Category Archives: ANTIMICROBIALS

A Rash of Beta-Lactam Allergies, Part 3: The Solution

This post is the last in a three-part series covering the management of beta-lactam allergies. Part 1 explained the enormous impact that penicillin allergies have on patient outcomes, while Part 2 discussed the different types of allergic reactions and the potential (or lack thereof) for beta-lactam allergy cross reactivity. This last post will cover the methods used to assess beta-lactam allergies. Let’s jump right in!

There are a variety of strategies that can be used to assess a patient’s beta-lactam allergy, each having their own place in the allergy assessment algorithm. The following will be detailed in this post:

Detailed Patient Interview

Far and away the most important step in assessing a patient’s beta-lactam allergy is a detailed patient interview. An allergy evaluation is recommended by many of the top health organizations in the country, including the Center for Disease Control and Prevention (CDC), National Quality Forum, Infectious Diseases Society of America (IDSA), American Board of Internal Medicine (ABIM), and the American Academy of Allergy, Asthma & Immunology (AAAAI).1 Just a minute or two of questioning the patient can yield an entirely different story than the allergy history in the medical chart. Some common questions I bring up with patients include:

  • How many years ago did the reaction occur?
  • What type of reaction did you have?
  • Do you remember the details of the reaction? Did you have to go to the emergency room?
  • How long after starting the medication did the reaction occur?
  • How was the reaction managed?
  • What happened when the medication was stopped?
  • Have you tolerated other forms of penicillin since the reaction? Have you had Keflex (cephalexin), Augmentin (amoxicillin/clavulanate), or amoxicillin?
    • Using brand names to question patients in this situation is important, as many patients wouldn’t recognize the jumble of letters that is amoxicillin/clavulanate

You can develop your own arsenal of questions to ask patients, but the important part is to talk to them. No further strategies are needed if you can rule out the documented allergy just from a 90-second conversation.

Medication History

The other piece that is absolutely necessary before proceeding is looking through the patient’s medication history yourself. If a patient with a documented penicillin allergy received ceftriaxone without issue on an admission last year, you can go ahead and give full-dose ceftriaxone during this admission if needed. The patient interview and medication history review can rule out >50% of documented allergies in my experience. In these situations, you can skip directly to the last section of this post: allergy re-labelling.

Direct Challenge

In patients with a very low probability of allergic reaction, a beta-lactam antibiotic can usually be given without pause. Situations where you can rule out an allergy based on patient interview or medication history can be “challenged” directly. This means giving the full dose of the preferred antibiotic and monitoring for any adverse effects. Some institutions also give a direct oral amoxicillin challenge with 250-500 mg of amoxicillin once prior to the intended beta-lactam initiation. If the patient can tolerate amoxicillin, any penicillin antibiotic can be given in the future without fear of experiencing an IgE-mediated reaction.

Graded Challenge

When you are not able to completely rule out an allergic reaction, a graded challenge is often the next logical step in hospitalized patients. Graded challenges are used when there is a low probability of an allergic reaction, but there is still a degree of discomfort giving the entire dose up front. In general, 10% of the full dose is given, the patient is monitored closely for 30 minutes, and then the full dose is given if no issues arise. If the patient tolerates these doses, you can rule out immediate hypersensitivity reactions and document the tolerance in the medical record, which will be discussed at the end of this post.

Snippet of graded challenge guideline table from Brigham & Women’s Hospital

Desensitization

In patients who have confirmed or a high probability of severe IgE-mediated reactions to beta-lactams, but a beta-lactam is necessary for treatment, desensitization can be used. The desensitization procedure usually involves at least 12 doses of escalating concentrations of the required medication. This procedure requires incredibly close monitoring, which at most hospitals requires admission to the intensive care unit for administration. If a patient is able to tolerate desensitization, the patient must then begin regularly scheduled doses of the beta-lactam immediately upon the protocol completion. If doses are missed, the patient must be desensitized again. Desensitization does not rule out the allergy. The patient is still considered allergic to that agent, but can tolerate the medication for the course required in that instance.

Penicillin Skin Testing

Penicillin (PCN) skin testing has increased in popularity recently due to its relative ease of use and efficacy at ruling out IgE-mediated allergic reactions. In addition to rescue medications that should be handy just in case (diphenhydramine, methylprednisolone, and epinephrine) the skin test consists of 4 elements:

Initially, a percutaneous puncture test is done on the patient’s forearm with each of the elements and if tolerated, an intradermal test of each is also performed. The entire process generally takes around 45-60 minutes to complete and offers a negative predictive value for penicillin allergies of ~99%.2 Debate has surrounded the cost (both time and materials for the procedure), but multiple studies have now shown penicillin skin testing to be a cost-saving venture.2-5

Penicillin skin testing seems like a no-brainer, carrying the lowest risk of the procedures discussed thus far and its low overall cost for the health system. But in many institutions, it’s unclear who will perform the testing when allergy consultation is not available. In a 2015 survey of 736 infectious diseases providers, 57% responded saying that they do not have local options for skin testing.6 Does your institution?

The people of Twitter have spoken and it resulted in similar responses, with 62% of respondents not having penicillin skin testing available at their institution. Previous studies have reported on the successes of penicillin skin testing performed by allergists,7-9 & many more antimicrobial stewardship programs,10 infectious diseases fellows/physicians,11 nurses,12 and pharmacists.13,14 If you’ve read this far into the post, you likely are interested in allergy skin testing, so I’d implore you to own the process if your institution doesn’t already have skin testing available! ALK provides some excellent instructional videos on their website to guide you through the testing process. Pharmacists aren’t licensed to perform skin testing in all 50 states, but they are in many of them, which this 2019 article did an admirable job exploring.15

Allergy re-labelling

The last fundamental step in navigating beta-lactam allergies is updating the patient’s allergy label. With all of the previous interventions, the allergy documentation can be further described in the medical record, with desensitization being the only intervention that does not rule out IgE-mediated reactions altogether.

Green denotes interventions that can lead to allergy de-labelling. Red denotes the only intervention that should not lead to de-labelling

In an ideal world, inaccurate allergy labels should be removed from the medical record. Unfortunately, this practice often leads to redocumentation of the allergy at a later admission however.16 Many hospitals have integrated innovative ways to improve this repetitive cycle, as seen via providers’ personal experiences here, here, and here. For those without the tech support for any of this functionality though, the best thing to do is to document, document, document.

Summary

The majority of penicillin allergy labels do not belong to patients with true allergies and these unnecessary labels lead to worse patient outcomes. We should all strive for more accurate and detailed allergy documentation in our patients, which all starts with a patient interview. All of the interventions discussed above can be used to remove/relabel a beta-lactam allergy, with the exception of desensitization.

For those looking to learn more, I highly recommend a recent review published in JAMA that goes into further detail on penicillin allergies.17 Make sure to check out the supplementary material too, it has some super helpful resources, including a full allergy toolkit for penicillin skin testing and oral amoxicillin challenges!

Previous posts in this series:

A Rash of Beta-Lactam Allergies, Part 1: The Problem

A Rash of Beta-Lactam Allergies, Part 2: The Education

References

  1. Blumenthal KG, Shenoy ES, Wolfson AR, et al. Addressing inpatient beta-lactam allergies: a multihospital implementation. J Allergy Clin Immunol Pract. 2017;5:616-625
  2. Jones BM, Bland CM. Penicillin skin testing as an antimicrobial stewardship initiative. Am J Health-Syst Pharm. 2017;74:232-7
  3. Mattingly TJ, Meninger S, Heil EL. Penicillin skin testing in methicillin-sensitive staphylococcus aureus bacteremia: A cost-effectiveness analysis. PLoS One. 2019; 14(1):e0210271. doi: 10.1371/journal.pone.0210271
  4. Jones BM, Avramovski N, Concepcion AM, Crosby J, Bland CM. Clinical and Economic Outcomes of Penicillin Skin Testing as an Antimicrobial Stewardship Initiative in a Community Health System. Open Forum Infect Dis. 2019;6(4): ofz109. doi: 10.1093/ofid/ofz109
  5. Rimawi RH, Cook PP, Gooch M, et al. The impact of penicillin skin testing on clinical practice and antimicrobial stewardship. J Hosp Med. 2013;8(6):341-345
  6. Trubiano JA, Beekmann SE, Worth LJ, et al. Improving antimicrobial stewardship by antibiotic allergy delabeling: evaluation of knowledge, attitude, and practices throughout the Emerging Infections Network. Open Forum Infect Dis. 2016; 3(3):ofw153
  7. Blumenthal KG, Wickner PG, Hurwitz S, et al. Tackling inpatient penicillin allergies: Assessing tools for antimicrobial stewardship. J Allergy Clin Immunol. 2017;140:154-161
  8. Macy E, Shu YH. The Effect of Penicillin Allergy Testing on Future Health Care Utilization: A Matched Cohort Study. J Allergy Clin Immunol Pract. 2017;5(3):705-710
  9. Park M, Markus P, Matesic D, Li JT. Safety and effectiveness of a preoperative allergy clinic in decreasing vancomycin use in patients with a history of penicillin allergy. Ann Allergy Asthma Immunol. 2006;97(5):681-687
  10. Leis JA, Palmay L, Ho G, et al. Point-of-Care β-Lactam Allergy Skin Testing by Antimicrobial Stewardship Programs: A Pragmatic Multicenter Prospective Evaluation. Clin Infect Dis. 2017;65(7):1059-1065
  11. Heil EL, Bork JT, Schmalzle SA, et al. Implementation of an Infectious Disease Fellow-Managed Penicillin Allergy Skin Testing Service. Open Forum Infect Dis. 2016;3(3):ofw155
  12. Macy E, Roppe LB, Schatz M. Routine Penicillin Skin Testing in Hospitalized Patients with a History of Penicillin Allergy. Perm J. 2004;8(3):20-24
  13. Chen JR, Tarver SA, Alvarez KS, Tran T, Khan DA. A Proactive Approach to Penicillin Allergy Testing in Hospitalized Patients. J Allergy Clin Immunol Pract. 2017;5(3):686-693
  14. Wall GC, Peters L, Leaders CB, Wille JA. Pharmacist-managed service providing penicillin allergy skin tests. Am J Health Syst Pharm. 2004;61(12):1271-1275
  15. Bland CM, Bookstaver PB, Griffith NC, et al. A practical guide for pharmacists to successfully implement penicillin allergy skin testing. Am J Health Syst Pharm. 2019;76(3):136-147
  16. Rimawi RH, Shah KB, Cook PP. Risk of redocumenting penicillin allergy in a cohort of patients with negative penicillin skin tests. J Hosp Med. 2013;8(11):615-618
  17. Shenoy ES, Macy E, Rowe T, Blumenthal KG. Evaluation and management of penicillin allergy: a review. JAMA. 2019;321(2):188-199

A Rash of Beta-Lactam Allergies, Part 2: The Education

This post is the second in a three-part series covering the management of beta-lactam allergies, all to be released on FOAMid over the last few months of 2019. Part 1 explained the enormous impact that penicillin allergies have on patient outcomes. Today we’ll discuss the different types of allergic reactions and the potential for beta-lactam allergy cross reactivity. Let’s jump right in!

Types of Allergic Reactions

The most common way of grouping immune-mediated hypersensitivity reactions is through the Gell & Coombs classification method.2 Using this scheme, there are four types of allergic reaction:

Type I reactions are IgE-mediated reactions and commonly referred to as immediate-type hypersensitivity reactions, since they occur minutes to hours post-exposure to an allergen. Type I reactions include anaphylaxis, angioedema, hypotension, flushing, wheezing, hives, and urticaria.

Both types II and III reactions are IgG-mediated.
Type II reactions, or cytotoxic reactions, include hemolytic anemia, thrombocytopenia, and neutropenia.
Type III reactions are immune complex reactions, and include serum sickness, glomerulonephritis, and arthritis.

Last, but certainly not least, are type IV reactions, which are T-cell mediated.
Type IV reactions are commonly referred to as delayed hypersensitivity reactions, despite Types II, III, and IV all technically being delayed in nature by days to weeks post-exposure to an allergen. A maculopapular rash, interstitial nephritis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome are all considered type IV reactions.

Cross-Reactivity Risk

As discussed in the first post, many recorded antibiotic allergies are not true allergies. But when a patient does actually have a true penicillin allergy, what are the chances that the patient will have a similar reaction to other beta-lactams?

While we would generally avoid penicillins in this situation, other beta-lactams like cephalosporins and carbapenems could potentially be used. Previous studies of 10-25% cross-reactivity between cephalosporins and penicillins were primarily reported prior to 1982, when cephalosporin manufacturing processes were often contaminated with penicillin.12 Since then, the documented rate of cross-reactivity has dropped dramatically, shown in the table below.12

*not all cephalosporins are created equal (see comments below)

Cephalosporins

  • Cephalosporins that do not share a side chain with penicillin have a cross-reactivity risk of <2%
  • Cephalosporins that do share a similar side chain to penicillins (ex. cefoxitin and penicillin) have a cross-reactivity risk that is much higher

Side chain similarities don’t guarantee cross-reactivity, but they do increase the risk above the previously stated 2% threshold

But hold on, I thought the cause of beta-lactam allergies was the core beta-lactam ring that everyone remembers from their undergraduate years?

Penicillin molecule with the highlighted beta-lactam ring

Not so fast. While this plays a part, more recent literature has shown that the R1 and R2 side chains also play a role in the allergy potential of cephalosporins. I have adopted and updated a table from an excellent 2008 review paper by Daryl DePestel and colleagues below.3

In this table, the 3s, 6s, and 7s stand for similar R1 or R2 side chains, as described in the cephalosporin skeleton molecule, also seen below.

  • The R1 side chain is at the 7-position on the cephalosporin molecule and the 6-position on the penicillin molecule.
  • The R2 side chain is at the 3-position, which only differs among cephalosporins and not penicillins.

There are a couple of important clinical points to note from this table. Probably most important for clinical practice is that cefazolin does not share side chains with any other beta-lactam agents. This can have huge consequences on the use of cefazolin in practice, especially when it comes to surgical site prophylaxis and the treatment of methicillin-susceptible Staphylococcus aureus infections, both situations that could use cefazolin as first line therapy.

And while aztreonam is known as a beta-lactam with limited cross-reactivity due to dissimilar side chains, it does actually share a side chain with ceftazidime and the more recently approved ceftolozane (marketed in combination with tazobactam).

Aztreonam & Carbapenems

Speaking of aztreonam, we’ve spent the majority of this post discussing cephalosporin cross-reactivity risk. Now let’s spend a bit of time reviewing the other agents defined in the initial table in this post: carbapenems and aztreonam. Cross-reactivity between these agents and penicillins is minimal, as seen by a number of studies published by an Italian group headed by Antonino Romano and Francesco Gaeta.4,7,9

In their 2013 analysis, they found no patients had an allergic reaction to carbapenems, despite all 204 patients having a well-demonstrated T-cell-mediated hypersensitivity reaction to other beta-lactams (mostly penicillin).7

They went on to look at IgE-mediated hypersensitivity in their 2015 study, which found yet again no cases of hypersensitivity with either carbapenems OR aztreonam this time in a cohort of 212 patients with proven penicillin allergies.4

Then in 2016, they went back to T-cell-mediated hypersensitivity, examining 214 patients with proven reactions to penicillins and testing them against aztreonam. Once again, zero patients reacted to the aztreonam test doses or full dose.9

At this point, you may be questioning if the Italian group ever saw any reactions in their trial outcomes. The last study presented above that showed no reactions with aztreonam though tested more than just aztreonam. They also looked at cephalosporins and saw an 18.7% chance of positive skin testing with aminocephalosporins (cephalexin, cefadroxil, cefaclor).9 If you refer back to the previous cross-reactivity table, you can see that these three agents share a side chain with ampicillin and amoxicillin.

So while side chains play a key role in determining cross-reactivity among cephalosporins, we can be fairly confident that carbapenems and aztreonam are safe to administer in the majority of situations, especially when a non-severe penicillin allergy is documented. This will be covered in more detail in the next (and final) installment of “A Rash of Beta-Lactam Allergies,” coming to you soon!

Other posts in this series:

A Rash of Beta-Lactam Allergies, Part 1: The Problem

A Rash of Beta-Lactam Allergies, Part 3: The Solution

References

  1. Blumenthal KG, Peter JG, Trubiano JA, Phillips EJ. Antibiotic Allergy. Lancet. 2019; 393(10167):183-198
  2. Coombs P, Gell PG. Classification of allergic reactions responsible for clinical hypersensitivity and disease. In: G RR, P.G.H Gell, eds. Clinical aspects of immunology. Oxford, UK: Oxford University Press, 1968; 575-596
  3. Frumin J, Gallagher JC. Allergic cross-sensitivity between penicillin, carbapenem, and monobactam antibiotics: what are the chances? Ann Pharmacother. 2009; 43:304-315
  4. Gaeta F, Valluzzi RL, Alonzi C, Maggioletti M, Caruso C, Romano A. Tolerability of aztreonam and carbapenems in patients with IgE-mediated hypersensitivity to penicillins. J Allergy Clin Immunol. 2015; 135:972-976
  5. Joint Task Force on Practice Parameters; American Academy, American College, & Joint Council of Allergy, Asthma and Immunology. Drug allergy: an updated practice parameter. Ann Allergy Asthma Immunol. 2010; 105:259-273
  6. Legendre DP, Muzny CA, Marshall GD, Swiatlo E. Antibiotic hypersensitivity reactions and approaches to desensitization. Clin Infect Dis. 2014; 58(8):1140-1148
  7. Romano A, Gaeta F, Valluzzi RL, et al. Absence of cross-reactivity to carbapenems in patients with delayed hypersensitivity to penicillins. Allergy. 2013; 68:1618-1621
  8. Romano A, Gaeta F, Arribas Poves MF, Valluzzi RL. Cross-reactivity among beta-lactams. Curr Allergy Asthma Rep. 2016; 16:24
  9. Romano A, Gaeta F, Valluzzi RL, Maggioletti M, Caruso C, Quaratino D. Cross-reactivity and tolerability of aztreonam and cephalosporins in subjects with a T cell-mediated hypersensitivity to penicillins. J Allergy Clin Immunol. 2016; 138:179-186
  10. Romano A, Valluzzi RL, Caruso C, Maggioletti M, Quaratino D, Gaeta F. Cross-reactivity and tolerability of cephalosporins in patients with IgE-mediated hypersensitivity to penicillins. J Allergy Clin Immunol Pract. 2018; 6(5):1662-1672
  11. Shenoy ES, Macy E, Rowe T, Blumenthal KG. Evaluation and management of penicillin allergy: a review. JAMA. 2019; 321(2):188-199
  12. Trubiano JA, Stone CA, Grayson ML, et al. The 3 Cs of antibiotic allergy-classification, cross-reactivity, and collaboration. J Allergy Clin Immunol Pract. 2017; 5(6):1532-1542

A Rash of Beta-Lactam Allergies, Part 1: The Problem

This post marks part 1 of a 3-part series covering the management of beta-lactam allergies, all to be released on FOAMid over the next couple of months.

  1.  This post, “The Problem,” provides background and the impact of a reported beta-lactam allergy
  2. “The Education” will delve into the types of allergic reactions, as well as cross reactivity potential among beta-lactam antibiotics
  3. “The Solution” will then explore how to best assess a patient’s documented allergy

With that, let’s jump right in!

Overview

A whopping 10% of the general population has a reported penicillin (PCN) allergy. But only 1-10% of these people have a true allergy when tested. This leaves us with about 0.1-1% of the general population with a true penicillin allergy.

Why is there such a discrepancy between reported allergies and true allergies? A lot of it comes from inaccurate allergy histories, like the patient with GI upset as a child, but the allergy listed as an “unknown reaction.” Or better yet, the patient whose mother had an allergy and thus everyone in the family has been given that scarlet letter in their medical record.

Another important and lesser known reason for the allergy discrepancy is that 78% of patients with immediate hypersensitivity to penicillin see their penicillin allergy fade after 10 years (from this 1981 study). So those adult patients with childhood reactions? The odds are that they aren’t still allergic decades later.

Why should we care?

When it comes to infectious diseases, beta-lactam antibiotics are often our first- and second-line options for treatment. A documented penicillin allergy can essentially knock a practitioner down to third-line treatment in some situations. In just highlighting a few common infections and organisms, look at how often beta-lactams are brought up:

When a patient has a documented penicillin allergy, studies have proven that beta-lactam usage decreases while non-beta-lactam usage increases (Lee 2000, as well as half of the citations provided at the end of this post). And when beta-lactams are avoided, patients tend to do worse.

Impact on Patient Outcomes

The impact of a penicillin allergy is real and detrimental to our patients. Rather than bore you with paragraphs upon paragraphs detailing the many studies looking into this fact, here are some take-home points hyperlinked to the primary literature supporting the claims:

Penicillin allergy patients:

There is clear evidence that reported beta-lactam allergies pose a problem on the path to prescribing optimal treatment in infectious diseases. We can combat the issue however through education and assessment techniques.

More to come in parts 2 and 3 of “A Rash of Beta-Lactam Allergies”!

Other posts in this series:

A Rash of Beta-Lactam Allergies, Part 2: The Education

A Rash of Beta-Lactam Allergies, Part 3: The Solution

References

  1. Al-Hasan MN, Acker EC, Kohn JE, Bookstaver PB, Justo JA. Impact of penicillin allergy on empirical carbapenem use in gram-negative bloodstream infections: an antimicrobial stewardship opportunity. Pharmacotherapy. 2017; 38(1):42-50
  2. Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications: a scientific statement for healthcare professionals from the American Heart Association. Circulation. 2015; 132:1435-1486
  3. Blumenthal KG, Lu N, Zhang Y, Li Y, Walensky RP, Choi HK. Risk of meticillin resistant Staphylococcus aureus and Clostridium difficile in patients with a documented penicillin allergy: population based matched cohort study. BMJ. 2018; 361:k2400
  4. Blumenthal KG, Ryan EE, Li Y, Lee H, Kuhlen JL, Shenoy ES. The impact of a reported penicillin allergy on surgical site infection risk. Clin Infect Dis. 2018; 66(3):329-336
  5. Borch JE, Andersen KE, Bindslev-Jensen C. The prevalence of suspected and challenge-verified penicillin allergy in a university hospital population. Basic Clin Pharmacol Toxicol. 2006; 98:357-362
  6. Bratzler DW, Dellinger EP, Olsen KM, et al. Clinical practice guidelines for antimicrobial prophylaxis in surgery. Surg Infect. 2013;14(1):73-156
  7. Charneski L, Deshpande G, Smith SW. Impact of an antimicrobial allergy label in the medical record on clinical outcomes in hospitalized patients. Pharmacotherapy. 2011; 31(8):742-747
  8. Conway EL, Lin K, Sellick JA, et al. Impact of penicillin allergy on time to first dose of antimicrobial therapy and clinical outcomes. Clin Ther. 2017; 39(11):2276-2283
  9. Huang KHG, Cluzet V, Hamilton K, Fadugba O. The impact of reported beta-lactam allergy in hospitalized patients with hematologic malignancies requiring antibiotics. Clin Infect Dis. 2018; 67(1):27-33
  10. Jeffres MN, Narayanan PP, Shuster JE, Schramm GE. Consequences of avoiding β-lactams in patients with β-lactam allergies. J Allergy Clin Immunol. 2016; 137(4):1148-1153
  11. Kalil AC, Metersky ML, Klompas M, et al. Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis. 2016; 63(5):e61-e111
  12. Lee CE, Zembower TR, Fotis MA, et al. The incidence of antimicrobial allergies in hospitalized patients: implications regarding prescribing patterns and emerging bacterial resistance. Arch Intern Med. 2000;160(18):2819-2822
  13. Macy E, Ngor EW. Safely diagnosing clinically significant penicillin allergy using only penicilloyl-poly-lysine, penicillin, and oral amoxicillin. J Allergy Clin Immunol Pract. 2013; 1:258-263
  14. Macy E, Contreras R. Health care use and serious infection prevalence associated with penicillin “allergy” in hospitalized patients: A cohort study. J Allergy Clin Immunol. 2014; 133(3):790-796
  15. Solensky R. The time for penicillin skin testing is here. J Allergy Clin Immunol Pract. 2013; 1(3):264-265
  16. Stevens DL, Bisno AL, Chambers HF et al. Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America. Clin Infect Dis. 2014; 59(2):e10-e52
  17. Sullivan TJ, Wedner HJ, Shatz GS, Yecies LD, Parker CW. Skin testing to detect penicillin allergy. J Allergy Clin Immunol. 1981; 66(3):171-180
  18. Trubiano JA, Chen C, Cheng AC, et al. Antimicrobial allergy ‘labels’ drive inappropriate antimicrobial prescribing: lessons for stewardship. J Antimicrob Chemother. 2016; 71:1715-1722
  19. Tunkel AR, Hartman BJ, Kaplan SL, et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis. 2004; 39:1267-1284
  20. van Dijk SM, Gardarsdottir H, Wassenberg MW, Oosterheert JJ, de Groot MC, Rockmann H. The high impact of penicillin allergy registration in hospitalized patients. J Allergy Clin Immunol Pract. 2016; 4:926-931

5 random facts about antimicrobials

Who doesn’t love to pick up random bits of information while they’re in line for their coffee or their morning signout? Here are 5 helpful pieces of information on antimicrobials to start off your day!

1.Cefepime vs. Piperacillin-tazobactam
Cefepime – cephalosporin
– DOES NOT cover gut anaerobes
– DOES NOT cover Enterococcus spp.
Piperacillin-tazobactam – penicillin derivative
– DOES cover gut anaerobes
– DOES cover penicillin-sensitive Enterococcus spp.

Antibiotic Cefepime Piperacillin/tazobactam
Class Cephalosporin Penicillin derivative
Gut anaerobic coverage? No Yes
Enterococcus coverage? No Yes (if susceptible)

 

2. Cephalosporins in general DO NOT cover Enterococcus spp.

3. Ertapenem vs. meropenem vs. imipenem vs. doripenem
Ertapenem – DOES NOT cover Pseudomonas spp.
Meropenem/Imipenem/Doripenem – DO cover Pseudomonas spp.
*None of the carbapenems cover MRSA

4. Ineffective antimicrobials
Daptomycin – inactivated by the surfactant in the lungs
– DO NOT use daptomycin to treat lung infections
*Remember: Linezolid, Lung (you can use Linezolid for lung infections)

Echinocandins (ex. micafungin, caspofungin, anidulafungin) – do not reach therapeutic levels in the urinary tract
– DO NOT use echinocandins to treat pyelonephritis or urinary tract infections

Tigecycline – accumulates in the tissues and has low concentration levels in the bloodstream
– DO NOT use tigecycline to treat bloodstream infections

5. Bone marrow toxicity due to linezolid increases after 2 weeks of exposure
– Avoid using linezolid for more than two weeks at a time when possible

 

Do you have any random facts of ID knowledge? Let me know in the comments section below!

 

References:

1. Mandell, Douglas, and Bennett. Principles and practice of infectious diseases. Philadelphia, PA: Churchill Livingstone/Elsevier, c2010. 7th edition.
2. Zhanel, G.G. et al. 2007. Comparative review of the carbapenems. Drugs. 67(7):1027-1052.
3. Gerson, S.L. et al. 2002. Hematologic effects of linezolid: summary of clinical experience. Antimicrobial Agents and Chemotherapy. 46(8): 2723-2726.
4. Malani, A.N. et al. 2014. Candida urinary tract infections: treatment options. 5(2): 277-284.
5. Jeu, L. et al. 2004. Daptomycin: a cyclic lipopeptide antimicrobial agent. Clinical Therapeutics. 26(11): 1728-1757.

Peer-reviewed by Jeff Pearson, PGY-2 pharmacy resident

Oral vs. IV antimicrobials

What’s the difference between oral (PO) and IV medications? When do you use PO vs. IV antimicrobials? When are they interchangeable? These are the questions we’ll address in this post.

info intravenously picture
by Dalya Ferguson, MD

Bioavailability is an important concept to understand when considering IV to PO interchange.

Bioavailability = the measure of the amount of an orally administered medication that reaches the bloodstream.

Antimicrobials with >90% bioavailability are the antimicrobials we can target for
IV to PO interchange.

Antimicrobials where bioavailability >90%:
(therefore, can be switched to PO)

  • Metronidazole
  • Fluoroquinolones (levofloxacin, moxifloxacin, *ciprofloxacin has ~70% bioavailability but still has enough to achieve adequate levels in the bloodstream)
  • Trimethoprim-Sulfamethoxazole
  • Tetracyclines (doxycycline, minocycline)
  • Linezolid
  • Rifampin
  • Fluconazole/Voriconazole
  • Clindamycin
  • Azithromycin (only ~40% bioavailable, but the concentration achieved by
    oral ingestion is just as effective as IV for treatment)

 

IV medication = medication given intravenously
– medication takes effect immediately after the infusion
– administers a bolus of the medication quickly (within 5 minutes)
– requires an IV line
– bypass first pass metabolism in the liver

PO medication = medication administered per oral route
– medication takes effect in ~30 minutes to 6 hours
– requires ability to swallow, absorb the medication, and also undergoes
first pass metabolism prior to reaching the circulatory system

Why is PO preferable to IV?

  • Cheaper3
  • Does not require IV access
  • Easier and faster to administer
  • No IV complications (i.e. phlebitis, thrombosis, bloodstream infection)
  • Avoidance of a long-term catheter such as a PICC line
  • Less unnecessary fluid administration

 

When to consider IV antimicrobials?

  • when patient is unable to take PO or unable to absorb the medication
  • when you want immediate effect of the medication
  • when the spectrum of activity desired is only available with IV antibiotics
  • when no PO option is available to treat the pathogen
  • when PO medications will not achieve high enough concentrations or penetrations to the location of the infection
    • Critically ill patients; sepsis/bacteremia
    • Endocarditis
    • CNS/ocular infection
    • Osteomyelitis/Septic arthritis (*a study is currently under way, looking at whether certain oral antibiotics are non-inferior to IV antibiotics in
      bone infections7)
      *You may occasionally see these syndromes treated with oral antibiotics, because each case is different. But in general, consider these syndromes as ones where IV antibiotics are preferred, especially as initial therapy.

 

TAKE HOME POINTS:

  • IV antimicrobials are NOT “stronger” or “better” than oral antimicrobials
    – it depends on each individual medication
  • PO antibiotics should be used unless there is a reason to use IV antibiotics (and not the other way around)
  • When PO and IV versions of an antimicrobial are similar, make every concerted effort to make sure your patients are not on IV medications unnecessarily

 

Questions? Comments? Suggestions for future posts? Leave a comment below.

 

 

References:

  1. Kwong, L.H et al. (2015). An unsupported preference for intravenous antibiotics. PLoS medicine, 12(5): e1001825. DOI: 10.1371/journal.pmed.1001825
  2. MacGregor, R.R. et al. (1997). Oral administration of antibiotics: a rational alternative to the parenteral route. 24: 457-467. PMID: 9114201
  3. Chan, R. et al. (1995). Oral versus intravenous antibiotics for community acquired lower respiratory tract infection in a general hospital: open, randomized, controlled trial. BMJ. 310: 1360-1362. PMID: 7787537
  4. Baddour et al. (2016). Infective Endocarditis in Adults: Diagnosis, Antimicrobial Therapy, and Management of Complications. Circulation. 132: 1435-1486.
    DOI: 10.1161/CIR.0000000000000296.
  5. Tunkel, A.R. et al. (2004). Practice Guidelines for the Management of Bacterial Meningitis. CID. 39: 1267-1284. DOI: 10.1086/425368
  6. World Health Organization, Occupational Health. (date published unknown). Comparison of pharmacokinetics and efficacy of oral and injectable medicine [Powerpoint slides]. Retrieved from http://www.who.int/occupational_health/activities/5injvsora.pdf
  7. Li, H.K et al. (2015). Oral versus intravenous antibiotic treatment for bone and joint infections (OVIVA): study protocol for a randomized controlled trial. BMC Trials. 16:583. DOI: https://doi.org/10.1186/s13063-015-1098-y
  8. Wisplinghoff, H. et al. (2004). Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study. Clin Infect Dis. 39(3): 309-317. DOI: 0.1086/421946

 

Peer-reviewed by Jeff Pearson, 2nd year PharmD resident

Antimicrobials: spectrum of activity

One of the most difficult concepts to understand is the spectrum of activity of different antimicrobials. We are all taught each antimicrobial in silos of the other ones and I always found it difficult to create conceptual charts in my head. Thankfully, I’ve found some amazing charts on the internet (from reputable sources, of course) that shows antimicrobials in relation to one another that may be helpful to you.

Here, I will present the best ones I’ve found so far for antibiotics, antivirals, and antifungals for you to use as a reference guide. At the bottom, I will list a few caveats to take into account when using these charts, because as always, ID is never as simple as the charts imply.

Antibiotics

Antibiotic spectrum of activityIntensive Care Drug Manual: Wellington ICU. Appendix 5.

Re-writing the fine print of the chart in case it’s not easily readable:
*For simplicity, atypical organisms are not included above. Partial columns indicate incomplete coverage. ESBL-producing organisms are not susceptible to most antibiotics containing a beta-lactam ring; carbapenems are the usual agent of choice.
1: C. difficile should only be treated with metronidazole or vancomycin
2: ESCHAPPM are β-lactamase producing organisms. These are Enterobacter, Serratia, Citrobacter freundii, Hafnia, Acinetobacter/Aeromonas, Proteus (not mirabilis), Providencia & Morganella morganii. See my 1st post on SPICE organisms for more info.
3: Not effective against Clostridium

4: Metronidazole is not effective against Peptostreptococcus
5: Teicoplanin is not effective against Enterococcus faecium
6: Gentamicin is not appropriate mono therapy for Staphylococcus aureus & should only be used in conjunction with a β-lactam
7: Due to increasing MIC, Cefuxorime is not recommended therapy for Moraxella
8: Although it has other actions, Ceftazidime should only be used for Pseudomonas

*This chart is intended as a guide, pending specific identification & sensitivities – it does not replace expert ID advice. Local antibiotic sensitivities & preferences will vary.

My notes:
ClindamycinCommunity-acquired MRSA strains have been found to be resistant to clindamycin and thus, this is often not a safe option for empiric therapy against MRSA.
Rifampin
usually used as an adjunct with another antibiotic against most infection. Would not recommend its use in isolation against infections.
Co-trimazole/Trimethoprim
would not use against enterococcus or empirically against MRSA in the hospital/ICU
Moxifloxacin — has some anaerobic coverage while levofloxacin and ciprofloxacin do not.
Metronidazole – no longer the 1st choice for C.diff infection. Instead, use PO vancomycin or PO fidaxomicin. (Thanks to a commenter for pointing that out to me!)

 

Antivirals

This chart was made by me but inspired by Aliyah Baluch, MD, Msc from USF who did an amazing review of antimicrobials used in stem cell transplant recipients. I thought it was a great way to demonstrate the spectrum of activity of antivirals and I hadn’t seen anything similar prior to that. Check out IDpodcasts.net for other lectures on ID topics.

 

antiviral spectrum of activity

*This chart only covers the herpes virus family, and does not include other virus families
*Just because foscarnet and cidofovir are considered the most broad-spectrum of the bunch does not mean they are always the best options. These drugs are quite toxic and should only be used in special circumstances, often with the involvement of an ID specialist.

Antifungals

This is a great chart taken from a wonderful review on antifungals from Mayo Clinic Proceedings.

Screenshot-2018-3-18 Current Concepts in Antifungal Pharmacology - pdfLewis, R.E. Mayo Clin Proc 2011

References:

1.Lewis, R.E. (2011). Current Concepts in Antifungal Pharmacology. Mayo Clinic Proceedings. 86(8):805-817. DOI: 10.4065/mcp.2011.0247
2.IDpodcasts.org: Bugs, Drugs, and Stem Cells podcast. July 2017. http://idpodcasts.net/podcasts/bugs-drugs-and-stem-cells/
3.Intensive Care Drug Manual: Wellington ICU. Appendix 5. Updated 2017. http://drug.wellingtonicu.com/
4.Santos, C.A.Q. (2016). Cytomegalovirus and other beta-herpesviruses. Seminars in Nephrology. 36(5): 351-361.
DOI: 10.1016/j.semnephrol.2016.05.012
5.Razonable, R.R. (2011).
Antiviral Drugs for Viruses Other Than Human Immunodeficiency Virus. Mayo Clinic Proceedings. 86(10): 1009–1026. DOI:  10.4065/mcp.2011.0309

Peer-reviewed by Jeffrey Pearson, 2nd year pharmacy resident

 

 

CNS penetration of antimicrobials

Have you ever noticed how the indicated dosages for antimicrobials increase for CNS infections? This is because antimicrobials have a difficult time penetrating the blood brain barrier and the blood-CSF barrier, leading to difficulty of some antimicrobials to achieve therapeutic concentration levels in the CSF to properly treat a CNS infection.

Overview-of-the-two-main-barriers-in-the-CNS-blood-brain-barrier-and-blood

(Bhaskar et al. 2010.)

Disclaimer: the penetration of antimicrobials into the CSF is much more complicated than three columns and a list of antibiotics. It’s been shown that levels of drugs differ between ventricular, cisternal, and lumbar CSF. Additionally, the treatment of CNS infections depends on more than just the CNS penetration of a certain antimicrobial, thus if any questions arise, please discuss with your ID consultants and ID pharmacists.

For the sake of this review, we will keep it simple.

Antimicrobials can be broken down into 3 rough
categories:

Excellent/Good penetration of the CSF Good penetration only in inflamed meninges Poor penetration of the CSF
Fluoroquinolones Glycopeptides (vancomycin) Beta-lactams3
TMP/SMX Macrolides (azithromycin) Aminoglycosides
Metronidazole Rifampin Tetracyclines (doxy, tigecycline)
Chloramphenicol Ethambutol Clindamycin4
Fosfomycin1 Daptomycin
Isoniazid Colistin
Pyrazinamide Fusion inhibitors (enfurvitide)
Zidovudine Tenofovir
5-flucytosine Amphotericin B5
Voriconazole/fluconazole Echinocandins
Pyrimethamine Itraconazole/posaconazole
Atovaquone?2
Albendazole >>> Praziquantel

1 only FDA-approved for UTI treatment
2 no studies have been published looking at CNS penetration; however has been used successfully in clinical CNS infections
3 overcome by increase in dosages – higher dosages of beta-lactams obtain adequate levels in the CSF and tend to be 1st line agents in bacterial meningitis due to their efficacy and bactericidal properties
4 however has been shown to effectively treat susceptible CNS infections
5 however clinical trials have shown good outcomes when used in treatment of CNS infections

*If the class of drug was not mentioned in this list, it is likely because no studies have been done to assess CNS penetration of that drug.

Why are beta-lactams recommended for empiric
bacterial meningitis treatment?  

Despite the poor CSF penetration, beta-lactams have the most research documenting successful treatment of community-acquired meningitis compared to other antibiotic classes.

  • When the beta-lactam dose is increased, CNS penetration increases.
  • Beta-lactams are well-tolerated even at high dosages
  • Ceftriaxone treats S. pneumoniae, N. meningitidis, H.influenzae, and many aerobic gram-negatives such as E.coli and K. pneumoniae.

*Vancomycin is added to empiric regimens to treat the ceftriaxone-resistant S. pneumoniae strains that have been seen in community-acquired meningitis.

empiric meningitis tx IDSA guidelines                                                            (IDSA practice guidelines for Bacterial Meningitis, 2004.)

TAKE HOME POINTS:

  • Not all antimicrobials penetrate the BBB. Take into account an antimicrobial’s CNS penetration properties when treating CNS infections
  • Beta-lactams are still 1st line therapy for empiric meningitis treatment due to their efficacy against the most common pathogens and ability to achieve high levels with increased doses of the medication
  • When treating CNS infections, deviation from the guidelines warrants involvement of the ID pharmacist and the ID consult team to ensure the best treatment regimen for the patient

 

 

References:

1. Bhaskar, S., Tian, F. et al. (2010). Multifunctional Nanocarriers for diagnostics, drug delivery and targeted treatment across blood-brain barrier: Perspectives on tracking and neuroimaging. Particle and fibre toxicology. 7(1)3. DOI: 10.1186/1743-8977-7-3.
2. Nau, R., Sorgel, F, and Eiffert, H. (2010). Penetration of Drugs through the Blood-Cerebrospinal fluid/Blood-Brain Barrier for the treatment of central nervous system infections. Clinical Microbiology Reviews. 23(4): 858-883. DOI: 10.1128/CMR.00007-10
3. Letendre, S. (2011). Central nervous system complications in HIV disease: HIV-associated neurocognitive disorder. Topics in antiviral medicine. 19(4): 137-142.
4. Marra, C. (2014). Central nervous system penetration of ARVs: Does it matter? [powerpoint]. Presented at Northwest Aids Education and Training Center on May 15th, 2014.
5. Cherubin, C.E., Eng, R.H, et al. (1989). Penetration of newer cephalosporins into cerebrospinal fluid. Review of Infectious Diseases.11(4):526-548.
6. Tunkel, A.R., Hartman, B.J, et al. (2004). Practice Guidelines for the management of bacterial meningitis. CID. 39:1267-1284.

Peer-reviewed by Jeffrey Pearson, 2nd year ID pharmacy resident

 

 

Bactericidal vs. Bacteriostatic antibiotics

Does it matter whether we use a bactericidal antibiotic or a bacteriostatic one? Surely, the bactericidal one would be more effective, right? The answer is not that simple.

Bactericidal = antibiotics that kill bacteria

Bacteriostatic = antibiotics that inhibit the growth of bacteria (i.e. prevent the bacteria from continuing to grow/proliferate) without killing bacteria in vitro OR it is able to kill the bacteria in vitro but at a slower rate than bactericidal agent does.

– there is thought out there that bacteriostatic agents require more activity from the immune system to eradicate the bacteria (this has not been studied well in literature and there is no data to support or negate this hypothesis).

Bactericidal drugs:                                          Bacteriostatic drugs:
Aminoglycosides                                                Glycylcyclines (tigecycline)
Beta-lactams                                                        Lincosamides (clindamycin)
Fluoroquinolones                                               Macrolides (azithromycin, fidaxomicin)
Glycopeptides (vancomycin)                           Oxazolidinones (linezolid, tedizolid)
Lipopeptides (daptomycin)                             Streptogramins (quinipristin/dalfopristin)
Nitroimidazoles/nitrofurans                           Sulphonamides (sulfamethoxazole)
(metronidazole/nitrofurantoin)                     Tetracyclines
Rifampin

*Keep in mind – bactericidal and bacteriostatic effects depend on several factors, including the amount of:
1) bacterial inoculum: the burden of bacteria can change the antibiotic’s properties
2) the pathogen: certain antibiotics are “cidal” to certain pathogens, while “static” to others
–examples:
a)  vancomycin is “cidal” against staph and strep, but “static” against enterococci
b) azithromycin is “cidal” against strep, but “static” against staph
c) linezolid may be “cidal” against strep, but “static” against staph/enterococci
3) medium/location of infection: certain antibiotics are more effective in certain parts of the body (IV vancomycin doesn’t penetrate GI mucosa, tigecycline doesn’t achieve high concentrations in the bloodstream, etc.)

Why could this be potentially clinically irrelevant?

A systematic review published in CID in 2017 looked at all the 59 randomized-controlled trials on clinical outcomes when using bactericidal vs. bacteriostatic agents. They found that 49 (81%) of the trials showed no differences in clinical outcomes when using “cidal” vs. “static” agents.

Similarly, studies demonstrated that using linezolid (a bacteriostatic agent) against MRSA was non-inferior to vancomycin (a bactericidal agent) against MRSA.
Because clinical outcomes depend on 3 factors:

  1. The host
  2. The pathogen
  3. The drug (with many internal factors coming into play as listed below
    -Tissue penetration
    -Pharmacokinetics
    -Drug interactions
    -Optimal dosing

TAKE-HOME POINTS:

  1. Antibiotics can be bacteriostatic for some pathogens and bactericidal for others
  2. Clinical outcomes depend on a variety of factors and the bactericidal property of an antibiotic ultimately appears to have little clinical relevance.

References:

  • Nemeth, J., Oesch, G., and Kuster, S.P. 2015. Bacteriostatic versus bactericidal antibiotics for patients with serious bacterial infections: systematic review and meta-analysis. Journal of antimicrobial chemotherapy. 70:382-395.
  • French, G.L. 2006. Bactericidal agents in the treatment of MRSA infections – the potential role of daptomycin. Journal of Antimicrobial Chemotherapy. 58 (6): 1107-1117.
  • Wald-Dicker, N, Holtom, P, and Spellberg, B. 2017. Busting the myth of “static vs. cidal”: A systemic literature review. CID
  • Panckey, G.A. and Sabath, L.D. 2004. Clinical relevance og bacteriostatic versus bactericidal mechanisms of action in the treatment of gram-positive bacterial infections. CID, 38(6): 864-870.