Cephalosporins are a class of β-lactam antibiotics derived from the fungus Cephalosporium.  This class of antibiotics works by inhibiting bacterial cell wall synthesis by binding to penicillin binding proteins, causing bacterial cell lysis.  Specific examples of penicillin binding proteins include carboxypeptidases and endopeptidases; these penicillin binding protein enzymes normally form the peptide cross links between peptidoglycans in bacterial cell walls.  However, in the presence of beta-lactam antibiotics, formation of these cross-links is disrupted, the cell wall becomes osmotically unstable, and bacteria burst from osmotic pressure.  Cephalosporins are both bactericidal and time dependent, meaning that they effectively kill susceptible bacteria as long as the plasma concentration of the antibiotic remains above the minimum inhibitory concentration between doses. 

The structures of the agents in this class vary greatly, but they generally share commonalities around a β-lactam ring (e.g. the “square” four membered ring).  In the figure, the functional group R2 determines both the anti-bacterial spectrum coverage and β-lactamase resistance, while R1 determines metabolism and pharmacokinetic parameters of the cephalosporin.

These drugs are renally eliminated and doses must be adjusted when renal dysfunction is present.  The most common adverse reactions to cephalosporins are gastrointestinal upset and an allergic reaction in the form of a rash.  Due to their structural similarities with penicillins, there is a slight chance individuals with penicillin allergies may experience cross-reactivity with cephalosporins.  What was once thought to be a 10% risk of cross-reactivity is now thought to be attributed to cross-contamination during manufacturing processes and is now believed to be closer to 1% with first generation cephalosporins and less likely with other generations.  The third and fourth generation cephalosporins have side chains that generally render them dissimilar enough to penicillins so as to not lead to cross-sensitivity; thus, individuals with a history of hives to penicillins can usually tolerate the newer cephalosporins without any problems.  However, to be on the safe side, in general, all cephalosporins are usually avoided in individuals that report a history of anaphylactic reactions to penicillins.

Resistance to cephalosporins arises via two different mechanisms.  Target-mediated resistance occurs when bacteria have alterations in penicillin binding proteins that reduce a cephalosporin’s affinity for binding to penicillin binding proteins.  Another mechanism of resistance occurs if the bacteria acquire β-lactamase enzymes, known as cephalosporinases, capable of lysing and opening the β-lactam ring, rendering the molecule inactive. 

There are various cephalosporins available on the market today.  They are commonly divided into different groups, called generations, based on the structure of their side chains, and thus their antimicrobial activities.

1^st Generation Cephalosporins

First generation cephalosporins have good activity against gram-positive bacteria including penicillinase-producing streptococci and staphylococci and modest activity against gram-negative rods such as K. pneumonia, P. mirabilis, and E. coli.  However, they offer no reliable anaerobic coverage.   They, along with some penicillins, are often drugs of choice for methicillin-susceptible Staphylococcus aureus (MSSA).  Agents in this class include cephalexin, cefazolin, and cefadroxil.  Cephalexin is often used orally to treat skin infections and cellulitis. Cefazolin is commonly administered during surgery to prevent infections of the surgical site.    Chemically, cefazolin contains a N-methyl thiotetrazole (NMTT) functional group which has been linked to specific adverse effects.  Specifically, when alcohol is consumed, a disulfiram-like reaction characterized by unpleasant side effects like severe nausea and vomiting can occur when drugs with NMTT side chains are taken.  The NMTT chemical ring also interferes with vitamin K formation and can lead to an increased bleeding risk in some patients. 

2^nd Generation Cephalosporins

Second generation agents include cefuroxime, cefoxitin, cefotetan, cefprozil, and cefaclor.  As a group, the second generation cephalosporins sacrifice some activity against gram-positive bacteria in favor of gaining more gram-negative coverage.  These drugs possess gram-negative coverage for H. influenza and M. catarrhalis, organisms that commonly cause upper respiratory tract infections as well as coverage for E. coli and other gram negative bacteria that cause uncomplicated urinary tract infections.  The drugs cefoxitin and cefotetan have added benefits of possessing anaerobic coverage for B. fragilis, a cause of intra-abdominal infections.  Cefotetan also has the NMTT functional group mentioned above with cefazolin and may produce a disulfiram-like reaction if alcohol is consumed; this side chain may also increase bleeding risk.  Cefaclor has been associated with a non-allergic rash caused by reactive intermediates that acetylate proteins and produce immunogenic complexes; however, this reaction is not a contraindication to use of other cephalosporins or penicillins.

3^rd Generation Cephalosporins

Ceftriaxone, cefotaxime, ceftazidime, cefixime, cefpodoxime, cefdinir, and ceftibuten are considered third generation cephalosporins.  Third generation cephalosporins cannot be used to treat staphylococcal or anaerobic infections, but do possess coverage against pneumococcal organisms.  Furthermore, third generation cephalosporins exhibit enhanced gram-negative activity and are useful for treating infections caused by Enterobacteriaceae, Serratia spp., and N. gonorrhea.  Ceftriaxone is often used to treat serious community-acquired pneumonia infections, but since it does not cover pseudomonas, it is not be an appropriate choice for health-care acquired pneumonia.   On the other hand, ceftazidime is a drug of choice for treating infections caused by P. aeruginosa including lung infections.  In the presence of central nervous system inflammation, ceftriaxone and cefotaxime can cross the blood brain barrier and can be used in combination with other drugs to treat meningitis.  Although most third generation drugs are eliminated predominantly by the kidneys, ceftriaxone has dual elimination with the kidneys and liver and can cause pseudocholelithiasis, which is a feeling like a person has a gall stone -- a situation that usually resolves after the medication is stopped.  In addition, ceftriaxone can precipitate in the gall bladder and lead to stone formation; in attempt to avoid this, the drug should never be administered with intravenous calcium.  Due to their relatively broad spectrum against normal gut bacterial flora, the agents in this generation are commonly implicated in causing C. difficile-associated diarrhea.

4^th Generation Cephalosporin

Cefepime is considered to be a fourth generation cephalosporin.  It combines the gram-positive coverage of the first generation cephalosporins with the gram-negative coverage of the third generation cephalosporins.  Like ceftazidime of the third generation agents, cefepime lacks anaerobic coverage but is active against P. aeruginosa.  It is the broadest spectrum cephalosporin and is the drug of choice for Enterobacter spp.  Its use is often reserved for empiric treatment in hospitalized patients when coverage for gram-positive organisms, Enterobacteriaceae, or Pseudomonas spp is needed.

Rebecca Kramer, Kelly Karpa

Cephalosporins are a class of β-lactam antibiotics derived from the fungus Cephalosporium.  This class of antibiotics works by inhibiting bacterial cell wall synthesis by binding to penicillin binding proteins, causing bacterial cell lysis.  Specific examples of penicillin binding proteins include carboxypeptidases and endopeptidases; these penicillin binding protein enzymes normally form the peptide cross links between peptidoglycans in bacterial cell walls.  However, in the presence of beta-lactam antibiotics, formation of these cross-links is disrupted, the cell wall becomes osmotically unstable, and bacteria burst from osmotic pressure.  Cephalosporins are both bactericidal and time dependent, meaning that they effectively kill susceptible bacteria as long as the plasma concentration of the antibiotic remains above the minimum inhibitory concentration between doses. 

The structures of the agents in this class vary greatly, but they generally share commonalities around a β-lactam ring (e.g. the “square” four membered ring).  In the figure, the functional group R2 determines both the anti-bacterial spectrum coverage and β-lactamase resistance, while R1 determines metabolism and pharmacokinetic parameters of the cephalosporin.

These drugs are renally eliminated and doses must be adjusted when renal dysfunction is present.  The most common adverse reactions to cephalosporins are gastrointestinal upset and an allergic reaction in the form of a rash.  Due to their structural similarities with penicillins, there is a slight chance individuals with penicillin allergies may experience cross-reactivity with cephalosporins.  What was once thought to be a 10% risk of cross-reactivity is now thought to be attributed to cross-contamination during manufacturing processes and is now believed to be closer to 1% with first generation cephalosporins and less likely with other generations.  The third and fourth generation cephalosporins have side chains that generally render them dissimilar enough to penicillins so as to not lead to cross-sensitivity; thus, individuals with a history of hives to penicillins can usually tolerate the newer cephalosporins without any problems.  However, to be on the safe side, in general, all cephalosporins are usually avoided in individuals that report a history of anaphylactic reactions to penicillins.

Resistance to cephalosporins arises via two different mechanisms.  Target-mediated resistance occurs when bacteria have alterations in penicillin binding proteins that reduce a cephalosporin’s affinity for binding to penicillin binding proteins.  Another mechanism of resistance occurs if the bacteria acquire β-lactamase enzymes, known as cephalosporinases, capable of lysing and opening the β-lactam ring, rendering the molecule inactive. 

There are various cephalosporins available on the market today.  They are commonly divided into different groups, called generations, based on the structure of their side chains, and thus their antimicrobial activities.

1^st Generation Cephalosporins

First generation cephalosporins have good activity against gram-positive bacteria including penicillinase-producing streptococci and staphylococci and modest activity against gram-negative rods such as K. pneumonia, P. mirabilis, and E. coli.  However, they offer no reliable anaerobic coverage.   They, along with some penicillins, are often drugs of choice for methicillin-susceptible Staphylococcus aureus (MSSA).  Agents in this class include cephalexin, cefazolin, and cefadroxil.  Cephalexin is often used orally to treat skin infections and cellulitis. Cefazolin is commonly administered during surgery to prevent infections of the surgical site.    Chemically, cefazolin contains a N-methyl thiotetrazole (NMTT) functional group which has been linked to specific adverse effects.  Specifically, when alcohol is consumed, a disulfiram-like reaction characterized by unpleasant side effects like severe nausea and vomiting can occur when drugs with NMTT side chains are taken.  The NMTT chemical ring also interferes with vitamin K formation and can lead to an increased bleeding risk in some patients. 

2^nd Generation Cephalosporins

Second generation agents include cefuroxime, cefoxitin, cefotetan, cefprozil, and cefaclor.  As a group, the second generation cephalosporins sacrifice some activity against gram-positive bacteria in favor of gaining more gram-negative coverage.  These drugs possess gram-negative coverage for H. influenza and M. catarrhalis, organisms that commonly cause upper respiratory tract infections as well as coverage for E. coli and other gram negative bacteria that cause uncomplicated urinary tract infections.  The drugs cefoxitin and cefotetan have added benefits of possessing anaerobic coverage for B. fragilis, a cause of intra-abdominal infections.  Cefotetan also has the NMTT functional group mentioned above with cefazolin and may produce a disulfiram-like reaction if alcohol is consumed; this side chain may also increase bleeding risk.  Cefaclor has been associated with a non-allergic rash caused by reactive intermediates that acetylate proteins and produce immunogenic complexes; however, this reaction is not a contraindication to use of other cephalosporins or penicillins.

3^rd Generation Cephalosporins

Ceftriaxone, cefotaxime, ceftazidime, cefixime, cefpodoxime, cefdinir, and ceftibuten are considered third generation cephalosporins.  Third generation cephalosporins cannot be used to treat staphylococcal or anaerobic infections, but do possess coverage against pneumococcal organisms.  Furthermore, third generation cephalosporins exhibit enhanced gram-negative activity and are useful for treating infections caused by Enterobacteriaceae, Serratia spp., and N. gonorrhea.  Ceftriaxone is often used to treat serious community-acquired pneumonia infections, but since it does not cover pseudomonas, it is not be an appropriate choice for health-care acquired pneumonia.   On the other hand, ceftazidime is a drug of choice for treating infections caused by P. aeruginosa including lung infections.  In the presence of central nervous system inflammation, ceftriaxone and cefotaxime can cross the blood brain barrier and can be used in combination with other drugs to treat meningitis.  Although most third generation drugs are eliminated predominantly by the kidneys, ceftriaxone has dual elimination with the kidneys and liver and can cause pseudocholelithiasis, which is a feeling like a person has a gall stone -- a situation that usually resolves after the medication is stopped.  In addition, ceftriaxone can precipitate in the gall bladder and lead to stone formation; in attempt to avoid this, the drug should never be administered with intravenous calcium.  Due to their relatively broad spectrum against normal gut bacterial flora, the agents in this generation are commonly implicated in causing C. difficile-associated diarrhea.

4^th Generation Cephalosporin

Cefepime is considered to be a fourth generation cephalosporin.  It combines the gram-positive coverage of the first generation cephalosporins with the gram-negative coverage of the third generation cephalosporins.  Like ceftazidime of the third generation agents, cefepime lacks anaerobic coverage but is active against P. aeruginosa.  It is the broadest spectrum cephalosporin and is the drug of choice for Enterobacter spp.  Its use is often reserved for empiric treatment in hospitalized patients when coverage for gram-positive organisms, Enterobacteriaceae, or Pseudomonas spp is needed.

Rebecca Kramer, Kelly Karpa

Macrolides consist of a large lactone ring with several deoxy sugars. Erythromycin and clarithromycin are representative examples. These drugs bind to the 50S subunit, near the peptidyltransferase centre (PTC). Therefore, the growing peptide cannot “lean over” and is kept in the A site. The subsequent events, i.e. the shifting of the “uncharged” tRNA to E site and ribosomal sliding movement, will not occur. GI disturbances and rash are common. There are rare occurrences of cholestatic hepatitis. Erythromycin is also a P450 inhibitor. One use of erythromycin is against S. pneumoniae if there is penicillin allergy. Common mechanisms of resistance to macrolides include decreased drug permeability, active drug efflux and most important of all, ribosomal alteration. The 50S ribosomal subunit is methylated, and this affects not only macrolide binding but also that of lincosamides (i.e. clindamycin) and streptogramins. This type of resistance is therefore referred to as MLS B-type resistance. The MLS B-type resistance is widespread across many bacterial species.

Telithromycin is a ketolide based on macrolides, but with a ketone and carbamate group. The ketone group decreases its susceptibility to MLS B-type resistance and active drug efflux while the carbamate group increases binding strength to ribosome. Antibacterial spectrum of telithromycin is similar to macrolides, but with better potency. However, potentially fatal hepatoxicity has limited its use.

Links to PubChem entries: azithromycin, clarithromycin, telithromycin. These entries provide the key physico-chemical and pharmacological properties of the drugs. Synopses of individual reports on adverse drug reactions and examples of available drug formulations are also provided.

Dr Willmann Liang

β-lactam antibiotics are so-called because they all contain a β-lactam ring in their chemical structures. In general these antibiotics act to inhibit bacterial wall synthesis. They are broad-spectrum antibiotics with activity against both Gram +ve and Gram -ve bacterial strains.

Subgroups include: penicillin derivatives (penams) which are discussed in more detail below, cephalosporins (cephems), monobactams, carbapenems, and carbacephems (which are reviewed more extensively in other topics within this Drugs for Infections module.

Bacteria can produce β-lactamase as a mechanism of acquired resistance to β-lactam antibiotics. Co-administration of β-lactamase inhibitors can partially mitigate resistance.

β-lactamase-sensitive penicillins

Ampicillin is inactivated by penicillinases. Since the majority of staphylococci and E. coli strains and some Haemophilus influenzae strains are now resistant to ampicillin, it should not be used in the hospital setting or without first considering the likelihood of resistance. The main indications for ampicillin treatment are exacerbations of chronic bronchitis and middle ear infections due to Streptococcus pneumoniae and H. influenzae, and for urinary-tract infections.

A fixed-dose combination of ampicillin plus flucloxacillin (co-fluampicil) is available to treat streptococci or staphylococci infections such as cellulitis.

Amoxicillin, a derivative of ampicillin with improved oral absorption, has a similar antibacterial spectrum. It is notably used for the treatment of Lyme disease.

Co-amoxiclav (amoxicillin + clavulanic acid) is active against β-lactamase-producing bacteria that are resistant to amoxicillin, such as resistant strains of Staph. aureus, E. coli, and H. influenzae, as well as many Bacteroides and Klebsiella spp. Its use should be restricted to the treatment of infections likely, or known, to be caused by amoxicillin-resistant β-lactamase producing bacterial strains.

Benzylpenicillin (Penicillin G) is inactivated by gastric acid so has to be delivered by injection. It is effective against many streptococcal (including pneumococcal), gonococcal, and meningococcal infections, anthrax, diphtheria, gas-gangrene, and leptospirosis. Some pneumococci, meningococci, and gonococci strains are less sensitive to benzylpenicillin. Although benzylpenicillin is active against tetanus, treatment with metronidazole is the preferred option.

Benzathine benzylpenicillin is given by intramuscular injection to treat early syphilis and late latent syphilis.

Phenoxymethylpenicillin (Penicillin V) is similarly active to benzylpenicillin but is acid-resistant, so can be delivered orally. The principal indications for its use are respiratory-tract infections in children, streptococcal tonsillitis, and for continuing benzylpenicillin-initiated treatment when clinical response has begun. Phenoxymethylpenicillin should not be used for meningococcal or gonococcal infections.

Penicillinase- and β-lactamase-resistant penicillins

Flucloxacillin is not inactivated by penicillinases so it is effective against infections caused by penicillin-resistant staphylococci, and this is its principal use. It is acid-resistant and orally active.

Temocillin is stable against a wide range of β-lactamases. Its use should be reserved for the treatment of infections caused by β-lactamase-producing strains of Gram -ve bacteria, including those that are resistant to third-generation cephalosporins. Temocillin is not active against Pseudomonas aeruginosa or Acinetobacter spp.

Antipseudomonal penicillins

Piperacillin (a ureidopenicillin) is only available in a fixed-dose combination with the β-lactamase inhibitor tazobactam.

Ticarcillin (a carboxypenicillin) is only available in a fixed-dose combination with β-lactamase inhibiting clavulanic acid.

Both of these preparations are broad spectrum antibiotics that are effective against a range of Gram +ve , Gram -ve bacteria, and anaerobic bacteria. Piperacillin + tazobactam is active against a wider range of Gram -ve organisms than ticarcillin + clavulanic acid and it is more active against Pseudomonas aeruginosa. Neither of these antibacterials combat MRSA. They are typically used to treat septicaemia, hospital-acquired pneumonia, and complicated infections involving the urinary tract, skin and soft tissues, or intra-abdomen. Co-administration of an aminoglycoside (e.g. gentamicin) with these antipseudomonal penicillin preparations effectively combats severe pseudomonas infections.

Bacteria replicate DNA via a unique enzyme called DNA gyrase (or topoisomerase II). DNA at the replication fork exist in a positively-supercoiled arrangement and the structure is strained. DNA gyrase nicks one strand of the DNA (say at a supercoiled segment behind) and reseals the strand after it un-coils at the front. This process restores the usual, negatively-supercoiled and stabilised, unstrained state. Another enzyme, topoisomerase IV, acts to untangle the newly replicated DNA. Both topoisomerases II & IV can be inhibited by fluoroquinolones, but activity against topoisomerase II is more clinically relevant at present.

Ciprofloxacin is a representative example of fluoroquinolones, so named because compounds in the class possess a fluorine. Fluoroquinolones inhibit the activity of DNA gyrase, thus stopping DNA replication. Drugs in this class should be avoided in pregnant women (concerning fetus) and those under age 18 as the developing bones and cartilage will be affected. Unwanted effects are infrequent and mild, but ciprofloxacin is a known cytochrome P450 inhibitor. Thus, interactions with other P450 inhibitors such as theophylline can produce CNS effects such as headache, dizziness and convulsions.

Fluoroquinolones have a broad spectrum of antibacterial activity, but usage is best reserved for Gram-negative (Gm-) bacteria, including against Acinetobacter baumannii & Pseudomonas aeruginosa (combined with aminoglycoside), Haemophilus influenzae, enterobacteria (Enterobacter, E. coli, K. pneumoniae). Resistance to fluoroquinolones may arise most commonly when the structure of DNA gyrase is altered. This may result in weaker drug-binding or a binding site that is shielded from the drug. It should also be noted that inactivation by acetylation occurs via an enzyme that does the same to aminoglycosides.

Links to PubChem entries: ciprofloxacin (a second-generation fluoroquinolone); levoflaxacin (a third-generation fluoroquinolone); moxifloxacin (a fourth-generation fluoroquinolone). These entries list the key physico-chemical and pharmacological properties of these fluoroquinolone drugs. Synopses of individual reports on adverse drug reactions are included, as are examples of various drug formulations on the market.

Dr Willmann Liang

Bacteria replicate DNA via a unique enzyme called DNA gyrase (or topoisomerase II). DNA at the replication fork exist in a positively-supercoiled arrangement and the structure is strained. DNA gyrase nicks one strand of the DNA (say at a supercoiled segment behind) and reseals the strand after it un-coils at the front. This process restores the usual, negatively-supercoiled and stabilised, unstrained state. Another enzyme, topoisomerase IV, acts to untangle the newly replicated DNA. Both topoisomerases II & IV can be inhibited by fluoroquinolones, but activity against topoisomerase II is more clinically relevant at present.

Ciprofloxacin is a representative example of fluoroquinolones, so named because compounds in the class possess a fluorine. Fluoroquinolones inhibit the activity of DNA gyrase, thus stopping DNA replication. Drugs in this class should be avoided in pregnant women (concerning fetus) and those under age 18 as the developing bones and cartilage will be affected. Unwanted effects are infrequent and mild, but ciprofloxacin is a known cytochrome P450 inhibitor. Thus, interactions with other P450 inhibitors such as theophylline can produce CNS effects such as headache, dizziness and convulsions.

Fluoroquinolones have a broad spectrum of antibacterial activity, but usage is best reserved for Gram-negative (Gm-) bacteria, including against Acinetobacter baumannii & Pseudomonas aeruginosa (combined with aminoglycoside), Haemophilus influenzae, enterobacteria (Enterobacter, E. coli, K. pneumoniae). Resistance to fluoroquinolones may arise most commonly when the structure of DNA gyrase is altered. This may result in weaker drug-binding or a binding site that is shielded from the drug. It should also be noted that inactivation by acetylation occurs via an enzyme that does the same to aminoglycosides.

Links to PubChem entries: ciprofloxacin (a second-generation fluoroquinolone); levoflaxacin (a third-generation fluoroquinolone); moxifloxacin (a fourth-generation fluoroquinolone). These entries list the key physico-chemical and pharmacological properties of these fluoroquinolone drugs. Synopses of individual reports on adverse drug reactions are included, as are examples of various drug formulations on the market.

Dr Willmann Liang

Bacteria must generate their own precursors to nucleic acids. Para-aminobenzoic acid (PABA), together with a pteridine derivative and glutamic acid are needed to synthesise these precursors. The first step is catalysed by dihydropteroate synthetase (DHPS) to generate dihydropteric acid. A second enzyme, dihydrofolate synthetase (DHFS), adds glutamic acid and produces dihydrofolic acid. The last step, via dihydrofolate reductase (DHFR), yields tetrahydrofolic acid (THF). THF is then utilised in other pathways to generate nucleic acids. Notable unwanted effects of sulphonamides include photosensitivity, topical hypersensitivity and in severe cases, Stevens-Johnson syndrome and toxic epidermal necrolysis.

Sulfonamides are compounds that possess a structure similar to PABA. These PABA analogues compete with the authentic PABA for DHPS, thus suppressing dihydropteroic acid production, and subsequently less THF is produced. Humans can obtain THF from diet, so blocking DHPS only affects bacteria. In fact, humans do not have DHPS. Trimethoprim is a pteridine analogue that blocks the activity of DHFR. Humans have DHFR, but trimethoprim is much more potent to bacterial DHFR. Trimethoprim is often given together with a sulphonamide (commonly sulfomethoxazole). The combined formulation is called co-trimoxazol. Co-trimoxazole interferes with THF synthesis at two points, i.e. concomittant inhibition of both DHPS and DHFR. The combined form serves to potentiate drug effect. Drug resistance is also less likely to be a problem as the susceptible bacteria are under attack at two points of the same biochemical pathway.

Long-term use of co-trimoxazole may bring about the expected unwanted effect of folate deficiency if dietary intake is below normal. Co-trimoxazole has a broad spectrum of antibacterial activity, but enterococci and P. aeruginosa are intrinsically resistant.

Co-trimoxazole can be used against methicillin-resistant Staphylococcus aureus (MRSA) together with drainage, as well as against extended-spectrum beta-lactamase-producing (ESBL+) E. coli and Klebsiella pneumoniae infections in the urinary tract. Resistance to co-trimoxazole may come in several forms. More commonly, bacteria may possess the ability to produce large amounts of PABA or DHFR, thereby the drugs are rendered useless. Another common mechanism is mutations causing alterations in the drug-binding site(s) of DHPS or DHFR and decreased drug affinity.

Dr Willmann Liang