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.

Did you know about the updated perinatal guidelines?

(I had previously posted this a couple of weeks ago, but took it down since I was waiting for the "thumbs-up" from the powers that be.  Apologies for the re-post.)

New DHHS Perinatal Guidelines: Part I

There had been some controversy about the dosing of zidovudine for prevention of mother-to-child transmission (MTCT) of HIV – one institution had been dosing the medication based on the WHO recommendations (twice-daily) and our institution had been dosing it based on the DHHS guidelines (four-times daily).  There had been discussion on which one was the “right” dosing; however, after reviewing the most recent DHHS recommendations for prevention of perinatal HIV infection¹, we sheepishly concluded that twice-daily dosing would be appropriate.

Pediatric ACTG 076 showed that the administration of intravenous zidovudine to mothers who were HIV-1 infected (and who did not receive antepartum antiretrovirals) in the intrapartum period and the administration oral zidovudine (dosed at 2 mg/kg PO q6h) to the neonate reduced perinatal HIV infection to 8.3% from 25.5%.²  The study took place in the United States and showed a dramatic decrease of perinatal HIV infection; intravenous zidovudine and infant prophylaxis was strongly recommended from then on for MTCT prevention.

Although one of the most prominent studies of MTCT prevention suggested dosing of zidovudine every 6 hours, the recent international studies dosed the neonatal zidovudine at 4 mg/kg PO q12h and has been shown to be effective.  Although there are no head-to-head trials to compare the new dosing regimen to the ACTG 076 dosing, the DHHS has applied the successes from the studies to change the 2010 recommendations to the twice-daily dosing to reduce the burden of frequent administration. 

The q12h dosing also seems practical from the pharmacokinetic viewpoint: one study suggested that the exposure between the two dosing regimens are similar³, zidovudine is primarily metabolized through the glucuronidation pathway and is eliminated through the renal system, which is initially immature in the neonate (t_1/2 = 4 hours vs. 1.5 hours in adults).³  Additionally, the intracellular half-life of zidovudine is much longer than the serum half-life, which drives the pharmacodynamic effect of zidovudine.⁴

DHHS Perinatal Guidelines: Infant Antiretroviral Prophylaxis

Gestational Age	2010	2011
> 35 weeks	2 mg/kg/dose PO q6h	4 mg/kg/dose PO q12h
30-35 weeks	2 mg/kg/dose PO q12h, increase to 2 mg/kg/dose PO q8h at 2 weeks of age	Same
< 30 weeks	2 mg/kg/dose PO q12h, increased to 2 mg/kg/dose PO q8h at 4 weeks age	Same

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. Sep. 14, 2011; pp 1-207. Available at http://aidsinfo.nih.gov/contentfiles/PerinatalGL.pdf.

2.     Connor EM, Mofenson LM. Zidovudine for the reduction of perinatal human immunodeficiency virus transmission: pediatric AIDS Clinical Trials Group Protocol 076--results and treatment recommendations. Pediatr Infect Dis J. 1995;14:536-41. PMID: 7667060

3.     Moodley D, Pillay K, Naidoo K, et al. Pharmacokinetics of zidovudine and lamivudine in neonates following coadministration of oral doses every 12 hours. J Clin Pharmcol. 2001;41:732-41. PMID: 11452705

4.     Flynn PM, Rodman J, Lindsey JC, et al. Intracellular pharmacokinetics of once versus twice daily zidovudine and lamivudine in adolescents. Antimicrob Agents Chemother. 2007;51:3516-22. PMID: 17664328.

An Introduction...

Thank you for your interest in this blog!  (Or if you accidentally came upon this, I hope you find it interesting.)  The idea of starting a blog on various infectious diseases drug information (ID DI) was mostly to keep a log of questions that come up over the month and for "fun" as well.  Hopefully this will be interesting and somewhat informative for some of you.

About me, briefly: Completed Pharm.D. in 2008, PGY1 Pharmcy Practice Residency in 2009, and PGY2 HIV/ID Residency in 2010 (primarily HIV care). Currently practicing as a "Clinical Specialist, Infectious Diseases" in a free-standing pediatric academic hospital, spending half of my time on the Antimicrobial Stewardship Program (ASP) and the other half rounding with the ID team.

Disclaimer (of course there has to be a disclaimer): although questions will be researched to the best of my ability, doing your own verification and research would be prudent. (Blogs, even if evidence-based, probably are not the most reputable of sources.) (And besides, I'm sure that you are in the academic field so think of it as fulfilling your academic duties.)  Additionally, we know that information advances quickly as time goes on, so keep in mind that dated posts may not be up-to-date.  Other disclaimer stuff: the ideas and thoughts expressed in this blog does not reflect the people I may represent inadvertently. Other medical-legal stuff: these postings are not recommendations for health care management or treatment.  If you are seeking health care recommendations, do contact your primary care provider.

Watch for weekly postings!