Think twice before you prescribe these common medications

American physicians are overprescribing antibiotics. The CDC estimates that about 47 million antibiotic courses are prescribed annually for infections that don’t require antimicrobial therapy. That’s a whopping 30% of antibiotic prescriptions that are deemed unnecessary. These statistics point to much-needed restraint of prescribing practices in the clinic and emergency room.

One obvious consequence of antibiotic over-prescription is drug resistance, which the CDC addresses in an updated report, Antibiotic Use in the United States, 2020 Update: Progress and Opportunities. But in addition to drug resistance, which is a public-health crisis, antibiotics can lead to numerous adverse effects, and unintended consequences—some of which can be deadly.

Let’s consider some commonly prescribed antibiotics, and their potential adverse effects.

Penicillin V potassium

This β-lactam antibiotic is used to treat pneumonia or other types of upper respiratory reaction; ear, skin, gum, mouth, and throat infections; and scarlet fever. It can also be used to prevent rheumatic fever, which is a complication of strep throat that causes inflammation of the heart valves. Intriguingly, it can also be used to treat anthrax and diphtheria infections, as well as providing prophylaxis to prevent heart-valve damage secondary to dental procedures.

In addition to allergic reactions, Penicillin V can result in nausea, vomiting, diarrhea, abdominal pain, black hairy tongue, and vulvovaginal disorders.

The efficacy of β-lactam antibiotics depends on their time above minimum inhibitory concentration (MIC) of the unbound drug concentration in the blood, which is dosage related. In an article published in BMJ, experts recommend a dosage of 800 mg four times a day (16 g total) compared with 1,000 mg three times daily (30 g total) to attain MIC. Lower dosages, however, could lead to fewer adverse effects, improved adherence, lower impact to the microbiota, lower antibiotic burden in the community, and lower cost. But will a smaller dosage cure bacterial infections?  

In a clinical trial involving 433 patients aged 6 years and older with pharyngotonsillitis caused by group A streptococci, As reported in the BMJ article, researchers compared the effects of these different regimens. The primary outcome was a clinical cure exhibited at 5 to 7 days following the conclusion of antibiotic treatment.

The researchers found that the cure rate was 89.6% in the 5-day group and 93.3% in the 10-day group. Furthermore, bacteriological eradication was 80.4% in the 5-day group vs 90.7% in the 10-day group. Patients in the 10-day group experienced a greater number of negative side effects for an extended duration and took longer to feel relief from symptoms.

“Penicillin V four times daily for five days was non-inferior in clinical outcome to penicillin V three times daily for 10 days in patients with pharyngotonsillitis caused by group A streptococci,” the authors wrote. “The number of relapses and complications did not differ between the two intervention groups. Five day treatment with penicillin V four times daily might be an alternative to the currently recommended 10 day regimen.”

Cephalosporins

Cephalosporins are antimicrobials categorized into five generations, with robust coverage against gram-negative and gram-positive bacteria. Broad coverage makes them useful in combating a wide variety for infections including skin/soft tissue, respiratory, central nervous system, and blood.

In general, cephalosporins have few adverse effects and are safe. The most common adverse reactions are nausea, vomiting, abdominal pain, and anorexia. Although less likely, other adverse reactions include hypersensitivity, disulfiram-like reaction when combined with alcohol, vitamin K deficiency, drug-induced nephrotoxicity when taken with aminoglycosides, and pseudomembranous colitis.

This drug can also cause drug-induced immune hemolytic anemia (DIIHA), a condition that doesn’t harm the red blood cells unless the patient starts to make IgG antibodies against the drug. With DIIHA, the antibody will bind red blood cells, thus resulting in hemolysis. Cefotetan and ceftriaxone are the most common types of cephalosporin to cause DIIHA.

One particularly concerning adverse effect of cephalosporins that is widely under-recognized is their potential to cause deadly central nervous system reactions, according to the authors of a retrospective study published in the Journal of Neurological Sciences. These effects can be neurological or psychiatric and include encephalopathy, confusion, convulsion, myoclonia, status epilepticus, coma, and hallucinations. Chief offenders included  cefepime, ceftriaxone, ceftazidime, cefotaxime, and cefazolin, which were mostly administered intravenously.

“[I]t would be relevant to warn healthcare professionals. Investigations (EEG, though plasma levels and renal function) can be precious tools for clinicians to make a prompt diagnosis and improve patients' outcomes,” the authors concluded.

Aminoglycosides

Aminoglycosides are potent, broad-spectrum antibiotics that inhibit protein synthesis, and have been a key player in antimicrobial therapy ever since streptomycin was first used in the 1940s. Other aminoglycosides that subsequently came to market included neomycin, kanamycin, gentamicin, netilmicin, and tobramycin. 

The introduction of third-generation cephalosporins, carbapenems, and fluoroquinolones in the 1980s led to a shift away from aminoglycoside use, because these other drugs were viewed as less toxic with broader coverage. Increasing resistance to these agents, as well as a better understanding of aminoglycoside resistance, has led to renewed interest in aminoglycosides, with the development of new aminoglycosides such as arbekacin and plazomicin. These newer agents have proven useful in fighting multidrug-resistant pathogens—especially in combination with other antimicrobial agents.

Common adverse effects of aminoglycosides include ototoxicity, nephrotoxicity, and neuromuscular blockade, with patients advised to look out for associated symptoms. Ototoxicity is of major concern and affects 2%-45% of adults. This ototoxicity is dose-dependent and can be either vestibular or cochlear in nature. Specifically, gentamicin, streptomycin, and tobramycin are more apt to result in vestibular damage, and amikacin more likely results in cochlear damage.

According to the research, such ototoxicity is likely induced by the formation of reactive oxygen species [ROS] within the inner ear, which causes damage to vestibular and cochlear sensory cells, as well as cochlear neurons. Although vestibular loss is usually reversible, hearing loss is usually permanent, thus there’s been much interest in preventing this dreaded consequence of aminoglycoside use.

According to the authors of a review published in Frontiers in Cellular Neuroscience, “Aside from drug monitoring, efforts aimed at preventing aminoglycoside ototoxicity have focused on mitigating the damage effects of ROS [reactive oxygen species] since in vivo and in vitro studies show ROS production in cochlear hair cells following aminoglycoside treatment. Protection against aminoglycoside ototoxicity has also been demonstrated by a wide array of antioxidants (eg, lipoic acid, Coenzyme Q10, N-acetylcysteine, vitamin E and salicylates).” 

They added, “A growing number of reports indicate that the mechanism of ROS generation and the role of ROS in aminoglycoside induced cell death may be more complicated than initially proposed. For example, in vitro experiments show the depletion of glutathione (a major ROS scavenger) does not increase susceptibility to aminoglycoside induced cell death suggesting alternate roles for ROS.”

Macrolides

Erythromycin, roxithromycin, azithromycin, and clarithromycin are all macrolides and useful in treating skin/soft tissue, respiratory, sexually transmitted, H. pylori, and atypical mycobacterial infections. These drugs share a similar spectrum of antimicrobial activity to penicillins and make good alternatives to β-lactam in people who are allergic. Of note, bacteria are often cross-resistant to penicillins and macrolides. These drugs also have immunomodulatory and anti-inflammatory effects, making them useful in the treatment of conditions including cystic fibrosis.

The most common negative side effects of macrolides include abdominal discomfort, cramps, nausea, vomiting, and diarrhea. Of note, erythromycin ethyl succinate has a lower frequency of gastrointestinal adverse effects than do other forms of erythromycin. Increasing the number of doses per day may alleviate gastrointestinal distress.

In a population-based study published in the BMJ, researchers examined the correlation between macrolide prescription during pregnancy and major malformations, cerebral palsy, epilepsy, attention deficit hyperactivity disorder, and autism spectrum disorder in children. Their results were troubling, and point to the potential teratogenic effects of macrolides.

“Prescribing macrolide antibiotics during the first trimester of pregnancy was associated with an increased risk of any major malformation and specifically cardiovascular malformations compared with penicillin antibiotics,” the authors concluded. “Macrolide prescribing in any trimester was associated with an increased risk of genital malformations. These findings show that macrolides should be used with caution during pregnancy and if feasible alternative antibiotics should be prescribed until further research is available.” 

Clindamycin

Clindamycin belongs to a class of medications called lincomycin antibiotics and is usually bacteriostatic, but at higher concentrations is bactericidal. This antibiotic is active against gram-positive bacteria and anaerobic organisms. It is used to treat infections of the lungs, skin, female reproductive organs, and internal organs.

Adverse effects of clindamycin include vomiting, nausea, joint pain, heartburn, odynophagia, and vaginal discharge. More serious adverse effects include blistering skin, difficulty breathing or swallowing, decreased urination, and swelling of the face, tongue, lips, arms.

Of particular concern, clindamycin has been closely linked with resistant strains of Clostridium difficile in hospitalized patients. In a large study examining adverse effects of clindamycin administration in postpartum patients, researchers found that this agent prescribed for conditions such as postpartum endometriosis not only increased the relative risk of C. difficile infection but also acute kidney injury (although absolute risk was still low).