Fungal Peritonitis + Voriconazole

Fungal peritonitis has been haunting us lately and the last few cases have involved Candida krusei, which is intrinsically resistant to fluconazole and has dose-dependent susceptibility with itraconazole.¹  Although I feel relatively comfortable with fluconazole and the echinocandins (kinda) for candidal peritonitis, I hadn’t had much experience with voriconazole in this setting.  (I was looking for an oral option for our patients, because the last thing we really needed was a catheter line associated blood stream infection.)  I looked at my trusty sources to see if there were any data about the penetration of voriconazole in peritoneal fluid (Lexicomp and Micromedex), but alas, there was no information available; however, given the wide distribution of the drug (4.6 L/kg), it suggests that there may be some distribution into peritoneal fluid.²

There is one pharmacokinetic study available that examined the distribution of voriconazole in peritoneal fluid.³  A total of five patients, who were undergoing peritoneal dialysis (PD), were in the study; a 200 mg single-dose of voriconazole was administered to each of the participants and serum and peritoneal dialysate concentrations of voriconazole were drawn.  It appears that voriconazole distributes into the peritoneal fluid, reaching maximum concentrations at the same time as the plasma.  Peritoneal clearance of voriconazole was minimal and the group suggested that dose adjustment was not needed for patients undergoing PD.

Pharmacokinetic Parameter	Study Group, Plasma	Study Group, Dialysate	Population (multiple 200 mg dose)
Cmax (mcg/mL)	0.55 ± 0.20	0.25 ± 0.09	2.08
Tmax­ ­(h)	2.4 ± 0.7	2.8 ± 0.5	1-2.8
AUC24h (mcg*h/mL)	5.8 ±1.3	--	19.86
t1/2 (h)	8.1 ± 1.3	--	6
Clearance/F (mL/min)	440 ± 77	3.7 ±0.6	--
Dialysate/Plasma concentration	--	0.66 ± 0.11	--

Although it appears that voriconazole distributes well into the peritoneal fluid (about 65% of the serum concentration), this was a single-dose study; multiple doses would be able to demonstrate if the distribution is consistent with time.  Also, only peak concentrations were obtained; although serum trough concentrations of voriconazole may be more predictive of efficacy, “trough” peritoneal concentrations may help determine if it is sufficient to treat fungal infections.  Lastly, this study was performed in uninfected patients undergoing peritoneal dialysis; it appears that general management of fungal peritonitis is to remove the PD catheter early and initiate hemodialysis in the patient in addition to antifungal therapy.⁴  The loss of volume in the peritoneal space as well as inflammation may increase the concentration of voriconazole in the fluid; however, further studies are needed to explore this avenue.   

Even though C. albicans is the primary culprit associated with fungal peritonitis, other Candida sp. and non-yeast species have been increasingly noted which has required the use of more broad-spectrum antifungals; although echinocandins have an FDA-labeled indication for disseminated candidiasis (including peritonitis), the role of other triazole antifungals have not been fully established for peritonitis.⁴  When searching the primary literature, there are a number of cases where voriconazole was used successfully to treat peritonitis associated with fungi, including Fusarium, non-albicans Candida, Aspergillus sp., C. bertholletiae (although it was found to be resistant to voriconazole), P. lilacinus (in combination with terbenifine), N. pseudofischeri, and O. gallopava.^4-11  While there are successes, it should be noted that mortality associated with severe fungal peritonitis is high (up to 50%), despite appropriate antifungal pharmacotherapy.^4,10

1.       Pappas PG, Kauffman CA, Andes D, et al. Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis. 2009;48:503-35.  Available at: http://www.idsociety.org/uploadedFiles/IDSA/Guidelines-Patient_Care/PDF_Library/Candidiasis.pdf

2.       VFEND® (voriconazole) Prescribing Information. Pfizer Inc. New York, NY. Updated November 2011.  Available at: http://labeling.pfizer.com/ShowLabeling.aspx?id=618

3.       Peng LW, Lien YH. Pharmacokinetics of single, oral-dose voriconazole in peritoneal dialysis patients. Am J Kidney Dis. 2005;45:162-6.

4.       Matuszkiewicz-Rowinska J. Update on fungal peritonitis and its treatment. Perit Dial Int. 2009;29:s161-5. PMID: 13270208

5.       Pimentel JD, Dreyer G, Lum GD. Peritonitis due to Cunninghamella bertholletiae in a patient undergoing continuous ambulatory peritoneal dialysis.  J Med Microbiol. 2006;55:115-8. PMID:16388039

6.       Chang BP, Sun PL, Huang FY, et al. Paecilomyces lilacinus peritonitis complicating peritoneal dialysis cured by oral voriconazole and terbinafine combination therapy. J Med Microbiol. 2008;57:1581-4. PMID: 19018033

7.       Ghebremedhin B, Bluemel A, Neumann KH, Koenig B, Koenig W. Peritonitis due to Neosartorya pseudofischeri in an elderly patient undergoing peritoneal dialysis successfully treated with voriconazole. J Med Microbiol. 2009;58:678-82. PMID: 19369533

8.       García-Martos P, Gil de Sola F, Marín P, García-Agudo L, García-Agudo R, Tejuca F, Calle L. Fungal peritonitis in ambulatory continuous peritoneal dialysis: description of 10 cases. Nefrologia. 2009;29:506-17. PMID: 19935994

9.       Wong JS, Schousboe MI, Metcalf SS, et al. Ochroconis gallopava peritonitis in a cardiac transplant patient on continuous ambulatory peritoneal dialysis. Transpl Infect Dis. 2010;12:455-8. PMID: 20534037

10.   Montravers P, Mira JP, Gangneux JP, Leroy O, Lortholary O. A multicentre study of antifungal strategies and outcome of Candida spp. peritonitis in intensive-care units. Clin Microbiol Infect. 2011;17:1061-7. PMID: 20825438

11.   Ulusoy S, Ozkan G, Tosun I, et al. Peritonitis due to Aspergillus nidulans and its effective treatment with voriconazole: the first case report. Perit Dial Int. 2011;31:212-3. PMID: 21427255

Intermittent amphotericin?

Amphotericin B (AmB) is a polyene antifungal agent that is frequently used to treat invasive yeast and mold infections and is available in conventional and lipid formulations.  AmB deoxycholate has a long half-life (terminal half-life of 15 days) and distributes into well into the tissues; practitioners in the past have taken advantage of these pharmacokinetic parameters: instead of dosing conventional AmB on a daily basis, it would be dosed on as an alternative-day schedule.  (The package insert recommends a maximum dose of 1 mg/kg IV daily or 1.5 mg/kg IV on alternate days.¹)  Besides the most obvious advantage of giving the medication less frequently, it also meant that patients were going to experience less infusion-related reactions such as fever, chills, hypotension, and phlebitis (no news about decreasing the risk of nephrotoxicity with this alternative dosing).  However, there is scare clinical data available that supports the use of intermittent dosing of AmB deoxycholate, but anecdotal reports suggest that the outcomes are similar (per the 2 people in my group who have actually had anecdotal use of intermittent AmB).

Conventional AmB is well known to be associated with nephrotoxicity, and newer formulations have been developed to decreased the risk of nephrotoxicity; lipid-formulations AmB has become increasingly utilized due to its safety and lower risk of infusion reactions.  Because the half-life of liposomal AmB is also prolonged (100-153 hours), I was asked if there was any clinical data that suggested that alternate-day dosing had similar outcomes as traditional daily dosing.  In theory, dosing liposomal AmB should be possible, unfortunately, there are virtually no studies that explored alternate day dosing for treatment (in humans, at least).  Although it has been suggested that in conventional AmB has concentration-dependent activity, the PK/PD (pharmacokinetic/pharmacodynamic) targets of liposomal AmB may not be the same and further investigation would aid in determining more novel dosing.²  

Some studies suggest high-dose intermittent liposomal AmB is safe and feasible at 7.5-10 mg/kg/dose IV weekly.³ Additionally, there have been limited studies assessing the efficacy of intermittent liposomal AmB for fungal prophylaxis in patients undergoing chemotherapy for hematological malignancies (primarily acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS)) or stem cell transplantation, which have been summarized below.  Overall, the data is conflicting and the study designs are varied and have small numbers; some studies suggest that intermittent liposomal AmB can decrease the risk of IFI in neutropenic patients, but some suggest that there is no difference.  Although azoles, such as voriconazole, appear to be preferred for IFI prophylaxis in hematological malignancy patients (oral formulation, less toxicity), liposomal AmB may be used due to contraindications to azoles; although intermittent dosing is potentially an option for patients requiring longer prophylaxis, it appears that comparative trials between standard and intermittent dosing is needed.

PMID	Patient Population	Intervention	Outcome (IFI)
10197802 (1999)	Adult, n = 161 (auto- or allo-HSCT)	Randomization: LAmB 2 mg/kg IV three times weekly vs. placebo	Suspected: 31/74 vs. 40/87 (NS) Proven: 0/74 vs. 3/87 (NS) (This study suggests that the prophylaxis group had lower fungal colonization rates)
11820258 (2001)	Pediatric, n = 29 (AML, HR-ALL, MDS, severe aplastic anemia, stage IV neuroblastoma, auto-HSCT)	Partial randomization: Prophylaxis (LAmB   1 mg/kg IV three times weekly) vs. “early intervention”	Probable: 5/16 vs. 5/13 (NS) Proven: 0/16 vs. 1/13 (NS)
16766594 (2006)	Adult, n = 140 (232 neutropenic episodes) (expected neutropenia > 10 days or auto-HSCT	Randomization: LAmB 50 mg IV every other day vs. placebo	1st neutropenic episode: Probable and Proven: 5/75 vs. 20/57 (p = 0.001) All episodes: Probable and Proven: 5/110 vs. 22/109 (p < 0.01) (This study suggested the LAmB decreased risk for developing Aspergillosis but not Candidasis)
18430130 (2008)	Adults, n = 30	Randomization: LAmB 3 mg/kg IV daily vs. LAmB 10 mg/kg IV day 1, then 5 mg/kg IV days 3 and 6	Probable and Proven: 3/15 vs. 0/15 (no statistical analysis mentioned)
21895857 (2011)	Pediatric, n = 44 (46 neutropenic episode) (HR-ALL, AML, relapse ALL, AML, HR-NHL, severe aplastic anemia) Historical control, n = 39, (45 cases)	Prophylaxis: LAmB2.5 mg/kg IV twice weekly	Probable: 0/46 vs. 2/45 (p = 0.01) Proven: 0/46 vs. 5/45 (p = 0.01)

1.     Gallis HA, Drew RH, Pickard WW. “Amphotericin B: 30 years of clinical experience.” Reviews Infect Dis. 1990;12:309-29.

2.     Lestner JM, Howard SJ, Goodwin J, et al. “Pharmacokinetics and pharmacodynamics of amphotericin B deoxycholate, liposomal amphotericin B, and amphotericin B lipid complex in an in vitro model of invasive pulmonary aspergillosis.” Antimicrob Agents Chemother. 2010;54:3432-41.

3.     Ellis M. “New dosing strategies for liposomal amphotericin B in high-risk patients.” Clin Microbiol Infect. 2008;14:55-64.

Cefoxitin testing in S. aureus

I was recently reviewing antibiotics on a patient and came across this microbiology result:

Source: Sputum

Results: Few presumptive Staph aureus; organism does not grow for identification and susceptibility testing by automated method.

Susceptibilities by Kirby-Bauer Method

               

Drug	Result	Interpretation
Cefoxitin	17 mm	R
Erythromycin	3 mcg/mL	I
Clindamycin	0.25 mcg/mL	S
Penicillin	32 mcg/mL	S
Linezolid	4 mcg/mL	S
Trimethoprim/Sulfamethoxazole	32 mcg/mL	R
Vancomycin	1.5 mcg/mL	S

I remembered some tidbits from a microbiology rotation about cefoxitin testing in S. aureus and thought this might be a good ID pearl for our pharmacy residents.  We teach our residents to look at the susceptibility interpretation for oxacillin to determine if the S. aureus is methicillin-susceptible or resistant (which makes a huge difference in selecting antimicrobials); but what do we do if there isn’t an oxacillin interpretation?

There are some cases where the automated machine can’t get a good read on the MIC of oxacillin for S. aureus; the microbiology lab will set up a culture on a plate with a cefoxitin disk as a surrogate marker to determine oxacillin susceptibility, which has a high sensitivity and specificity.¹ Currently, the CLSI guidelines recommend a zone of inhibition ≤ 21 mm to detect resistance to cefoxitin.²  Therefore, one would just need to look at the reading for the cefoxitin – if it’s susceptible, then it should be MSSA and if it’s resistant, MRSA.  (Interestingly enough, the lab had reported the above culture as “susceptible” and from this review, was corrected to “resistant”.)

You might ask: Why don’t we use oxacillin instead? Apparently, it seems the zone of inhibition created by oxacillin is hard to read (can be fuzzy) and can lead to misinterpretations, whereas the zone of inhibition from cefoxitin is much more clear (I couldn’t find a good image of this).  Additionally, oxacillin should be read under transmitted light for the best interpretation.³ There are a few studies that compare sensitivity and specificity of cefoxitin to oxacillin for detection of mecA; however, most of these were performed with the previous CLSI standard (cefoxitin zone diameter ≤ 19 for resistance) and new recommendations has increased the sensitivity and specificities of the test.  Lastly, cefoxitin is also a better inducer of the mecA gene (the gene responsible for the production of PBP2a, which is an altered PBP than beta-lactams have a low affinity to) than oxacillin; however, this means that cefoxitin detects only mecA-mediated oxacillin resistance, but fortunately, that’s the primary mechanism of resistance for S. aureus in the United States.

1.       Fernandes CJ, et al. Cefoxitin resistance as a surrogate marker for the detection of methicillin-resistant Staphylococcus aureus. J Antimicrob Chemother. 2005;55:506-10.

2.       CLSI. Performance standards for antimicrobial susceptibility testing; Twenty-first informational supplement. CLSI document M100-S21. Wayne, PA: Clinical and Laboratory Standards Institute; 2011.

3.       Broekema NM, et al. Comparison of cefoxitin and oxacillin disk diffusion methods for detection of mecA-mediated resistance in Staphylococcus aureus in a large-scale study. J Clinical Microbiol. 2009;47:217-9.

I can't order mebendazole anymore...?

Mebendazole tablets (anthelmintic)

Recently discontinued from the US market (October 27, 2011); Teva Pharmaceuticals was the sole manufacturer for mebendazole and no statement for the discontinuation was provided.  Other anthelmintics (abendazole, ivermectin, praziquantel, pyrantel) are still available (no active shortages).

Mebendazole Indication	Alternative Treatment
Hookworm (A. duodenale, N. americanus)	1st line: Albendazole, pyrantel
Roundworm (A. lumbricoides)	1st line: Albendazole, pyrantel 2nd line: Nitazoxanide, ivermectin
Pinworm (E. vermicularis)	1st line: Albendazole, pyrantel 2nd line: Ivermectin
Whipworm (T. trichiura)	1st line: Albendazole 2nd line: Ivermectin
Capillariasis (C. phillipinensis; unlabeled use)	1st line: Albendazole
Giardiasis (G. duodenalis; unlabeled use)	1st line: Metronidazole, tinidazole, nitazoxanide 2nd line: Albendazole, paromomycin
Filarasis (M. perstans; unlabeled use)	1st line: Albendazole
Visceral larva migrans (Toxocariasis; unlabeled use)	1st line: Albendazole

Resources:

1.     American Society of Health-System Pharmacists. “Drug shortages: Discontinued Drugs.”  http://www.ashp.org/DrugShortages/NotAvailable/. Accessed April 22, 2012.

2.     American Society of Health-System Pharmacists. “Drug shortages: Current Drugs.”  http://www.ashp.org/DrugShortages/Current/. Accessed April 22, 2012.

3.     American Academy of Pediatrics.  Red Book: 2009 Report of the Committee on Infectious Diseases. 28^th Edition. Elk Grove Village, IL: American Academy of Pediatrics;2009.

4.     Wilson CM and Freedman DO. “Antiparasitic Agents.”  Principles and Practice of Pediatric Infectious Diseases. 3^rd Edition. Philidephia, PA:Elsevier, Inc.; 2008.

Did you know that another part was also updated?

Perinatal Guidelines: Part II

All children born to HIV-seropositive women are recommended to initiate antiretroviral (ARV) therapy; however, the decision in selecting ARVs for prophylaxis depends on the situation.  There are a few settings to consider for neonatal prophylaxis:

1.    HIV-positive mother who was on antepartum HAART and is virologically controlled

2.    HIV-positive mother was NOT on antepartum HAART (with or without intrapartum IV zidovudine)

3.    HIV-positive mother who was on antepartum HAART but is NOT virologically controlled

4.    HIV-positive mother was has known ARV-resistant virus

In setting 1, neonates should receive 6 weeks of oral zidovudine (AZT); the most recent dosing recommendation was discussed in the previous blog.  In settings 3 and 4, it is highly recommended to contact the National HIV/AIDS Clinicians’ Consultation Center Perinatal HIV Hotline (available at 1.888.448.8765) to discuss the optimal combination of ARVs.  The 2011 Prevention of Mother to Child Transmission has new recommendations for ARV prophylaxis in setting 2.

Previously, it was recommended to provide 6 weeks of AZT, a single-dose of nevirapine (NVP) and 7 days of lamivudine (3TC) to neonates; it was recognized that even a single dose of nevirapine could lead to drug-resistant virus and a “tail” of 3TC could decrease the risk.  However, side effects, such as neutropenia, were more common in this combination of ARVs.

The NICHD HPTN 040/PACTG 1043 sought to compare the efficacy and safety of 3 regimens to prevent intrapartum transmission of HIV-1 in neonates whose mothers did not receive antepartum HAART (but could receive intrapartum IV AZT:

1.    AZT x 6 weeks alone (n = 566)

2.    AZT x 6 weeks with 3 doses of NVP (n = 562)

3.    AZT x 6 weeks with 3TC and nelfinavir (NFV) x 2 weeks (n = 556)

Of the 1684 neonates who were evaluable for the study, 140 neonates were infected with HIV, of which 47 were from intrapartum transmission. The transmission rate in each group: AZT alone group = 4.9%, AZT + NVP = 2.2%, and AZT +3TC/NFV = 2.5%; the rate was considered significantly lower in the patients who received combination therapy compared to AZT alone (p = 0.045 for both).  A high viral load (the median viral load was log ₁₀ 4.17) and drug abuse was associated with intrapartum transmission of HIV; I think that this is particularly interesting since the current guidelines recommend a Cesarean section if the viral load > 1000 copies/mcL and in this study, a majority of women had a natural birth (65%) and transmission was not associated with the mode of birth.  On the other hand, there were a small number of patients with intrapartum transmission and the study may not have been powered to look at this association.  When looking at safety of the ARVs, it was found that group 3 had a significantly higher rate of neutropenia (p < 0.0001); other factors, such as anemia, transaminitis, or thrombocytopenia was similar amongst all groups.

Due to the increased efficacy in comparison to AZT alone, and lesser toxicity in comparison to the 3-drug regimen, it is now recommended to provide 6 weeks of AZT and 3 doses of NVP to the neonate where HIV-seropositive mothers did not receive antepartum HAART.

Of note, the infants included in this study were NOT breastfed; formula was provided to the family through the study.  The ideal ARV regimen for neonates who are breastfed by HIV-seropositive mothers is still under investigation.

1.       Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission. Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States. May 24, 2010; pp 1-117.

2.       Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission. Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States. Sep. 14, 2011; pp 1-207. Available at http://aidsinfo.nih.gov/contentfiles/PerinatalGL.pdf.

3.       Nielsen-Saines K, Watts DH, Santos VV, et al. Phase III randomized trial of the safety and efficacy of three neonatal antiretroviral regimens for preventing intrapartum HIV-1 transmission (NICHD HPTN 040/PACTG 1043). Paper presented at: 18th Conference on Retroviruses and Opportunistic Infections (CROI); Feb. 27-Mar 3, 2011; Boston, MA.