are able to efficiently hydrolyze penicillins, 1
Alexian Brothers Medical Center, Elk Grove Village, IL, USA University of Wisconsin Hospital and Clinics, Madison, WI, USA 3 Northwestern Memorial Hospital, Chicago, IL, USA 4 Rush University Medical Center, Chicago, IL, USA 2
Corresponding Author: Nicholas G. Panos, PharmD, BCPS, Neuroscience Intensive Care, Department of Pharmacy, Rush University Medical Center, 1653 W Congress Parkway, Chicago, IL 60612, USA. Email: [email protected]
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Annals of Pharmacotherapy XX(X)
cephalosporins, and carbapenems.3 Treatment of these serious infections caused by MDR Gram-negative organisms is often difficult because there are few antibiotics that retain susceptibility and are able to attain therapeutic concentrations in the cerebrospinal fluid (CSF). These infections often require unique combinations of intraventricular and systemic antibiotic therapy with broad-spectrum agents to achieve microbiological and clinical resolution of the infection. Treatment of these infections is usually limited to polymixins such as colistin, aminoglycosides, and/or tigecycline with variable clinical success. Due to pharmacokinetic data suggesting poor CSF penetration of colistin and aminoglycosides when administered intravenously, many clinicians have resorted to utilizing intrathecal or intraventricular (IVT) administration of these antimicrobials to treat patients with MDR CNS infections to acheive higher concentrations at the site of infection.1,4-6 We report the case of a patient with a KPC-Klebsiella pneumoniae ventriculitis who attained microbiological eradication with combination IVT antimicrobial therapy consisting of colistin and gentamicin plus systemic antimicrobials.
Case A 43-year-old woman with a past medical history of a right internal carotid artery stroke complicated by hemorrhagic conversion and hydrocephalus requiring a hemicraniectomy and ventriculoperitoneal shunt (VPS) placement in 2010 presented to an outside hospital. She was admitted from a skilled nursing facility, with increased right-sided gaze deviation, aphasia, fever, and tachycardia. She was found to have an elevated white blood cell count to 21.5 × 109/L, with concern for pneumonia and left-foot ulceration. After a computed tomography (CT) scan of the head revealed hydrocephalus and increased right ventricle size, the patient was transferred to our facility for management of a suspected ventriculitis. On admission to our facility, the patient was started on vancomycin 15 mg/kg intravenous piggy back (IVPB) every 12 hours (goal trough of 15-20 µg/mL) and cefepime 2 g IVPB every 8 hours. On hospital day 2, the VPS was removed, and an extraventricular drain (EVD) was placed. CSF analysis and cultures from the outside hospital ruled out a ventriculitis, and the antibiotics were discontinued. The patient was then placed on cefazolin 1 g IVPB every 8 hours for EVD prophylaxis, per neurosurgery team preference. On hospital day 4, cefepime 2 g IVPB every 12 hours and vancomycin 15 mg/kg every 12 hours were restarted because of fever, leukocytosis, neurological exam changes, and right upper-extremity tenderness thought to be either a hematoma or abscess. A right upper-extremity ultrasound with aspiration of the fluid collection was done to rule out an abscess and CSF cell counts and cultures were obtained to rule out ventriculitis. On hospital day 11, after the cultures from right upper-extremity fluid aspiration and CSF
returned with no growth, all antibiotics were discontinued and cefazolin 1 g IVPB every 8 hours was restarted for EVD prophylaxis, per neurosurgery team preference. Because of continued clinical signs of ventriculitis, vancomycin and cefepime were restarted on hospital day 15, with a targeted length of therapy of 2 weeks. On hospital day 26, a new VPS was placed after it was determined that there was no further concern for CNS infection since daily CSF cultures remained negative. Unfortunately, 3 days after the VPS was placed, the patient suddenly began to have projectile vomiting and became febrile and hypotensive with neurological exam changes. The patient was pan cultured (including CSF), and a CT scan of the head, chest, abdomen, and pelvis were performed to determine the cause of the patient’s sudden change in clinical exam. In addition, vancomycin and cefepime were discontinued, and meropenem 1 g IVPB every 12 hours (renally adjusted as a result of acute kidney injury from distributive shock) and linezolid 600 mg IVPB every 12 hours were started. The patient also received a dose of tobramycin 7 mg/kg IVPB; however, it was not continued. Over the course of the next 3 days, cultures from the urine grew Candida glabrata and C tropicalis. A CT scan of the abdomen and pelvis showed what appeared to be a chronic bilateral hip synovitis not related to the acute infectious process. Based on these findings, the patient was continued on meropenem and linezolid for ventriculitis and started on liposomal amphotericin B 1 mg/kg IVPB every 24 hours which was changed to fluconazole 400 mg IVPB every 24 hours to complete a 14 day course for complicated cystitis from the Candida species found in the urine. The patient’s condition improved over the next 10 days. On hospital day 41, because of new onset of abdominal tenderness and transependymal edema that was noted on head CT, there was concern for an abdominal pseudocyst. An abdominal CT was performed, which was suspicious for an infected pseudocyst. The VPS was externalized, and cultures were obtained from both the CSF and the VPS abdominal incision site. Preliminary Gram stain from the cultures on hospital day 41 showed Gram-negative rods from both culture sites. On hospital day 42, the VPS was removed, a new EVD was placed, and antibiotics were broadened to colistimethate sodium 2.5 mg/kg IVPB every 12 hours, colistimethate sodium 10 mg IVT daily, cefepime 2 g IVPB every 8 hours, and gentamicin 7 mg/kg IVPB every 24 hours; meropenem was discontinued. On hospital day 45, the CSF culture from hospital day 41 grew KPC K pneumoniae sensitive only to gentamicin, colistin, and tigecycline, based on the modified Hodge test (Table 1). The patient’s fever curve had continued to show an upward trend; therefore, the infectious diseases service recommended adding IVT gentamicin 10 mg daily to the antibiotic regimen on hospital day 45. Because the compatibility of colistimethate sodium and gentamicin in solution together is unknown, the administration of the IVT agents
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Nevrekar et al Table 1. Microbiological Sensitivity of Klebsiella pneumoniae. MIC (µg/mL): Susceptibility Interpretation Drug Amikacin Amoxicillin/Clavulanate Aztreonam Cefazolin Cefepime Cefoxitin Ceftriaxone Colistin Ertapenem Gentamicin Imipenem Levofloxacin Piperacillin/Tazobactam Ticarcillin/K Clavulanate Tigecycline Tobramycin Trimethoprim/Sulfonamide
Hospital Day 41; Source: CSF
Hospital Day 41; Source: Abdominal Wound
Hospital Day 47; Source: CSF
>32: Resistant — >16: Resistant — >16: Resistant — >32: Resistant 0.50: Susceptible >4: Resistant ≤4: Susceptible >8: Resistant — >64: Resistant >64: Resistant 2.00: Susceptible >8: Resistant >2/38: Resistant
>32: Resistant >16/8: Resistant >16: Resistant >16: Resistant >16: Resistant >16: Resistant >32: Resistant 0.50: Susceptible >4: Resistant ≤4: Susceptible >8: Resistant >4: Resistant >64: Resistant >64: Resistant 2.00: Susceptible >8: Resistant >2/38: Resistant
32: Intermediate >16/8: Resistant >16: Resistant — >16: Resistant — >32: Resistant 0.25: Susceptible >4: Resistant ≤4: Susceptible >8: Resistant — >64: Resistant >64: Resistant 2.00: Susceptible >8: Resistant >2/38: Resistant
Abbreviations: MIC, minimum inhibitory concentration; CSF, cerebrospinal fluid.
by neurosurgery was separated by 12 hours to prevent a potential chemical and physical incompatibility within the CSF. On hospital day 46, the abdominal incision site culture from hospital day 41 reported KPC K pneumoniae sensitive only to gentamicin, colistin, and tigecycline and MDR P aeruginosa sensitive only to amikacin and piperacillintazobactam. Antibiotics were changed to tigecycline 100 mg IVPB once, then 50 mg IVPB every 12 hours; amikacin 15 mg/kg IVPB every 24 hours; and continuation of the IVT gentamicin and colistimethate sodium. After 4 days of dual IVT therapy, the IVT colistimethate sodium was discontinued on hospital day 48 because the isolate was susceptible to gentamicin. All subsequent CSF cultures from hospital day 49 were negative. The patient continued to receive IVT gentamicin for a total of 21 days after the first negative CSF culture on hospital day 49. The systemic amikacin was renally adjusted after pharmacokinetic analysis and continued for 14 days for the treatment of the MDR P aeruginosa. In addition, the systemic tigecycline was given for a total of 21 days for the treatment of the KPC K pneumoniae together with the IVT gentamicin. After the course of antibiotics, the patient was cured from her infections. CSF cultures drawn 3 days after the completion of the IVPB tigecycline and IVT gentamicin confirmed cure of the ventriculitis. In addition, a CT scan confirmed resolution of the abdominal abscess prior to the placement of a VPS, which was scheduled at a later date. Despite successful treatment of the patient’s MDR infections, the patient’s family opted to initiate comfort measures because of the poor prognosis
related to her previous ischemic stroke and potential for further infectious complications after placing a new VPS. The patient was transferred to hospice care on hospital day 79.
Discussion Ventriculitis is a major cause of morbidity and mortality in patients with ventricular shunts and EVDs.1 Because MDR pathogens are often the cause of ventriculitis, clinicians are forced to resort to unique modes of antimicrobial delivery due to variable drug penetration across the blood-brain barrier and into the CSF, as well as lack of susceptibility data. The major challenge of treating ventriculitis caused by KPC-producing Enterobacteriaceae is the ability to maintain adequate and consistent concentrations of the antimicrobials within the CSF without causing adverse effects. To overcome these issues, IVT antibiotics are often utilized to treat ventriculitis because they can be directly administered through an EVD and achieve higher CSF concentrations compared with antimicrobials administered intravenously. A recent retrospective study by Wang et al7 found a 73.3% cure rate when IVT colistin, gentamicin, or amikacin monotherapy was utilized for postneurosurgical Gram-negative bacillary meningitis or ventriculitis. In addition, the mean period to sterilize the CSF after appropriate IVT antibiotic treatment was 6.6 days, and there were no associated adverse events.7 Colistin is a rapidly bactericidal, concentration-dependent antimicrobial agent that binds to and disrupts cell
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Annals of Pharmacotherapy XX(X)
membrane phospholipids of Gram-negative bacteria causing cell lysis.8 Colistin is commonly administered as colistin methanesulfonate (CMS), which is converted to active colistin by hydrolysis of methanesulfonate radicals. Despite the risk of renal and neurological toxicity, the use of colistin for the treatment of MDR organisms is becoming more common because of increasing resistance to preferred antimicrobial agents. Unfortunately, colistin and CMS have poor CSF penetration in the presence and absence of inflamed meninges. Intravenous colistin only attains 25% of serum concentrations in the CSF.5,6 A pharmacokinetic analysis of colistin penetration into the CSF in humans showed a CSF to serum concentration ratio of 0.051:0.057.6 Attaining an effective AUC/MIC (area under curve/minimum inhibitory concentration) in the CSF using intravenous colistin is difficult with the current US Clinical and Laboratory Standards Institute susceptibility MIC breakpoint of 2 µg/mL for K pneumoniae. Because of poor agar diffusion characteristics of colistin and limited predictive accuracy of the disk diffusion test, colistin susceptibility is measured utilizing Etest strips at our institution with the European Committee on Antimicrobial Susceptibility testing (EUCAST) breakpoints of 2 µg/mL (S), 4 µg/mL (I), and 8 µg/mL (R) for Enterobacteriaceae.9 The Infectious Diseases Society of America (IDSA) clinical practice guidelines for bacterial meningitis support the use of IVT antimicrobials for the treatment of difficultto-eradicate or MDR CSF infections despite none of the agents being US Food and Drug Administration approved for this indication.1 The recommended empirical dosages of gentamicin and colistin based on case reports and series are 1 to 8 mg and 10 mg daily, respectively, with dose and interval adjustments based on the ability to achieve adequate concentrations. A recent study by Imberti et al8 found that IVT-administered CMS at doses of ≥5.22 mg/d resulted in CSF concentrations of colistin continuously above the MIC of 2 µg/mL, and measured values of trough concentrations ranged between 2.0 and 9.7 µg/mL. The researchers did not observe neurotoxicity with the intraventricular administration of CMS, but the patients were mechanically ventilated and sedated, which may have limited their ability to determine the presence of an adverse drug effect. Therefore, because of variable clearance of colistin from the CSF and the wide range of recommended IDSA doses of IVT colistin, this study supported our decision to utilize high-dose IVT colistin of 10 mg daily. A retrospective study reported that combination therapy with IVT gentamicin and systemic anti-infectives resulted in higher cure rates and lower rates of relapse than intravenous therapy alone.10 These study results were supported by that of Ziaka et al,11 who found that the maximum steadystate concentration of colistin (Cmax) in the CSF was statistically higher in patients who received a combination of intravenous and intraventricular therapy and remained
above the MIC at all time points compared than in those who received intravenous therapy alone. By combining intraventricular and systemic therapy, our patient was able to achieve sustained microbiological cure after the completion of therapy. Our patient’s KPC Klebsiella pneumoniae isolate showed susceptibility to colistin and gentamicin, with a MIC of less than 0.5 and 4 µg/mL, respectively. Because her CSF cultures remained positive after 3 days of IVT colistin 10 mg daily, as monotherapy, the infectious diseases service added IVT gentamicin 10 mg daily separated from IVT colistin by 12 hours to minimize the risk of an adverse drug event. Our patient received dual IVT therapy for 4 days, followed by IVT gentamicin plus systemic tigecycline therapy for 21 days from the first negative CSF culture. There are several cases reported in the literature where MDR A baumanii CNS infections have been successfully treated with IVT colistin or combinations of IVT and IV agents.1,4,5 Patel et al2 published a case report of a patient with MDR A baumanii, coagulase-negative Staphylococcus spp, and methicillin-resistant Staphylococcus aureus ventriculitis who was successfully treated with prolonged IVT tobramycin and colistin and systemic rifampin and colisitin. This is the first reported case of a KPC-producing K pneumoniae successfully treated with dual IVT-administered antibiotics in combination with systemic therapy. Although the use of the combination therapy and source control resulted in favorable microbiological outcomes, the patient’s family decided to place her in hospice because of her poor prognosis after her initial ischemic stroke and high risk for reinfection if a new VPS were to be placed. As MDR infections, such as KPCs, become more common, future studies using combination IVT antimicrobial therapy for bacterial ventriculitis are needed to further support the use of this treatment modality. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
References 1. Tunkel AR, Hartman BJ, Kaplan SL, et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis. 2004;29:1267-1284. 2. Patel JA, Pacheco SM, Postelnick M, et al. Prolonged triple therapy for persistent multidrug-resistant Acinetobacter baumanii ventriculitis. Am J Health Syst Pharm. 2011;68:15271531.
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Nevrekar et al 3. Tumbarello M, Viale P, Viscoli C, et al. Predictors of mortality in bloodstream infections caused by Klebsiella pneumoniae carbapenemase–producing K. pneumoniae: importance of combination therapy. Clin Infect Dis. 2012;55:943-950. 4. Lopez-Alvarez B, Martin-Laez R, Farinas MC, et al. Multidrug-resistant Acinetobacter baumanii ventriculitis: successful treatment with intraventricular colisitin. Acta Neurochir (Wien). 2009;151:1465-1472. 5. Kasiakou SK, Rafailidis PI, Liaropouos K, et al. Cure of posttraumatic recurrent multiresistant Gram-negative rod meningitis with intraventricular colistin. J Infect. 2005;50:348-352. 6. Markantonis SL, Markou N, Fousteri M, et al. Penetration of colistin into cerebrospinal fluid. Antimicrob Agents Chemother. 2009;53:4907-4910. 7. Wang JH, Lin PC, Chou CH, et al. Intraventricular antimicrobial therapy in postneurosurgical Gram-negative bacillary meningitis or ventriculitis: a hospital-based retrospective study. J Microbiol Immunol Infect. 2012;12:00204-00206.
8. Imberti R, Cusato M, Accetta G, et al. Pharmacokinetics of colistin in cerebrospinal fluid after intraventricular administration of colistin methanesulfonate. Antimicrob Agents Chemother. 2012;56:4416-4421. 9. Galani I, Kontopidou F, Souli M, et al. Colistin susceptibility testing by Etest and disk diffusion methods. Int J Antimicrob Agents. 2008;31:434-439. 10. Tangden T, Enblad P, Ullberg M, et al. Neurosurgical Gram-negative bacillary ventriculitis and meningitis: a retrospective study evaluating the efficacy of intraventricular gentamicin therapy in 31 consecutive cases. Clin Infect Dis. 2011;11:1310-1316. 11. Ziaka M, Markantonis SL, Fousteri M, et al. Combined intravenous and intraventricular administration for colistin methanesulfonate in critically ill patients with central nervous system infection. Antimicrob Agents Chemother. 2013;57:1938-1940.
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