Antibiotics are medicines used to prevent and treat bacterial infections. They work by killing bacteria or preventing them from multiplying. Choosing the right antibiotic to treat an infection is important. You want one that targets the specific bacteria causing the infection, without causing significant side effects. The strongest antibiotics are usually reserved for serious bacterial infections that are resistant to other antibiotics. They are often broader spectrum, meaning they target a wide range of bacteria, but that also increases the risk of side effects. Let’s discuss the strongest antibiotics available and when they may be used.
Penicillins
Penicillin was the first antibiotic discovered in 1928 by Alexander Fleming. It is in a class of antibiotics called beta-lactams, which work by interfering with the synthesis of the bacterial cell wall, causing the wall to weaken and bacteria to burst. Penicillins are bactericidal, meaning they kill bacteria. There are several types of penicillins, including:
- Natural penicillins: penicillin G and penicillin V, effective against gram-positive, gram-negative, spirochete and anaerobic bacteria. Often used for skin infections, respiratory infections, anthrax, syphilis.
- Antistaphylococcal penicillins: methicillin, nafcillin, oxacillin, cloxacillin. Effective against staph bacteria resistant to penicillin.
- Aminopenicillins: ampicillin and amoxicillin, with broader spectrum against some gram-negative bacteria. Used for sinus, skin, urinary tract infections.
- Antipseudomonal penicillins: carboxypenicillins like ticarcillin and ureidopenicillins like piperacillin, effective against Pseudomonas aeruginosa.
Some of the strongest penicillins include carbenicillin, ticarcillin, and piperacillin. They have an extended spectrum against Pseudomonas aeruginosa and other resistant gram-negative bacteria. However, widespread use promotes development of resistant bacteria.
Side Effects of Penicillins
Common side effects of penicillins include nausea, vomiting, diarrhea, fungal infections, and allergic reactions like rash, hives, swelling, and anaphylaxis. The incidence of serious allergic reaction is around 1-10%. Penicillins are generally safe for most people when used appropriately.
Cephalosporins
Cephalosporins are beta-lactam antibiotics closely related to penicillins. They interfere with bacterial cell wall synthesis, causing cell lysis and death. Cephalosporins are broadly classified by generation based on spectrum of activity:
- First generation: cefazolin, cephalexin. Effective against gram-positives like Staph, Strep, limited gram-negative activity.
- Second generation: cefuroxime, cefoxitin. Added activity against more gram-negatives like E. coli, Klebsiella, Proteus.
- Third generation: cefotaxime, ceftazidime, ceftriaxone. Even greater gram-negative coverage against Pseudomonas, Enterobacter.
- Fourth generation: cefepime, with broader gram-positive and -negative activity.
- Fifth generation: ceftaroline. Active against MRSA (methicillin-resistant Staph aureus).
The later generation cephalosporins have expanded gram-negative coverage, however also promote more antibiotic resistance. Ceftazidime or cefepime may be used for serious Pseudomonas infections like hospital-acquired pneumonia. Ceftaroline treats MRSA infections.
Side Effects of Cephalosporins
Common side effects of cephalosporins are similar to penicillins, including diarrhea, nausea, rash, allergic reaction. About 1-3% of patients experience hypersensitivity reactions. Cephalosporins are relatively safe antibiotics, although increased generation tends to cause more adverse effects.
Carbapenems
Carbapenems are a class of beta-lactam antibiotics with a broad spectrum of antibacterial activity. They have a unique structure that makes them resistant to breakdown by most beta-lactamase enzymes produced by some bacteria. This allows them to remain effective against certain resistant bacteria. Examples of carbapenems include:
- Imipenem
- Meropenem
- Ertapenem
- Doripenem
Imipenem and meropenem have the strongest activity against both gram-positive and gram-negative bacteria, including Pseudomonas, Acinetobacter, and Enterobacter. They can only be given intravenously. Ertapenem is administered intravenously or intramuscularly, with activity against gram-negatives like E. coli and anaerobes. Doripenem also covers Pseudomonas.
Carbapenems penetrate the central nervous system and are used for bacterial meningitis. They are often reserved as last-line therapy for multidrug-resistant infections when other antibiotics have failed.
Side Effects of Carbapenems
Carbapenems commonly cause nausea, diarrhea, rash, and infusion-related reactions. About 2% of patients experience allergic reactions, which are more common in those with penicillin allergies. Overuse of carbapenems has led to increasing resistance. They should be limited to highly resistant infections when needed.
Aminoglycosides
Aminoglycosides like gentamicin, tobramycin, and amikacin are very potent, broad spectrum antibiotics. They inhibit bacterial protein synthesis, stopping growth. Aminoglycosides have bactericidal activity against both gram-positive and gram-negative bacteria, including Pseudomonas, Acinetobacter, and Enterococci. The exact mechanism of aminoglycoside uptake into bacterial cells is not fully understood. They are used to treat a variety of infections:
- Serious Pseudomonas infections – pneumonia, sepsis
- Enterococcal endocarditis
- Gram-negative bacteremia and sepsis
- Urinary tract infections resistant to other antibiotics
- Intra-abdominal infections
However, aminoglycosides can only be given intravenously and penetrate tissues poorly. They are often combined with another antibiotic like penicillins or cephalosporins for synergistic effect. The addition of aminoglycosides also prevents the development of resistant bacterial mutants during therapy.
Side Effects of Aminoglycosides
Unfortunately, aminoglycosides carry the risk of kidney toxicity and permanent hearing loss. Kidney function must be monitored closely, and duration of therapy should be limited. Other side effects include dizziness, rash, and neuromuscular blockade. Due to their toxicities, aminoglycosides should only be used for specific resistant infections when necessary.
Glycopeptides
Glycopeptides like vancomycin and teicoplanin inhibit bacterial cell wall synthesis, with potent gram-positive coverage against Staphylococci, Streptococci, and Enterococci species. Vancomycin is considered a “drug of last resort”, reserved for serious infections not treatable with other antibiotics:
- Methicillin-resistant Staphylococcus aureus (MRSA)
- Multi-drug resistant Streptococcus pneumoniae
- Ampicillin-resistant enterococcal endocarditis
- Clostridium difficile colitis
Teicoplanin has a similar spectrum but is not available in the US, only in Europe. The efficacy of glycopeptides has been reduced over decades with increasing resistance. They must be given intravenously over prolonged courses which leads to side effects.
Side Effects of Glycopeptides
Up to 10% of patients on vancomycin experience side effects like fever, chills, rash, nausea, phlebitis, nephrotoxicity, and ototoxicity. Rapid infusion can cause “red man syndrome” – flushing, erythema, pruritus. Glycopeptides should be reserved for infections where needed to limit resistance and toxicity.
Oxazolidinones
Oxazolidinones like linezolid are a new class of synthetic antibiotics used for multi-drug resistant, gram-positive bacteria like MRSA, Streptococcus, and Vancomycin-resistant Enterococcus (VRE). Linezolid binds to bacterial ribosomes, inhibiting protein synthesis. It is bacteriostatic, meaning it stops bacterial growth but doesn’t actively kill bacteria. Linezolid is used to treat skin infections, pneumonia, and bacteremia when resistant to other antibiotics. Tedizolid is another newer oxazolidinone with once daily dosing.
Side Effects of Oxazolidinones
Potential side effects of linezolid include headache, diarrhea, nausea, and thrombocytopenia with prolonged use. There are significant drug interactions with serotonergic agents like SSRIs that can lead to serotonin syndrome. Resistance to linezolid is beginning to emerge as well. Nonetheless, oxazolidinones remain important antibiotics for VRE, MRSA, and resistant gram-positive infections.
Polymyxins
Polymyxins like polymyxin B and colistin are cationic polypeptide antibiotics that damage the outer cell membrane of gram-negative bacteria, leading to death. Polymyxins have activity against most gram-negative organisms including Pseudomonas, Acinetobacter, Klebsiella, and E. coli. Colistin is specifically used to treat multidrug-resistant Pseudomonas and Acinetobacter infections:
- Ventilator-associated pneumonia
- Bloodstream infections
- Urinary tract infections
- Meningitis
Colistin was discovered decades ago but fell out of favor due to high rates of nephrotoxicity and neurotoxicity. However, it has re-emerged given increasing gram-negative resistance. It remains a last-line drug for pan-resistant gram-negative bacteria when all other options have failed.
Side Effects of Polymyxins
Up to 60% of patients on polymyxin B or colistin therapy experience kidney damage. High rates of neurotoxicity are also seen, with reports of paresthesia, muscle weakness, and even paralysis. The use of polymyxins should be carefully considered given the potential for severe adverse effects.
Conclusion
When choosing an antibiotic to treat an infection, the key is to select the agent with the narrowest spectrum necessary to cover the most likely pathogens. Broad spectrum antibiotics like carbapenems, aminoglycosides, and polymyxins should be reserved for highly resistant infections unresponsive to other classes due to their potential for significant side effects and resistance. Culture data helps guide appropriate antibiotic selection. Duration of therapy should also be optimized to prevent overuse. With growing antimicrobial resistance, protecting the efficacy of our strongest antibiotics is crucial.
