Pivmecillinam

Pivmecillinam belongs to the pharmacological class of Beta-Lactam Antibiotics.

Pivmecillinam has been approved to relieve symptoms and also for the treatment and maintenance of urinary tract infections.

Pivmecillinam is well absorbed from the gastrointestinal tract. The oral Bioavailability is found to be 60-70%. Pivmecillinam is rapidly hydrolyzed via non-specific esterases in the blood to its active form, mecillinam. Pivmecillinam is mainly via urine which is approx. 60-70% as mecillinam via bile. The elimination half-life of pivmecillinam was found to be approximately one hour.

The common side effects involving the use of Pivmecillinam are nausea, vomiting, headache, diarrhea, headache, upset stomach, etc.

Pivmecillinam is available in the form of Tablets.

Pivmecillinam is approved in the U.S., U.K., Germany, Japan, Malaysia, India, and China.

Pivmecillinam belongs to the pharmacological class of Beta-Lactam Antibiotics.

Pivmecillinam is the pivaloyloxymethyl ester of mecillinam. It interferes with the bacterial cell wall with its high specificity against the penicillin-binding protein 2 (PBP-2), making it different from other penicillins.

Pivmecillinam has been approved to relieve symptoms and also for the treatment and maintenance of urinary tract infections.

The time to peak plasma concentration of Pivmecillinam is about 1-1.5 hours (mecillinam).

Pivmecillinam is available in the form of tablets.

Pivmecillinam can be used in the following treatment:

• Urinary Tract Infection

Pivmecillinam can help to relieve symptoms and also for the treatment and maintenance of urinary tract infections.

Pivmecillinam is approved for use in the following clinical indications:

• Urinary tract infection

Tablet: To be taken as a whole with water.

200mg, 400mg

Tablet

• Dosage Adjustments in Pediatric Patients:

Children and Adolescents >6 years of age and weight >40 kg: Oral: 20 to 40 mg/kg/day.

Avoid high-acid foods like citrus fruits and juices like orange and grapefruit, soda, and chocolates.

Alcohol intake might lead to nausea, vomiting and headache

Multivitamins and antacids contain minerals, primarily magnesium, calcium, aluminum, iron or zinc, which bind to the antibiotic and refrain it from working. Spacing them at least for 2 hours after Pivmecillinam administration is recommended.

Pivmecillinam may is contraindicated under the following conditions:

• Patients with known hypersensitivity to cephalosporins.
• Any conditions were resulting in impaired transit through the esophagus.
• Genetic metabolism anomalies are known to be leading to severe carnitine deficiency, which includes carnitine transporter defect, methylmalonic aciduria, or propionic acidemia.

The physician should closely monitor the patients and keep pharmacovigilance as follows:

• Endocrine and Metabolism

Long-term treatment or frequently repeated treatment courses should be used with caution as Pivmecillinam (pivmecillinam hydrochloride) has been associated with increased excretion of carnitine in urine and a reduction of serum carnitine. During absorption, Pivmecillinam is hydrolyzed to pivalic acid and mecillinam. Pivalic acid is excreted partly as a conjugate with carnitine. Treatment with pivalic acid liberating antibiotics for a duration of 22 and 30 months in children resulted in total muscle carnitine depletion to 10% of reference values. However, no adverse clinical effects were reported, which could be associated with primary or secondary carnitine deficiency. Following 7 to 10 days of treatment at the highest recommended doses of Pivmecillinam there was a significant reduction in serum carnitine which returned to the normal range within two weeks of stopping therapy. Despite these reductions in serum carnitine, total body stores of carnitine were reduced by approximately 10%. The increased excretion of carnitine associated with the use of Pivmecillinam is considered to be without clinical significance in short-term treatment.

• Gastrointestinal

Pseudomembranous colitis which is caused by Clostridium difficile might occur. In the case of diarrhea, the possibility of pseudomembranous colitis should be considered, as well as appropriate actions should be taken. It si advised that Pivmecillinam tablets must be taken with at least half a glass of fluid due to the risk of esophageal ulceration.

• Hematologic

Pivmecillinam should not be used by patients suffering from porphyria, as pivmecillinam had been connected to acute attacks of porphyria.

• Renal

Even though Pivmecillinam has exhibited characteristic low toxicity of the penicillins, periodic assessment of the renal hepatic and hematopoietic functions should be made during prolonged therapy. Pivmecillinam is excreted mostly by the kidneys. In patients with renal Impairment, the dosage administered should be reduced in proportion to the degree of loss of renal function. In severe renal function impairment, it is suggested that the plasma level of the drug be monitored to avoid excessive concentrations. The passage of any penicillin from the blood into the brain is facilitated by inflamed meninges and during cardiopulmonary bypass. In the presence of these conditions and particularly when accompanied by renal failure, sufficiently high penicillin serum concentrations can be obtained to produce central nervous system adverse effects. These include myoclonia, convulsive seizure and depressed consciousness. Although these reactions have not yet been reported for Pivmecillinam, physicians should be aware of the possibility of their occurrence.

• Sensitivity

Serious and occasionally fatal hypersensitivity (anaphylactoid) reactions had been reported in patients receiving penicillin. The reactions are more likely to occur in persons with a history of sensitivity to multiple allergens. Before therapy with Pivmecillinam, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins/ other allergens. If an allergic reaction occurs, the administration of Pivmecillinam should be discontinued and appropriate therapy instituted. The possibility of superinfections with mycotic or bacterial pathogens should be kept in mind during the therapy. If superinfections, usually involving Pseudomonas or Candida, or hypersensitivity reactions occur, the Pivmecillinam should be discontinued and/or appropriate therapy instituted.

• Susceptibility/Resistance Development of Drug-Resistant Bacteria

Prescribing Pivmecillinam in the absence of a proven or strongly suspected bacterial infection which is unlikely to provide the benefit to the patient and risks the development of drug-resistant bacteria.

Usage of alcohol should be avoided while on Pivmecillinam medication, as alcohol can worsen the effects of any underlying disease condition, including conditions such as dizziness, blurred vision, etc.

It was found that at therapeutic doses of Pivmecillinam no effects on breastfed newborns/infants are anticipated. Pivmecillinam can be used during breastfeeding.

Category B

The clinical data on pregnant women which is more than 1000 pregnancy outcomes, indicates that no malformities nor feta/neonatal toxicity of pivmecillinam. Pivmecillinam can be used in pregnancy if clinically needed.

No sufficient scientific evidence is traceable regarding the use and safety of Pivmecillinam in concurrent use with any particular food.

The adverse reactions related to Pivmecillinam can be categorized as follows:

• Fungal or bacterial superinfection
• Carnitine deficiency
• Acute porphyria.
• Thrombocytopenia.
• Vertigo
• Nausea
• Diarrhea
• Vomiting
• Abdominal pain
• Esophageal ulcer
• Dyspepsia
• Oesophagitis
• Mouth ulceration
• Fatigue
• Vulvovaginal mycotic infection
• Porphyria
• Headache
• Dizziness
• Rash, pruritus
• Urticaria
• Clostridium difficile infection,
• Pseudomembranous colitis

The clinically relevant drug interactions of Pivmecillinam are briefly summarized here:

• Simultaneous administration of the drug probenecid reduces the excretion of penicillins and hence increases the blood level of the antibiotic.

• Clearance of methotrexate from the body is to be reduced by the concurrent use of penicillins. The bactericidal effect of penicillins can be hindered by concurrent administration of products with bacteriostatic effects, for instance erythromycin and tetracyclines.

• Concurrent treatment with valproic acid, valproate/other medication liberating pivalic acid is to be be avoided due to the increased risk of carnitine depletion.

The following are the side effects involving Pivmecillinam :

• Nausea
• Diarrhea

• Pregnancy

Category B

The clinical data on pregnant women whihc is more than 1000 pregnancy outcomes, indicates that no malformative nor feto/neonatal toxicity of pivmecillinam. Pivmecillinam can be used in pregnancy if clinically needed.

• Lactation

It was found that at therapeutic doses of Pivmecillinam no effects on breastfed newborns/infants are anticipated. Pivmecillinam can be used during breastfeeding.

• Pediatric

Children above > 6 years and weighing > 40 kg: 20-40 mg/kg/day divided into 3 doses with a

maximum of 1200 mg per day. The recommended duration of treatment is 3-7 days.

• Geriatric

Renal excretion of mecillinam is found to be delayed in the elderly, but the significant accumulation pivmecillinam is not likely at the recommended adult dosage of the drug Pivmecillinam, hence dosage adjustment is not necessary.

Physicians should be knowledgeable and vigilant about the treatment and identification of overdosage of Pivmecillinam.

There is no experience of overdosage with Pivmecillinam (pivmecillinam hydrochloride) tablets.

However, excessive doses of Pivmecillinam are likely to induce nausea, vomiting, abdominal pain, and diarrhea.

Pharmacodynamics

Pivmecillinam is a pivaloyloxymethyl ester of amdinocillin that is well absorbed orally but broken down to amdinocillin in the intestinal mucosa. It is active against gram-negative organisms and is used for amdinocillin.

Pharmacokinetics

• Absorption, Distribution, and Biotransformation:

Following oral administration of 200 mg and 400 mg pivmecillinam, peak mecillinam concentrations of approximately 1.5 µg/mL and three µg/mL, respectively, are attained within 1-1½ hours after dosing. The Bioavailability of orally administered pivmecillinam is found to be approximately 60-70%. The bioavailability of pivmecillinam is not affected by taking tablets with food.

• Elimination:

The elimination half-life of mecillinam is foudn to be about 1 hour. Pivmecillinam is excreted primarily in the urine with some biliary excretion. Mecillinam is largely excreted by the kidneys by filtration as well as active tubular secretion. Probenecid, which is said to inhibit tubular secretion, also inhibits the elimination of mecillinam. Approximately 60-70% of the mecillinam reaching the systemic circulation is found to be excreted unchanged in urine, almost all within the first six hours after dosing, resulting in urine concentrationsmore than 200 mg/L after oral administration of a 400 mg tablet.

• https://go.drugbank.com/drugs/DB01605
• https://www.mims.com/malaysia/drug/info/pivmecillinam?mtype=generic
• https://pdf.hres.ca/dpd_pm/00044078.PDF
• https://www.medicines.org.uk/emc/product/4982/smpc#gref
• https://file.wuxuwang.com/hma/FI_H_0696_002_FinalSPC.pdf
• https://www.netdoctor.co.uk/medicines/infection/a8150/Pivmecillinam-pivmecillinam/
• https://www.drugs.com/international/pivmecillinam.html