Overview

Piperacillin belongs to the ß-lactam antibiotics which are active against a range of gram-positive and gram-negative aerobic and anaerobic bacteria. However, it has less activity against bacteria harbouring certain ß-lactamase enzymes, as the enzyme will chemically inactivate piperacillin. Hence, it is commonly combined with a ß-lactamase inhibitor such as tazobactam to enhance the activity against many of these resistant organisms.¹

In Malaysia, there are currently seven (7) products containing piperacillin registered with the Drug Control Authority (DCA), all of which are injectable combination products of piperacillin and tazobactam.²

Haemophagocytic Lymphohistiocytosis (HLH) is a life-threatening syndrome caused by pathologic over-activation of the immune system, specifically histiocytes and lymphocytes. HLH is characterised by clinical features of extreme systemic inflammation, such as fever, skin rashes, hepatosplenomegaly, cytopenias, hyperferritinaemia, hypertriglyceridaemia, hypofibrinogenaemia, and haemophagocytosis.^3-5

Background of the Safety Issue

The European Medicines Agency (EMA) has requested all product registration holders for products containing piperacillin/tazobactam and single-component piperacillin to update the package inserts with the risk of haemophagocytic lymphohistiocytosis.⁵

According to the EMA, cases of HLH have been observed in patients following treatment of piperacillin/tazobactam or piperacillin single-component longer than 10 days.⁵ In a published case series, clinical symptoms of HLH in three (3) children were reported to have improved following cessation of piperacillin/tazobactam in combination with corticosteroid therapy (e.g. intravenous prednisolone/methylprednisolone), one of which involved the addition of Intravenous human immunoglobulin (IVIG).³

HLH has high mortality rates and a delay in diagnosis of HLH is often the greatest barrier to favourable outcomes owing to the rarity of HLH, variety of clinical presentations, and non-specific clinical and laboratory findings.^4,6 Besides, it is difficult to differentiate bacteria-induced HLH from antibiotic-induced HLH, as bacterial infections themselves can induce HLH.³

Adverse Drug Reaction Reports⁷

To date, the NPRA has received 1,215 reports with 2,123 adverse events suspected to be related to piperacillin-containing products. The most frequently reported adverse events were pruritus (342), followed by rash maculo-papular (212) and rash (171). Thus far, no local reports of haemophagocytic lymphohistiocytosis have been received.

Advice for Healthcare Professionals

• Be aware that early detection and timely treatment of piperacillin-induced HLH are critical for improving clinical outcomes while minimising morbidity and mortality.
• Consider the possibility of HLH when patients requiring long-term piperacillin or piperacillin/tazobactam develop prolonged fever and/or other early clinical manifestations of pathologic immune activation.
• If the diagnosis of HLH is established, promptly discontinue piperacillin or piperacillin/tazobactam therapy and initiate appropriate management.
• Report all suspected adverse events associated with piperacillin-containing products to the NPRA.

NPRA has completed a review of this safety issue and a directive [Ruj. Kami: NPRA.600-1/9/13 (13) Jld.1] has been issued for all registration holders of products containing piperacillin to update the local package inserts to reflect this safety information.

References:

1. National Pharmaceutical Regulatory Agency (NPRA). TAZOCIN EF (Piperacillin sodium/Tazobactam sodium) [Package Insert]. 2021 Oct [cited 2022 Jul 13]. The Malaysian Product Registration Database (QUEST). Available from: http://www.npra.gov.my
2. National Pharmaceutical Regulatory Agency (NPRA). QUEST3+ Product Search [Internet]. 2022 [cited 2022 Jul 13]. Available from: https://www.npra.gov.my
3. Miyabayashi H, Kumaki S, Sato A, Onuma R, Noguchi R, Sato T, Metoki T, Watanabe Y, Tazawa Y, Imaizumi M, Kitaoka S. Onset of Hemophagocytic Lymphohistiocytosis during Piperacillin-Tazobactam Therapy in Three Children with Acute Focal Bacterial Nephritis. Tohoku J Exp Med. 2018 May;245(1):55-59. Available from: https://doi.org/10.1620/tjem.245.55 
4. Johns Hopkins Medicine. Hemophagocytic Lymphohistiocystosis [Internet]. 2022 [cited 2022 Jul 13]. Available from: https://www.hopkinsmedicine.org/health/conditions-and-diseases/hemophagocytic-lymphohistiocystosis
5. European Medicines Agency (EMA). Pharmacovigilance Risk Assessment Committee (PRAC) Recommendations on signals. Adopted at the 27-30 September 2021 PRAC meeting [Internet]. 2021 Oct 25 [cited 2022 Jul 13]. Available at: https://www.ema.europa.eu/en/documents/prac-recommendation/prac-recommendations-signals-adopted-27-30-september-2021-prac-meeting_en.pdf
6. McClain KL, Eckstein O. Clinical features and diagnosis of hemophagocytic lymphohistiocytosis [Internet]. UpToDate. 2022 May 6 [cited 2022 Jul 13]. Available from https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-hemophagocytic-lymphohistiocytosis#:~:text=Hemophagocytic%20lymphohistiocytosis%20(HLH)%20is%20an,and%20adults%20of%20all%20ages
7. National Pharmaceutical Regulatory Agency. The Malaysian National ADR Database [Internet]. 2022 [cited 2022 Jul 13]. Available from: https://www.npra.gov.my (access restricted)

DISCLAIMER

This publication is aimed at health professionals. The information is meant to provide updates on medication safety issues, and not as a substitute for clinical judgement. While reasonable care has been taken to verify the accuracy of the information at the time of publication, the NPRA shall not be held liable for any loss whatsoever arising from the use of or reliance on this publication.

Written by: Wang Khee Ing
Reviewed/Edited by: Choo Sim Mei, Lim Sze Gee, Noor'ain Shamsuddin, Dr. Azuana Ramli