Mecillinam: Amidinopenicillin against gram-negative pathogens in urinary tract infections

Mecillinam (also amdinocillin) is a beta lactam antibiotic from the special class of amidinopenicillins. It was developed in Denmark in the 1970s and has a unique, very narrow spectrum of activity against Enterobacterales with particular affinity for Escherichia coli, the main causative agent of uncomplicated urinary tract infections. Mecillinam itself is available intravenously (Selexidin), while the oral form is used as pivmecillinam (Pivmelam, Selexid), a prodrug with significantly better oral bioavailability.

In Scandinavia, mecillinam or pivmecillinam has been standard therapy for acute uncomplicated cystitis for decades and has resulted in one of the lowest resistance rates of E. coli in urinary tract infections worldwide. With the reapproval of pivmecillinam in Germany in 2018, a highly effective narrow-spectrum antibiotic with low resistance pressure has also been introduced here, which is recommended as first-line therapy in current guidelines for uncomplicated cystitis.

Mechanism of action

Mecillinam is a beta lactam antibiotic with an atypical, highly selective binding to PBP2 (penicillin-binding protein 2) in gram-negative bacteria. PBP2 is responsible for maintaining the rod shape of bacteria. Selective inhibition leads to characteristic spherical deformation of the bacteria (osmotically unstable spheroplasts) followed by lysis.

This specific PBP2 binding distinguishes mecillinam from other beta lactams, which typically bind to multiple PBPs simultaneously. This results in a very narrow spectrum of activity covering almost exclusively Enterobacterales (E. coli, Klebsiella pneumoniae, Proteus mirabilis, Enterobacter, Citrobacter). Gram-positive bacteria including Staphylococcus saprophyticus (second most common UTI pathogen) are largely resistant. Pseudomonas aeruginosa, Enterococcus faecalis, and anaerobes are insensitive.

Mecillinam is renally excreted in high concentrations and accumulates in urine, which explains its antibacterial effect in the urinary tract. Pharmacokinetically, intravenous mecillinam is rapidly distributed with a half-life of approximately 1 hour, requiring frequent dosing. Pivmecillinam (oral prodrug) is hydrolyzed to mecillinam in the intestine.

Indications

• Acute uncomplicated cystitis in women: First-line therapy according to German S3 guideline 2017
• Acute uncomplicated pyelonephritis: in mild cases and confirmed susceptible pathogens
• Asymptomatic bacteriuria in pregnancy: safe option with extensive clinical experience
• Prophylaxis of recurrent urinary tract infections: off-label, at low dose
• Bacteriuria in diabetics: in symptomatic UTI

Mecillinam has a very narrow indication limited to urinary tract infections, as systemic concentrations are usually insufficient for other infections. This is an advantage in terms of antibiotic stewardship.

Dosage and administration

Pivmecillinam (oral prodrug, available in Germany): 400 mg three times daily over 3 days for acute cystitis. For pyelonephritis 400 mg three times daily over 7 to 14 days.

Mecillinam intravenously: not available in Germany, in Scandinavia 200 to 400 mg every 6 hours.

Administration: with sufficient water, with or without food. Take upright or sitting, as the tablet can cause esophageal irritation.

In renal insufficiency: at eGFR below 30 ml/min possibly reduced efficacy due to lower urine concentration; still often clinically effective, individual assessment required.

Duration of therapy: for uncomplicated cystitis only 3 days, which reduces resistance pressure and is highly effective.

Adverse effects

Common: generally well tolerated. Nausea, diarrhea, abdominal pain, rash, pruritus, vaginal candidiasis.

Occasional: vomiting, headache, allergic reactions, elevated liver transaminases.

Rare but important: anaphylactic reactions (beta lactam allergy), severe skin reactions (Stevens Johnson syndrome), Clostridioides difficile associated diarrhea, hypoglycemia and carnitine deficiency with long-term pivmecillinam therapy (through pivalate binding to carnitine), interstitial nephritis.

Important: mecillinam is contraindicated in known beta lactam allergy due to possible cross-reactivity. Carnitine deficiency is a specific adverse effect of pivalate binding in pivmecillinam, clinically relevant only with very prolonged use or in at-risk patients.

Drug interactions

• Probenecid: prolongs half-life by inhibiting renal tubular secretion
• Other beta lactam antibiotics: do not co-prescribe without indication
• Methotrexate: can reduce renal MTX clearance in high-dose therapy
• Hormonal contraceptives: theoretical reduction through microbiome changes, clinically of little relevance
• Valproic acid: pivalic acid binding to carnitine can lead to hyperammonemia

Special precautions

Pregnancy: Mecillinam and pivmecillinam are considered safe and are a preferred option in Scandinavian countries for acute cystitis and asymptomatic bacteriuria in pregnancy. Long clinical experience without evidence of teratogenicity. Breast-feeding: Use possible, minimal transfer into breast milk without clinical relevance for the infant.

Antibiotic stewardship: the narrow spectrum of activity and low resistance development make mecillinam an excellent antibiotic in stewardship terms. Fluoroquinolones and cephalosporins should be avoided if possible in uncomplicated cystitis.

Resistance situation: in Germany, E. coli resistance to mecillinam is currently below 5 percent, significantly better than fluoroquinolones (over 20 percent), cotrimoxazole (over 30 percent), or cefuroxime (approximately 10 percent).

In pyelonephritis: Mecillinam is effective in upper UTI, although levels in kidney tissue and blood are lower than in urine. In case of suspected urosepsis or severe disease, parenteral antibiotics with better tissue penetration are preferred.

You might also be interested in

• Pivmecillinam hydrochloride, the orally available prodrug
• Fosfomycin, another first-line therapy for cystitis
• Nitrofurantoin, classic UTI therapy
• Cotrimoxazole, alternative UTI therapy
• Ciprofloxacin, fluoroquinolone with reserved indication

Frequently asked questions

Sources

• AWMF S3 guideline uncomplicated urinary tract infections
• Gelbe Liste, Mecillinam and pivmecillinam active substance profile
• BfArM, Federal Institute for Drugs and Medical Devices
• EMA Technical information pivmecillinam products