October 2015 FAQs

Can angiotensin receptor blockers (ARBs) be administered to patients who develop angioedema on angiotensin-converting enzyme inhibitor (ACEI) therapy?

Background

In 2011, angiotensin-converting enzyme inhibitors (ACEIs) were the 5^th most commonly dispensed class of medications in the United States, accounting for 164 million prescriptions.¹ The benefits of ACEIs in patients with cardiovascular disease, including hypertension, heart failure, left ventricular hypertrophy, and in patients post myocardial infarction are well described in previous literature.² Angiotensin-converting enzyme inhibitors have also been shown to slow the progression of chronic kidney disease in both diabetic and non-diabetic patients. Although ACEIs are generally well tolerated, patients administered these agents should be regularly monitored by a healthcare professional for continued efficacy and development of adverse effects.³ Adverse effects associated with use of ACEIs range from mild to severe, and include cough, dizziness, hyperkalemia, and angioedema.⁴

Angioedema is a rare, but potentially life-threatening, adverse effect of ACEIs.⁴ The incidence of ACEI-induced angioedema is estimated to be 0.1% to 8%.⁵ Patients with angioedema will typically present with burning or painful swelling of subcutaneous or submucosal tissue of the upper respiratory, and less commonly, the gastrointestinal tract.⁶ The edema is described as non-pitting, erythematous or skin-colored, and having ill-defined margins. The presence of concomitant wheals is important to evaluate, as their appearance may lead to a diagnosis of urticaria rather than angioedema.⁷ Angioedema secondary to administration of ACEIs will usually present with symptoms localized to the oral and perioral areas. There are no laboratory tests to diagnose ACEI-induced angioedema, although it is mandatory to screen for C1 inhibitor deficiency (a diagnostic marker for hereditary angioedema) in patients who develop angioedema while on ACEI therapy. A clinical diagnosis of ACEI-induced angioedema is only made based on regression of symptoms following discontinuation of therapy.⁴

Etiology and pathophysiology

There are several etiologies of angioedema, including those related to allergies, drugs, and deficiency of C1 inhibitor, as well as those that are idiopathic or due to miscellaneous causes.⁶ Major risk factors for the development of ACEI-induced angioedema are black race and C1-inhibitor deficiency, although many other genetic and environmental factors have shown mixed association in the literature.⁸

Although the exact mechanism by which angioedema secondary to ACEI  administration occurs is not completely understood, increased levels of circulating bradykinin are thought to be a driving force.⁶ Angiotensin-converting enzyme inhibitors directly inhibit the breakdown of bradykinin to inactive metabolites leading to increased levels of circulating active bradykinin. Patients with low levels of other bradykinin metabolizing enzymes such as aminopeptidase P and carboxypeptidase N are thought to be at a higher risk for development of angioedema following initiation of ACEI therapy.⁹ Bradykinin interacts with vascular B-2 receptors leading to increased vascular permeability and associated clinical signs and symptoms of angioedema.¹⁰ The elevation of bradykinin is thought to be self-limiting, with reported decreases of 93% upon withdrawal of ACEI therapy.⁹ Angioedema secondary to C1-inhibitor deficiency is also thought to be bradykinin-mediated, thus leading to some similarities in the management of both etiologies.

The onset of angioedema after the initiation of an ACEI greatly varies from one day to upwards of 10 years; however, about 50% of patients who develop angioedema will show symptoms within the first week of treatment.⁴ The primary management of patients with ACEI-induced angioedema includes prompt discontinuation of the offending agent and airway assessment. Antihistamines, epinephrine, and corticosteroids have not shown significant benefits in the management of angioedema associated with elevated levels of bradykinin; however, these agents are often inadvertently provided in emergency situations.^4,11 In severe cases, such as those in which patients have a compromised airway, there are several pharmacologic interventions with varied levels of supporting literature.⁴ A decrease in activity of circulating bradykinin levels can be achieved with fresh frozen plasma or bradykinin receptor type 2 antagonists such as icatibant. Purified C1- inhibitor concentrates (Berinert^Ò, Cinryze^Ò, and Ruconest^Ò) and kallikrein inhibitors (ecallantide) work to inhibit production of bradykinin. In addition to pharmacologic interventions, severe cases should be evaluated for endotracheal intubation or urgent tracheostomy.

Relapse of angioedema has been reported for up to 6 months following discontinuation of ACEI therapy.⁴ Patients diagnosed with ACEI-induced angioedema should not be challenged with another ACEI, as angioedema is a class effect. Additionally, continuing patients on ACEI therapy after development of angioedema puts them at a 10-fold increase of angioedema recurrence.⁸

Transition to angiotensin receptor blocker therapy

Angiotensin receptor blockers (ARBs) indirectly increase levels of bradykinin via upregulation and stimulation of unblocked angiotensin II type 2 receptors.¹⁰ This upregulation leads to an increase in bradykinin, in addition to prostaglandins and nitric oxide, and may lead to the development of angioedema. There are data, however, that suggest angioedema associated with ARB administration is less severe when compared to ACEI-induced angioedema.¹² Guidelines published by the Academy of Allergy, Asthma & Immunology (AAAI) state that although there is a modest risk of recurrent angioedema in patients who are switched from an ACEI to an ARB, most patients can be safely transitioned.¹¹

A meta-analysis of 4 studies has shown that the risk of developing angioedema after transitioning from ACEI to ARB therapy is estimated to be 2.5% (95% confidence interval [CI], 0% to 6.6%); for confirmed cases of angioedema the risk is estimated to be 1.5% (95% CI 0% to 5.1%).¹³ The individual studies are summarized in Table 1. Current literature comparing incidence of angioedema amongst various antihypertensive agents suggests that the risk of developing angioedema while receiving ARB therapy is about half that of ACEI therapy.^10,14

Table 1. Evidence for angiotensin receptor blocker use after angioedema (AE) with an angiotensin-converting enzyme inhibitor.^15-18

Discussion

Similarly to ACEIs, ARBs are effective in the management of select patients with cardiovascular disease and chronic kidney disease.¹⁹ Although ACEIs are first-line agents for patients with heart failure, coronary artery disease, or post myocardial infarction, ARBs may be used in patients with intolerance to ACEIs, such as those with a history of ACEI-induced angioedema.

Transitioning patients to ARB therapy after development of ACEI-induced angioedema is generally supported by the literature, although uncertainties related to this practice remain. In clinical trials, the true incidence of ACEI-induced angioedema may be underestimated, since most trials that use these agents exclude patients with a history of angioedema.¹⁰ Additionally, whether all ARBs are truly safe for patients with ACEI-induced angioedema remains unknown, because only candesartan and telmisartan were studied.

Healthcare providers may transition patients from an ACEI to an ARB only after careful evaluation of the benefits of therapy weighed against the risks of recurrent angioedema. Because ARBs can indirectly increase circulating bradykinin, patients should be made aware that ARB therapy may lead to the development of angioedema. Additionally, as recurrence may occur months after discontinuation of an ACEI, caution should be made to avoid falsely labeling a patient as experiencing ARB-induced angioedema, when in fact angioedema may be due to the previous ACEI administration.

Of note, there are limited data that describe the incidence of angioedema with aliskiren, a direct renin inhibitor. In 2011, a pooled analysis of 13 randomized controlled trials of aliskiren in patients with hypertension reported angioedema/urticaria event rates ranging from 0.2% to 0.5%.²⁰ A subsequent meta-analysis reported a 0.13% incidence of angioedema in patients administered aliskiren.¹⁴ Most recently, a 2012 retrospective cohort study found a similar incidence of angioedema between patients administered either ACEIs or aliskiren, however there were significantly fewer patients receiving aliskiren therapy.²¹ Overall, the relative paucity of data limits the ability to assess the association of aliskiren therapy with risk of angioedema. The AAAI guidelines do not recommend aliskiren for patients who have a history of ACEI-induced angioedema.¹¹

Conclusion

Overall, patients with a history of ACEI-induced angioedema may be safely switched to an ARB in most situations. Providers should have an open dialogue with their patients to discuss the benefits and risks of transitioning to ARB therapy. Patients should be made aware of the signs and symptoms of angioedema, and instructed to immediately seek medical attention should symptoms arise. There is no preferred ARB agent that has been shown to lessen the risk of angioedema, thus patient specific factors such as indication, co-morbid conditions, dosing regimen, and cost should guide ultimate therapy. Switching patients to aliskiren is not recommended due to the relative lack of data on risk of recurrent angioedema.

References:

1.IMS Institute for Healthcare Informatics. The use of medicines in the United States: Review of 2011. IMS Health website. https://www.imshealth.com/ims/Global/Content/Insights/IMS%20Institute%20for%20Healthcare%20Informatics/IHII_Medicines_in_U.S_Report_2011.pdf. Published 2012. Updated 2012. Accessed July 28, 2015.

2.Benavente D, Chue CD, Ferro CJ. The importance of renin-angiotensin blockade in patients with cardio-renal disease. J Ren Care. 2010;36(Suppl 1):97-105.

3.James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: Report from the panel members appointed to the eighth joint national committee (JNC 8). JAMA. 2014;311(5):507-520.

4.Bezalel S, Mahlab-Guri K, Asher I, Werner B, Sthoeger ZM. Angiotensin-converting enzyme inhibitor-induced angioedema. Am J Med. 2015;128(2):120-125.

5.Campo P, Fernandez TD, Canto G, Mayorga C. Angioedema induced by angiotensin-converting enzyme inhibitors. Curr Opin Allergy Clin Immunol. 2013;13(4):337-344.

6.Grigoriadou S, Longhurst HJ. Clinical immunology review series: An approach to the patient with angio-oedema. Clin Exp Immunol. 2009;155(3):367-377.

7.Cicardi M, Zanichelli A. Diagnosing angioedema. Immunol Allergy Clin North Am. 2013;33(4):449-456.

8.Hoover T, Lippmann M, Grouzmann E, Marceau F, Herscu P. Angiotensin converting enzyme inhibitor induced angio-oedema: A review of the pathophysiology and risk factors. Clin Exp Allergy. 2010;40(1):50-61.

9.Cugno M, Nussberger J, Cicardi M, Agostoni A. Bradykinin and the pathophysiology of angioedema. Int Immunopharmacol. 2003;3(3):311-317.

10.Knecht SE, Dunn SP, Macaulay TE. Angioedema related to angiotensin inhibitors. J Pharm Pract. 2014;27(5):461-465.

11.Zuraw BL, Bernstein JA, Lang DM, et al. A focused parameter update: Hereditary angioedema, acquired C1 inhibitor deficiency, and angiotensin-converting enzyme inhibitor-associated angioedema. J Allergy Clin Immunol. 2013;131(6):1491-1493.

12.Beavers CJ, Dunn SP, Macaulay TE. The role of angiotensin receptor blockers in patients with angiotensin-converting enzyme inhibitor-induced angioedema. Ann Pharmacother. 2011;45(4):520-524.

13.Haymore BR, DeZee KJ. Use of angiotensin receptor blockers after angioedema with an angiotensin-converting enzyme inhibitor. Ann Allergy Asthma Immunol. 2009;103(1):83-84.

14.Makani H, Messerli FH, Romero J, et al. Meta-analysis of randomized trials of angioedema as an adverse event of renin-angiotensin system inhibitors. Am J Cardiol. 2012;110(3):383-391.

15.Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (TRANSCEND) Investigators, Yusuf S, Teo K, et al. Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: A randomised controlled trial. Lancet. 2008;372(9644):1174-1183.

16.Malde B, Regalado J, Greenberger PA. Investigation of angioedema associated with the use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. Ann Allergy Asthma Immunol. 2007;98(1):57-63.

17.Cicardi M, Zingale LC, Bergamaschini L, Agostoni A. Angioedema associated with angiotensin-converting enzyme inhibitor use: Outcome after switching to a different treatment. Arch Intern Med. 2004;164(8):910-913.

18.Granger CB, McMurray JJ, Yusuf S, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: The CHARM-alternative trial. Lancet. 2003;362(9386):772-776.

19.Dezsi CA. Differences in the clinical effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: A critical review of the evidence. Am J Cardiovasc Drugs. 2014;14(3):167-173.

20.White WB, Bresalier R, Kaplan AP, et al. Safety and tolerability of the direct renin inhibitor aliskiren in combination with angiotensin receptor blockers and thiazide diuretics: A pooled analysis of clinical experience of 12,942 patients. J Clin Hypertens (Greenwich). 2011;13(7):506-516..

21.Toh S, Reichman ME, Houstoun M, et al. Comparative risk for angioedema associated with the use of drugs that target the renin-angiotensin-aldosterone system. Arch Intern Med. 2012;172(20):1582-1589.

Prepared by:
Katherine Zych, PharmD
PGY2 Drug Information Resident
University of Illinois at Chicago
College of Pharmacy
October 2015

The information presented is current as July 13, 2015. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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What are the data to support the use of ethanol lock therapy to decrease catheter-related infections in pediatric patients?

Introduction

Catheter-related infections (CRIs) can lead to serious bloodstream infections which are a major source of morbidity and mortality.  Catheter-related bloodstream infections (CR-BSIs) have mortality rates ranging from 12% to 25% in adult and pediatric patients.¹  In addition, these infections are associated with increased healthcare costs and length of stay.^2,3  Studies have shown that in the pediatric population, an average of 5.3 CR-BSIs occur per 1000 catheter days with a median of 3.5 CR-BSIs per 1000 catheter days.²  Common risk factors associated with CR-BSIs in the pediatric intensive care unit include arterial catheterization, prolonged catheterization, use of extracorporeal life support, and genetic abnormalities.  Catheter-related infections can originate from biofilm formation on the inner surface of catheters.³  The pathogens that form on biofilms are less susceptible to antibiotics and have been shown to exhibit up to a 1000-fold decrease in susceptibility due to decreased antibiotic penetration through biofilm.⁴

Treatment recommendations for CR-BSIs include empiric antibiotic therapy for gram-positive and gram-negative bacteria.  Agents should cover common organisms such as coagulase-negative Staphylococci, Enterococcus spp., Staphylococcus aureus, Enterobacter spp, and Candida albicans.²  In addition, for infections involving candidemia and persistent bacteremia, catheter removal is recommended.  Although systemic antimicrobial therapy is used as a primary treatment modality, studies have shown that cure rates in the pediatric population vary from 45% to 90% when only systemic therapy is used.⁵  The Infectious Diseases Society of America (IDSA) Guidelines for Prevention of Intravascular Catheter-Related Infections recommends the use of antimicrobial locks in conjunction with systemic antimicrobial therapy in patients with long-term catheters and a history of multiple CR-BSIs.⁶  However, the use of antimicrobial locks potentially poses a problem for development of antibiotic resistance due to the fact that pathogens that form on biofilms are less susceptible to antibiotics.^4,5

To circumvent the issue regarding antimicrobial resistance, ethanol locks have been utilized in the management of CR-BSIs.  Ethanol lock therapy (ELT) is a technique used for the treatment and prophylaxis of CR-BSIs that involves instilling ethanol into a catheter lumen, leaving it to dwell, then aspirating or flushing the contents.⁵  Ethanol exhibits antimicrobial properties through nonspecific protein denaturation.  It is fungicidal and bactericidal and has been shown to degrade biofilm.  In vitro studies have shown that 70% ethanol has been effective in eradicating common pathogens within 2 hours of exposure.⁷  The purpose of this review is to present the evidence behind the use of ethanol locks for decreasing CR-BSIs in the pediatric population.

Literature Summary

Efficacy

The majority of literature available on the use of ELT assessed its efficacy in treating and/or preventing CR-BSIs.  Pertinent information from a select number of studies including study design, population, endpoints, protocol, and outcomes are presented in the table below.

Table 1. Published studies on the efficacy of ethanol lock therapy in treating and preventing CR-BSIs in pediatric patients.

The majority of studies were retrospective analyses and the most common population studied was children with intestinal failure requiring central venous access for long-term parenteral nutrition.^12,13,15,16  Among these studies, administration times varied from weekly to daily.  One quality improvement analysis retrospectively collected data on catheter infection rates before adding ELT to standard of care, after which the investigators prospectively assessed the impact of this intervention.⁸   The results after implementation showed significant and sustained reduction in infection rates.  Overall, ELT was consistently effective in treating and/or preventing CR-BSIs in this patient population.

Although CR-BSIs are commonly caused by bacterial pathogens, fungal species may also be a source of infection.  Guidelines from the IDSA recommend catheter removal with fungal infections.⁶  In a case report involving 3 patients with Candida spp. infections in which catheter removal was not immediately possible, systemic antifungal therapy was used in conjunction with ELT.¹⁷  After a minimum of 72 hours after completion of ELT, blood cultures for each patient were negative for Candida infection, indicating successful treatment with ELT and systemic antifungals.  In a retrospective study measuring the sterilization of infected central lines after ELT in patients with CR-BSI, 7 of 80 episodes of CR-BSI were due to fungal pathogens.  Six of the 80 episodes achieved short-term sterilization post-ELT and 3 of 6 retained their central lines.¹⁴   Although the utility of ELT in the treatment of catheter infections involving fungal pathogens is unclear, these preliminary results warrant further investigation.

Another population included in these studies was children with bleeding disorders.  One retrospective chart review showed that ELT was effective in treating antimicrobial resistant CR-BSIs, with catheter salvage observed in 87% of patients.¹¹  In another study consisting of 3 case reports of patients with hemophilia A, ELT also proved to be efficacious in clearing infections.¹⁸   Two of these patients failed ELT after only 24 hours of therapy, but were then reinitiated for 72 hours with successful eradication of infection.

In addition to the data above, increasing evidence for the efficacy of ELT in the treatment and prophylaxis of CR-BSIs is evident in 2 meta-analyses.^19,20  In one meta-analysis involving pediatric patients with intestinal failure, 4 studies were analyzed for pooled effectiveness and safety of ELT in comparison with heparin locks in terms of CR-BSI rates and catheter replacements.¹⁹    The pooled mean difference in the CR-BSI rate between use of heparin and ethanol locks was 7.67 per 1000 catheter days (95% confidence interval [CI] 5.87, 9.47).  Compared to heparin locks, ethanol locks decreased CR-BSI rates by 81% (relative reduction [RR] 0.19, 95% CI 0.12, 0.32; p<0.00001).  The pooled mean difference in the number of catheter replacements between use of heparin and ethanol locks was 5.07 (95% CI 1.13, 9.03) which demonstrated a reduction in catheter replacements by 72% (RR 0.28, 95% CI 0.06, 1.23; p=0.09) with use of ethanol locks.  The authors concluded that ELT is a more effective alternative to heparin locks in pediatric patients with intestinal failure.

Another meta-analysis also analyzed the use of ELT on CR-BSI treatment and prophylaxis in various adult and pediatric studies.²⁰  The majority of prophylaxis and treatment studies were performed in the pediatric population (7 of 13 prophylaxis studies, 8 of 9 treatment studies); however, the results of the meta-analysis included both adult and pediatric studies. All of the ELT prophylaxis studies reported a decrease in the rate of infection, with only 8 studies showing a significant difference.  Collectively, a decrease from 9.11 to 1.92 per 1000 catheter days with the initiation of ELT was observed in studies that reported a decrease in the rate of infection.  The percent decrease in infection rate ranged from 53% to 91%, which was consistently significant in each study.  Only 9 studies reported rates of catheter removal.  An overall range of 0.57 to 8.2 per 1000 catheter days was observed for the rate of catheter removal across all studies. Three studies showed a decrease in the rate of infected catheter removal, but these decreases were not statistically significant.  Overall, the reported rate of catheter removal showed a decrease from 6.13 to 1.85 per 1000 catheter days, and a range of percent decrease from 30% to 100% with ELT.  In all prophylaxis studies in pediatrics, a 70% ethanol concentration was used with a varied frequency of administration including daily, 3 times weekly, or once weekly.  Studies that demonstrated significant findings used a minimum dwell time of 2 hours.  The volume of ethanol used was either the volume needed to fill the catheter or a set volume that ranged from 0.5 to 2 mL.

In the treatment studies, systemic antimicrobials were always used in combination with ELT.²⁰  In all of these studies, the rate of clinical cure ranged from 67% to 100% with ELT.  An overall combined clinical cure rate of 90% (192/213) was observed.  Of note, the definition of clinical cure varied between studies, with the time of negative cultures ranging from 1 day to 30 days after the end of ELT.  In studies where clinical cure was not achieved with ELT, the most common pathogens identified were S aureus, coagulase-negative Staphylococci, and polymicrobial infections.  The rates of line salvage across studies ranged from 71% to 100%, with a combined rate of 84% (179/213).  In some studies, clinical cure was initially achieved but subsequently failed, resulting in catheter removal.  The most common pathogens implicated in line removal caused by infection were Staphylococcus epidermidis, Enterococcus faecium, and Candida glabrata.  Similar to the prophylaxis studies, 70% ethanol was used in the majority of studies with most dwell times ranging from 12 to 24 hours with a duration of treatment varying from 1 to 14 days. The volume of ethanol used was either the catheter volume or a set volume that ranged from 0.5 to 2 mL. Adverse events were low across all studies.  The reported reactions included tiredness, headaches, dizziness, facial flushing, nausea, lightheadedness, mild elevations in liver function tests, and alcohol taste. Overall, the meta-analysis concluded that ELT may be beneficial when used for prevention or treatment of CR-BSIs, and prospective, randomized, placebo-controlled studies are needed to confirm its utility in these situations.

Safety

Among the studies presented in Table 1, ELT was also well tolerated across all studies.  Symptomatic adverse effects were reported in 2 studies and included facial flushing, irritability, and mildly elevated liver enzymes, and dyspnea.^5,12  Other adverse effects of concern include the functionality of the catheters including line thrombosis, catheter occlusion, catheter leakage/tear, and catheter dysfunction with prophylactic therapy.^8,10,11,13

A common concern with the use of ELT is adverse events associated with therapy.  A pilot infusion study administered 0.4 mL of 70% ethanol (a common volume used in ELT) to infants (mean age of 3.5 ± 2.4 months), weighing ≤6 kg with and without liver dysfunction.²¹  Blood alcohol concentrations (BACs) were measured 5 minutes and 1 hour after the infusion.  Other outcomes included evidence of hepatic injury, hypoglycemia, and hypokalemia.  Results showed that flushing ELT appeared to be safe in infants weighing >4 kg based on measured BAC and post-dose hepatic panels.  Predicted 5-minute BACs (0.008%) were consistent with measured 5-minute BACs (0.011%) in all patients except one.  Eight of 10 BACs measured after 5 minutes were undetectable, and all ten 1-hour BACs were undetectable. Infusion of small doses of ethanol were consistent with the American Academy of Pediatrics’ recommendation of maintaining BACs <0.025% for oral medications containing alcohol.  The patients had no evidence of hepatic injury, and none experienced hypoglycemia or hypokalemia 1-hour post-dose. Furthermore, the authors collected peaks and 1-hour concentrations that suggested that these patients should not experience accumulation of ethanol and should potentially tolerate daily use of ELT if necessary.  A limitation to this study was that the design was a small pilot study, which warrants further investigation into long-term safety in this population. 

Conclusion

Catheter-related bloodstream infections are among the most important complications in vascular access and can lead to significant morbidity and mortality in the pediatric population.  Due to the increasing incidence of resistance associated with antimicrobials, antimicrobial locks may soon become ineffective in treating and preventing CR-BSIs. Furthermore, pathogens associated with these types of infections have exhibited 1000-fold decrease in susceptibility due to lack of antimicrobial biofilm penetration.  Ethanol lock therapy has emerged as an option to treat and prevent CR-BSIs.  Ethanol acts as a protein denaturant and can penetrate and sterilize biofilms, thereby eliminating the risk of resistance.  The available evidence suggests that ELT may be an effective, safe, and well-tolerated alternative to antimicrobial locks for decreasing CR-BSIs in the pediatric population, however, the strength of the evidence is limited due to the retrospective nature of the trials, small sample sizes, and differing definitions of CR-BSI.  The 2009 IDSA recommendations for management of CR-BSIs state that there is insufficient data to recommend ELT for treatment of CR-BSIs. However, publications since 2009 have demonstrated a possible benefit with ELT use.  Although ELT has been shown to be well tolerated across all studies, there is potential for adverse effects on catheter functionality.

References

1. Centers for Disease Control and Prevention (CDC). Vital signs: central-line associated bloodstream infections—United States, 2001, 2008, and 2009. MMWR Morb Mortal Wkly Rep. 2011;60(8):243-248.
2. Smith MJ. Catheter-related bloodstream infections in children. Am J Infect Control. 2008;36(10):s173.e1-s173.e3.
3. O’Grady NP, Alexander M, Burns LA, et al. Guidelines for the prevention of intra-vascular catheter-related infections. Clin Infect Dis. 2011;52(9):e162-193.
4. Donlan RM, Costerton JW. Biofilms: survival mechanisms of clinically relevant microorganisms. Clin Microbiol Rev. 2002;15(2):167-193.
5. Valentine KM. Ethanol lock therapy for catheter-associated blood stream infections in a pediatric intensive care unit. Pediatr Crit Care Med. 2011;12(6):e292-e296.
6. Mermel LA, Allon M, Bouza E, et al. Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infections: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis. 2009;49(1):1-45.
7. Wolf J, Shenep JL, Clifford V, et al. Ethanol lock therapy in pediatric hematology and oncology. Pediatr Blood Cancer. 2013;60(1):18-25.
8. Ardura MI, Lewis J, Tansmore JL. Central catheter-associated bloodstream infection reduction with ethanol lock prophylaxis in pediatric intestinal failure. JAMA Pediatr. 2015;169(4):324-331.
9. Chaudhary M, Bilal MF, Du W, et al. The impact of ethanol lock therapy on length of stay and catheter salvage in pediatric catheter-associated bloodstream infection. Clin Pediatr. 2014;53(11):1069-1076.
10. Abu-El-Haija M, Schultz J, Rahhal R. Effects of 70% ethanol locks on rates of central line infection, thrombosis, breakage, and replacement in pediatric intestinal failure. J Pediatr Gastroenterol Nutr. 2014;58(6):703-708.
11. Rajpurkar M, McGrath E, Joyce J, et al. Therapeutic and prophylactic ethanol lock therapy in patients with bleeding disorders. Haemophilia, 2014;20(1):52-57.
12. Pieroni KP, Nespor C, Ng M, et al. Evaluation of ethanol lock therapy in pediatric patients on long-term parenteral nutrition. Nutr Clin Pract. 2013;28(2):226-231.
13. Cober MP, Kovacevich DS, Teitelbaum DH. Ethanol-lock therapy for the prevention of central venous access device infections in pediatric patients with intestinal failure. JPEN J Parenter Enteral Nutr. 2011;35(1):67-73.
14. McGrath E, Salloum R, Chen X, et al. Short-dwell ethanol lock therapy in children is associated with increased clearance of central-line associated bloodstream infections. Clin Pediatr. 2011;50(10):943-951.
15. Jones BA, Hull MA, Richardson DS, et al. Efficacy of ethanol locks in reducing central venous catheter infections in pediatric patients with intestinal failure. J Pediatr Surg. 2010;45(6):1287-1293.
16. Mouw E, Chessman K, Lesher A, et al. Use of an ethanol lock to prevent catheter-related infections in children with short bowel syndrome. J Pediatr Surg. 2008;43(6):1025-1029.
17. Blackwood, RA, Klein KC, Micel LN, et al. Ethanol locks therapy for resolution of fungal catheter infections. Pediatr Infect Dis J. 2011;30(12):1105-1107.
18. Rajpurkar M, Boldt-Macdonald K, Mclenon R, et al. Ethanol lock therapy for the treatment of catheter-related infections in haemophilia patients. Haemophilia. 2009;15(6):1267-1271.
19. Oliveira C, Nasr A, Brindle M, et al. Ethanol locks to prevent catheter-related bloodstream infections in parenteral nutrition: a meta-analysis. Pediatrics. 2012;129(2):318-329.
20. Tan M, Lau J, Guglielmo J. Ethanol locks in the prevention and treatment of catheter-related bloodstream infections. Ann Pharmacother. 2014;48(5):607-615.
21. Chhim RF, Crill CM, Collier HK, et al. Ethanol lock therapy: a pilot infusion study in infants. Ann Pharmacother. 2015;49(4):431-436.

Prepared by:
Duchess Domingo, PharmD
PGY2 Pediatric Resident
College of Pharmacy
University of Illinois at Chicago
October 2015

The information presented is current as of August 10, 2015.  This information is intended as an educational piece and should not be used as the sole source for clinical decision making.

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What is the cross-reactivity of penicillins and carbapenems in a patient with a penicillin allergy?

Introduction

Carbapenems are the broadest class of antibiotics and are used for various gram positive, gram negative and anaerobic infections.¹ It is common to use carbapenems for hospital-acquired infections when there is a risk for multi-drug resistant organisms. Because penicillin allergies are the most commonly reported drug allergies, it is important to determine the cross-reactivity between penicillins and carbapenems in this era of multi-drug resistant organisms.²

It is hypothesized that the cause of allergies to beta-lactam antibiotics is due to the structure of the beta-lactam ring or to the side chains that differ between antibiotics.³ Most of the US population is thought to be allergic to the core beta-lactam ring structure that is common between all penicillins, cephalosporins and carbapenems. However, in Europe there is a large portion of the population that is thought to be allergic to the R-group side chain of the penicillin structure. This side chain differs between each penicillin, cephalosporin and carbapenem. Penicillins contain a 5-member thiazolidine ring attached to the beta-lactam ring, while cephalosporins contain a 6-member dihydrothiazine ring instead.⁴ Carbapenems have a carbon double bond in place of sulfur in the attached thiazolidine ring, and monobactams such as aztreonam differ in structure in that they contain the beta-lactam ring yet do not have an attached sulfur ring whatsoever. These differences in structure lead to varying degrees of immunogenicity and cross-reactivity.

There are 2 main types of allergies to penicillin; type I, or IgE-mediated, and type IV, or T-cell mediated.⁴ IgE-mediated allergies typically occur immediately within minutes to an hour, but can occur up to 6 hours after exposure to the drug. This type of hypersensitivity is mediated by IgE antibodies, and typically manifests as urticaria or anaphylaxis and can be serious or even fatal. ⁵ T-cell mediated allergies are not mediated by antibodies.⁴ The timing of these types of hypersensitivity reactions typically depends on whether it is the first exposure to the allergen or a subsequent exposure. The reaction after the first exposure typically occurs at least 3 to 4 days later, yet a reaction after subsequent exposures will occur much sooner at approximately 1 to 2 hours after administration of the causative agent. Because the timing of these reactions occurs much later than IgE-mediate reactions which are immediate, they are also known as delayed hypersensitivity reactions.

Patient-reported allergies to beta-lactams have been shown to occur in up to 20% of patients admitted to hospitals, but it was found that only 1% to 10% had IgE-mediated reactions after skin testing.⁴ Furthermore, only 0.2% of these reactions were anaphylactic type reactions. Skin testing for IgE-mediated hypersensitivity reactions therefore appears to be an important procedure to identify patients at risk of a reaction. Skin testing can be done with the major and minor determinants of penicillin.⁵ Benzylpenicilloyl poly-L-lysine (Pre-pen) and penicillin G are the reagents that are commercially available for skin testing procedures.

Historically, it was commonly reported that the cross-reactivity between penicillins and carbapenems was 47.4%, which was derived by Saxon et al. in 1988.⁶ This research sought to characterize the incidence of cross-reactivity between imipenem and penicillin by skin testing patients with both reagents. Approximately half of the patients who reacted to a penicillin skin test also had a reaction to the imipenem skin test. Since this research was conducted, there have been numerous other studies performed in order to further investigate this high incidence of cross-reactivity. However, there has not been further research that has shown a rate as high as 47%. This research, summarized in Table 1, ranges from chart reviews to systematic reviews and varies widely in terms of design and patient populations studied.

Literature

Systematic review

A systematic review was conducted evaluating IgE-mediated allergic reactions in both adults and children.³ The review included 6 prospective studies, 4 retrospective studies, 12 case reports, and comprised 854 patients. Eight hundred thirty-eight patients previously had a reaction to penicillin, while 12 patients previously reacted to a cephalosporin and 4 had reactions to a penicillin and a cephalosporin. The results of this systematic review determined that the incidence of any type of reaction (IgE or non-IgE) to a carbapenem in patients with a previous proven or suspected reaction to penicillin was 36 of 838, or 4.3%. Of these, there was one patient who had a proven IgE-mediated reaction and 19 who had possible IgE-mediated reactions, resulting in a rate of IgE-mediated hypersensitivity reactions of 2.4% (20 of 838). Of the patients who first had a positive skin test to penicillin, only 1 of 295 patients or 0.3% had any type of reaction to a carbapenem, and this reaction was possibly IgE mediated. However, the incidence in cross-reactivity between cephalosporins and carbapenems may be higher than that of penicillins and carbapenems. Of the 12 patients who had a previous IgE-mediated cephalosporin reaction, 3 of 12 or 25% had an allergic reaction to a carbapenem. Of these 3 reactions, 1 was possibly IgE mediated and 2 were non-IgE mediated.

Prospective studies

IgE-mediated (immediate) hypersensitivity

A recent prospective study was conducted by Gaeta et al in order to assess the cross-reactivity of carbapenems and aztreonam in patients with IgE-mediated hypersensitivity to penicillins.⁷ This study involved 212 patients with positive skin tests to penicillins who then underwent skin tests to each antibiotic separately; aztreonam, imipenem-cilastatin, meropenem and ertapenem. All patients had negative skin tests to these agents, and 211 of 212 underwent challenges to the drugs. All patients tolerated the challenges; however pre-treatment skin testing is still recommended by the investigators.

T-cell-mediated (delayed) hypersensitivity

A similar study was conducted 2 years prior by the same investigators.⁸ However, this study involved T-cell mediated hypersensitivity reactions rather than IgE-mediated reactions. A total of 204 patients aged 15 to 79 years underwent a similar protocol that involved skin testing with penicillins, imipenem-cilastatin, meropenem, and ertapenem, and subsequently challenging those patients who had negative results. These challenges were performed by first administering one-hundredth of a therapeutic dose of each drug intravenously, then the following week administering one-tenth of a therapeutic dose, followed by a full therapeutic dose in another week as long as all results remained negative. This protocol was modified slightly after 30 challenges to exclude the step of administering one-hundredth of the therapeutic dose, and also moving the therapeutic dose from one week post-challenge to one hour post-challenge. Consistent with the study conducted in 2015, all patients had negative skin tests to carbapenems and also tolerated the challenges. The results of this study suggest that the rate of T-cell mediated cross-reactivity between penicillins and carbapenems is very low; however, research from 2009 by Schiavino et al demonstrated differing results.⁹ In this study, patients with a cell-mediated reaction to beta-lactam antibiotics were given a skin patch test to imipenem-cilastatin. Four of 73 patients (5.5%) had a positive patch test to both imipenem-cilastatin and a penicillin. The patients who tested negative were then given a challenge test dose by intramuscular injection. This was done by administering imipenem-cilastatin intramuscularly at increasing doses of 10 mg, 20 mg, and 40 mg every half hour. Then one week later, patients received increasing doses of 80 mg, 160 mg and 260 mg every half hour. None out of the 64 patients tested had a clinical reaction to the intramuscular dose.

Cross-reactivity of cephalosporins and carbapenems

A study investigating the relationship between a documented cephalosporin allergy and cross-reactivity to penicillins, carbapenems and aztreonam was conducted in 2010.¹⁰ This study examined 98 patients who had positive skin test results to cephalosporins and skin tested them with penicillins, aztreonam, imipenem/cilastatin and meropenem. Results showed that 25.5% of patients with a cephalosporin allergy also had a positive skin test result or IgE assay to penicillins, 3.1% to aztreonam, 2% to imipenem-cilastatin and 1% to meropenem. After administering challenges of meropenem, imipenem/cilastatin, aztreonam and amoxicillin, only 1 patient did not tolerate a full dose of imipenem/cilastatin and developed an urticarial reaction. These data show that cross-reactivity between cephalosporins and penicillins is much higher than that of cephalosporins and carbapenems.

Although many studies use skin testing as a means to verify the presence or absence of hypersensitivity, one study from 2008 chose to mimic real world practice by foregoing any skin testing procedure.¹¹ One-hundred ten patients who reported a penicillin allergy were divided into non-anaphylaxis and anaphylaxis reaction groups and prospectively evaluated while on meropenem therapy. The non-anaphylaxis group of patients (n=59) included those who had an unknown reaction or experienced a drug fever or drug rash, and the anaphylaxis group (n=51) included patients who had a definite IgE-mediated anaphylactic reaction to penicillin. These patients were treated for 1 to 4 weeks with meropenem and none exhibited any allergic reaction.

Pediatrics

Despite the large amount of literature involving adult patients with hypersensitivity reactions to penicillins, there was also a study conducted in 2009 involving children aged 13 to 14 years with IgE-mediated hypersensitivity reactions to penicillins.¹²The results of this study showed an incidence of 0.8% (1 of 124 patients) cross-reactivity between penicillins and imipenem/cilastatin from skin testing. However, of the 123 patients that completed a challenge with imipenem/cilastatin, no reactions were observed. The drug challenge protocol was consistent with those used in studies mentioned above These same investigators conducted a similar study with meropenem which included 82 of the children from the 2009 study, and found an incidence of cross-reactivity of 0.9% (1 of 108 patients).¹³ The 107 subjects with negative skin tests tolerated challenges with no reactions observed. Of note, it was the same patient in both studies who exhibited hypersensitivity reactions to both imipenem and meropenem, and the investigators mentioned that it is hard to discern whether this was a separate hypersensitivity reaction to carbapenems or cross-reactivity.

Retrospective reviews

Although prospective studies and systematic reviews are typically the gold standard for research, there are some larger chart reviews published that are also helpful to review in this clinical debate.¹⁴ Wall et al reviewed 958 patients with a penicillin allergy and subsequently investigated whether a carbapenem was received and if any hypersensitivity reaction may have occurred. This study included patients with both suspected IgE-mediated reactions as well as non IgE-mediated reactions, such as Stevens-Johnsons syndrome, serum sickness, or interstitial nephritis. Five patients in this study had a presumed reaction to a carbapenem, yet only 1 out of these 5 patients was also allergic to penicillin. These data show that the rate of hypersensitivity reactions in patients with a history of penicillin allergy was 0.31%, and the rate of those who did not have a history of penicillin allergy was 0.63%.

Another retrospective chart review was performed on 266 patients at the Cleveland Clinic in 2004.¹⁵ These patients were divided into those who reported a hypersensitivity to penicillin in the past (n=163) and those who did not (n=103). Records were then reviewed to determine whether the patients had developed a hypersensitivity reaction to meropenem or imipenem-cilastatin in the past. Fifteen out of 163 patients (9.2%) screened had experienced a hypersensitivity reaction, however 4 of 103 patients (3.9%) without a penicillin allergy also developed a hypersensitivity reaction. Using a z score, the rates of hypersensitivity reactions were not significantly different between those who reported a penicillin allergy and those who did not.

Table. Summary of literature describing cross-reactivity between pencillins and carbapenems.^{3, 7, 8-15}

Abbreviations: CBP=carbapenem; N/A=not available; PCN=penicillin.

Conclusion

Overall, there are several diverse studies characterizing the cross-reactivity between penicillins and carbapenems. These studies differ in design, patient population, incidence of cross-reactivity and overall recommendations. With the exception of a small number of studies, it seems as though the vast majority of data suggest that the cross-reactivity of penicillins and carbapenems is very low. Many penicillin-allergic patients did not exhibit a positive skin test to carbapenems, and many of these patients received therapy with a carbapenem and tolerated it well. There are no known data to suggest that one carbapenem produces more allergic reactions than another.

It is also important to note that although a very small number of patients with a penicillin allergy may have a reaction to a carbapenem, it is also believed that some patients who do not have a penicillin allergy still have a risk of developing a reaction to a carbapenem.¹⁵

Many of the investigators recommend skin testing procedures for patients thought to have a hypersensitivity reaction to penicillins before administering a carbapenem.¹¹Skin testing appears to be an accurate predictor of the risk of hypersensitivity reactions; however, it is not always feasible to perform. Carbapenems are often used as empiric therapy for septic patients who require antibiotics within a timely manner to decrease mortality. In this instance, one article demonstrated patients tolerating carbapenem therapy even when skin testing was not performed.

If a patient does have a known severe hypersensitivity reaction to a carbapenem, occasionally a desensitization procedure can be recommended for patients who have a life threatening infection.¹ Small doses of the drug are administered to patients and then gradually increased in order to bind to all of the IgE antibodies before an anaphylactic reaction can occur. One recommendation of how to approach gradually increasing doses is to administer 1% of the dose, followed by 10% of the dose in an hour, then the full dose an hour after that.³ However, this is a dangerous procedure that should be done in an intensive care unit setting with epinephrine, equipment and a ventilator expert nearby.¹

Although there may be a small risk of cross-reactivity between penicillins and carbapenems, it is also important to consider the risk to the patient associated with infection. A valid concern is that many patients who require carbapenems have serious infections with potentially multi-drug resistant organisms, and these infections can be fatal. A risk-benefit analysis of the infection versus a potential cross-sensitivity reaction should always be performed when a decision about a patient is being made.

References

1. Petri WA. Penicillins, cephalosporins, and other β-lactam antibiotics. In: Brunton LL, Chabner BA, Knollmann BC, eds. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 12^th ed. New York, NY: McGraw-Hill; 2011. http://accesspharmacy.mhmedical.com. Accessed August 11, 2015. Accessed August 6, 2015.

2. Terico AT, Gallagher JC. Beta-lactam hypersensitivity and cross-reactivity. J Pharm Pract. 2014;27(6):530-544.

3. Kula B, Djordjevic G, Robinson JL. A systematic review: can one prescribe carbapenems to patients with IgE-mediated allergy to penicillins or cephalosporins? Clin Infect Dis. 2014;59(8):1113-1122.

4. Mirakian R, Leech SC, Krishna MT, et al. Management of allergy to penicillins and other beta-lactams. Clin Exp Allergy. 2015;45(2):300-327.

5. Management of Persons Who Have a History of Penicillin Allergy. Centers for Disease Control and Prevention website. http://www.cdc.gov/std/treatment/2010/penicillin-allergy.htm. Updated January 28, 2011. Accessed August 6, 2015.

6. Saxon A, Adelman DC, Patel A, Hajdu R, Calandra GB. Imipenem cross-reactivity with penicillin in humans. J. Allergy Clin Immunol. 1988;82(2):213-7.
    
7. 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(4):972-976.

8. Romano A, Gaeta F, Valluzzi RL, et al. Absence of cross-reactivity to carbapenems in patients with delayed hypersensitivity to penicillins. Allergy. 2013;68(12):1618-1621.

9. Schiavino D, Nucera E, Lombardo C, et al. Cross-reactivity and tolerability of imipenem in patients with delayed-type, cell-mediated hypersensitivity to beta-lactams. Allergy. 2009;64(11):1644-1648.

10. Romano A, Gaeta F, Valluzzi RL, Caruso C, Rumi G, Bousquet PJ. IgE-mediated hypersensitivity to cephalosporins: cross-reactivity and tolerability of penicillins, monobactams and carbapenems. J Allergy Clin Immunol. 2010;125(5):994-999.

11. Cunha BA, Hamid NS, Krol V, Eisenstein L. Safety of meropenem in patients reporting penicillin allergy: lack of allergic cross reactions. J Chemother. 2008;20(2):233-237.

12. Atanasković-Marković M, Gaeta F, Gavrović-Jankulović M, Velicković TC, Valluzzi RL, Romano A. Tolerability of imipenem in children with IgE-mediated hypersensitivity to penicillins. J Allergy Clin Immunol. 2009;124(1):167-169.

13. Atanasković-Marković M, Gaeta F, Medjo B, Viola M, Nestorović B, Romano A. Tolerability of meropenem in children with IgE-mediated hypersensitivity to penicillins. Allergy. 2008;63(2):237-240.

14. Wall GC, Nayima VA, Neumeister KM. Assessment of hypersensitivity reactions in patients receiving carbapenem antibiotics who report a history of penicillin allergy. J Chemother. 2014;26(3):150-153.

15. Sodhi M, Axtell SS, Callahan J, Shekar R. Is it safe to use carbapenems in patients with a history of allergy to penicillin? J Antimicrob Chemother. 2004;54(6):1155-1157.

Prepared by:
Maressa Santarossa
PGY1 Pharmacy Practice Resident
College of Pharmacy
University of Illinois at Chicago
October 2015

The information presented is current as July 31, 2015. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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