Penicillin substitutes: safe alternatives when you're allergic or resistant

If you can't take penicillin because of allergy or resistance, there are several antibiotics your doctor can consider. The right choice depends on the infection type, local resistance patterns, and your medical history. Below I list common options, why doctors pick them, and what to watch for.

Common alternatives

Cephalosporins like cephalexin and cefixime are often used for respiratory, skin, and urinary infections. They work similarly to penicillin but many people who report a penicillin allergy can take them safely. Still, tell your clinician about any serious immediate reactions to penicillin — hives, swelling, or breathing trouble — because cross-reactions, while less common than once thought, can occur.

Macrolides such as azithromycin and erythromycin are a go-to when penicillin can’t be used for respiratory infections or certain sexually transmitted infections. Azithromycin is popular because of short courses and fewer stomach problems for many users. Be careful if you have heart rhythm issues or take medicines that affect heart rhythm — macrolides can change the heartbeat in some cases.

Tetracyclines including doxycycline are useful for skin infections, acne, and atypical pneumonias. They aren’t for children under eight or pregnant people because they affect bone and teeth development. Doxycycline also helps treat tick-borne infections and certain resistant bacteria.

Trimethoprim-sulfamethoxazole (co-trimoxazole) covers many skin and urinary pathogens and is often chosen for MRSA skin infections. Watch for allergy to sulfa drugs and interactions with blood thinners or diabetes medicines.

Clindamycin treats skin and soft tissue infections and works well when oral therapy is needed for anaerobic bacteria. It can cause diarrhea more often than some other options; report severe gut signs to your doctor.

Fluoroquinolones like levofloxacin and moxifloxacin are broad-spectrum and effective for many serious infections, but they carry higher risks — tendon problems, nervous system effects, and others — so doctors reserve them when other options are unsuitable.

How to choose and stay safe

Never pick an antibiotic yourself. A swab, urine test, or throat culture can guide the right drug and shorten therapy. If you have a listed allergy, ask if testing for penicillin allergy is an option — many people labeled allergic are actually tolerant. Tell your clinician about other medicines, kidney or liver issues, pregnancy, or breastfeeding; these change the safest choices.

Watch for allergic reactions, worsening symptoms, or severe side effects and seek care quickly. If you have recurrent infections, your provider may send a culture to check resistance and tailor treatment.

Finish the full course as prescribed even if you feel better quickly. Keep a written list of antibiotics and reactions in your phone or wallet. If you start new symptoms like severe rash, breathing problems, high fever, or belly pain, stop the drug and contact emergency care. Pharmacies can flag allergies — ask them to note your record. Always.