Amoxicillin trihydrate

Abdominal CT was notable for acute pancreatitis with no pseudocyst formation (Fig. a and b Axial plane showing infiltration of the peripancreatic fat planes by soft tissue attenuation complicated with inflammation. No pancreatic ductal dilatation or discrete peripancreatic fluid collections observed. Based on clinical presentation and CT findings, patient was diagnosed with mild acute pancreatitis with Bedside Index of Severity in Acute Pancreatitis (BISAP) score of 0 ( Fig.

b Normal caliber common bile duct ? 7 mm demonstrated.

Endoscopic ultrasonography was done as outpatient by the gastroenterologist on the case and ruled out biliary microlithiasis.

Patient had no hypertriglyceridemia (his triglyceride (TG): 142 mg/dL), never had endoscopic retrograde cholangiopancreatography (ERCP), no hypercalcemia (his corrected calcium (Ca): 9.3 mg/dL), no steroids taken, no known malignancy, no infection, no trauma, no exposure to scorpions. The most plausible link for his pancreatitis was his use of amoxicillin/clavulanic acid prior to presentation given that he had a similar presentation when he took the same antibiotic several years ago but was not diagnosed with pancreatitis since he did not seek medical attention at that time. Additionally, patient denied intake of any other penicillin agents. Identifying the cause of acute pancreatitis can be somewhat challenging especially when trying to identify a certain drug as the causative agent.

Drugs are responsible for approximately 0.1–2% of acute pancreatitis incidents with most information about drug-induced pancreatitis being collected from case reports and case series which means that true incidence can be even higher [1,2,3,4]. There is no one main mechanism behind drug-induced acute pancreatitis, but several potential mechanisms are currently based on theories.

Of the proposed mechanisms include: pancreatic duct constriction with localized angioedema and arteriolar thrombosis, cytotoxic and metabolic effects, and hypersensitivity reactions [2].

As well as drugs with side effects of hypertriglyceridemia and chronic hypercalcemia that are considered risk factors for acute pancreatitis [2]. The diagnosis of drug-induced acute pancreatitis requires a diagnosis of acute pancreatitis and ruling out all other etiologies.

Etiologies that were ruled out in this case comprise all possible causes of pancreatitis: gallstones, biliary sludge and microlithiasis, alcohol, smoking, hypertriglyceridemia, scorpion venom, post endoscopic retrograde cholangiopancreatography (ERCP), hypercalcemia, steroids intake, malignancy, infection, trauma, vascular amoxicillin trihydrate 500mg disease [1,2,3,4]. Based on American College of Gastroenterology guidelines, consideration for genetic testing for

hereditary

Immunoglobulin G4 level was 24 mg/dL (reference range: 1–100 mg/dL) which amoxicillin and clavulanate potassium 875 ruled out autoimmune pancreatitis.

The evidence found to implicate a certain drug to the development of acute pancreatitis is often inadequate especially when the mechanism is unknown. proposed a classification system of drug-induced acute pancreatitis. This system was based on the number of case reports found in the literature, the available rechallenge data, latency period and ability to exclude other causes of acute pancreatitis [6].

After reviewing summary of drug induced acute pancreatitis based on drug class, we found that ampicillin and penicillin are considered

class

If the pancreatitis resolves after discontinuation of the drug, suspicion for drug-induced pancreatitis increases.

A firm diagnosis can be reasonably established with a rechallenge of the offending drug

that

Table 2 shows the comparison between our patient’s case with published data in the literature.

Drug-induced acute pancreatitis remains rare but should not be disregarded when medical practitioners are faced with a patient presenting with acute pancreatitis with no obvious cause. Being familiar with reports of drugs causing acute pancreatitis can be helpful in identifying the causality and association with a certain drug.

Despite the fact that DIP can have a benign course with good prognosis, fatal outcomes still occur and thus DIP should not be overlooked.

This case describes a patient with DIP after the intake of amoxicillin/clavulanic acid and when all other common causes of acute pancreatitis were excluded. We again stress on the importance of identifying and reporting cases of DIP to raise awareness among physicians and clinicians.

We also stress on the importance of encouraging scientists and researchers to better understand the mechanism of developing drug-induced acute pancreatitis. Overcoming stability challenges during continuous intravenous administration of high-dose amoxicillin using portable elastomeric pumps.

Contributed equally to this work with: Guillaume Binson, Claire Grignon.

Roles Investigation, Methodology, Writing – original draft. Affiliations Department of Pharmacy, University Hospital of Poitiers, Poitiers, France, CIC Inserm, Poitiers, France. Contributed equally to this work with: Guillaume Binson, Claire Grignon. Roles Investigation, Methodology, Writing – original draft. Affiliation Department of Pharmacy, University Hospital of Poitiers, Poitiers, France.

Roles Conceptualization, Writing – review & editing.

Affiliation Department of Infectious Diseases, University Hospital of Poitiers, Poitiers, France.

Affiliation

Department

Affiliation Department of Pharmacokinetics, University Hospital of Poitiers, Poitiers, France.

Affiliation Department of Infectious Diseases, University Hospital of Poitiers, Poitiers, France.

Roles Methodology, Validation, Writing – review & editing.

Affiliations CIC Inserm, Poitiers, France, Department of Pharmacokinetics, University Hospital of Poitiers, Poitiers, France.

Roles Conceptualization, Methodology, Project administration, Supervision, Writing – review & editing.

Affiliations Department of Pharmacy, University Hospital of Poitiers, Poitiers, France, CIC Inserm, Poitiers, France. Overcoming stability challenges during continuous intravenous administration of high-dose amoxicillin using portable elastomeric pumps. Guillaume Binson, Claire Grignon, Gwenael Le Moal, Pauline Lazaro, Jeremy Lelong, France Roblot, Nicolas Venisse, Antoine Dupuis. Published: August 16, 2019 https://doi.org/10.1371/journal.pone.0221391. Article Authors Metrics Comments Media Coverage Peer Review.

While treatment of serious infectious diseases may require high-dose amoxicillin, continuous infusion may be limited by lack of knowledge regarding the chemical stability of the drug.

Therefore, we have performed a comprehensive study so as to determine the chemical stability of high-dose amoxicillin solutions conducive to safe and effective continuous intravenous administration using portable elastomeric pumps.

First, amoxicillin solubility in water was assessed within the range of 25 to 300 mg/mL. Then, amoxicillin solutions were prepared at different concentrations (25, 50, 125, 250 mg/mL) and stored in different conditions (5±2°C, 25±1°C, 30±1°C and 37±1°C) to investigate the influence of concentration and temperature on the chemical stability of amoxicillin. Finally, its stability was assessed under optimized conditions using a fully validated HPLC-UV stability-indicating method.

Degradation products of amoxicillin were investigated by accurate mass determination using high-resolution mass spectrometry.

Amoxicillin displayed limited water solubility requiring reconstitution at concentrations below or equal to 150 mg/mL. Amoxicillin degradation were time, temperature as well as concentration-dependent, resulting in short-term stability, in particular at high concentrations. Four degradation products of amoxicillin have been identified.

Among them, amoxicilloic acid and diketopiperazine amoxicillin are at risk of allergic reaction and may accumulate in the patient.

Optimized conditions allowing for continuous infusion amoxicillin for ear infection baby of high-dose amoxicillin has been determined: amoxicillin should be reconstituted at 25 mg/mL and stored up to 12 hours at room temperature (22 ± 4°C) or up to 24 hours between 4 and 8°C.

Citation: Binson G, Grignon C, Le Moal G, Lazaro P, Lelong J, Roblot F, et al.

(2019) Overcoming stability challenges during continuous intravenous administration of high-dose amoxicillin using portable elastomeric pumps. Editor: Jose das Neves, University of Porto, PORTUGAL. Received: June 19, 2019; Accepted: August 7, 2019; Published: August 16, 2019. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the manuscript. Funding: The authors received no specific funding for this work.

Competing interests: The authors have declared that no competing interests exist.

The management of several serious infectious diseases such as bone and joint infections as well as infective endocarditis, requires intravenous administration of high-dose amoxicillin (100–300 mg/kg/day) over a prolonged period, ranging from a few weeks to several months [1–4].

?-Lactams are time-dependent antibiotics, meaning that their efficacy depends on the time that free serum concentrations remain above the minimal inhibitory concentration (MIC) during the dosing interval [5].

It has been demonstrated that continuous infusion maintains concentrations above the MIC for a longer period of time within the dosing interval [6].

Moreover, mounting evidence from clinical studies indicates that continuous infusion of time-dependent ?-lactam antibiotics may improve clinical success [7–9]. Therefore it may be well-founded to administrate ?-Lactams using continuous infusion in patients suffering from serious infectious disease. However, despite the possible clinical benefits of this mode of administration, one of the practical concerns related to continuous infusion is the limited stability of certain antibiotic agents. Indeed, stability issues have to be taken into consideration when implementing drug administration, in order to ensure drug efficacy and safety.

Regarding ?-lactam antibiotics, not knowing how long they remain stable during infusion may be a limiting factor for continuous administration [10,11]. Furthermore, for several decades, intravenous antimicrobials have been administered increasingly in outpatient settings, in particular thanks to the use of portable devices [12,13]. Outpatient parenteral antimicrobial therapy (OPAT) allows for early hospital discharge, and further reduces costs with fewer nursing and clinic visits [14]. Moreover, OPAT improves quality of life, and portable elastomeric pumps gives patients more flexibility and control over their treatment [15]. Among the important aspects described in OPAT practice guidelines, drug stability has been underlined as a crucial point to be taken into consideration to ensure efficacy and safety of antimicrobial therapy [12,16,17].

In a recent survey, osteomyelitis, prosthetic joint infections and endocarditis were the most commonly reported indications for OPAT [18].

In treatment of these infectious diseases, continuous infusion of high-dose amoxicillin may be limited by lack of knowledge of the chemical stability of the drug.

Indeed, very few studies are available in the literature regarding the stability of amoxicillin in aqueous solution for intravenous administration and results regarding long-term

stability

The aim of this work was to propose safe and effective conditions for continuous intravenous administration of high-dose amoxicillin using portable elastomeric pumps. For that purpose we performed a comprehensive

study

Amoxicillin powder used for calibration of the method was purchased from Sigma-Aldrich (Sigma-Aldrich, France) while amoxicillin sodium powder for solution for

injection

was

Portable elastomeric pumps Infusor (48 mL, 2 mL/h) and FOLFusor (240 mL, 10 mL/h), were obtained from Baxter (Baxter, France) and portable elastomeric pumps Accufuser (480 mL, 20 mL/h) from Wym (Wym, France). The Infusor and FOLFusor reservoirs are made of synthetic polyisoprene and the Accufuser reservoir is made of medical silicone. Amoxicillin solubility was assessed within the range 25 to 300 mg/mL by dissolving a vial of amoxicillin sodium, equivalent to amoxicillin 2 g, in adequate volume of sterile water for injection.

The vial was vortexed for 10 min, centrifugated at 3500 G for 10 min and the amoxicillin concentration was determined in the supernatant. To determine the optimal volume of dilution for amoxicillin reconstitution, we investigated the influence of the concentration on the chemical stability of amoxicillin.

Amoxicillin solutions

were

immediately

To determine the best storage conditions during amoxicillin infusion we investigated the influence of temperature on the chemical stability of amoxicillin. Amoxicillin solutions were prepared at a concentration of 125 mg/mL (6 g of amoxicillin were reconstituted with 48 ml of sterile water for injection), in order to fill an Infusor (nominal volume of 48 mL, flow rate of 2 mL/h). The filled elastomeric pumps were then stored for 24 hours at different temperature conditions: 5 ± 2°C in a refrigerated chamber (Precision, Thermo Scientific, France), 25 ± 1°C, 30 ± 1°C and 37 ± 1°C, in a climate chamber (Air concept, FirLabo, France).