These drugs don’t mix with antibiotics

By Naveed Saleh, MD, MS, for MDLinx
Published August 16, 2019

Key Takeaways

The FDA typically approves about 30 new drugs a year. In 2017, however, a high-water mark was set when 46 medications came to market—setting a record for the previous 21 years. That same year, the European Union approved a whopping 92 medicines—an increase from 81 drugs in 2016.

Although physicians are often alerted of potential drug-drug interactions, the sheer number of drugs out there can make it nearly impossible to remember all of them (most of them? some of them?), and often requires reference. So, it’s a good idea to review the potential for interactions with commonly prescribed drugs, such as antibiotics.

Here are six classes of antibiotic drugs that can interact dangerously with other drugs.


In general, penicillins should not be taken with methotrexate, a disease-modifying antirheumatic drug used to treat psoriasis, rheumatoid arthritis, and some types of malignancy. Penicillin antibiotics decrease the ability of the kidneys to clear methotrexate from the body, leading to nausea, stomach pain, yellowing of the eyes or skin, dark urine, fever, fatigue, and a host of other negative side effects that require immediate medical attention. Of note, some members of the penicillin family, such as amoxicillin, can be safely combined with methotrexate.

When combined with allopurinol, a drug used to treat gout, amoxicillin can result in allopurinol hypersensitivity syndrome, which is marked by rash, fever, and internal organ involvement that can last 2 to 6 weeks. This concerning side effect most commonly presents in patients with chronic renal insufficiency due to the buildup of allopurinol. Physicians should avoid prescribing amoxicillin to any patient with a previous history of hypersensitivity to allopurinol.


Cephalosporins possess inherent anticoagulant properties that can increase bleeding risk in those taking warfarin. If a patient needs these antibiotics, increased warfarin monitoring or dose adjustment may be required. Other antibiotics that potentiate the effects of warfarin include clarithromycin, erythromycin, metronidazole, and trimethoprim-sulfamethoxazole. These effects take about a week to kick in.


Various agents can lower the absorption on fluroquinolones, thus decreasing their effect. Many of these agents are available in over-the-counter supplements, including divalent cations (calcium and magnesium) and trivalent cations (aluminum and ferrous sulfate), which combine to create insoluble complexes in the intestines. These ions can be found in over-the-counter zinc supplements, multivitamins, and antacids.

Here is a list of other drugs that don’t mix well with fluoroquinolones:

  • Theophylline
  • Ropinirole
  • Probenecid
  • Tizanidine
  • Glibenclamide
  • NSAIDs
  • Cyclosporine
  • Cisapride
  • Tricyclic antidepressants
  • Steroids


Some researchers have suggested that macrolides can cause heart problems, while others have shown that such concerns about macrolides causing cardiotoxicity may be overblown.

For instance, according to the authors of systematic review published in Die Pharmazie in 2010: “Macrolides may induce cardiotoxicity themselves when used alone. When co-administered, they may also increase the risk of other drugs that potentially prolong the QTc interval or induce Tdp. Therefore, early and correct adjustment of the dosage, close daily ECG monitoring and the avoidance of co-administration of other known QT-prolonging agents should be used in order to prevent the development of adverse effects.”

Now, here’s what the investigators of a more recent study published in the Journal of the American Heart Association concluded: “Controlling for covariates explains much of the adverse cardiac risk associated with antimicrobial use found in other studies. Most antimicrobials are not associated with risk of cardiac events, and others, specifically azithromycin and clarithromycin, may pose a small risk of certain cardiac events. However, the modest potential risks attributable to these antimicrobials must be weighed against the drugs’ considerable and immediate benefits.”

To be on the safe side, it’s probably best that patients avoid taking the following drugs with macrolides:

  • Terfenadine, astemizole, and mizolastine
  • Tolterodine
  • Amisulpride
  • Statins


Because the body does not metabolize aminoglycosides, aminoglycoside activity is unchanged by the induction or inhibition of metabolic enzymes, such as those in the cytochrome P450 system. Certain medications may increase the risk of renal toxicity with aminoglycoside use, including:

  • Diuretics
  • Radiographic contrast exposure
  • ACE inhibitors
  • NSAIDs
  • Cisplatin
  • Amphotericin

All physicians are aware that aminoglycosides can lead to ototoxicity. And as mentioned, they also can cause renal toxicity. Although ototoxicity in these cases is usually permanent, nephrotoxicity can be reversed. Although rare, other adverse effects of these antibiotics include neuromuscular blockade and hypersensitivity reactions.


Rifampicin and rifabutin can decrease the efficacy of oral contraceptive pills. To avoid unintended pregnancy, condom use in conjunction with birth control is advised.


Finally, although not a medication in the traditional sense, alcohol and antibiotics usually make bad bedfellows. For instance, drinking alcohol while on metronidazole or tinidazole can result in symptoms that resemble a mega-hangover, such as hot flashes, stomach pain, and headaches.

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