Amoxicillin for stomach pain

The degradation rate was estimated using the slope of the linear regression curve corresponding to amoxicillin remaining (% of initial concentration) versus time profile. Stability was defined as less than 10% disappearance of the amoxicillin concentration, in compliance with the provisions of the US Pharmacopoeia concerning the acceptable limit of content of drug preparation settled at 90% [24], and with the European Pharmacopoeia, requiring that ?-Lactams solutions always contain at least 90% of intact molecule [25].

All samples were diluted to a concentration of 100 ?g/mL with ultrapure water and assayed for amoxicillin concentration using a high-performance liquid chromatography method coupled to UV detection (HPLC-UV).

The Elite LaChrom system (VWR, France) included a binary pump (Primaid 1110) used in isocratic mode, a single wavelength ultraviolet detector (L-2400), and an autosampler (L-2200) and was controlled using EZChrom Elite 3.3 software. Separation was

performed

The stability-indicating HPLC-UV method was validated in accordance with the guidelines of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Q2(R1) [26]. Briefly, the method was linear over the range 0–200 ?g/mL (r 2 > 0.9993) and the limit of quantification of amoxicillin was equal to 12.5 ?g/mL.

Precision of the method was high, according to intra-day and inter-day coefficients of variation,

calculated

Briefly, amoxicillin solutions (50 mg/mL, extemporaneous and kept stored 48 hours at 37°C) were injected onto the HPLC system connected to an ultra-high definition quadrupole

time-of-flight

LC-MS-measured accurate mass spectra were recorded across the range 50–1000 m/z with scan time settled at 0.1 s. The degradation products were identified by structure elucidation using the molecular ion exact mass determination and the collision-induced dissociation fragments obtained using HRMS. From 0 to 150 mg/mL, measured concentrations of amoxicillin are well-correlated to theoretical concentrations (Fig 1).

At concentrations greater than 150 mg/mL, measured amoxicillin concentrations are systematically lower than theoretical values, underlining the incomplete solubility of amoxicillin in water at high concentration.

Each value is the mean of three independent determinations ± standard deviation. Whatever the nominal concentration prepared and whatever the storage conditions selected, amoxicillin concentration decreases over time, demonstrating that amoxicillin is unstable in aqueous solution.

Amoxicillin degradation rate increases depending on the initial concentration: from -0.75%/h to -3.34%/h at 25 mg/mL and 250 mg/mL respectively, leading to concentrations after 24-hour storage ranging from 83% to 13% of the initial concentration (Fig 2). Amoxicillin chemical stability depends on initial concentration: the higher the concentration, the less stable the antibiotic. The horizontal line indicates the limit set by the Pharmacopoeias (90% of initial drug concentration). Moreover, amoxicillin degradation rate increases depending on storage temperature: from -1.92%/h to -3.29%/h at 5°C and 37°C mg/mL respectively, leading to concentrations after

24-hour

The

horizontal

The high doses of amoxicillin required for treatment of severe infections should be administrated over a long period, and preferably by continuous intravenous administration [1–9].

According to the limited volume of medical devices available for continuous drug infusion, particularly the portable devices used for OPAT, highly concentrated solutions of amoxicillin need to be prepared, leading to issues regarding solubility.

In this study, we have demonstrated for the first time that amoxicillin has to be reconstituted at concentrations below or equal to 150 mg/mL to achieve complete solubility, which is mandatory in order to ensure accurate drug dosage and efficacy when using intravenous administration mode.

Moreover, incomplete solubility of a drug may lead to particles in solutions, which may induce serious harmful effects such as pulmonary embolism or systemic inflammatory response syndrome [27–29]. Therefore, an appropriate volume of solvent is required for the reconstitution of amoxicillin to ensure safe administration, excluding the use of low-volume devices such as syringes or small volume portable pumps, when high doses of amoxicillin are to be administrated.

This work confirms that amoxicillin degradation is time, temperature and concentration-dependent, resulting in short-term stability of amoxicillin solutions for infusion, particularly at high concentrations. Consequently, continuous infusion of the high-dose amoxicillin recommended to treat serious infectious diseases requires applying rigorous conditions of administration especially for OPAT. Elastomeric pumps are commonly used in the setting of OPAT and are available in different volumes and flow rates to allow proper administration of a drug [30].

Therefore, we have investigated different volumes and flow rates through the use of different devices in order to determine which one best helps to achieve amoxicillin concentration-dependent stability.

Regarding storage temperature, elastomeric pumps may be used in different conditions, refrigerated or not. Moreover, it has been demonstrated that the temperature of drug solutions in elastomeric pumps may dramatically increase over the day, especially for amoxicillin a45 uses continuous infusion, reaching a

maximum

In this context, we have investigated the impact of potentially different storage temperatures on amoxicillin stability in order to determine the optimal conditions for its administration. Few previous studies have investigated amoxicillin stability in solutions, using varying solvents and concentrations, and different temperatures and containers for storage [19–23].

Most of them report limited stability unsuitable for continuous infusion over a long period. One study has assessed amoxicillin stability in elastomeric pumps and reports results contradictory to ours concerning amoxicillin degradation [21]. Indeed, the authors claim a stability of amoxicillin for 24h-48h up to 40 mg/ml, when stored at 20°C or 35°C. However, these conclusions do not comply with international guidelines regarding the acceptable drug degradation limit of less than 10% [24,25].

Furthermore, even under the same conditions, the degradation rates of amoxicillin reported in this paper are lower than ours, as well as those reported by others under similar conditions [20,22,23]. In fact, it should be noted that the analytical method proposed in this study was

not

stability

This issue raises the need for clinicians to seek pharmaceutical expertise in order to assess the level of proof of the analytical methods used to provide data having clinical impact [33].

Despite the lack of consistent data on amoxicillin stability, some authors have investigated the suitability of continuous intravenous administration of high-dose amoxicillin in patients [23,34].

demonstrated that continuous infusion of amoxicillin provides fewer low concentrations than intermittent administration, they reported highly inconstant amoxicillin plasma concentrations using this administration mode, despite adapted doses [34]. Moreover, despite continuous administration of high-doses amoxicillin (12 g/day), Arensdorff et al.

observed, very low amoxicillin plasma concentrations (0.9 and 2.4 mg/mL) in two out of the nine patients enrolled [23]. In both these studies, amoxicillin unstability may have resulted in inaccurate dose administration, leading to suboptimal or ineffective concentrations in treated patients, with respect to the MIC of the bacteria involved in the infection.

Clearly, while the great variability in amoxicillin plasma levels is due to many factors, unstability issue should not be ruled out as a causal factor.

Last but not least, drug degradation may lead to toxic byproducts [17]. Regarding amoxicillin we have identified four degradation products, Among them, amoxicilloic acid and

diketopiperazine

Hydroxyphenylglycyl amoxicillin acid and amoxicillin penilloic acid have also been described by others [35,36].

None of these degradation products have antimicrobial activity, but amoxicilloic acid and diketopiperazine amoxicillin are at risk of allergic reaction, of the same order of magnitude as those observed with amoxicillin [37,38].

In addition, it has been demonstrated that the amoxicilloic acid concentrations

measured

This issue could partly explain the side effects reported in patients treated with high-dose amoxicillin. In conclusion, according to the experiments carried out in this work, the optimal conditions for the administration of continuous infusion of high-dose amoxicillin using portable elastomeric pumps have been defined.

First of all, amoxicillin has to be diluted in order to obtain a final concentration of 25 mg/ml, allowing for complete dissolution and long-term stability. Dilution should be performed in sterile water for injection combined with 0.9% sodium choride for injection (50:50, v:v) in order to maintain osmolarity at a level (approximately 280 mOsm/L, data no shown) suitable for intravenous infusion using peripheral access [16]. Dilution in dextrose should be avoided since lower stability using this solvent has been demonstrated [20].

Then, under these optimized conditions, the elastomeric pump may be stored at ambient temperature (22 ± 4°C) for 12 hours, requiring filling an elastomeric pump every 12 hours

for

In addition, it is important to store the elastomeric pump at a temperature below 26°C, which implies not holding the device near the body or under clothing during the day, and keeping it beside the head, outside of the blankets when the patient is bedridden.

Finally, amoxicillin may remain stable over the entire day under the same conditions, provided that the elastomeric pump is stored between

+4°C

We wish to thank Jeffrey Arsham, an American medical translator, for his highly helpful reading of our original text.

Changes and new listings for four antibiotics on the PBS.

On 1 April 2020, four antibiotics listed on the PBS General Schedule (Section 85) had changes made to their listings and new listings added for the treatment of a range of infections, such as acute cystitis, streptococcal pharyngitis or tonsillitis

and

amoxicillin amoxicillin + clavulanic acid

cefalexin

See the PBS website for complete details for each item, including the specific infections. These are also listed in Table 1 at the end of this article.

The listing changes and new listings aim to promote antimicrobial stewardship, by reducing inappropriate, inadvertent repeat prescribing when initiating a course of antibiotics.