ORIGINAL ARTICLE Year : 2021  |  Volume : 46  |  Issue : 4  |  Page : 255-257

Vancomycin-related thrombocytopenia in neonates: are Sudanese infants more prone? Case reports and literature review

Suhair A.R Osman Hassan MD, MRCP-CH, FRCP-CH 
Department of Paediatrics, Red Sea University, Sea Ports Corporation Hospital (SPCH) and Paediatric Teaching Hospital, Port, Sudan

Date of Submission17-Apr-2021Date of Acceptance18-May-2021Date of Web Publication18-May-2022

Correspondence Address:
Suhair A.R Osman Hassan
Faculty of Medicine, Red Sea University, Port Sudan
Sudan

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/ejh.ejh_19_20

Background With the improvement of neonatal care in the country and survival of the preterm infants and sick neonates, many arising problems are being observed. One of these is the significant presence of neonatal thrombocytopenia and the need for lots of platelet transfusions per an infant. Many neonatal factors can cause thrombocytopenia, but we observed severe, prolonged thrombocytopenia in infants who received specifically vancomycin for sepsis or other medical/surgical conditions. Literature search revealed that vancomycin can cause immune thrombocytopenia by inducing platelet antibodies, though this is scarcely described in neonates.
Participants and methods This is a hospital-based longitudinal study held in NICU during February 2017 to February 2019. All admitted neonates (term and preterm) who received vancomycin were involved, but those with maternal thrombocytopenia, systemic lupus erythematosus (SLE), maternal eclampsia/HELLP (Haemolysis, Elevated Liver enzymes, Low Platelets) syndrome, and Intr Uterine Growth Rrestriction (IUGR) were excluded.
Results Of 117 infants admitted in this period, 68 infants fulfilled the inclusion criteria. The severe decline in platelet count observed on the second to third day of vancomycin treatment continued throughout the treatment and started to rise 2–3 days after discontinuation. During treatment with vancomycin, platelet transfusion 2–3 times a day was observed not to raise platelet level significantly, but it prevented serious bleeding.
Conclusion Vancomycin-induced thrombocytopenia in neonate is a rising new problem in NICUs. The authors may need to add adjunctive intravenous immunoglobulins or methylprednisolone or change the dosing system to smaller frequent doses, given over longer time, to overcome this serious problem.

Keywords: neonatal thrombocytopenia, platelet Abs, severe bleeding, vancomycin

How to cite this article:
Osman Hassan SA. Vancomycin-related thrombocytopenia in neonates: are Sudanese infants more prone? Case reports and literature review. Egypt J Haematol 2021;46:255-7
How to cite this URL:
Osman Hassan SA. Vancomycin-related thrombocytopenia in neonates: are Sudanese infants more prone? Case reports and literature review. Egypt J Haematol [serial online] 2021 [cited 2022 May 20];46:255-7. Available from: http://www.ehj.eg.net/text.asp?2021/46/4/255/345383   Introduction 

With the improvement of neonatal care in our country and survival of the preterm infants and sick neonates, we started to observe many problems arising. Of them is the significant presence of neonatal thrombocytopenia and the need for lots of platelet transfusions per infant. Many factors can cause neonatal thrombocytopenia, mainly sepsis, Intr Uterine Growth Rrestriction (IUGR), infant of mother with eclampsia/HELLP (Haemolysis, Elevated Liver enzymes, Low Platelets) syndrome, infant of mother with alloimmune thrombocytopenia, and infant of mother with systemic lupus erythematosus (SLE). Moreover, thrombocytopenia is a recognized adverse effect of a wide range of medications like chemotherapeutic and immunosuppressive agents that suppress hematopoiesis and produce pancytopenia, but a few agents inhibit megakaryocytopoiesis and produce isolated thrombocytopenia. This effect occurs through immune and less often through non‐immune mechanisms [1],[2]. Although drug-induced thrombocytopenia (DITP) can be suspected in any case with acute thrombocytopenia during drug use, detection of an antibody that reacts with normal platelets during therapy can help diagnosis of DITP. A convenient method to detect drug-dependent Abs is flow cytometry [3],[4], but this test is not widely available. Vancomycin, a glycopeptide antibiotic, produced naturally by Amycolatopsis orientalis   (previous streptomyces/Norcadia orientalis), is widely used for the treatment of resistant bacteria like methicillin-resistant Staphylococcus aureus, methicillin-resistant Streptococcus epidermidis, and coagulase-negative Staphylococci [5],[6],[7],[8],[9],[10],[11],[12]. Its adverse reactions include fever, chills, phlebitis, chest pain, hypotension, muscle spasm, ototoxicity, nephrotoxicity, neutropenia, fixed drug eruptions, and rarely, pancytopenia and Stevens–Johnson syndrome. It is also associated with hypersensitivity reactions like anaphylaxis and red man syndrome (or red neck syndrome) as a result of histamine release. Red man syndrome, being the most commonly known adverse reaction to vancomycin, is characterized by flushing of the upper body with pruritus [1],[2]. Vancomycin is rarely being implicated as a cause of thrombocytopenia and is often overlooked as a culprit, explaining the limited data available on its immune effect [11]. Although it is associated with the most severe form of DITP, there are few reports in the literature on vancomycin-induced thrombocytopenia (VIT), such as two cases in neonates [3],[4], one case in children [5], few cases in adults [6],[7],[8], and only one report in infants [16]. Annette and his colleagues have studied clinical and laboratory findings in 29 patients who developed thrombocytopenia while receiving vancomycin, compared with another 25 patients who received vancomycin and did not develop thrombocytopenia. They presented evidence that thrombocytopenia was caused by vancomycin-dependent, platelet-antibodies [immunoglobulin (Ig)G, IgM], whereas there was no Abs detected in patients with no thrombocytopenia. They observed that vancomycin-induced immune thrombocytopenia can even cause life-threatening bleeding (wet purpura), unlike thrombocytopenia caused by other drugs. They concluded that the detection of vancomycin-dependent antiplatelet antibodies (VDP-Abs) in vancomycin-treated patients who developed thrombocytopenia, and the absence of VDP-Abs in patients given vancomycin and did not develop thrombocytopenia indicates that these antibodies are the cause of the thrombocytopenia [6]. This means that not all patients who receive vancomycin develop thrombocytopenia, or other vancomycin adverse reactions; this fact needs to be searched. Vancomycin as a cause of thrombocytopenia can be overlooked unless a high index of suspicion is applied, otherwise prolonged use or change to another antibiotic(s) for the assumed nonresolved sepsis will be the action [3]. Treatment of DIT is with platelet transfusions, especially if thrombocytopenia is severe or bleeding occurs, whereas intravenous immunoglobulins (IVIG), corticosteroids, rituximab, and plasma exchange are reserved for patients with resistant thrombocytopenia and severe bleeding [1],[8],[14],[15],[16]. Unfortunately, it seemed that previous vancomycin exposure leads to rapid platelet destruction within hours upon re-exposure (anamnestic response); hence, it is important to check the pre-exposure and postexposure serum for vancomycin-induced antiplatelet Abs to avoid its use in the future infection [17]. We started to observe severe, prolonged thrombocytopenia in newborns who received vancomycin for sepsis or other medical/surgical conditions in our neonatal unit (NICU). They needed multiple platelet transfusions, with their thrombocytopenia improved when vancomycin was discontinued. Literature search revealed that vancomycin can cause immune thrombocytopenia by inducing platelet antibodies, though this is scarcely described in neonates [3],[4]. To our knowledge, there is no literature on VIT in Sudan or Arabic countries, and this reflection is the 1st report. By reporting this study, we wanted to raise the awareness among our colleagues on the strong presence of this vancomycin effect in the Sudanese neonates.

  Participants and methods 

This is an observational, hospital-based, longitudinal study held in our NICU (Sea Ports Corporation Hospital/Port Sudan) in the period February 2017 to February 2019. Ethycal approval from the ethical committee of the SPCH is obtained before collecting the data. All admitted neonates (term and preterm) who received vancomycin were involved, but those with maternal thrombocytopenia, SLE, maternal eclampsia/HELLP syndrome, and IUGR were excluded from this study.

  Results 

Of 117 newborn admitted in this period, 68 (58%) fulfilled the inclusion criteria: five (7.4%) term neonates were surgical cases (two underwent ventriculoperitoneal shunt for congenital hydrocephalus and three underwent laparotomy for intestinal obstruction), four (5.9%) newborn were admitted with congenital pneumonia, 44 (64.7%) with early-onset sepsis, and 15 (22%) with late-onset sepsis.

In all cases, the severe decline in platelet count was observed on the second to third day of vancomycin treatment (ranged: 9000–33 000, mean=21 000), which continued throughout the treatment, and started to rise 1–3 days after discontinuation (mean=2 days), to normalize at around 4–7 days (mean=5.5 days). During treatment with vancomycin, platelet transfusion 8–12 hrly was observed not to increase platelets level, but it has prevented serious bleeding like intracranial hemorrhage and pulmonary hemorrhage; this might point to the presence of a platelet scavenger (Abs).

  Discussion 

It seemed that Sudanese newborn are more susceptible to VIT, specifically compared with other nations, as this was reported in all Sudanese neonates who received this drug (100%), whereas there are only two reported neonatal VIT worldwide till the moment. It seemed also that Sudanese neonates are prone to VIT specifically than other vancomycin-induced adverse reactions, as none of them had been observed to develop vancomycin-induced red man syndrome, and the only single case of red man syndrome we encountered in our NICU, was owing to ciprofloxacin in a twin preterm, and we did not encounter any other vancomycin adverse reaction in this study.

Although the test to detect vancomycin-induced IgG or IgM Abs to platelets is not available in our territories, it looked clear that this significant neonatal thrombocytopenia is closely related to vancomycin, as even when platelet count decreased with sepsis, it decreased critically to nadir when vancomycin was started and continued, to start rising after discontinuation of the culprit drug. This effect was also observed in nonseptic neonates who received vancomycin as a prophylaxis for surgical procedures, precluding the sole effect of sepsis as a cause of thrombocytopenia. In this study, the observance of the time for platelets to go nadir and the time to start rising after drug discontinuation is in agreement with the reports of VIT in all different age groups reported, except one report by Quan-Yao Chen in 2018 on a young infant (3 months) who reported 17 days for the platelet to recover completely to normal after vancomycin discontinuation.

In spite of its serious adverse reactions, vancomycin is a badly needed drug in NICUs and ICUs. Its dosing system may need revision concerning amount, duration of the dose (usually given over I hour), and frequency, as some of its adverse reactions are related to the rate of infusion (red man syndrome) or it may need adjunct therapy with antihistamine, methylprednisolone, or IVIG. This field needs more study and research to make a safe use of this valuable drug. Patients, especially neonates and young children, receiving long courses of vancomycin should undergo vigilant monitoring of their blood count to check for VIT. Knowing this will avoid physicians to continue vancomycin, or change to another, on the assumption of unresolving sepsis.

  Conclusion 

VIT is present in neonates, and it seemed that Sudanese neonates are more prone than other nations, an issue that needs more research. Moreover, as we cannot avoid its use, we may need to compete its adverse reactions by using adjunctive IVIG, methylprednisolone, or changing the dosing system to a smaller, frequent doses, each taking over more than the stated 60 min.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 

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