Antibiotics: Understanding their Classifications

Antibiotics are classified into two primary categories based on their effects on bacteria: ^8,9  

• Bactericidal
• Bacteriostatic

Bactericidal drugs are designed to kill bacteria outright by inhibiting cell wall synthesis, disrupting bacterial enzymes, and interfering with protein translation processes, leading to cell death. Bacteriostatic antibiotics inhibit bacterial growth and reproduction without directly causing bacterial death. This is accomplished by inhibiting essential processes such as protein synthesis or deoxyribonucleic acid  (DNA) replication. By targeting these vital functions, bacteriostatic antibiotics prevent bacteria from proliferating and allow the body’s immune system to effectively eliminate the bacteria over time. However, this distinction is not absolute. In large concentrations, some bacteriostatic drugs may kill susceptible bacterial species, while certain bactericidal drugs may only inhibit the growth of some bacteria. Therefore, selection should not solely rely on whether the drug is bactericidal or bacteriostatic. It should prioritize factors such as the minimum bactericidal concentration (MBC), the lowest concentration of an antibiotic required to eradicate 99.99% of the bacterial population present, and the minimum inhibitory concentration (MIC), the lowest concentration of an antibiotic that inhibits visible growth of bacteria. Typically, bactericidal antibiotics are favored for severe infections, where rapid bacterial eradication is crucial, particularly in patients with compromised immune systems. Bacteriostatic antibiotics are commonly used to treat less severe infections, where slowing bacterial growth allows the body’s immune system to clear the infection.^1,8,9

Bactericidal Antibiotics that Inhibit Cell Wall Synthesis

Bactericidal antibiotics that inhibit cell wall synthesis prevent bacteria from constructing and maintaining a protective outer covering, compromising its integrity and eventually leading to bacterial death. Within this class, antibiotics are either beta-lactam or non-lactam. Beta-lactam antibiotics are those with a characteristic beta-lactam ring in their chemical structure. This ring binds to and inhibits the activity of enzymes, which are essential for bacterial cell wall synthesis. Beta-lactam antibiotics include penicillins, cephalosporins, monobactams, and carbapenems. Non-lactam antibiotics encompass a diverse range of antimicrobial agents that exhibit alternative mechanisms of action, such as inhibition of protein synthesis, nucleic acid synthesis, or disruption of bacterial cell membranes. While non-lactam antibiotics may not contain the characteristic beta-lactam ring, they are equally vital in treating bacterial infections and contribute to the diverse arsenal of antimicrobial agents available to healthcare providers. Non-lactam antibiotics include lipopeptides, lipoglycopeptides, glycopeptides, polypeptides, and phosphonates.^1,8,9

Beta-Lactam Bactericidal Antibiotics

Penicillin, discovered in 1929 and clinically introduced in 1943, represents the first natural antibiotics isolated. Derived from fungi, penicillin targets cell wall synthesis by binding to penicillin-binding proteins. Penicillins primarily target gram-positive bacteria and certain gram-negative cocci, proving effective against various infections, including syphilis, clostridial infections, and endocarditis. Penicillins such as amoxicillin and ampicillin extend their activity to include certain gram-negative bacilli and are used for urinary tract infections, meningitis, respiratory infections, and more. Penicillinase-resistant penicillins target resistant Staphylococcus aureus strains, while broad-spectrum penicillins address infections caused by Pseudomonas aeruginosa and other susceptible bacteria. For infections caused by bacteria that produce enzymes that render beta-lactam antibiotics ineffective, penicillins are often administered with beta-lactamase inhibitors like clavulanate or sulbactam. Despite their efficacy, penicillins should be used cautiously during pregnancy, weighing the benefits against potential risks. However, they are generally considered safe for use during breastfeeding.^1,10

Clinically introduced in 1964, cephalosporins are potent broad-spectrum antibiotics that target cell wall synthesis in a wide range of bacteria, including both gram-positive and gram-negative strains. Cephalosporins are categorized into different generations, each offering varying levels of activity and coverage against different bacterial species. First-generation cephalosporins are effective against gram-positive cocci and are commonly used for skin and soft-tissue infections. Second-generation cephalosporins and cephamycins target gram-positive cocci and certain gram-negative bacilli, while third generation cephalosporins are efficacious against haemophilus influenzae and enterobacterales. Fourth generation cephalosporins, like cefepime, combine enhanced activity against gram-negative bacilli with effectiveness against gram-positive cocci. A recent addition, 5th-generation cephalosporins such as ceftaroline and ceftobiprole, target methicillin-resistant S. aureus (MRSA) and certain strains of enterococcus faecalis. Although cephalosporins are generally safe during pregnancy with no significant fetal risks demonstrated, caution is advised during breastfeeding due to potential alterations in infant bowel microbiota.^1,11

Monobactams are a unique class of antibiotics, with aztreonam only available for clinical use. Discovered in 1981, aztreonam is derived from a synthetic molecule based on SQ 26,180 from chromobacterium violaceum. Monobactams target cell wall synthesis and are effective against specific gram-negative bacteria, including enterobacterales and pseudomonas aeruginosa, but not anaerobes or gram-positive bacteria. Typically, aztreonam is reserved for severe aerobic gram-negative infections, especially in patients with beta-lactam allergies who still require beta-lactam therapy. Their resistance to metallo-beta-lactamases adds therapeutic value in resistant infections. While cross-hypersensitivity is rare, caution is advised with ceftazidime and cefiderocol. During pregnancy, aztreonam use depends on the risk-benefit assessment. However, monobactams safety during breastfeeding is generally accepted. In renal failure, dosages need to be reduced.^1,12

Carbapenems, such as ertapenem, imipenem, and meropenem, are part of a class of antibiotics originally isolated from actinomycetes species. Discovered in 1976 and clinically introduced in 1985, they are potent broad-spectrum antibiotics that disrupt bacterial cell wall synthesis, making them effective against numerous bacteria, including challenging strains like Pseudomonas aeruginosa and Enterococcus faecalis. Administered via injection, carbapenems are often combined with aminoglycosides to enhance therapeutic outcomes. Imipenem is usually co-administered with cilastatin and sometimes relebactam to prolong its effectiveness. While structurally akin to penicillins, carbapenems may induce allergic reactions in individuals sensitive to penicillins. Common applications of carbapenems include treating severe infections like gangrene, sepsis, pneumonia, and abdominal and urinary tract infections, especially those caused by bacteria resistant to other antibiotics. Excluding ertapenem, these antibiotics are effective against pseudomonas and enterococcal infections. Although animal studies show no fetal harm, data on pregnant women are scarce. Carbapenems present in breast milk may affect the infant’s gut bacteria balance.^1,13,14

Non-Lactam Bactericidal Antibiotics

Glycopeptides are potent antibiotics derived from actinomycetes. Currently, vancomycin is the only glycopeptide available for clinical use. Glycopeptides target cell wall synthesis, particularly the D-Ala-D-Ala termini of lipid II and is effective against a broad range of gram-positive cocci and bacilli, including many strains of resistant staphylococcus aureus and coagulase-negative staphylococci. Vancomycin is primarily administered parenterally due to poor gastrointestinal absorption and is crucial for managing serious infections and endocarditis. However, its efficacy against methicillin-susceptible S. aureus is limited. Despite being an alternative for treating pneumococcal meningitis, its efficacy can be compromised due to inconsistent penetration into the cerebrospinal fluid. Vancomycin is also used orally for clostridioides difficile-induced diarrhea. While its use during pregnancy or breastfeeding is generally discouraged due to potential risks, vancomycin may be considered in certain situations where the benefits outweigh the drawbacks. However, its use during breastfeeding is discouraged due to potential adverse effects on the infant’s gastrointestinal microbiota.^1,15

Lipoglycopeptides are intravenous bactericidals that combat gram-positive bacteria by impeding cell wall synthesis and disrupting membrane integrity. Antibiotics in this category include dalbavancin, oritavancin, teicoplanin, and telavancin. Telavancin has a shorter half-life, while dalbavancin and oritavancin offer extended half-lives for single-dose regimens. Lipoglycopeptides target a broad spectrum of gram-positive bacteria, encompassing streptococci, enterococcus faecalis, enterococcus faecium, and methicillin-resistant or vancomycin-intermediate-resistant Staphylococcus aureus strains. Notably, oritavancin demonstrates efficacy against vancomycin-resistant enterococci harboring the vanA gene. Telavancin is used for complex skin infections and pneumonia, while dalbavancin and oritavancin primarily treat acute bacterial skin infections. Though lipoglycopeptides present risks to fetal development in animal studies, their impact on pregnant women remains underexplored, urging cautious use. Additionally, data on breast milk excretion is limited. Thus, lipoglycopeptides should be employed during pregnancy only when potential benefits outweigh fetal risks.^1,16

Lipopeptides constitute a unique class of bactericidal antibiotics with a distinct mechanism of action. They bind to bacterial cell membranes, leading to rapid depolarization and potassium efflux, which disrupts DNA, RNA, and protein synthesis, ultimately causing concentration-dependent bacterial death. Daptomycin is the only clinically used lipopeptide. Daptomycin exhibits broad-spectrum activity against gram-positive bacteria, including multidrug-resistant strains. It is primarily employed for infections caused by vancomycin- and methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. However, resistance may develop during therapy, leading to persistent or relapsing infections. In pneumonia, daptomycin may be inferior to ceftriaxone, possibly due to its binding to pulmonary surfactant, which diminishes its activity in the alveolar epithelial lining fluid. Animal studies have not indicated fetal risk with daptomycin, but human pregnancy data are limited to case reports, and its placental crossing extent remains uncertain. Depending on the indication and severity of illness, using daptomycin during pregnancy may be considered. Although daptomycin enters breast milk, its low oral availability makes its effects on breastfeeding infants unclear.^1,17

Polypeptides are a class of bactericidal antibiotics first discovered in 1939 and introduced clinically in 1941. They attack the bacterial cell wall, forming ion channels that increase membrane permeability, inhibiting cell wall synthesis to cause cell death. While most polypeptides are used topically due to negligible systemic absorption, polypeptides such as colistin and polymyxin B exhibit rapid concentration-dependent bactericidal activity against many gram-negative bacilli, including pseudomonas aeruginosa and acinetobacter species. However, they are ineffective against certain bacteria and obligate anaerobes. In hospitals, IV colistin has seen increased use against extensively drug-resistant gram-negative bacilli, particularly in serious systemic infections like ventilator-associated pneumonia and bacteremia. Still, its use is limited due to toxicity, and it is typically reserved for cases with no less toxic options. Combining polymyxins with other antibiotics, such as meropenem, is common for treating multidrug-resistant bacteria. The effectiveness of these combinations has not been extensively studied in clinical trials.^1,18

Phosphonates represent a novel class of antibiotics with a unique chemical structure. Produced by Streptomyces fradiae, phosphonates target cell wall synthesis in bacteria by inhibiting MurA (UDP-GlcNAc3-enolpyruvyltransferase), disrupting peptidoglycan production. Fosfomycin is a phosphonate that exhibits broad-spectrum activity against both gram-positive and gram-negative organisms, including antibiotic-resistant strains like MRSA, VRE, ESBL-producing and carbapenem-resistant Klebsiella pneumoniae, and fluoroquinolone-resistant Escherichia coli. Oral fosfomycin is primarily indicated for uncomplicated urinary tract infections, while IV fosfomycin may be used for infections with multidrug-resistant organisms at various sites. Fosfomycin crosses the placenta but is generally considered safe for treating cystitis during pregnancy. Use of phosphonates is cautioned for breastfeeding women due to the unknown amount of fosfomycin excreted in breast milk.^1,19

Bactericidal Antibiotics That Inhibiting Bacterial Enzymes or Protein Translation

Bactericidal antibiotics that inhibit bacterial enzymes or protein translation disrupt essential enzymatic reactions or protein synthesis pathways vital for bacterial survival and reproduction, ultimately leading to bacterial death. This category includes fluoroquinolones, mupirocin, sulfonamides, azoles, nitrofurans, and ansamycins.^1,8,9

Fluoroquinolones represent a significant class of antibiotics renowned for their bactericidal activity against a diverse range of bacterial pathogens. With their discovery dating back to 1962 and their subsequent clinical introduction in the same year, fluoroquinolones, including ciprofloxacin, inhibit DNA synthesis by targeting DNA gyrase and topoisomerase IV enzymes, both crucial for bacterial DNA replication. Fluoroquinolones are categorized into older and newer groups, with drugs like ciprofloxacin, norfloxacin, and ofloxacin belonging to the former, while delafloxacin, gemifloxacin, levofloxacin, and moxifloxacin fall under the latter category. These antibiotics exhibit broad-spectrum activity against a plethora of bacterial pathogens, including haemophilus influenzae, pseudomonas aeruginosa, mycobacterium tuberculosis, and various enterobacterales. Despite their effectiveness, several newer fluoroquinolones have been withdrawn from the market due to systemic toxicity concerns. Also, they are no longer recommended as the primary treatment for conditions like gonorrhea due to increasing resistance.^1,20

Mupirocin is a potent antibacterial agent that was discovered in 1971 and clinically introduced in 1985. It targets protein synthesis, explicitly inhibiting isoleucyl t-RNA synthetase, which disrupts bacterial RNA synthesis. One of the main advantages of mupirocin is its negligible systemic absorption when applied topically, minimizing the risk of systemic side effects. Mupirocin’s 2% topical preparation is particularly effective in treating various skin infections such as impetigo, minor superficial secondarily infected skin lesions, and staphylococcus aureus nasal carriage. However, it is important to note that chronic therapy with mupirocin may lead to the development of mupirocin-resistant staphylococci, which can limit its long-term effectiveness. Despite its efficacy, mupirocin may cause mild local adverse effects when applied to denuded skin or mucous membranes, including itching and burning sensations.^1,21

Azoles, like metronidazole, represent a class of bactericidal antibiotics crucial in combating various infections. Discovered in 1959 and introduced clinically in 1960, metronidazole induces DNA damage upon entering bacterial cell walls, inhibiting DNA synthesis in susceptible microorganisms. Oral metronidazole demonstrates excellent absorption, with intravenous administration reserved for cases where oral treatment is not feasible. The antibiotic distributes widely in body fluids and can penetrate cerebrospinal fluid, achieving high concentrations at the site of infection. Its spectrum of activity encompasses infections caused by obligate anaerobes, including intra-abdominal, pelvic, soft-tissue, periodontal, and odontogenic infections. Metronidazole also has proven to be effective against certain protozoan parasites such as trichomonas vaginalis, entamoeba histolytica, and giardia intestinalis (lamblia). Notably, it stands as the first-line treatment for bacterial vaginosis.^1,22

Nitrofurans, such as nitrofurantoin, was discovered in 1945 and clinically introduced in 1953. Nitrofurans target DNA synthesis to induce DNA damage and acts on common uropathogens, including escherichia coli, staphylococcus saprophyticus, and enterococcus faecalis. They are primarily indicated for the treatment or prophylaxis of uncomplicated lower urinary tract infections (UTIs) and may reduce the frequency of recurrent UTIs in women. Nitrofurantoin also remains a viable option for treating uncomplicated cystitis caused by these pathogens. However, most strains of proteus, providencia, morganella, serratia, acinetobacter, and pseudomonas species exhibit resistance, limiting nitrofurantoin’s spectrum. Nitrofurantoin is exclusively available for oral administration. Following a single dose, serum drug levels remain minimal, yet therapeutic concentrations are achieved in urine. Animal studies suggest nitrofurantoin is generally safe during pregnancy, with no observed fetal risks. However, nitrofurantoin is contraindicated during labor or delivery due to potential risks of neonatal hemolytic anemia arising from its interference with immature red blood cell enzyme systems. Nitrofurantoin should be avoided during the first month of breastfeeding as it enters breast milk, posing a risk of hemolytic anemia in neonates, particularly those with hyperbilirubinemia.^1,23

Ansamycins, including rifamycins, rifampin, rifabutin, and rifapentine, are a class of antibiotics that target nucleic acid synthesis by inhibiting bacterial DNA-dependent RNA polymerase, thereby impeding RNA synthesis. These antibiotics demonstrate efficacy against a spectrum of bacteria, including most gram-positive and certain gram-negative bacteria and mycobacterium species. Orally administered, they exhibit excellent absorption, resulting in broad distribution throughout body tissues and fluids, including cerebrospinal fluid. Rifampin accumulates in polymorphonuclear granulocytes and macrophages, aiding bacterial clearance from abscesses. Rifampin finds application in treating tuberculosis, atypical mycobacterial infections, leprosy, staphylococcal infections, legionella infections, pneumococcal meningitis, and prevention for close contacts of patients with meningococcal or Haemophilus influenzae type B meningitis. Rifabutin serves as an alternative to rifampin in tuberculosis regimens for HIV-positive patients receiving antiretroviral therapy due to its lower potential for inducing cytochrome P-450 metabolic enzymes. Rifapentine is utilized in treating pulmonary and latent tuberculosis.^1,24

Bacteriostatic Antibiotics

Bacteriostatic antibiotics prevent bacterial growth and reproduction but do not necessarily kill bacteria. Bacteriostatic antibiotics do this by interfering with bacterial protein production, DNA replication, or other aspects of bacterial cellular metabolism. They work with the immune system to remove the microorganisms from the body. High concentrations of some bacteriostatic agents are also bactericidal. Prevalent bacteriostatic antibiotics include sulfonamides, aminoglycosides, tetracyclines, macrolides, streptogramins, lincosamides, amphenicols, oxazolidinones, and pleuromutilin.^1,8,9

Sulfonamides represent a class of synthetic bacteriostatic antibiotics renowned for inhibiting the pathway that converts p-aminobenzoic acid to dihydropteroate, a crucial process for bacterial folate synthesis and subsequent purine and DNA synthesis. Unlike humans, who obtain folate from dietary sources, bacteria heavily rely on this pathway, rendering them vulnerable to sulfonamide action while sparing human DNA synthesis, to a certain extent. Sulfonamides are available in various formulations for oral, topical, and ophthalmic use. These antibiotics are typically well-absorbed orally and have extensive distribution throughout the body. Clinically, sulfonamides treat a variety of infections. When used alone or combined with other drugs, they treat nocardiosis, urinary tract infections, and chloroquine-resistant falciparum malaria. Topical formulations offer targeted approaches for localized infections. These include silver sulfadiazine and mafenide acetate for burns, sulfanilamide for vaginitis, and sulfacetamide for superficial ocular infections. Notably, sulfasalazine stands out for its oral use in managing inflammatory bowel disease.^1,25

Aminoglycosides are potent antibiotics used primarily for severe bacterial infections, particularly those caused by gram-negative bacteria like Pseudomonas aeruginosa. They inhibit bacterial protein synthesis by binding to the 30S ribosome, impeding bacterial protein production. These drugs are poorly absorbed orally but are effective when administered intravenously or intramuscularly. They distribute well into extracellular fluid but poorly into specific body compartments. Aminoglycosides are active against many gram-negative bacilli but lack efficacy against anaerobes and most gram-positive bacteria. Aminoglycosides such as tobramycin, gentamicin, and amikacin are effective against P. aeruginosa. Gentamicin and tobramycin are often used alongside broad-spectrum beta-lactams for severe infections. In endocarditis treatment, aminoglycosides like gentamicin may be combined with other antibiotics for streptococcal or enterococcal infections.^1,26

Tetracyclines are a class of bacteriostatic antibiotics that inhibit bacterial protein generation by binding to the 30S subunit of bacterial ribosome. Examples include doxycycline, eravacycline, minocycline, and omadacycline. Absorption rates vary, with doxycycline and minocycline being absorbed better than tetracycline. Generally, tetracyclines penetrate well into most body tissues and fluids, with minocycline having high concentrations in tears and saliva. They are effective against a range of pathogens, including rickettsiae, spirochetes, helicobacter pylori, vibrio species, and some staphylococcus aureus strains. However, resistance is observed in some pneumococcal strains and group A beta-hemolytic streptococci. Minocycline is preferred for methicillin-resistant S. aureus infections. Doxycycline has been shown to be more tolerable for infections caused by rickettsiae, chlamydia, bronchitis exacerbations, Lyme disease, brucellosis, anthrax, plague, tularemia, granuloma inguinale, syphilis, and malaria prophylaxis against chloroquine-resistant P. falciparum.^1,27

Macrolides such as erythromycin, azithromycin, and fidaxomicin are a class of antibiotics that bind to the 50S subunit of bacterial ribosomes, thereby inhibiting bacterial protein synthesis. First discovered in 1952, these antibiotics are relatively poorly absorbed orally, with fidaxomicin being minimally absorbed and active only locally in the gastrointestinal tract. Food can affect macrolide absorption, with varying effects depending on the specific formulation. Once absorbed, macrolides diffuse well into body fluids, with the exception of cerebrospinal fluid, and are concentrated in phagocytes. They are active against various pathogens, including aerobic and anaerobic gram-positive cocci, mycoplasma pneumoniae, chlamydia trachomatis, legionella species, and borrelia burgdorferi. Macrolides are typically considered the drug of choice for group A streptococcal and pneumococcal infections when penicillin cannot be used. They are also often used empirically for lower respiratory tract infections due to their activity against atypical respiratory pathogens.^1,28

Streptogramins are antibiotics used in combination to treat serious infections, especially skin infections, caused by bacteria resistant to other antibiotics. Streptogramins work by inhibiting bacterial protein synthesis, preventing the bacteria from producing the proteins they need to grow and multiply. Streptogramins such as quinupristin and dalfopristin are administered intravenously, typically through a central catheter inserted into a large central vein, such as in the neck, or through a peripherally inserted central catheter (PICC) threaded to a large central vein in the upper arm. These antibiotics target various bacteria, including streptococci and staphylococci (including resistant strains), some gram-negative anaerobic bacilli, clostridium perfringens, peptostreptococcus species, and atypical respiratory pathogens like mycoplasma pneumoniae, chlamydophila pneumoniae, and legionella pneumophila. Streptogramins inhibit enterococcus faecium, including vancomycin-resistant strains, but enterococcus faecalis is resistant.^29,30

Lincosamides are bacteriostatic antibiotics that impede bacterial protein synthesis, specifically the 50S ribosomal subunit, which is essential for bacterial growth and multiplication. Clindamycin is well-absorbed orally and can be given parenterally. It distributes well in body fluids, with the exception of cerebrospinal fluid, and is concentrated in phagocytes. Lincosamides like clindamycin treat various infections, including those resistant to other antibiotics, including anaerobes, community-acquired methicillin-resistant staphylococcus aureus, and macrolide-resistant streptococcus pneumoniae. Clindamycin is often part of combination therapy for various infections, including toxigenic streptococci infections, cerebral toxoplasmosis, babesiosis or falciparum malaria, and pneumocystis jirovecii pneumonia. Topical clindamycin is also used for acne treatment. However, it is unsuitable for central nervous system infections.^29,31

Oxazolidinones are a class of synthetic bacteriostatic antibiotics introduced clinically in 2000. They target the 50S ribosomal subunit, preventing bacteria from multiplying. Linezolid and tedizolid are examples of oxazolidinones that exhibit activity against a wide range of pathogens, including streptococci, enterococci (including vancomycin-resistant strains), staphylococci (including methicillin-resistant S. aureus and other resistant strains), mycobacteria (including mycobacterium tuberculosis), and anaerobes such as fusobacterium, prevotella, porphyromonas, bacteroides species, and peptostreptococci. These antibiotics are typically reserved for treating severe infections, especially when other antibiotics have proven ineffective. Oxazolidinones have become critical therapeutic options in the management of multidrug-resistant bacterial infections.^29,32

Amphenicols such as chloramphenicol are antibiotics that inhibit bacterial protein synthesis by binding to the 50S subunit of the ribosome. Amphenicols were introduced clinically in 1949 and are well absorbed orally but are typically administered intravenously. Amphenicols are distributed widely in body fluids, including cerebrospinal fluid, and are excreted in urine. Chloramphenicol exhibits a broad spectrum of activity against gram-positive and gram-negative cocci and bacilli, including anaerobes, as well as against rickettsia, mycoplasma, chlamydia, and chlamydophila species. However, chloramphenicol is no longer the preferred choice for most infections due to its potential for bone marrow toxicity, the availability of alternative antibiotics, and the emergence of resistance. It is reserved for infections caused by multidrug-resistant bacteria susceptible to this type of antibiotic, and specific conditions like plague meningitis or endophthalmitis, where other drugs penetrate poorly.³³