- Email: [email protected]
A New Method for the Treatment of Chronic Fungal Meningitis: Continuous Infusion into the Cerebrospinal Fluid for Coccidioidal Meningitis
CASE REPORT
A New Method for the Treatment of Chronic Fungal Meningitis: Continuous Infusion into the Cerebrospinal Fluid for Coccidioidal Meningitis Carol D. Berry, MD, David A. Stevens, MD, Eric I. Hassid, MD, Demosthenes Pappagianis, MD, PhD, Edie L. Happs, RN and Kamran Sahrakar, MD
Abstract: Coccidioidal meningitis is a lethal disease, and current therapy is not curative or is burdened with serious toxicities and logistic difficulties. In a patient with refractory disease, continuous infusion amphotericin B therapy was given via a programmable implanted pump into the cisternal subarachnoid space. The patient progressively responded, evidenced clinically and by laboratory studies. Drug delivery issues were addressed during this course that could guide future use of this modality, which is a promising novel avenue of therapy for chronic meningitis. Key Indexing Terms: Fungal meningitis; Coccidioidomycosis; Antifungal therapy; Intrathecal therapy; Amphotericin B. [Am J Med Sci 2009;338(1):79–82.]
C
occidioidal meningitis is a particularly devastating form of coccidioidomycosis, with a mortality of 100% within 2 years, if untreated.1 The introduction of amphotericin B (AmB) radically changed the outlook for this disease. Although conventionally formulated (deoxycholate) AmB is ineffective by the intravenous route, intermittent intrathecal administration, given by injection at lumbar, cisternal, or ventricular sites, cures many patients.1– 4 However, intrathecal AmB is associated with serious side effects and logistic delivery problems.1–3 The introduction of the azole antifungals offered the advantages of good response rates, few side effects, and the convenience of oral therapy,5 but cure seemed unattainable.6 This has led to a reexploration of intrathecal AmB with or without azoles,3 with the aim of achieving a more rapid response and possibly cure via the AmB, and via the combination, reducing the duration of intrathecal AmB and, thus, attendant side effects.
From the Department of Medicine, Kaiser Permanente South Sacramento Medical Center (CDB, ELH, KS), Sacramento, California; Department of Medicine, Santa Clara Valley Medical Center and California Institute for Medical Research (DAS), San Jose, California; Department of Medicine, Stanford University Medical School (DAS), Stanford, California; Institute for Restorative Health (EIH), Davis, California; and University of California School of Medicine (DP), Davis, California. Submitted December 2, 2008; accepted in revised form January 30, 2009. Eric I. Hassid reports receiving teaching honoraria from Medtronics subsequent to the therapy described. The remaining authors have not disclosed any potential conflicts of interest. This study was supported by the Kaiser Permanente Medical Group. Presented, in part, in the Infectious Diseases Society of America, Annual Meeting, October 2007, San Diego (selected for poster presentation rounds), abstract 171, and in the 52nd Annual Meeting of the Coccidioidomycosis Study Group, San Diego, April 2008. Correspondence: David A. Stevens, MD, Department of Medicine, Santa Clara Valley Medical Center, 751 South Bascom Avenue, San Jose, CA 95128-2699 (E-mail: [email protected]).
CASE REPORT Background A 23-year-old African American man was admitted on July 8, 2000 following an automobile accident, in which he was the driver. At that time, he was dysphasic, uncoordinated, and unable to process information. There was a long-standing history of developmental delay and autism, and it was later learned that he had experienced headaches for 2 weeks before the accident. Computed tomography and magnetic resonance imaging scans showed mild enlargement of the third and fourth ventricles. It was concluded that an alteration in his consciousness had caused the accident, not the reverse. From July 16 to July 21, his symptoms and signs worsened: increased frontal headache, disorientation, combative behavior, and worsened gait, and he developed chills. Neurologic examination showed poor response to stimuli, no purposeful gaze, aphasia, and possible auditory and visual hallucinations. A lumbar puncture was performed (Table 1) with an opening pressure of 190 mm water. His neurologic abnormalities improved after the lumbar puncture. A diagnosis of coccidioidal meningitis was enabled by the cerebrospinal fluid (CSF) results (Table 1). Oral fluconazole (FCZ) therapy 800 mg daily was initiated. Although his headache had decreased after the initiation of FCZ, in August, he experienced diplopia, dysgraphia, acalculia, inability to concentrate, epileptiform activity, and left arm weakness. Neurologic examination revealed papilledema and a left Babinski sign. MRI showed increased hydrocephalus and lesions in the cerebellum. Dexamethasone was started, and a ventriculoperitoneal shunt placed. In October, he experienced tremors, but his papilledema cleared, dexamethasone was discontinued, and, except for the acalculia, his symptoms markedly improved from December to September to such degree that he surreptitiously stopped taking FCZ. In September 2001, however, he experienced vomiting and headaches. Imaging revealed increased hydrocephalus. An occluded shunt was diagnosed and a new one placed. A ventricular culture taken at surgery grew Coccidioides. This mycelial form isolate had a minimum inhibitory concentration (MIC) and minimum fungicidal concentration 8 to FCZ of 12.5 and 25 g/mL, and to AmB of 8 and 8 g/mL, respectively. Because of this persisting infection and a rise in his lumbar CSF leukocytes (WBC) from a nadir of 53 to 135/mm3, and persisting elevated protein ⬎1000 mg/dL and CSF coccidioidal complement-fixing (CF) antibody titer 1:128 (Table 1), intravenous liposomal AmB10 was initiated in October in addition to resumption of FCZ. During the month of therapy, he experienced tremulousness, worsening gait, memory deficits, slowed motor activity, and vomiting. Although some AmB was detectable in the CSF, and the isolate was killed in the CSF, the
The American Journal of the Medical Sciences • Volume 338, Number 1, July 2009
79
Berry et al
TABLE 1. Lumbar Cerebrospinal Fluid Date 7/16/2000 to 7/25/2000a 10/17/2000 11/28/2000 10/8/2001 11/9/2001 12/26/2001 2/21/2002 5/16/2002 11/1/2002 1/28/2004 6/7/2006
WBC
Protein (mg/dL)
Glucose (mg/dL)
CF
238–434 133 53 135 220 52 20 10 7 4 9
186–252 1423 1402 1024 1746 435 78 83 63 83 61
24–30 ⬍20 27 22 24 16 22 24 28 35 51
1:16 1:128 1:128 1:128 1:512 1:32 1:8 1:8 1:4 1:4 1:2
IL; KL
AmB (g/mL)
1:16; 1:16 ⬍1:4; ⬍1:4
0.076 ⬍0.06
a
Range for 3 cerebrospinal fluids during interval (2 for CF). WBC, leukocytes/cu mm; CF, coccidioidal complement-fixing antibody titer7; IL, inhibitory level (highest 2-fold dilution with complete inhibition 关0 of 0 – 4⫹ growth range兴, with 4⫹ in controls 关conditions as per Ref. 8兴); KL, killing level (highest 2-fold dilution demonstrating ⱖ96% killing of initial inoculum of 2000 arthroconidia/mL).8 AmB, amphotericin B in g/mL,9 lower limit of sensitivity of assay 0.06 g/mL; FCZ excluded by use of a FCZ-resistant bioassay organism. IL and KL dilution series begins with 1 part CSF to 3 parts medium (1:4).8
CSF WBC rose to 220/mm3, protein to 1746 mg/dL, and CSF CF to 1:512 (Table 1). It should be noted that the killing assay result would aggregate not only the effect of the AmB measured, but also that of the unassayed FCZ and possibly host defense molecules,11 including cytokines, which may act in concert with antifungals.12 Therapeutic monitoring of FCZ indicated sufficient absorption and adherence. A total of 4.6 g liposomal AmB had been given. It was clear this course had also failed. Pump Infusion Therapy In mid-November, we elected to attempt intrathecal AmB deoxycholate therapy using a continuous programmable pump (Medtronics, Minneapolis, MN) (Figure 1). This decision was made for logistic reasons specific to this patient (he was judged a poor candidate for recurrent intermittent therapy, via intrathecal or reservoir injection, owing to anticipated noncompliance). The proposed course of therapy was submitted to the Institutional Review Board of Kaiser Sacramento. Oral FCZ
FIGURE 1. Synchromed II Programmable Pump, model 8637; right, with pump connector, tubing, and intrathecal catheter model 8731; left, Programmer model 8840. Courtesy Medtronic Neurological, Medtronic, Minneapolis, MN.
80
was continued. A catheter was introduced via retromastoid craniectomy into his cisternal subarachnoid space. At surgery, the arachnoid at that site was noted as markedly thickened. This site would deliver drug to the locus of maximum coccidioidal disease, the basilar meninges. The catheter was tunneled subcutaneously to connect with the subcutaneously implanted 18-mL pump and reservoir in the lower abdomen (Figure 2). The reservoir was filled with 1 mg/mL AmB solution in water, programmed to deliver a daily dose ascending over 3 weeks from 0.05 to 0.5 mg/d. The stability of AmB at body temperature in this reservoir was unknown. At the end of November, sampling of the reservoir revealed that the concentration of AmB (bioassay)9 was 169.6 g/mL, verified by demonstrating that the reservoir fluid diluted in broth inhibited the patients’ isolate at a dilution of 1:256 and killed it at the same dilution. However, the concentration represented an 83% deterioration of the drug during this 13-day residence in the reservoir, illustrating that a lower dose than intended had been delivered, presumably a progressively smaller fraction as active drug daily over this time interval.
FIGURE 2. Pump and reservoir in place in patient’s abdominal wall. Volume 338, Number 1, July 2009
Continuous CSF Infusion Therapy
The reservoir was refilled and programmed to deliver 0.5 mg/d, and over the next month, he demonstrated improved cognition, coordination, gait, appetite, and gained weight. His CSF WBC fell to 52/mm3, protein to 435 mg/dL, CSF CF to 1:32 (Table 1). At no point did he experience any of the toxicities ascribed to intermittent intrathecal AmB1– 4; he did not require either antiemetics or medication for pain. In late December, it was noted at the time of refilling that the reservoir was emptying more slowly, resulting in a delivery of only a calculated average of 0.45 mg/d for the month. The residual reservoir AmB concentration was 62.4 g/mL, a ⬎90% deterioration during this 28-day residence in the reservoir. The reservoir fluid residual bioactivity still inhibited and killed the (saved) isolate at 1:32 dilution. The CSF AmB concentration had fallen below a detectable level and no longer inhibited his isolate. Because of the declining pumping and the documented decay of drug over time, the concentration of AmB added to the reservoir was increased to 1.5 mg/dL. The declining pumping was presumed to be due to clogging at the distal end of the catheter, owing to inflammation or fibrosis, mechanical tissue obstruction, or possibly deleterious effects of the deoxycholate detergent on reservoir materials. In February, the reservoir was emptying very slowly, only a calculated average of 0.03 mg/d AmB would have been delivered for 2 months. Moreover, the residual reservoir AmB concentration was only 2.7 g/mL at the end of the period, a ⬎99% deterioration during 48-day residence in the reservoir. His CSF WBC had fallen to 20/mm3, protein to 78 mg/dL, and CSF CF to 1:8 (Table 1). In March, the reservoir was not emptying at all, but despite slight increase in ventricular size, he remained neurologically improved and stable. A calculated total of 13.6 mg AmB had been given intrathecally. Given his stable improved neurologic situation since the initial months’ reservoir therapy, despite an unintentional marked tapering of his daily dose received to miniscule levels, and a device that was hardly functioning, we elected to observe his further course. No further AmB was delivered to the reservoir, it has been replenished only with sterile water in the hopes of retaining some patency. The patient has remained neurologically stable, with gradual further improvement in cognition, since March 2002, with no further worsening of hydrocephalus. In autumn 2002, the pump spontaneously resumed pumping at close to desired rate. His CSF WBC has fallen to ⱕ10/mm3, protein to ⱕ83 mg/dL, CSF CF to 1:2, and his CSF glucose normalized (Table 1). His serum CF (a more distant reflection of activity of his coccidioidal central nervous system focus)7 had similarly fallen from 1:256, before the pump, to 1:16. He was able to advance his education through a 2-year to a more demanding 4-year college program.
DISCUSSION This experience documents a remarkable clinical (and laboratory monitoring) response of a patient with severely symptomatic, relapsed unresponsive coccidioidal meningitis, who then responded to continuous cisternal infusion of AmB. Despite mechanical difficulties with the pump-catheter system, resulting, in effect, in an abbreviated and tapering course of intrathecal therapy less than originally intended, drug decay and a relatively high AmB, MIC, and minimum fungicidal concentration,13 he has shown no signs of disease activity in a 6-year follow-up. In addition, the continuous infusion method was achieved without any of the well-described complications of intrathecal AmB therapy.1– 4 © 2009 Lippincott Williams & Wilkins
A current prevailing hypothesis, derived from animal experimentation, regarding the pharmacokinetic-pharmacodynamic parameter that governs AmB efficacy is that it is dependent on the ratio of peak drug concentration (Cmax) to MIC.14 Assuming this is correct, one might not expect a good result with a continuous infusion methodology, which prolongs the presence of drug, but lessens the Cmax/MIC ratio. There are several possible explanations for this apparent contradiction. One, it is possible that continuous infusion provides a sufficient drug concentration at the site of infection to achieve a necessary Cmax, beyond which further elevation of drug concentration is unnecessary. This may be, particularly, the case when the drug is given directly onto the infected target tissue. The “killing level” (1:256, later 1:32), assayed from the pump, of the drug against his organism, even after drug decay and against an organism whose MIC would be considered resistant,13 would support this interpretation. Moreover, the spherule-endospore form found in the host is likely more susceptible to AmB than the mycelial form,15 although parasitic form testing is rarely performed, owing to difficulties in converting isolates to that form in vitro and maintaining them as such. Second, a separate CSF compartment is qualitatively different than a whole animal; in particular, even in the presence of this degree of inflammation, the protein concentration is much lower than serum, and the binding to central nervous system tissue may have different kinetics than in other body sites, thus, creating a different pharmacodynamic paradigm. Finally, Coccidioides has a slower doubling time16,17 than the opportunistic fungi that have been used to derive the pharmacokinetic-pharmacodynamic parameters in animals. Thus, it may be advantageous to have drug continuously present, enabling an effective concentration to be present at a critical time in Coccidioides cell division. The device used is employed commonly for other indications, such as continuous CSF antispasmodic or analgesic medication, and its implantation (into the lumbar space for therapy of dystonia or pain) is a standardized neurosurgical procedure. The pump can be programmed for continuous delivery, as we did, or it can be configured to deliver intermittent pulse doses, mimicking intermittent delivery of doses as in usual intrathecal therapy for coccidioidal meningitis.1– 4 Complications of these pump systems are described, including catheter displacement, focal scar formation, irritation or compression of nerves, or granuloma formation at the distal tip, which can lead to myelopathy, but these are rare events.18,19 There are obvious advantages to drug delivery via a pump: the ability to avoid repeated (and with ongoing inflammation, likely increasingly traumatic) lumbar or cisternal punctures, the ability to only intermittently load the reservoir, which also lessens the risk of contamination compared with repeated thecal punctures, and the ability to adjust the dose given, to the patient’s degree of response, via altering the reservoir concentration or the infusion rate, achievable by external wireless programming. Ultrasound can further simplify refilling.20 This case also points out areas of drug delivery that require improvement before this approach can be generally applied. The slowing and eventual transient cessation of the pumping was not deleterious, but might be in other severe cases. If the cessation was due to a pump problem, rather than obstruction at the distal end of the catheter, such problem may benefit from alteration of the pump, and if due to obstruction, by alteration of the catheter characteristics. The decay of active drug documented might be remedied by more frequent refilling of the reservoir, or an alternative drug formulation.
81
Berry et al
In summary, we present a new method of intrathecal antifungal drug delivery. Further exploration of this approach offers promise of a more effective and less toxic therapeutic option for difficult cases of chronic fungal meningitis. REFERENCES 1. Einstein HE, Holeman CW Jr, Sandidge LL, et al. Coccidioidal meningitis. The use of amphotericin B in treatment. Calif Med 1961; 94:339 – 43. 2. Williams PL. Coccidioidal meningitis. Ann N Y Acad Sci 2007;1111: 377– 84.
liposomal amphotericin against coccidioidal meningitis in rabbits. Antimicrob Agents Chemother 2002;46:2420 – 6. 11. Ahluwalia M, Brummer E, Sridahr S, et al. Isolation and characterization of an anticryptococcal protein present in human cerebrospinal fluid. J Med Micro 2001;50:83–9. 12. Stevens DA. Combination immunotherapy and antifungal chemotherapy. Clin Infect Dis 1998;26:1266 –9. 13. National Committee for Clinical Laboratory Standards. Reference method for broth dilution antifungal susceptibility testing of conidiumforming filamentous fungi. Proposed standard M38-A. Wayne (PA): National Committee for Clinical Laboratory Standards; 2002.
3. Stevens DA, Shatsky SA. Intrathecal amphotericin in the management of coccidioidal meningitis. Semin Respir Infect 2001;16:263–9.
14. Andes D. Pharmacokinetics and pharmacodynamics in the development of antifungal compounds. Curr Opin Investig Drugs 2003;4: 991– 8.
4. Kelly PC. Coccidioidal meningitis. In: Stevens DA, editor. Coccidioidomycosis: a text. New York (NY): Plenum Medical Book Company; 1980. p. 163–93.
15. Collins M, Pappagianis D. Uniform susceptibility of various strains of Coccidioides immitis to amphotericin B. Infect Immun 1981;17:1049 –5.
5. Stevens DA, Clemons KV. Azole therapy of clinical and experimental coccidioidomycosis. Ann N Y Acad Sci 2007;1111:442–54. 6. Dewsnup DH, Galgiani JN, Graybill JR, et al. Is it ever safe to stop azole therapy for Coccidioides immitis meningitis? Ann Intern Med 1996;124:305–10. 7. Pappagianis D. Serologic studies in coccidioidomycosis. Semin Respir Infect 2001;16:242–50. 8. Stevens DA, Aristizabal BH. In vitro antifungal activity of novel azole derivatives with a morpholine ring, UR-9746 and UR-9751, and comparison with fluconazole. Diagn Microbiol Infect Dis 1997; 29:103– 6. 9. Hanson LH, Perlman AM, Clemons KV, et al. Synergy between cilofungin and amphotericin B in a murine model of candidiasis. Antimicrob Agents Chemother 1991;35:1334 –7. 10. Clemons KV, Sobel RA, Williams PL, et al. Efficacy of intravenous
82
16. Huppert M, Sun SH. Overview of mycology, and the mycology of Coccidioides immitis. In: Stevens DA, editor. Coccidioidomycosis: a text. New York (NY): Plenum Medical Book Company; 1980. Chapter 2, p. 21– 46. 17. Brosbe EA, Kietzman JN, Snellen JE. Time lapse cinemicrographic studies on behavior of Coccidioides immitis in vitro. In: Ajello L, editor. Coccidioidomycosis. Tucson (AZ): University of Arizona Press; 1967. p. 409 –14. 18. Protopapas MG, Bundock E, Westmoreland S, et al. The complications of scar formation associated with intrathecal pump placement. Arch Phys Med Rehabil 2007;88:389 –90. 19. Knox S, Atkinson RP, Stephens R, et al. Myelopathy as a complication of intrathecal drug infusion systems. Arch Neurol 2008;64:286 –7. 20. Hurdle MF, Locketz AJ, Smith J. A technique for ultrasound-guided intrathecal drug-delivery system refills. Am J Phys Med Rehabil 2007; 86:250 –1.
Volume 338, Number 1, July 2009
A New Method for the Treatment of Chronic Fungal Meningitis: Continuous Infusion into the Cerebrospinal Fluid for Coccidioidal Meningitis Carol D. Berry, MD, David A. Stevens, MD, Eric I. Hassid, MD, Demosthenes Pappagianis, MD, PhD, Edie L. Happs, RN and Kamran Sahrakar, MD
Abstract: Coccidioidal meningitis is a lethal disease, and current therapy is not curative or is burdened with serious toxicities and logistic difficulties. In a patient with refractory disease, continuous infusion amphotericin B therapy was given via a programmable implanted pump into the cisternal subarachnoid space. The patient progressively responded, evidenced clinically and by laboratory studies. Drug delivery issues were addressed during this course that could guide future use of this modality, which is a promising novel avenue of therapy for chronic meningitis. Key Indexing Terms: Fungal meningitis; Coccidioidomycosis; Antifungal therapy; Intrathecal therapy; Amphotericin B. [Am J Med Sci 2009;338(1):79–82.]
C
occidioidal meningitis is a particularly devastating form of coccidioidomycosis, with a mortality of 100% within 2 years, if untreated.1 The introduction of amphotericin B (AmB) radically changed the outlook for this disease. Although conventionally formulated (deoxycholate) AmB is ineffective by the intravenous route, intermittent intrathecal administration, given by injection at lumbar, cisternal, or ventricular sites, cures many patients.1– 4 However, intrathecal AmB is associated with serious side effects and logistic delivery problems.1–3 The introduction of the azole antifungals offered the advantages of good response rates, few side effects, and the convenience of oral therapy,5 but cure seemed unattainable.6 This has led to a reexploration of intrathecal AmB with or without azoles,3 with the aim of achieving a more rapid response and possibly cure via the AmB, and via the combination, reducing the duration of intrathecal AmB and, thus, attendant side effects.
From the Department of Medicine, Kaiser Permanente South Sacramento Medical Center (CDB, ELH, KS), Sacramento, California; Department of Medicine, Santa Clara Valley Medical Center and California Institute for Medical Research (DAS), San Jose, California; Department of Medicine, Stanford University Medical School (DAS), Stanford, California; Institute for Restorative Health (EIH), Davis, California; and University of California School of Medicine (DP), Davis, California. Submitted December 2, 2008; accepted in revised form January 30, 2009. Eric I. Hassid reports receiving teaching honoraria from Medtronics subsequent to the therapy described. The remaining authors have not disclosed any potential conflicts of interest. This study was supported by the Kaiser Permanente Medical Group. Presented, in part, in the Infectious Diseases Society of America, Annual Meeting, October 2007, San Diego (selected for poster presentation rounds), abstract 171, and in the 52nd Annual Meeting of the Coccidioidomycosis Study Group, San Diego, April 2008. Correspondence: David A. Stevens, MD, Department of Medicine, Santa Clara Valley Medical Center, 751 South Bascom Avenue, San Jose, CA 95128-2699 (E-mail: [email protected]).
CASE REPORT Background A 23-year-old African American man was admitted on July 8, 2000 following an automobile accident, in which he was the driver. At that time, he was dysphasic, uncoordinated, and unable to process information. There was a long-standing history of developmental delay and autism, and it was later learned that he had experienced headaches for 2 weeks before the accident. Computed tomography and magnetic resonance imaging scans showed mild enlargement of the third and fourth ventricles. It was concluded that an alteration in his consciousness had caused the accident, not the reverse. From July 16 to July 21, his symptoms and signs worsened: increased frontal headache, disorientation, combative behavior, and worsened gait, and he developed chills. Neurologic examination showed poor response to stimuli, no purposeful gaze, aphasia, and possible auditory and visual hallucinations. A lumbar puncture was performed (Table 1) with an opening pressure of 190 mm water. His neurologic abnormalities improved after the lumbar puncture. A diagnosis of coccidioidal meningitis was enabled by the cerebrospinal fluid (CSF) results (Table 1). Oral fluconazole (FCZ) therapy 800 mg daily was initiated. Although his headache had decreased after the initiation of FCZ, in August, he experienced diplopia, dysgraphia, acalculia, inability to concentrate, epileptiform activity, and left arm weakness. Neurologic examination revealed papilledema and a left Babinski sign. MRI showed increased hydrocephalus and lesions in the cerebellum. Dexamethasone was started, and a ventriculoperitoneal shunt placed. In October, he experienced tremors, but his papilledema cleared, dexamethasone was discontinued, and, except for the acalculia, his symptoms markedly improved from December to September to such degree that he surreptitiously stopped taking FCZ. In September 2001, however, he experienced vomiting and headaches. Imaging revealed increased hydrocephalus. An occluded shunt was diagnosed and a new one placed. A ventricular culture taken at surgery grew Coccidioides. This mycelial form isolate had a minimum inhibitory concentration (MIC) and minimum fungicidal concentration 8 to FCZ of 12.5 and 25 g/mL, and to AmB of 8 and 8 g/mL, respectively. Because of this persisting infection and a rise in his lumbar CSF leukocytes (WBC) from a nadir of 53 to 135/mm3, and persisting elevated protein ⬎1000 mg/dL and CSF coccidioidal complement-fixing (CF) antibody titer 1:128 (Table 1), intravenous liposomal AmB10 was initiated in October in addition to resumption of FCZ. During the month of therapy, he experienced tremulousness, worsening gait, memory deficits, slowed motor activity, and vomiting. Although some AmB was detectable in the CSF, and the isolate was killed in the CSF, the
The American Journal of the Medical Sciences • Volume 338, Number 1, July 2009
79
Berry et al
TABLE 1. Lumbar Cerebrospinal Fluid Date 7/16/2000 to 7/25/2000a 10/17/2000 11/28/2000 10/8/2001 11/9/2001 12/26/2001 2/21/2002 5/16/2002 11/1/2002 1/28/2004 6/7/2006
WBC
Protein (mg/dL)
Glucose (mg/dL)
CF
238–434 133 53 135 220 52 20 10 7 4 9
186–252 1423 1402 1024 1746 435 78 83 63 83 61
24–30 ⬍20 27 22 24 16 22 24 28 35 51
1:16 1:128 1:128 1:128 1:512 1:32 1:8 1:8 1:4 1:4 1:2
IL; KL
AmB (g/mL)
1:16; 1:16 ⬍1:4; ⬍1:4
0.076 ⬍0.06
a
Range for 3 cerebrospinal fluids during interval (2 for CF). WBC, leukocytes/cu mm; CF, coccidioidal complement-fixing antibody titer7; IL, inhibitory level (highest 2-fold dilution with complete inhibition 关0 of 0 – 4⫹ growth range兴, with 4⫹ in controls 关conditions as per Ref. 8兴); KL, killing level (highest 2-fold dilution demonstrating ⱖ96% killing of initial inoculum of 2000 arthroconidia/mL).8 AmB, amphotericin B in g/mL,9 lower limit of sensitivity of assay 0.06 g/mL; FCZ excluded by use of a FCZ-resistant bioassay organism. IL and KL dilution series begins with 1 part CSF to 3 parts medium (1:4).8
CSF WBC rose to 220/mm3, protein to 1746 mg/dL, and CSF CF to 1:512 (Table 1). It should be noted that the killing assay result would aggregate not only the effect of the AmB measured, but also that of the unassayed FCZ and possibly host defense molecules,11 including cytokines, which may act in concert with antifungals.12 Therapeutic monitoring of FCZ indicated sufficient absorption and adherence. A total of 4.6 g liposomal AmB had been given. It was clear this course had also failed. Pump Infusion Therapy In mid-November, we elected to attempt intrathecal AmB deoxycholate therapy using a continuous programmable pump (Medtronics, Minneapolis, MN) (Figure 1). This decision was made for logistic reasons specific to this patient (he was judged a poor candidate for recurrent intermittent therapy, via intrathecal or reservoir injection, owing to anticipated noncompliance). The proposed course of therapy was submitted to the Institutional Review Board of Kaiser Sacramento. Oral FCZ
FIGURE 1. Synchromed II Programmable Pump, model 8637; right, with pump connector, tubing, and intrathecal catheter model 8731; left, Programmer model 8840. Courtesy Medtronic Neurological, Medtronic, Minneapolis, MN.
80
was continued. A catheter was introduced via retromastoid craniectomy into his cisternal subarachnoid space. At surgery, the arachnoid at that site was noted as markedly thickened. This site would deliver drug to the locus of maximum coccidioidal disease, the basilar meninges. The catheter was tunneled subcutaneously to connect with the subcutaneously implanted 18-mL pump and reservoir in the lower abdomen (Figure 2). The reservoir was filled with 1 mg/mL AmB solution in water, programmed to deliver a daily dose ascending over 3 weeks from 0.05 to 0.5 mg/d. The stability of AmB at body temperature in this reservoir was unknown. At the end of November, sampling of the reservoir revealed that the concentration of AmB (bioassay)9 was 169.6 g/mL, verified by demonstrating that the reservoir fluid diluted in broth inhibited the patients’ isolate at a dilution of 1:256 and killed it at the same dilution. However, the concentration represented an 83% deterioration of the drug during this 13-day residence in the reservoir, illustrating that a lower dose than intended had been delivered, presumably a progressively smaller fraction as active drug daily over this time interval.
FIGURE 2. Pump and reservoir in place in patient’s abdominal wall. Volume 338, Number 1, July 2009
Continuous CSF Infusion Therapy
The reservoir was refilled and programmed to deliver 0.5 mg/d, and over the next month, he demonstrated improved cognition, coordination, gait, appetite, and gained weight. His CSF WBC fell to 52/mm3, protein to 435 mg/dL, CSF CF to 1:32 (Table 1). At no point did he experience any of the toxicities ascribed to intermittent intrathecal AmB1– 4; he did not require either antiemetics or medication for pain. In late December, it was noted at the time of refilling that the reservoir was emptying more slowly, resulting in a delivery of only a calculated average of 0.45 mg/d for the month. The residual reservoir AmB concentration was 62.4 g/mL, a ⬎90% deterioration during this 28-day residence in the reservoir. The reservoir fluid residual bioactivity still inhibited and killed the (saved) isolate at 1:32 dilution. The CSF AmB concentration had fallen below a detectable level and no longer inhibited his isolate. Because of the declining pumping and the documented decay of drug over time, the concentration of AmB added to the reservoir was increased to 1.5 mg/dL. The declining pumping was presumed to be due to clogging at the distal end of the catheter, owing to inflammation or fibrosis, mechanical tissue obstruction, or possibly deleterious effects of the deoxycholate detergent on reservoir materials. In February, the reservoir was emptying very slowly, only a calculated average of 0.03 mg/d AmB would have been delivered for 2 months. Moreover, the residual reservoir AmB concentration was only 2.7 g/mL at the end of the period, a ⬎99% deterioration during 48-day residence in the reservoir. His CSF WBC had fallen to 20/mm3, protein to 78 mg/dL, and CSF CF to 1:8 (Table 1). In March, the reservoir was not emptying at all, but despite slight increase in ventricular size, he remained neurologically improved and stable. A calculated total of 13.6 mg AmB had been given intrathecally. Given his stable improved neurologic situation since the initial months’ reservoir therapy, despite an unintentional marked tapering of his daily dose received to miniscule levels, and a device that was hardly functioning, we elected to observe his further course. No further AmB was delivered to the reservoir, it has been replenished only with sterile water in the hopes of retaining some patency. The patient has remained neurologically stable, with gradual further improvement in cognition, since March 2002, with no further worsening of hydrocephalus. In autumn 2002, the pump spontaneously resumed pumping at close to desired rate. His CSF WBC has fallen to ⱕ10/mm3, protein to ⱕ83 mg/dL, CSF CF to 1:2, and his CSF glucose normalized (Table 1). His serum CF (a more distant reflection of activity of his coccidioidal central nervous system focus)7 had similarly fallen from 1:256, before the pump, to 1:16. He was able to advance his education through a 2-year to a more demanding 4-year college program.
DISCUSSION This experience documents a remarkable clinical (and laboratory monitoring) response of a patient with severely symptomatic, relapsed unresponsive coccidioidal meningitis, who then responded to continuous cisternal infusion of AmB. Despite mechanical difficulties with the pump-catheter system, resulting, in effect, in an abbreviated and tapering course of intrathecal therapy less than originally intended, drug decay and a relatively high AmB, MIC, and minimum fungicidal concentration,13 he has shown no signs of disease activity in a 6-year follow-up. In addition, the continuous infusion method was achieved without any of the well-described complications of intrathecal AmB therapy.1– 4 © 2009 Lippincott Williams & Wilkins
A current prevailing hypothesis, derived from animal experimentation, regarding the pharmacokinetic-pharmacodynamic parameter that governs AmB efficacy is that it is dependent on the ratio of peak drug concentration (Cmax) to MIC.14 Assuming this is correct, one might not expect a good result with a continuous infusion methodology, which prolongs the presence of drug, but lessens the Cmax/MIC ratio. There are several possible explanations for this apparent contradiction. One, it is possible that continuous infusion provides a sufficient drug concentration at the site of infection to achieve a necessary Cmax, beyond which further elevation of drug concentration is unnecessary. This may be, particularly, the case when the drug is given directly onto the infected target tissue. The “killing level” (1:256, later 1:32), assayed from the pump, of the drug against his organism, even after drug decay and against an organism whose MIC would be considered resistant,13 would support this interpretation. Moreover, the spherule-endospore form found in the host is likely more susceptible to AmB than the mycelial form,15 although parasitic form testing is rarely performed, owing to difficulties in converting isolates to that form in vitro and maintaining them as such. Second, a separate CSF compartment is qualitatively different than a whole animal; in particular, even in the presence of this degree of inflammation, the protein concentration is much lower than serum, and the binding to central nervous system tissue may have different kinetics than in other body sites, thus, creating a different pharmacodynamic paradigm. Finally, Coccidioides has a slower doubling time16,17 than the opportunistic fungi that have been used to derive the pharmacokinetic-pharmacodynamic parameters in animals. Thus, it may be advantageous to have drug continuously present, enabling an effective concentration to be present at a critical time in Coccidioides cell division. The device used is employed commonly for other indications, such as continuous CSF antispasmodic or analgesic medication, and its implantation (into the lumbar space for therapy of dystonia or pain) is a standardized neurosurgical procedure. The pump can be programmed for continuous delivery, as we did, or it can be configured to deliver intermittent pulse doses, mimicking intermittent delivery of doses as in usual intrathecal therapy for coccidioidal meningitis.1– 4 Complications of these pump systems are described, including catheter displacement, focal scar formation, irritation or compression of nerves, or granuloma formation at the distal tip, which can lead to myelopathy, but these are rare events.18,19 There are obvious advantages to drug delivery via a pump: the ability to avoid repeated (and with ongoing inflammation, likely increasingly traumatic) lumbar or cisternal punctures, the ability to only intermittently load the reservoir, which also lessens the risk of contamination compared with repeated thecal punctures, and the ability to adjust the dose given, to the patient’s degree of response, via altering the reservoir concentration or the infusion rate, achievable by external wireless programming. Ultrasound can further simplify refilling.20 This case also points out areas of drug delivery that require improvement before this approach can be generally applied. The slowing and eventual transient cessation of the pumping was not deleterious, but might be in other severe cases. If the cessation was due to a pump problem, rather than obstruction at the distal end of the catheter, such problem may benefit from alteration of the pump, and if due to obstruction, by alteration of the catheter characteristics. The decay of active drug documented might be remedied by more frequent refilling of the reservoir, or an alternative drug formulation.
81
Berry et al
In summary, we present a new method of intrathecal antifungal drug delivery. Further exploration of this approach offers promise of a more effective and less toxic therapeutic option for difficult cases of chronic fungal meningitis. REFERENCES 1. Einstein HE, Holeman CW Jr, Sandidge LL, et al. Coccidioidal meningitis. The use of amphotericin B in treatment. Calif Med 1961; 94:339 – 43. 2. Williams PL. Coccidioidal meningitis. Ann N Y Acad Sci 2007;1111: 377– 84.
liposomal amphotericin against coccidioidal meningitis in rabbits. Antimicrob Agents Chemother 2002;46:2420 – 6. 11. Ahluwalia M, Brummer E, Sridahr S, et al. Isolation and characterization of an anticryptococcal protein present in human cerebrospinal fluid. J Med Micro 2001;50:83–9. 12. Stevens DA. Combination immunotherapy and antifungal chemotherapy. Clin Infect Dis 1998;26:1266 –9. 13. National Committee for Clinical Laboratory Standards. Reference method for broth dilution antifungal susceptibility testing of conidiumforming filamentous fungi. Proposed standard M38-A. Wayne (PA): National Committee for Clinical Laboratory Standards; 2002.
3. Stevens DA, Shatsky SA. Intrathecal amphotericin in the management of coccidioidal meningitis. Semin Respir Infect 2001;16:263–9.
14. Andes D. Pharmacokinetics and pharmacodynamics in the development of antifungal compounds. Curr Opin Investig Drugs 2003;4: 991– 8.
4. Kelly PC. Coccidioidal meningitis. In: Stevens DA, editor. Coccidioidomycosis: a text. New York (NY): Plenum Medical Book Company; 1980. p. 163–93.
15. Collins M, Pappagianis D. Uniform susceptibility of various strains of Coccidioides immitis to amphotericin B. Infect Immun 1981;17:1049 –5.
5. Stevens DA, Clemons KV. Azole therapy of clinical and experimental coccidioidomycosis. Ann N Y Acad Sci 2007;1111:442–54. 6. Dewsnup DH, Galgiani JN, Graybill JR, et al. Is it ever safe to stop azole therapy for Coccidioides immitis meningitis? Ann Intern Med 1996;124:305–10. 7. Pappagianis D. Serologic studies in coccidioidomycosis. Semin Respir Infect 2001;16:242–50. 8. Stevens DA, Aristizabal BH. In vitro antifungal activity of novel azole derivatives with a morpholine ring, UR-9746 and UR-9751, and comparison with fluconazole. Diagn Microbiol Infect Dis 1997; 29:103– 6. 9. Hanson LH, Perlman AM, Clemons KV, et al. Synergy between cilofungin and amphotericin B in a murine model of candidiasis. Antimicrob Agents Chemother 1991;35:1334 –7. 10. Clemons KV, Sobel RA, Williams PL, et al. Efficacy of intravenous
82
16. Huppert M, Sun SH. Overview of mycology, and the mycology of Coccidioides immitis. In: Stevens DA, editor. Coccidioidomycosis: a text. New York (NY): Plenum Medical Book Company; 1980. Chapter 2, p. 21– 46. 17. Brosbe EA, Kietzman JN, Snellen JE. Time lapse cinemicrographic studies on behavior of Coccidioides immitis in vitro. In: Ajello L, editor. Coccidioidomycosis. Tucson (AZ): University of Arizona Press; 1967. p. 409 –14. 18. Protopapas MG, Bundock E, Westmoreland S, et al. The complications of scar formation associated with intrathecal pump placement. Arch Phys Med Rehabil 2007;88:389 –90. 19. Knox S, Atkinson RP, Stephens R, et al. Myelopathy as a complication of intrathecal drug infusion systems. Arch Neurol 2008;64:286 –7. 20. Hurdle MF, Locketz AJ, Smith J. A technique for ultrasound-guided intrathecal drug-delivery system refills. Am J Phys Med Rehabil 2007; 86:250 –1.
Volume 338, Number 1, July 2009