Amoxicillin/clavulate for ESBL UTI?

Everyone falls a little behind in life (although my hiatus from writing is almost a year!), but instead of making excuses, I need to get myself in gear and start posting again. Here goes:

As most of the adult healthcare providers are aware of (and there is growing knowledge in the general population), there is an increasing amount of extended-spectrum beta-lactamase (EBSL)-producing organisms in the community; however, it seems that some of us in the pediatric side are still a little naïve to this. However, our renal/urology patients are definitely blowing our innocence out of the water and I feel like I see a new patient colonized with ESBL-producing about every few weeks or so. Unfortunately, their isolates are often resistant to oral antibiotics and have to be admitted for intravenous antibiotics for urinary tract infections (UTIs); although, sometimes you will get lucky and one will actually be amoxicillin/clavulante susceptible.

Some of our practitioners feel a little leery about using amoxicillin/clavulante alone for UTIs, mostly due to limited experience as well as the idea of how such an everyday antibiotic can work the same wonders as a broad-spectrum carbapenem. But it kind of makes some sense that the addition of clavulante might do the trick: beta-lactamase inhibitors can inhibit Ambler Class A ESBLs, whereas AmpC beta-lactamases (Ambler Class C) are not affected.¹ Phenotypic confirmation of ESBLs can be performed through disk diffusion. The zone of inhibition is compared between ceftazidime and cefotaxime alone and in combination with clavulanic acid and an increase of >= 5 mm confirms the presence of an ESBL (see figure).^2,3 The Clinical Laboratory Standards Institute recommends that all other penicillins, cephalosporins, and aztreonam be reported as “resistant” but does not indicate whether or not amoxicillin/clavulanate should be defaulted as non-susceptible when the MIC <= 8 mcg/mL.

There appears to be very limited studies about the clinical usage of amoxicillin/clavulante in this setting. One study of community-acquired uncomplicated cystitis caused by ESBL-producing E. coli suggests that amoxicillin/clavulate can often be successful if the organism is susceptible (MIC <= 8 mcg/mL) and less so if less susceptible (MIC ³ 16 mcg/mL), 93% vs. 56%.⁴  Additionally, the pharmacokinetic/pharmacodynamics properties of amoxicillin/clavulanate are maximized for uncomplicated UTIs due to the concentration of the antibiotic in the bladder. The challenge, however, is finding an isolate that is susceptible to this beta-lactam/beta-lactamase inhibitor combination since the resistance can be upwards of 70% in E. coli isolates. Thus, empiric use of amoxicillin/clavulanate should be avoided and other agents, such as nitrofurantoin or fosfomycin, can be considered as initial treatment (although treatment spectrum is limited to cystitis).⁵

However, the other question would be whether or not clavulanate in combination with other oral cephalosporins would be adequate as an oral outpatient therapy for UTIs? Which, hopefully, will be explored in the next week or so.

Figure 1. ESBL detection by disk diffusion.

1.     Drawz SM, Bonomo RA. Three decades of beta-lactamase inhibitors. Clin Microbiol Rev. 2010;23:160-201. PMID:20065329

2.     Clinical and Laboratory Standards Institute. 2011. Performance standards for antimicrobial susceptibility testing. Supplement M100-S21.Clinical and Laboratory Standards Institute, Wayne, PA.

3.     Kumar V, Sen MR, Nigam C, Gahlot R, Kumari S. Burden of different beta-lactamase classes among clinical isolates of AmpC-producing Pseudomonas aeruginosa in burn patients: a prospective study. Indian J Crit Care Med. 2012;16:136-140. PMID: 23188953

4.     Rodríguez-Baño J, Alcalá JC, Cisneros JM, et al. Community infections caused by extended-spectrum beta-lactamase-producing Escherichia coli. Arch Intern Med. 2008;168:1897-902. PMID: 18809817

5.     Meier S, Weber R, Zbinden R, Hasse B. Extended-spectrum β-lactamase-producing Gram-negative pathogens in community-acquired urinary tract infections: an increasing challenge for antimicrobial therapy. Infection. 2011;39:333-40. PMID: 21706226

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.