Pivmecillinam Hydrochloride (Monograph)

Drug class: Aminopenicillins

Medically reviewed by Drugs.com on Jul 10, 2024. Written by ASHP.

Introduction

Pivmecillinam hydrochloride is a penicillin class antibacterial. Pivmecillinam is a pro-drug of mecillinam (the active antibacterial moiety).

Uses for Pivmecillinam Hydrochloride

Pivmecillinam Hydrochloride has the following uses:

Pivmecillinam hydrochloride is indicated for the treatment of female patients 18 years of age and older with uncomplicated urinary tract infections (uUTI) caused by susceptible isolates of Escherichia coli, Proteus mirabilis and Staphylococcus saprophyticus.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of pivmecillinam and other antibacterial drugs, pivmecillinam should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

Pivmecillinam Hydrochloride Dosage and Administration

General

Pivmecillinam hydrochloride is available in the following dosage form(s) and strength(s):

Tablets: 185 mg of pivmecillinam

Dosage

The recommended dosage of pivmecillinam in female patients ≥18 years of age with uncomplicated urinary tract infections (uUTI) caused by susceptible isolates of Escherichia coli, Proteus mirabilis and Staphylococcus saprophyticus is one 185-mg tablet orally 3 times a day for 3 to 7 days as clinically indicated. Administer pivmecillinam with or without food.

Cautions for Pivmecillinam Hydrochloride

Contraindications

• Patients who have experienced a serious hypersensitivity reaction (e.g., anaphylaxis or Stevens-Johnson syndrome) to pivmecillinam hydrochloride or other beta-lactam antibacterial drugs (e.g., penicillins and cephalosporins).

• Patients with primary or secondary carnitine deficiency resulting from inherited disorders of mitochondrial fatty acid oxidation and carnitine metabolism, and other inborn errors of metabolism (e.g., methylmalonic aciduria, or propionic acidemia).

• Patients suffering from porphyria as pivmecillinam has been associated with acute attacks of porphyria.

Warnings/Precautions

Warnings

Hypersensitivity Reactions

Serious hypersensitivity reactions (anaphylaxis) have been reported in patients treated with pivmecillinam hydrochloride. These reactions are more likely to occur in individuals with a history of penicillin, cephalosporin, or carbapenem hypersensitivity or a history of sensitivity to multiple allergens. Before initiating therapy with pivmecillinam, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, carbapenems, and other beta-lactams because cross-hypersensitivity has been reported. Pivmecillinam is contraindicated in patients who have experienced a serious hypersensitivity reaction. If an allergic reaction occurs, discontinue the drug and institute appropriate therapy.

Severe Cutaneous Adverse Reactions

Severe Cutaneous Adverse Reactions (SCAR) including Acute Generalized Exanthematous Pustulosis (AGEP), Drug Reactions with Eosinophilia and Systemic Symptoms (DRESS), Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) have been reported with pivmecillinam. Monitor patients closely and discontinue the drug at the first signs or symptoms of SCAR or other signs of hypersensitivity.

Carnitine Depletion

Clinical manifestations of carnitine depletion may occur with pivalate-containing compounds, including pivmecillinam. Symptoms of carnitine depletion include hypoglycemia, muscle aches, fatigue, and confusion. Pivmecillinam is contraindicated in patients with primary or secondary carnitine deficiency due to inherited metabolic disorders known to cause carnitine depletion.

No clinical effects of decreased carnitine have been associated with short-term treatment of pivmecillinam. Clinically significant hypocarnitinemia has been observed in patients receiving long term treatment with the drug. Pivmecillinam is not recommended when prolonged antibacterial treatment is necessary. The effects on carnitine concentrations of repeated short-term courses of pivmecillinam are not known. In patients at risk for reductions in serum carnitine (e.g., patients with significant renal impairment or decreased muscle mass), consider alternative antibacterial therapies. Avoid concurrent treatment with valproic acid, valproate or other pivalate-generating drugs due to increased risk of carnitine depletion.

Acute Porphyria

Pivmecillinam is contraindicated in patients suffering from porphyria as the drug has been associated with acute attacks of porphyria. These episodes may be life-threatening, and include symptoms and signs such as anxiety, confusion, limb or abdominal pain, hyponatremia, seizures, and muscle weakness.

Clostridioides difficile-Associated Diarrhea

Clostridioides difficile-associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial agents, including pivmecillinam, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial drugs alters the normal flora of the colon and may permit overgrowth of C. difficile.

C. difficile produces toxins A and B that contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary because CDAD has been reported to occur over 2 months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplement, antibacterial drug treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Development of Drug-Resistant Bacteria

Prescribing pivmecillinam in the absence of a proven or strongly suspected bacterial infection or for prophylaxis is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Interference with Newborn Screening Test

Treatment of a pregnant individual with pivmecillinam prior to delivery may cause a false positive test for isovaleric acidemia in the newborn as part of newborn screening. Prompt follow-up of a positive newborn screening result for isovaleric acidemia is recommended.

Specific Populations

Pregnancy

Published observational studies on pivmecillinam use during the first trimester do not indicate an increased risk of major birth defects. There are limited studies on pivmecillinam use during pregnancy that evaluate the risk of miscarriage and other adverse maternal or fetal outcomes. These studies have methodological limitations hindering interpretation. No dose adjustment is required in pregnant women.

Developmental toxicity studies with pivmecillinam or mecillinam administered during organogenesis to rats and mice showed no evidence of embryo-fetal toxicity, including drug-induced fetal malformations, at doses approximately 3.4 or 7.9 times (rats) or 5.1 or 3.9 times (mice) higher than given to patients receiving the maximum recommended daily dose. Evidence of slight fetotoxicity (reduced ossification) was seen in offspring of rats that were given pivmecillinam during organogenesis at a dose approximately 10.2-fold higher than the maximum recommended daily human dose.

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Treatment of a pregnant individual with pivmecillinam prior to delivery may cause a false positive test for isovaleric acidemia in the newborn as part of newborn screening.

Lactation

There are insufficient data to exclude the presence of mecillinam in human milk. Mecillinam is present in animal milk. When a drug is present in animal milk, it is likely to be present in human milk. There are pharmacovigilance reports of adverse reactions with mecillinam exposure in breastfed infants, including rash and diarrhea. There are no data on the effects of mecillinam on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother`s clinical need for pivmecillinam and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition.

In a study of lactating cows given 8 mg/kg mecillinam IV, the concentration in milk was 0.1 and 0.7 μg/mL at 2 and 6 hours, respectively, and the total excretion in milk over the first 6 hours was 0.03% of the injected dose. The concentration of mecillinam in animal milk does not necessarily predict the concentration of drug in human milk.

Pediatric Use

The safety and effectiveness of pivmecillinam have not been established in pediatric patients.

Symptomatic hypocarnitinemia has been reported in pediatric patients outside the US on long term pivmecillinam therapy. In these cases, irritability, altered mental status, fatigue, muscle weakness, and vomiting have been observed. Pivmecillinam is not recommended when prolonged antibacterial treatment is necessary. Pivmecillinam is contraindicated in patients with primary or secondary carnitine deficiency.

Newborns exposed to pivmecillinam in utero prior to delivery may have a false positive newborn screening test for isovaleric acidemia. Prompt follow-up of a positive newborn screening result for isovaleric acidemia is recommended.

Geriatric Use

Of the total number of pivmecillinam-treated patients in the clinical trials evaluated for safety, 80/579 (14%) were 65 years of age and older, and 48/369 (13%) were 65 years of age and older in the pivmecillinam-treated patients evaluated for efficacy. A total of 19/579 (3%) of the pivmecillinam-treated patients evaluated for safety were 75 years of age and older and 12/369 (3%) were 75 years of age and older in the pivmecillinam-treated patients evaluated for efficacy.

No overall differences in safety or effectiveness of pivmecillinam have been observed between patients 65 years of age and older and younger adult patients.

Mecillinam pharmacokinetics data from geriatric patients are not available. pivmecillinam is known to be substantially excreted by the kidneys, and geriatric patients are anticipated to have reduced renal function. The clinical significance of these changes on efficacy or safety is unknown. The available safety information does not suggest a need for dosage adjustment.

Renal Impairment

Reductions in systemic elimination as well as urinary excretion of mecillinam are anticipated with decreases in renal function. The clinical significance of these changes on efficacy is unknown. The available safety information does not suggest a need for dosage adjustment.

Common Adverse Effects

The most common adverse reactions observed in ≥2% of the patients receiving pivmecillinam hydrochloride in clinical trials are nausea and diarrhea.

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Other Pivalate-Generating Drugs

Avoid concurrent treatment with valproic acid, valproate, or other pivalate-generating drugs. If concomitant use with pivmecillinam is necessary, counsel patients to monitor adverse reactions associated with carnitine depletion (e.g., hypoglycemia, muscle aches, fatigue, and confusion).

Pivmecillinam is a pivalate-generating prodrug. Pivalate can be activated to a coenzyme-A thioester in cells which is further converted to pivaloylcarnitine and excreted in urine. Pivalate elimination associated with concomitant use of pivmecillinam with other pivalate-generating drugs decreases carnitine concentrations in plasma which may increase the risk of carnitine depletion-associated adverse reactions.

Methotrexate

Clearance of methotrexate from the body can be reduced by concurrent use of drugs in the penicillin class, including pivmecillinam hydrochloride. Where possible, consider alternative therapy.

Drug Interference with Newborn Screening Test

Treatment of a pregnant individual with pivmecillinam hydrochloride prior to delivery may cause a false positive test for isovaleric acidemia in the newborn as part of newborn screening. Prompt follow-up of a positive newborn screening result for isovaleric acidemia is recommended.

Actions

Mechanism of Action

Pivmecillinam is the pro-drug containing the pivaloyloxymethylester of the amidinopenicillanic acid, mecillinam. Orally administered, pivmecillinam is well absorbed and subsequently rapidly hydrolyzed to mecillinam, the active antibacterial agent, by non-specific esterases present in blood, GI mucosa and other tissues. Mecillinam is a beta-lactam antibacterial drug with a targeted spectrum of activity. It is mainly active against gram-negative bacteria and works by interfering with the biosynthesis of the bacterial cell wall. Unlike the majority of other beta-lactam agents, which preferentially bind gram-negative PBP-1A, -1B or -3, mecillinam exerts high specificity against penicillin-binding protein-2 (PBP-2) in the gram-negative cell wall.

Pivmecillinam has been shown to be active against most isolates of the following microorganisms both in vitro and in clinical infections: Escherichia coli, Proteus mirabilis, and Staphylococcus saprophyticus. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for pivmecillinam against isolates of similar genus or organism group. However, the efficacy of pivmecillinam in treating clinical infections caused by these bacteria has not been established in adequate and well-controlled clinical trials: Citrobacter freundii, Enterobacter cloacae, Klebsiella pneumoniae, Klebsiella aerogenes, and Klebsiella oxytoca.

Mecillinam demonstrated in vitro activity against Enterobacterales in the presence of some beta-lactamases and extended-spectrum beta-lactamases (ESBL) of the following groups: CTX-M, SHV, TEM and AmpC. The inhibitory action of mecillinam on PBP-2 results in low cross-resistance with certain beta-lactams.

Advice to Patients

• Advise patients that allergic reactions, including serious allergic reactions, could occur with pivmecillinam and that serious reactions require immediate treatment. Ask patients about previous hypersensitivity reactions to penicillins, cephalosporins, carbapenems, and other beta-lactam antibacterials. Advise the patient to call their healthcare provider immediately if they develop a new rash, urticaria, drug eruptions, swelling of the face, difficulty in breathing or other symptoms of allergic reactions.

• Advise patients about the signs and symptoms of severe cutaneous adverse reactions. Advise the patient to discontinue pivmecillinam if they develop any type of skin rash, mucosal lesions or any other sign of hypersensitivity and to seek immediate medical attention.

• Advise patients to avoid use of valproic acid, valproate or other pivalate-generating drugs due to increased risk of carnitine depletion.

• Counsel patients that diarrhea is a common problem caused by antibacterial drugs, including pivmecillinam, and it usually ends when the drug is discontinued. Sometimes after starting treatment with antibacterial drugs, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as 2 or more months after taking the last dose of the drug. Advise patients to seek medical attention as soon as possible if this occurs.

• Patients should be counseled that antibacterial drugs including pivmecillinam should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When pivmecillinam is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by pivmecillinam or other antibacterial drugs in the future.

• Advise patients that treatment of a pregnant individual with pivmecillinam prior to delivery may cause a false positive test for isovaleric acidemia in the newborn as part of newborn screening and prompt follow-up of a positive result is recommended.

• If a dose of pivmecillinam is missed, instruct patients to take the dose as soon as possible. Instruct patients not to double the dose to make up for the missed dose.

Additional Information

AHFSfirstRelease™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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