Antimicrobial Drugs

Mechanisms of action

Azelaic acid is a dicarboxylic acid derivative found in whole grain cereals and animal products, and it is normally present in human plasma. In vitro , azelaic acid has activity against Propionibacterium acnes and Staphylococcus epidermidis . It is usually bacteriostatic but can be bactericidal in high concentrations. Its activity may be due to inhibition of microbial cellular protein synthesis. Azelaic acid also has anticomedonal effects by normalizing keratinization. It thins the stratum corneum, decreases the number and size of keratohyalin granules, and reduces the amount and distribution of filaggrin in the epidermis. Azelaic acid has antiproliferative effects against hyperactive and abnormal melanocytes, but it rarely causes hypo- or depigmentation of normally pigmented skin (see Table 127.2 ).

Benzoyl peroxide is bacteriostatic against P. acnes . Once absorbed by the skin, it is converted to benzoic acid. Its effects are believed to be due to oxidation of bacterial proteins by reactive oxygen species, which are released when the drug is decomposed by cysteine in the skin. Daily use of 10% benzoyl peroxide for 2 weeks decreases free fatty acids by 50% and P. acnes by 98%, which is comparable to results obtained after use of topical antibiotics for 4 weeks . Benzoyl peroxide also has keratolytic and desquamative effects.

Clindamycin is a semisynthetic lincosamide antibiotic that inhibits protein synthesis by binding to the bacterial 50S ribosomal subunit and is active against Gram-positive cocci and anaerobes including staphylococci, streptococci, P. acnes, Corynebacterium spp. , Clostridium spp., and Gardnerella vaginalis . Clindamycin may be either bacteriostatic or bactericidal, depending on the susceptibility of the infecting organism and the concentration achieved at the site of infection.

Erythromycin is a macrolide antibiotic that also inhibits protein synthesis by binding to the bacterial 50S ribosomal subunit and is active against Gram-positive cocci including group A β-hemolytic streptococci and Staphylococcus aureus, as well as some Gram-negative bacilli. Erythromycin also has anti-inflammatory properties.

Studies have shown that combining erythromycin or clindamycin with benzoyl peroxide is more effective for the treatment of acne than either of the former agents alone; clindamycin plus benzoyl peroxide is also more effective than benzoyl peroxide alone . These synergistic combinations may slow the development of antibiotic resistance, which is a significant issue with both erythryomycin and clindamycin. Several products containing these combinations are available.

Sodium sulfacetamide is a sulfonamide whose bacteriostatic effects involve disruption of folic acid synthesis (see Fig. 127.5 ). It is active against several Gram-positive and Gram-negative organisms. Some topical preparations combine sodium sulfacetamide with sulfur, which acts as a keratolytic as well as antimicrobial agent (see Ch. 129 ).

Metronidazole is a nitroimidazole with antioxidant and anti-inflammatory as well as antimicrobial effects against anaerobic bacteria. DNA strand breaking is its presumed mechanism of action.

Dapsone is a sulfone drug whose antimicrobial effects include inhibition of dihydropteroate synthase and prevention of bacterial folic acid synthesis. It also has anti-inflammatory effects that target neutrophils, inhibiting their chemotaxis and decreasing myeloperoxidase activity.

Indications

Azelaic acid, benzoyl peroxide, clindamycin, erythromycin, sodium sulfacetamide, and dapsone are used topically for mild to moderate inflammatory acne vulgaris. Azelaic acid may also be useful for melasma and other forms of hyperpigmentation. Benzoyl peroxide has been utilized for decubitus and stasis ulcers. Topical clindamycin and erythromycin can treat superficial bacterial infections of the skin, whereas topical clindamycin and metronidazole are both indicated for bacterial vaginosis. Sodium sulfacetamide and topical metronidazole are also used to treat rosacea.

Dosages

Topical antibacterial agents are usually used once or twice a day (see Table 127.2 ). A small amount of medication is applied in a thin layer onto clean, dry skin. Benzoyl peroxide cleansing bars and washes are used one to three times a day. Benzoyl peroxide shave cream is used like other shaving creams, and the mask is applied in a thin layer once a week, left on for 15 to 25 minutes, and then rinsed off.

Contraindications

The chief contraindication for these medications is a history of hypersensitivity to any component of the formulation. Azelaic acid preparations contain propylene glycol, which may be a sensitizer. Topical clindamycin should be used with caution in patients with a history of inflammatory bowel disease or antibiotic-associated colitis.

Major side effects

Adverse reactions to the topical antibacterial agents used to treat acne vulgaris and rosacea are usually mild and transient. Stinging is especially common with alcohol-containing solutions and pledgets. Table 127.2 lists side effects of individual drugs.

Interactions

Application of more than one topical medication simultaneously can increase or decrease the effect of one or both of the medications. Benzoyl peroxide may have additive irritant effects when used with other topical acne medications, and it can oxidize and thereby decrease the activity of tretinoin when these products are applied at the same time. Topically applied clindamycin may interact with other drugs as a result of systemic absorption, e.g. clindamycin has neuromuscular blocking properties and should be used with caution in patients receiving neuromuscular blocking agents. Clindamycin, erythromycin, and chloramphenicol may antagonize each other due to their similar mechanisms of action. Oral metronidazole may potentiate the anticoagulant effect of warfarin, resulting in a prolonged prothrombin time. It is not known whether topical preparations have the same effect. A temporary yellow–orange staining of the skin and hair occasionally occurs with concomitant use of topical dapsone and benzoyl peroxide, and systemic levels of dapsone increase if it is administered together with co-trimoxazole.

Pregnancy and lactation

Table 127.2 lists the FDA pregnancy categories of the topical antibacterial agents used to treat acne vulgaris and rosacea. In general, topical antibiotics are considered to be safe during pregnancy and lactation .

Azelaic acid has not been adequately studied in pregnant women, but there is limited systemic absorption of azelaic acid through topical application. Although passage of azelaic acid into breast milk may potentially occur, there have been no reported problems due to azelaic acid in nursing infants.

Studies on the effects of benzoyl peroxide in pregnancy have not been performed in either humans or animals. There may be systemic absorption of topically applied benzoyl peroxide, but it is not known whether benzoyl peroxide is excreted in breast milk; adverse effects have not been reported in nursing infants.

There are no adequate studies of topical clindamycin in pregnant or lactating women, although current CDC guidelines state that clindamycin vaginal cream is safe for the treatment of bacterial vaginosis during pregnancy. It is unknown whether topically applied clindamycin passes into breast milk. However, no serious adverse effects have been reported in nursing infants, and topical clindamycin is considered compatible with breastfeeding .

Studies on the effects of topical erythromycin in pregnancy have not been done in humans or animals, but it is presumed to be safe for pregnant women . Systemically administered erythromycin is excreted in breast milk, but it is not known whether topical erythromycin is excreted in breast milk. Erythromycin topical preparations have not been reported to cause problems in nursing infants and are considered to be compatible with breastfeeding . However, oral erythromycin administered to mothers during pregnancy or the early postpartum period may be associated with an increased risk of infantile pyloric stenosis.

Oral sulfonamides may increase the chance of kernicterus in newborns and should not be used late in pregnancy; however, absorption is minimal with topical application. Systemic sulfonamides are also excreted in breast milk and may cause kernicterus, anemia, and other adverse effects in nursing infants, especially those with glucose-6-phosphate dehydrogenase (G6PD) deficiency.

Topical metronidazole has not been studied in pregnant women, but it is presumed to be safe based on studies of vaginal and oral administration during pregnancy. Systemic metronidazole crosses the placental barrier and enters the fetal circulation; however, whether it has the potential to cause birth defects or other problems has been the subject of controversy, and the CDC no longer recommends that systemic administration be avoided during the first trimester. Topical metronidazole results in blood levels much lower than those achieved with systemically administered metronidazole. The small amounts of this medication that are absorbed are unlikely to cause problems in nursing infants.

Mechanisms of action

The mechanisms of action of the topical antibacterial agents used to treat superficial infections are also listed in Table 127.3 .

Mupirocin (pseudomonic acid A) is derived from Pseudomonas fluorescens . It is clinically active against staphylococci; groups A, B, C, and G streptococci; and some Gram-negative aerobic bacteria. It is usually bacteriostatic but may be bactericidal at high concentrations.

Retapamulin is the first drug in the pleuromutilin class, derived from fermentation of a mushroom, Clitopilus passeckerianus . It has activity against Streptococcus pyogenes and methicillin-susceptible S. aureus .

Neomycin and gentamicin are aminoglycoside antibiotics isolated from cultures of Streptomyces fradiae and Micromonospora purpurea , respectively. Neomycin is bactericidal against Gram-positive and Gram-negative bacteria including S. aureus, Escherichia coli, Haemophilus influenzae, Proteus spp., and Serratia spp. It is generally not effective against Pseudomonas aeruginosa . Gentamicin is effective against sensitive strains of group A β-hemolytic and α-hemolytic streptococci, S. aureus (coagulase-positive, coagulase-negative, and some penicillinase-producing strains), and Gram-negative bacteria including P. aeruginosa, Aerobacter aerogenes, E. coli, Proteus vulgaris , and Klebsiella pneumoniae .

Bacitracin is a cyclic polypeptide antibiotic produced by the Tracey I strain of Bacillus subtilis . It has a thiazolidine ring and peptide side chains. Bacitracin is active against Gram-positive organisms such as staphylococci, streptococci, corynebacteria, and clostridia.

Polymyxin B is a cyclic lipopeptide antibiotic isolated from the aerobic Gram-positive rod Bacillus polymyxa , a soil organism. It is rapidly bactericidal for various Gram-negative organisms, including P. aeruginosa, E. coli, K. pneumoniae, Enterobacter aerogenes, H. influenzae, Proteus mirabilis , and Serratia marcescens . It is not active against Gram-positive organisms.

Indications

Mupirocin, neomycin, gentamicin, bacitracin, and combination products containing polymyxin B are indicated for the treatment and prevention of superficial bacterial skin infections. The intranasal preparation made with the calcium salt of mupirocin is indicated for the eradication of nasopharyngeal carriage of S. aureus . Studies implicating nasal staphylococci as a potential source for wound infections and bacteremia suggest that intranasal application of mupirocin may decrease the incidence of infections in susceptible individuals (e.g. those with recurrent staphylococcal infections) . Decolonization of known S. aureus carriers with the use of mupirocin nasal ointment and chlorhexidine body wash for five days prior to Mohs micrographic surgery may reduce the risk of surgical site infection and be more effective than oral antibiotic prophylaxis on the day of surgery . Mupirocin has been shown to be as effective as systemic antibiotics for localized impetigo due to Streptococcus pyogenes or S. aureus in patients as young as 2 months of age . Retapamulin is indicated for the topical treatment of impetigo due to Str. pyogenes and methicillin-susceptible S. aureus in patients as young as 9 months of age.

Dosages

Table 127.3 outlines the formulations and dosing for the antibacterial agents used for the treatment of superficial skin infections. Intranasal mupirocin is applied into the nares two to four times a day for 5 to 14 days.

Contraindications

As with all topical medications, the main contraindication is a history of hypersensitivity to any component of the formulation.

Major side effects

Potential side effects of mupirocin include burning, stinging, pain, and pruritus, as well as erythema, edema, increased exudate, allergic contact dermatitis, headache, and nausea. Use of nasal mupirocin is occasionally associated with headaches, rhinitis, respiratory tract congestion, pharyngitis, dysgeusia, burning, stinging, and cough. Use of mupirocin on extensive areas of skin with decreased barrier function has been reported to cause renal toxicity from systemic absorption of polyethylene glycol. Retapamulin can cause application site irritation and pruritus.

Side effects of neomycin include allergic contact dermatitis in 5% to 15% of patients , in particular when neomycin is applied to cutaneous ulcerations and/or areas of chronic stasis dermatitis. The most common symptoms are pruritus, erythema, and edema. In the setting of impaired renal function, there is an increased risk of side effects related to systemic absorption; caution should also be exercised if the medication is used over extensive areas. Irreversible ototoxicity leading to hearing loss, nephrotoxicity, neuromuscular blockade, and death have been reported . Neomycin may also cause mast cell degranulation and histamine release .

Possible side effects of gentamicin include erythema, pruritus, edema, and photosensitization. There is a risk of producing gentamicin-resistant strains of Pseudomonas when this agent is applied to heavily colonized skin (e.g. leg ulcers).

Adverse effects of bacitracin include irritant and allergic contact dermatitis. Chronic stasis dermatitis predisposes to the latter. Anaphylaxis has been reported in patients with a history of multiple previous exposures when bacitracin was applied to open wounds.

There are few side effects from polymyxin B . Contact sensitization has been reported. Of note, some cross-reactivity exists between bacitracin and polymyxin B because they are both derived from Bacillus species.

Interactions

In studies utilizing E. coli , chloramphenicol interferes with the effect of mupirocin on bacterial RNA synthesis. Otherwise, there are no known significant drug interactions with the topical antibiotics used for superficial skin infections.

Pregnancy and lactation

Table 127.3 lists the FDA pregnancy categories of the topical antibacterials used to treat superficial infections.

Neither topical nor nasal mupirocin has been specifically studied in pregnant women. However, mupirocin has not been shown to cause birth defects or other problems in animal studies using rats and rabbits, and there is very little systemic absorption of topically applied mupirocin. It is not known whether topical or nasal mupirocin is excreted in breast milk. Topical neomycin has not been shown to cause human birth defects or problems in nursing infants. Animal studies have not been conducted with polymyxin B, and it is not known whether polymyxin B is excreted in breast milk.

Mechanism of action

Penicillins are β-lactam antibiotics that exert a bactericidal effect by binding to and inactivating penicillin-binding proteins in the bacterial cell wall. They are thought to inhibit bacterial cell wall synthesis by blocking the transpeptidase cross-linking of peptidoglycan chains ( Fig. 127.2 ).

The natural penicillins (penicillin G and penicillin V) are active against Gram-positive and Gram-negative cocci, most Gram-positive bacilli, and spirochetes. Penicillinase-resistant penicillins (methicillin, nafcillin and dicloxacillin), referred to as anti-staphylococcal penicillins, have greater efficacy against S. aureus . Aminopenicillins (ampicillin, amoxicillin) have an extended spectrum to include H. influenzae , E. coli , Salmonella and Shigella spp., and some other Gram-negative bacteria, but not Pseudomonas spp. Antipseudomonal penicillins (carbenicillin, ticarcillin and piperacillin) cover P. aeruginosa and B. fragilis . Carbenicillin and ticarcillin have no activity against Klebsiella spp., whereas mezlocillin, azlocillin and piperacillin do. Addition of the β-lactamase inhibitors clavulanic acid, sulbactam, tazobactam, and avibactam extends the spectrum of penicillins to include staphylococci and other β-lactamase-producing bacteria ( Fig. 127.3 ).

Indications

Penicillins are used for syphilis and streptococcal skin infections, such as erysipelas, as well as other cutaneous infections such as erysipeloid . Amoxicillin with clavulanic acid is the drug of choice for cat, dog, and human bites. It is useful also for acute paronychia. The penicillinase-resistant penicillins, e.g. dicloxacillin, are used for staphylococcal skin infections, including impetigo, folliculitis, and furunculosis; however, the incidence of methicillin-resistant Staphylococcus aureus (MRSA) is rising and sensitivity testing should be obtained when MRSA is a clinical concern. Amoxicillin may be used for Lyme disease when doxycycline is contraindicated. Penicillins are also used to treat non-cutaneous infections caused by susceptible bacteria, including pneumonia, gonorrhea, urinary tract infections, otitis media, and sinusitis.

Dosages

The pediatric and adult dosages of commonly used penicillins are listed in Table 127.5 . Amoxicillin and amoxicillin with clavulanic acid should be taken with food. Other penicillins should be taken on an empty stomach.

Contraindications

Penicillins are contraindicated in patients with known immediate-type (IgE-mediated) hypersensitivity to any penicillin, such as a history of penicillin-associated urticaria, angioedema, or anaphylaxis. However, only 10–20% of patients who report a history of allergy to penicillins have an allergy identified upon skin testing . Cross-reaction with penicillins occurs in approximately 2–15% of patients allergic to cephalosporins.

Skin testing for penicillin allergy utilizes: (1) the major allergen benzylpenicilloyl polylysine; (2) the minor allergens benzylpenicillin G, benzylpenicilloate, and penicilloyl propylamine; and (3) negative (saline) and positive (histamine) controls. Antihistamines should be avoided prior to testing. Patients who have had a life-threatening reaction to penicillin should be tested with 100-fold dilutions of the allergens before being tested with full-strength allergens in a monitored setting where treatment for anaphylaxis is available. Epicutaneous (prick) testing may be performed by placing drops of antigen solutions on the volar forearm and using a 26-gauge needle to pierce the epidermis without drawing blood. An epicutaneous test is positive if, within 15 minutes, the average wheal diameter is 4 mm larger than the wheal of negative controls. For intradermal testing, antigen solutions and controls are injected in the volar forearm. An intradermal test is positive if, 15 minutes after injection, the average wheal diameter is at least 2 mm greater than the initial wheal size and is also at least 2 mm greater than the negative controls.

Patients who report a history of penicillin allergy but are skin-test-negative to all major and minor allergenic determinants can use penicillin in a monitored setting. Skin-test-positive patients may be desensitized orally or intravenously in a hospital setting over ~4 hours. Rarely, serious IgE-mediated allergic reactions can occur. Blood tests can also be used to detect specific IgE directed against penicillin, but this method is less sensitive and informative than skin tests.

Major side effects

Drugs in the penicillin group cause hypersensitivity reactions characterized by urticaria, flushing, and pruritus in 5–15% of patients. In severe cases, anaphylaxis, shock, and even death may occur. In addition, penicillins can cause morbilliform and other exanthematous eruptions ( Fig. 127.4 ), which may be associated with fever and eosinophilia. Serum sickness-like reactions, Stevens–Johnson syndrome, toxic epidermal necrolysis, and pustular eruptions such as acute generalized exanthematous pustulosis develop less often. These drugs also occasionally lead to autoimmune phenomena, including hemolytic anemia or vasculitis. Of note, ampicillin and amoxicillin almost invariably cause a generalized morbilliform eruption in patients with infectious mononucleosis; this reaction is also more likely in patients with lymphocytic leukemia and those taking concomitant allopurinol.

Penicillins can induce acute interstitial nephritis characterized by proteinuria, hematuria, renal casts, eosinophilia, eosinophiluria, fever, arthralgias, and declining renal function. Prolonged use of penicillins may lead to reversible neutropenia, anemia, agranulocytosis, and platelet dysfunction. Penicillins can cause diarrhea, pseudomembranous colitis, and hepatic dysfunction. Treatment with penicillins is associated with oral or vaginal overgrowth of Candida spp. in ~10% of patients.

Interactions

Because probenecid blocks the secretion of penicillins in the distal renal tubules, concomitant administration of these two drugs increases the serum levels and duration of action of the penicillins. When amoxicillin or ampicillin is used concomitantly with allopurinol, there is an increased risk of morbilliform drug eruption, and when tetracyclines are used together with penicillins, the bactericidal effect of penicillins is decreased.

Pregnancy and lactation

Penicillins are pregnancy category B and are considered to be safe for use in nursing mothers.

Mechanism of action

Like the penicillins, the cephalosporins ( Table 127.6 ) are bactericidal β-lactam antibiotics that bind to penicillin-binding proteins and interfere with bacterial cell wall synthesis. First-generation cephalosporins are very effective against Gram-positive organisms (staphylococci and streptococci) and less effective against Gram-negative organisms; however, they are active against E. coli, Klebsiella , and Proteus spp. Second-generation cephalosporins are equally effective against Gram-positive and Gram-negative bacteria. Their spectrum includes all of the organisms covered by first-generation cephalosporins plus Enterobacter spp., Neisseria gonorrhea , and H. influenzae . Third-generation cephalosporins are more effective against Gram-negative bacteria than Gram-positive bacteria. Fourth-generation cephalosporins have an extended spectrum against Gram-negative (including Enterobacter and Klebsiella spp.) and Gram-positive organisms, but have minimal resistance to β-lactamase. Fifth-generation cephalosporins (e.g. ceftaroline) have activity against S. aureus including MRSA, Str. pyogenes , S. agalactiae , S. pneumoniae , H. influenzae , E. coli , and Klebsiella. Cephamycins, β-lactam antibiotics very similar to cephalosporins, are resistant to β-lactamase and have a broad spectrum, including E. coli, Klebsiella , Proteus , Serratia , and Bacteroides spp.

Indications

Cephalosporins are useful in staphylococcal and streptococcal skin and soft tissue infections. A first-generation agent such as cephalexin or cefadroxil is the cephalosporin of choice in uncomplicated skin infections such as impetigo, cellulitis, furunculosis, erysipelas, and ecthyma . However, with the exception of fifth generation agents (e.g. ceftaroline), MRSA is resistant to cephalosporins.

Dosages

See Table 127.7 for dosages of the more commonly used cephalosporins.