Pharmacology - An Illustrated Review

29. Antibacterial Drugs

Antibacterial agents act on the bacterial cell to disrupt the integrity of the cell structure or its metabolism (Fig. 29.1).

29.1 Inhibitors of Bacterial Cell Wall Synthesis

Antibacterial drugs that act as inhibitors of cell wall synthesis include the β-lactam antibiotics (listed in Table 29.1 with their structures shown in Fig. 29.2), bacitracin, and vancomycin. These agents have a high degree of selective toxicity against bacteria because mammalian cells do not have cell walls. Another category of agents, β-lactamase inhibitors, has been included in this section, as they augment the action of β-lactam antibiotics.

Structure of the bacterial cell wall

The peptidoglycan of the bacterial cell wall is composed of alternating units of polymers N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM). The polymers contain tetrapeptides that extend from the NAM residues. A pentaglycine bridge cross-links the tetrapeptides. In gram-positive bacteria, the cytoplasmic membrane is surrounded by a thick cell wall containing many layers of peptidoglycan and teichoic acids. In contrast, the cytoplasmic membrane of gram-negative bacteria is surrounded by a thin cell wall consisting of a few layers of peptidoglycan and an outer lipid bilayer containing polysaccharides and lipoproteins.

 

Gram-negative cell walls

The outer layer of gram-negative bacteria is a lipoprotein–lipopolysaccharide complex termed lipopolysaccharide or endotoxin. This component is composed of several polysaccharides linked to lipid A. The outermost portion of lipopolysaccharide is referred to as the O antigen and “flaps in the wind.” The lipid A moiety is responsible for the toxic portion of lipopolysaccharide. An area referred to as the periplasmic space is located between the cell wall and cell membrane. The “space” contains several proteins, including those that inactivate antibiotics (e.g., β-lactamase). The outer membrane of the cell wall of gram-negative microbes is somewhat selective and is not as permeable to antibiotics as is the cell wall of gram-positive organisms. Hence, the former organisms have become more important in human medicine during the antibiotic era.

 

Penicillin-binding proteins

The penicillin-binding proteins (PBPs) are transpeptidases and similar enzymes involved in bacterial cell wall synthesis. They were named based on their ability to bind penicillin before their functional roles were discovered. A single type of bacterium may contain 3 to 10 different PBPs. PBPs are located in the cytoplasmic membrane and catalyze several reactions involved in cross-linking the peptidoglycan of the cell wall. The major activity is transpeptidase, but some also have carboxypeptidase and endopeptidase activity. They all have active sites that bind β-lactam antibiotics.

 

  Table 29.1 image β-lactam Antibiotics

β-lactam Antibiotics

Individual Drugs

 

Penicillins

Narrow spectrum: penicillin G, penicillin V

Extended spectrum: amoxicillin, ampicillin, piperacillin, ticarcillin

Penicillinase-resistant: naficillin, oxacillin, cloxicillin, dicloxicillin, methicillin

 

Cephalosporins

First generation: cefazolin, cephalexin

Second generation: cefuroxime, cefaclor

Third generation: cefotaxime, ceftriaxone, ceftazidime

Fourth generation: cefepime, cefpirone

 

Others

Imipenem/cilastatin, aztreonam

 

Mechanism of action. The β-lactam antibiotics bind covalently to penicillin-binding proteins (PBPs) of bacterial cell membranes and inhibit their activity. One of the effects of this is that enzymes, such as transpeptidase, carboxypeptidase, and transglycosylase, are inhibited. Various strains of bacteria have different types of PBPs, which may account for their differential sensitivity to antibiotics. Incubation of susceptible bacteria with β-lactam antibiotics leads to morphological abnormalities and cell death. Cell lysis, when it occurs, may result from uncontrolled action of bacterial lytic enzymes (Fig. 29.3). These drugs are bactericidal.

Fig. 29.1 image Site of action of antibacterial agents.

Antibacterial agents act at different sites in the bacterial cell to promote cell lysis or inhibition of growth.

image

Fig. 29.2 image Chemical structure of β-lactam antibiotics.

The structural core of the β-lactam antibiotics is shown. The arrow points to the β-lactam ring that the compounds have in common. This is also the site at which resistant bacterial strains with β-lactamase activity can cleave the β-lactam ring and inactivate the antibiotics.

image

Fig. 29.3 image Penicillin G: structure, origin, and mechanism of action of penicillins.

Bacteria possess a cell wall composed of peptidoglycan molecules cross-linked to form a lattice. The enzyme transpeptidase is responsible for this cross-linkage. Penicillins disrupt cell wall synthesis by inhibiting transpeptidase. When bacteria are in their growth and replication phase, penicillins are bactericidal. Hypersensitivity (type I) is the most common adverse effect of penicillins; however, they can be neurotoxic at very high doses due to gamma-aminobutyric acid (GABA) antagonism.

image

Penicillins

Side effects

– Hypersensitivity (allergic) reactions are the most common toxic complication. There is a small incidence (5 to 10%) of cross-reactivity among the penicillins and cephalosporins.

– Central nervous system (CNS) dysfunction (lethargy, confusion, and seizures) may occur with high blood and cerebrospinal fluid (CSF) levels.

Hypersensitivity

Hypersensitivity results from immune responses against a normally innocuous antigen. These responses fall into two major categories.

1. Immediate hypersensitivity: Type I hyper-sensitivity is an allergic reaction to an antigen. It is mediated by IgE that attaches to mast cells and basophils, which de-granulate upon subsequent exposure to the same antigen, releasing substances such as histamine, leukotrienes, and prostaglandins. These substances are responsible for allergy symptoms, e.g., tissue swelling and itching. Type II hypersensitivity produces antibodies that then bind to antigens on the surface of the patient's own cells. This activates an immune response against the antigen, e.g., via the complement cascade. Alternatively, cells to which antibodies attach are killed by natural killer cells and macrophages (cytotoxicity). Type III hypersensitivity reactions occur when antigens and antibodies bind forming immune complexes. Deposition of these immune complexes in tissues (e.g., joints blood vessels, renal glomeruli) produces inflammation.

2. Delayed-type hypersensitivity: Type IV hypersensitivity occurs 2 to 3 days after exposure to the antigen. In this case, the antigen forms a complex with type 1 or 2 major histocompatibility complex, (MHC), which then activates cytotoxic T cells (CD8+) and helper T cells (CD4+). T-helper cells secrete interferon gamma, which induces the release of cytokines and mediates the immune response. Cytotoxic T cells kill target cells.

 

Resistance. Bacteria may acquire genes (usually via plasmids) to produce β-lactamase enzymes (e.g., penicillinase), which open the β-lactam ring and destroy the activity of the antibiotic (Fig. 29.4).

Natural Penicillins

Penicillin G and Penicillin V

Spectrum

– Narrow

– Both penicillin G and penicillin V are effective in mild to moderate streptococcal, staphylococcal, and pneumococcal infections, such as skin, ear, and respiratory infections.

Pharmacokinetics

– Penicillin G should be given parenterally because oral absorption is erratic due to instability in gastric acid.

– Penicillin G benzathine and penicillin G procaine are long-acting forms for intramuscular injection.

– Penicillin V is acid stable, so it is taken orally (Fig. 29.5).

– Neither penicillin G nor penicillin V penetrates cerebrospinal fluid (CSF).

Uses

– Endocarditis

– Skin infections

– Otitis media

– Strep throat

– Pneumonia

– Scarlet fever

– Syphilis

Side effects

– Hypersensitivity reactions

– Diarrhea, nausea, and vomiting can occur with penicillin V.

Endocarditis

Endocarditis is an infection of the endocardium of the heart. It occurs when bacteria from any source, e.g., dental procedures, periodontal tissues, gain entry to the blood and colonize the heart valves causing “vegetations.” This is more likely to occur with damaged or artificial heart valves. Causative bacteria include Streptococcus viridans, Enterococcus fecalis, and Staphylococcus aureus. Symptoms include fever, changing heart murmur, fatigue, weight loss, night sweats, hematuria, and splenomegaly (enlarged spleen). Complications of endocarditis include stroke (from embolic vegetations), heart failure, renal failure, and abscesses. Treatment involves an extended course (4-6 weeks) of IV antibiotic therapy, the choice of which is directed by blood culture of the causative bacteria.

 

Penicillinase-resistant Penicillins

Methicillin, Oxacillin, Cloxacillin, Dicloxacillin, and Nafcillin

– Parenteral agents: Methicillin, oxacillin, nafcillin

– Oral agents: Oxacillin, cloxacillin, dicloxacillin, nafcillin

Spectrum

– Very narrow

– Effective against gram-positive organisms and they remain useful if the bacteria produce penicillinase (Fig. 29.5)

Uses

– Infection due to Staphylococcus aureus (penicillinase-producing)

Note: These agents should not be used for penicillin G–susceptible organisms.

Methicillin-resistant Staphylococcus aureus (MRSA)

MRSA is an infection caused by Staphylococcus aureus exposure that is resistant to treatment by β-lactam antibiotics (e.g., methicillin, penicillin, and amoxicillin). It mostly occurs in hospitals (nosocomial) and other treatment centers. It tends to affect people with weakened immune systems. Staphylococcal infections, including MRSA, usually start with a boil on the skin, which can progress to form deep abscesses that enable the bacteria to penetrate into the bloodstream and bone. Treatment involves surgical drainage of abscesses and vancomycin therapy.

 

Fig. 29.4 image Disadvantages of penicillin G.

Penicillin G is inactivated by gastric acid, which cleaves the β-lactam ring. This can be circumvented by parenteral administration of the drug. The β-lactam ring is also opened by β-lactamases (e.g., penicillinase), which are produced by some staphylococcal strains rendering them resistant to penicillins. Penicillin G has a narrow spectrum of action. It is active against many gram-positive bacteria, gram-negative cocci, and spirochetes but is inactive against many gram-negative pathogens.

image

Extended-spectrum Penicillins

Ampicillin, Amoxicillin, and Ticarcillin

– Amino penicillin agents: Ampicillin and amoxicillin

– “Antipseudomonal” penicillin agent: Ticarcillin

Spectrum. These are extended-spectrum agents.

– These agents are active against some important gram-positive (e.g., Streptococcus pneumoniae, enterococci, staphylococci) and gram-negative pathogens (e.g., Haemophilus influenzaeEscherichia coli, and Proteus mirabilis).

– Susceptible β-lactamase-producing strains of Citrobacter, Enterobacter, E. coliH. influenzaeKlebsiella, Pseudomonas, Serratia, and Staphylococcus can be treated with ticarcillin/clavulanate.

Pharmacokinetics. Normally, these agents do not penetrate CSF, but they may penetrate CSF if the meninges are inflamed.

– Ampicillin penetrates CSF in neonates with meningitis.

Fig. 29.5 image Derivatives of penicillin G.

The derivatives of penicillin G have some advantages over their predecessor. Penicillin V has similar antibacterial properties to penicillin G but is stable in gastric acid and so can be given orally (as can the other derivatives shown). Oxicillin is one of the penicillins that are penicillinase resistant and is therefore useful in treating penicillinase-producing staphylococci infections. Amoxicillin has a broader spectrum of action than penicillin G, as it is active against more gram-negative pathogens.

image

Uses. Ampicillin is used for treatment of the following:

– Endocarditis (staphylococci, streptococci, E. coliP. mirabilis, and Salmonella). It is also used as a prophylactic agent in endocarditis. It is frequently used in combination with an amino-glycoside, such as gentamicin.

– Meningitis in newborns in combination with cefotaxime, with or without gentamicin

– Respiratory tract infections by susceptible S. aureus (including penicillinase-producing strains), Streptococcus (including S. pneumoniae and S. pyogenes, group A β-hemolytic streptococci), and H. influenzae (nonpenicillinase-producing strains only)

– Septicemia due to gram-positive organisms, such as streptococci, penicillin G–susceptible staphylococci, and enterococci

Amoxicillin is used for treatment of the following:

– Acute otitis media. If the illness is severe, or if the infection is being caused by β-lactamase-producing H. influenzae or Moraxella catarrhalis, amoxicillin is combined with clavulanate potassium (a β-lactamase inhibitor).

– Prophylaxis of bacterial endocarditis

– Primary treatment of Helicobacter pylori that causes gastric ulcers. Amoxicillin is part of clarithromycin-based triple therapy including clarithromycin and a proton pump inhibito r.

Ticarcillin is available in a fixed combination with clavulanic acid. This combination is used for treatment of the following:

– Infections of the lower respiratory tract, skin, bone, joints, urinary tract, peritoneum, and endometrium

– Septicemia

Note: These agents should not be used for the treatment of streptococcal or staphylococcal infections when a natural penicillin would be effective.

Side effects. Amoxicillin causes a maculopapular rash on the trunk of a small proportion of children who take it.

Contraindications. People with infectious mononucleosis, cytomegalovirus, and acute lymphoblastic leukemia should not be given amoxicillin, as they are highly likely to develop a rash.

Otitis media

Otitis media is a bacterial or viral infection of the middle ear, usually in children. It tends to occur following an upper respiratory tract infection, e.g., the common cold, which causes congestion and swelling of the nasal passages, throat, and eustachian tubes. Blockage of the eustachian tubes causes fluid accumulation in the middle ear. Symptoms include ear pain, hearing deficits, purulent discharge from the ear, balance problems, headache, loss of appetite, vomiting, and diarrhea. Children may also tug or pull the ear, cry more than usual, and be more irritable. Otitis media is usually self-resolving in 1 to 2 weeks and so no treatment may be indicated. NSAIDs may be taken for ear pain. Amoxicillin is usually the antibiotic of choice when antibiotics are indicated.

 

Piperacillin

Spectrum. Piperacillin is an extended-spectrum agent.

– This agent is active against susceptible strains of Pseudomonas, Proteus, E. coli, Enterobacter, some streptococci, and some anaerobic bacteria.

Pharmacokinetics. Piperacillin penetrates CSF, particularly when the meninges are inflamed, but it is not used for meningitis.

Uses

– Septicemia

– Acute and chronic respiratory tract infections

– Skin and soft tissue infections

– Urinary tract infections

Antibiotic penetration into cerebrospinal fluid

The ability of antibiotics to enter the brain depends on their plasma protein-binding properties, molecular size, lipid solubility, and degree of local inflammation. Penetration is greater for small, non-protein bound, lipid-soluble drugs. Drug penetration is also enhanced if the meninges are inflamed. Penicillin, amoxicillin, ampicillin, cefuroxime, ceftriaxone, cefotaxime, metronidazole, and vancomycin are useful in meningitis and brain abscesses.

 

Cephalosporins

This group of β-lactam antimicrobials includes the true cephalosporins (produced from Cephalosporium species) and cephamycins (produced from Streptomyces species). Cephamycins have greater resistance to β-lactamases and are classified into four “generations” based on their spectrum of antimicrobial activity, with each generation having increased activity against gram-negative bacteria. The newer agents also have improved pharmacokinetics, with half-lifes that allow a decrease in the frequency of dosing.

Side effects. Cephalosporins are generally relatively free of severe adverse reactions. The most common adverse effects are hypersensitivity reactions, most commonly observed as a maculopapular rash after several days of therapy.

First-generation Cephalosporins

Cefazolin, Cephalothin, Cephapirin, Cephradine, Cephalexin, Cefadroxil, and Cephradine

– Parenteral agents: Cefazolin, cephalothin, cephapirin, and cephradine

– Oral agents: Cephalexin, cefadroxil, and cephradine

Mechanism of action

– Same as for penicillins

Spectrum

– First-generation cephalosporins are effective against many gram-positive cocci and useful for treating staphylococcal and streptococcal infections.

– These agents are all susceptible to β−lactamase inactivation and are not effective for infections due to enterococci or methicillin-resistant staphylococcus aureus (MRSA).

Pharmacokinetics

– Cefazolin has the longest half-life, reaches the highest plasma levels after injection, and is least irritating of the parenteral agents, making it the best choice for intramuscular i njection.

– These agents do not penetrate CSF.

Uses

– Surgical prophylaxis

– Simple skin and soft tissue infections (parenteral cefazolin)

– Skin and urinary tract infections (oral cefadroxil)

Second-generation Cephalosporins

Cefuroxime, Cefamandole, Cefonicid, Cefoxitin, Cefotetan, Cefmetazole, Cefaclor, Cefuroxime Axetil, Cefpodoxime Proxetil, Cefprozil, and Loracarbef

– Parenteral agents: Cefuroxime, cefamandole, cefonicid, cefoxitin, cefotetan, and cefmetazole

– Oral agents: Cefaclor, cefuroxime axetil, cefpodoxime proxetil, cefprozil, and loracarbef

Spectrum

– The second-generation cephalosporins have a greater activity against gram-negative organisms, especially H. influenzae, while retaining some activity against gram-positive bacteria. They are also more resistant to β-lactamase. However, first-generation agents are preferred for most gram-positive indications, and third-generation agents are usually more active against gram-negative pathogens.

– Cefoxitin (a cephamycin) is probably the most notable drug of this class because of its activity against anaerobic bacteria.

Pharmacokinetics. Cefuroxime is the only second-generation agent that penetrates CSF.

Uses

– Upper and lower respiratory tract infections, sinusitis, and otitis media

– Urinary tract infections caused by E. coli, Klebsiella, and Proteus

– Surgical prophylaxis

– Mild intra-abdominal infections, for example, cholecystitis (cefoxitin)

Side effects

– Concurrent use of ethanol with cephalosporins that contain a methyltetrazolethiol side chain (cefamandole, cefotetan, cefmetazole, and cefoperazone) may result in a disulfiram-like reaction, including flushing, tachycardia, headache, sweating, thirst, nausea, and vomiting, due to inhibition of acetaldehyde metabolism.

– Competitive inhibition between the methyltetrazolethiol group and vitamin K–dependent carboxylase, which is responsible for converting clotting factors II, VII, IX, and X to their active forms, may lead to hypoprothrombinemia (low blood prothrombin levels). This problem may be averted by giving the patient a supplement of vitamin K.

Third-generation Cephalosporins

Cefotaxime, Ceftriaxone, Ceftazidime, Cefoperazone, Cefixime, Ceftizoxime, and Cefixime

– Parenteral agents: Cefotaxime, ceftriaxone, ceftazidime, cefoperazone, cefixime, and ceftizomine

– Oral agent: Cefixime

Spectrum

– Third-generation cephalosporins have further increased activity against gram-negative organisms, including H. influenzae; however, their potency against gram-positive microbes is generally inferior to first-generation agents. All third-generation cephalosporins are resistant to hydrolysis by β-lactamases. Their activity is variable against anaerobes, including Bacteroides fragilis.

— Ceftriaxone and cefotaxime have excellent activity against most strains of S. pneumoniae, including the vast majority of those resistant to penicillin.

– Ceftazidime has antipseudomonal activity.

Pharmacokinetics

– Penetration into CSF (ceftazidime and cefotaxime)

– Long half-life (ceftriaxone)

– Eliminated via biliary excretion (cefoperazone and ceftriaxone)

Uses

– Bacterial meningitis (ceftriaxone and cefotaxime)

– Community-acquired pneumonia protocol (ceftriaxone and cefotaxime)

– Treatment of Pseudomonas and all types of other gram-negative infections (ceftazidime).

Meningitis

Meningitis is inflammation of the meninges of the brain (pia mater and arachnoid), usually due to a viral infection but can also be caused by a bacterial or fungal infection. Symptoms include headache, stiff neck on passively moving chin toward chest, photophobia (sensitivity to light), irritability, drowsiness, vomiting, fever, seizures, and rashes (viral or meningococcal meningitis). Predisposing factors for meningitis include head injury (especially basal skull fracture), otitis media, sinusitis, mastoiditis, and a compromised immune system (e.g., carcinoma, AIDS, diabetes, splenectomy, immunosuppressant drugs). A lumbar puncture often provides a definitive diagnosis of meningitis. Blind treatment with a broad-spectrum antibiotic or prompt treatment with I.V. antibiotic(s) that are sensitive to the causative organism is required for bacterial meningitis. For viral meningitis, treatment includes bed rest and fluids but this normally resolves on its own in a week or two.

 

Fourth-generation Cephalosporins

Cefepime

Spectrum. Cefepime is an extended spectrum agent that is effective against the following:

– Gram-positive organisms, including MRSA

– Gram-negative organisms, including Pseudomonas aeruginosa

– Multiresistant gram-negative bacilli

It also exhibits significant activity against anaerobes and greater resistance to β-lactamases than third-generation cephalosporins.

Uses

– Infections caused by P. aeruginosa, including urinary tract infections, sepsis, and hospital-acquired pneumonia

– Used in combination with vancomycin for treatment of nosocomial meningitis

Other β-Lactam Antibiotics

Imipenem with Cilastatin

Mechanism of action. Imipenem binds to all PBPs and is also an irreversible β-lactamase inhibitor. Cilastatin prevents renal enzymes from breaking down imipenem and prolongs its effects.

Spectrum. Imipenem has the broadest spectrum of any β-lactam antibiotic.

Pharmacokinetics

– Imipenem is metabolized by a renal peptidase. To circumvent this, cilastatin, a specific inhibitor of the renal enzyme, is administered with imipenem. Cilastatin also prevents renal toxicity sometimes observed with imipenem alone. A 1:1 combination of imipenem:cilastatin is the only form available.

– Penetration into CSF is highly variable. It is not used for meningitis.

Uses

– Used to treat serious infections in which a mixture of gram-positive, gram-negative, and anaerobic bacteria may be involved

Resistance. Resistance can develop to these agents, especially in Pseudomonas species.

Side effects. Like other β-lactam antibiotics, imipenem has a low incidence of adverse reactions, but it may trigger seizures in epileptic patients and in patients with head trauma.

Aztreonam

Mechanism of action

– Same as for penicillins

Spectrum. Aztreonam is a narrow-spectrum agent with the following properties:

– Aztreonam is a potent antibiotic, with activity against only aerobic gram-negative bacteria. It is highly stable to β lactamases and does not induce β-lactamase enzymes.

– Limited cross-reactivity with other β-lactam antibiotics and so it is generally considered safe to administer to patients with a penicillin allergy.

– Aztreonam is synergistic with other β-lactam antibiotics and the aminoglycosides.

β-Lactamase Inhibitors

Many bacteria produce β-lactamase enzymes (e.g., penicillinase) that open the β-lactam ring and destroy the activity of the antibiotic. To combat this, β-lactamase inhibitors can be combined with β-lactam antibiotics (amoxicillin and ticarcillin) to further extend their usefulness. Many cephalosporins are resistant to β−lactamase enzymes.

Clavulanic Acid

Mechanism of action. Clavulanic acid is an irreversible inhibitor of many bacterial β-lactamases.

Sulbactam and Tazobactam

The properties of these drugs are similar to clavulanic acid.

– Sulbactam is marketed in combination with ampicillin.

– Tazobactam is marketed in combination with piperacillin.

Glycopeptide Antibiotic

Vancomycin

Mechanism of action. Vancomycin binds to the terminal D-alanine-D-alanyl peptide portion of the peptidoglycan precursor and inhibits bacterial cell wall synthesis. This is at a different step from β-lactam antibiotics. Bacterial autolysins subsequently cause cell wall lysis, so vancomycin is usually bactericidal.

Spectrum

– Active against gram-positive bacteria, including staphylococci, streptococci, and enterococci

Pharmacokinetics

– Vancomycin should not be given intramuscularly, as it causes tissue necrosis.

– When given intravenously, it must be administered slowly as a dilute solution to minimize thrombophlebitis, as well as flushing reactions associated with histamine release.

– Vancomycin is able to penetrate CSF in the presence of inflammation.

Uses. Vancomycin is indicated for susceptible pathogens in the bowel (even though it is not absorbed in the gastrointestinal [GI] tract), such as treatment of antibiotic-associated pseudomembranous colitis.

Resistance

– Seldom develops to vancomycin

Antibiotic-associated pseudomembranous colitis

Pseudomembranous colitis is inflammation of the colon due to superinfection with Clostridium difficile, a gram-positive bacillus. It typically occurs following a course of antibiotic treatment in which the normal gut commensal bacteria are eradicated, allowing C. difficile to colonize the gut unimpeded. The most common antibiotics that cause this condition are the penicillins, cephalosporins, fluoroquinolone, and clindamycin. Symptoms of pseudomembranous colitis include diarrhea, fever, and abdominal pain. It is treated with metronidazole or vancomycin.

 

Necrotizing fasciitis

Necrotizing fasciitis is a rare infection that penetrates into deeper layers of the skin and subcutaneous tissue and is able to spread along fascial planes. It can be caused by a variety of bacteria, including group A streptococci, S. aureus, Clostridium perfringens, and B. fragilis. Signs and symptoms include intense pain, signs of inflammation (although these may be absent if the infection is in deep tissues), diarrhea, vomiting, and fever. The patient will look very ill. The skin will blister and undergo necrosis. Treatment for this condition involves giving antibiotics such as penicillin, vancomycin, or clindamycin early in the process, often before the diagnosis has been confirmed. Necrotic tissue will require surgical débridement or amputation.

 

Other Inhibitors of Cell Wall Synthesis

Bacitracin

Mechanism of action. Bacitracin is a polypeptide antibiotic that inhibits the formation of bacterial cell walls by blocking peptidoglycan chain formation and is usually bactericidal.

Spectrum

– Active against gram-positive organisms

Pharmacokinetics. This agent is not absorbed after oral administration.

Uses

– The main use is for topical treatment of gram-positive infections on the skin or in the eye.

– Renal toxicity limits its usefulness to topical application, but it may be used in infants with staphylococcal pneumonia and empyema that are resistant to safer antibiotics.

Side effects

– Renal toxicity when given systemically

29.2 Inhibitors of Protein Synthesis

These agents exhibit selective toxicity for bacterial cells by binding to bacterial ribosomal subunits, which differ in structure from the mammalian ribosomal subunits. They inhibit bacterial protein synthesis.

Macrolide Antibiotics

Macrolide (large ring) antibiotics are characterized by the presence of a 14- or 15-member lactone ring. Erythromycin is the prototype of these antibiotics, but newer macrolides possess improved pharmacokinetic properties and modest changes in the antibacterial spectrum.

Mechanism of action. Macrolides bind to the P site of the 50S bacterial ribosomal subunit. They block protein synthesis when a large amino acid or a polypeptide is in the P site (Fig. 29.6).

Protein synthesis

The first stage in protein synthesis involves unzipping of the DNA double helix by RNA polymerase then transcription of DNA to mRNA (messenger RNA). This process occurs in the nucleus. mRNA (codon) migrates into the cytoplasm and attaches to a ribosome. Translation of mRNA into a protein occurs when transfer RNA (tRNA) and its accompanying amino acid bind to mRNA by forming complementary base pairs (anticodon). The amino acids join to form a polypeptide chain. Protein synthesis is stopped when a termination codon is translated, and the polypeptide chain is released from the ribosome.

 

Erythromycin

Erythromycin is available as the base (unstable in acid), stearate, ethylsuccinate, or estolate salt.

Spectrum. Erythromycin is a narrow-spectrum agent.

– Active against gram-positive bacteria (similar in spectrum to penicillin G), Chlamydia, and Legionella organisms

Pharmacokinetics

– The best absorption is obtained with the estolate salt.

– Erythromycin is distributed into total body water, but penetration into CSF is poor, even when the meninges are inflamed.

– Erythromycin is extensively metabolized in the liver; thus, dosage adjustments in renal failure are usually considered unnecessary.

Uses

– Mild to moderately severe infections of the upper and lower respiratory tract

Side effects

– Erythromycin is usually well tolerated, but many patients complain of gastric effects.

– Reversible intrahepatic obstructive jaundice may occur, especially with the estolate salt.

– Parenteral forms are highly irritating.

Resistance

– Develops rapidly

Jaundice

Jaundice refers to the yellow pigmentation of the skin, sclerae, and mucous membranes due to raised plasma bilirubin.

– Prehepatic (or hemolytic) jaundice. Excess bilirubin (e.g., from hemolysis) or an inborn failure of bilirubin metabolism results in unconjugated bilirubin remaining in the bloodstream. Unconjugated bilirubin is water-insoluble and so does not appear in urine.

– Hepatocellular (or hepatic) jaundice. In hepatocellular jaundice, there is diminished hepatocyte function leading to an increased amount of both conjugated and unconjugated bilirubin. Diminished hepatocyte function may follow cirrhosis, autoimmune diseases, drug damage (e.g., acetaminophen, barbiturates), or viral infections (e.g., hepatitis A, B, C; Epstein-Barr virus).

– Posthepatic (obstructive) jaundice. This form of jaundice usually occurs following blockage of the common bile duct by gallstones. In this case, plasma conjugated bilirubin rises. Conjugated bilirubin is water-soluble and appears in urine (making it dark). At the same time, less conjugated bilirubin passes into the gut and is converted to stercobilin, therefore feces appear paler.

 

Clarithromycin

Clarithromycin is a hydroxylated derivative of erythromycin.

Spectrum. Clarithromycin is a narrow-spectrum agent.

– Clarithromycin is somewhat more active against gram-positive pathogens, Legionella, and Chlamydia than erythromycin.

Pharmacokinetics

– Clarithromycin is much better absorbed after oral administration than erythromycin.

– No penetration into CSF

Uses

– Mainly used in triple therapy of H. pylori (see page 263)

Azithromycin

Azithromycin has a 15-member lactone ring.

Spectrum. Azithromycin is a narrow-spectrum agent.

– Azithromycin is more active than erythromycin against several gram-negative pathogens.

Pharmacokinetics

– The most unusual property of azithromycin is its uptake into several tissues (lung, tonsil, and cervix), where it maintains high concentrations for prolonged periods.

– Azithromycin's long half-life allows once-daily oral administration.

– No penetration into CSF

Uses

– Urethritis or cervicitis (Chlamydia trachomatis)

– Treatment of coexisting chlamydial infection in patients being treated for gonorrhea, as well as urogenital chlamydial infections in pregnant women

– Chlamydial pneumonia in infants and chlamydial conjunctivitis in neonates (C. trachomatis)

– Legionnaires disease (Legionella pneumophila)

– Mycobacterium avium-intracellulare complex

Lincomycin and Clindamycin (7-Chlorolincomycin)

Mechanism of action. These agents attach to the 50S ribosomal subunit at or near the erythromycin attachment site. They are chemically unlike but pharmacologically similar to erythromycin.

Spectrum. Lincomycin and clindamycin are narrow-spectrum agents.

– Active against gram-positive bacteria

– Excellent activity against anaerobic bacteria

Pharmacokinetics

– Lincomycin is poorly absorbed after oral administration, whereas the oral absorption of clindamycin is excellent and is not affected by food.

Fig. 29.6 image Protein synthesis and modes of action of antibacterial drugs.

Protein synthesis involves the translation of genetic sequences in messenger RNA (mRNA), transcribed from DNA. Peptide synthesis occurs in the ribosome, where transfer RNA (tRNA) delivers amino acids to mRNA. Adjacent amino acids are linked into a peptide chain by the enzyme peptide synthetase. Tetracyclines inhibit the binding of amino acyl-tRNA complexes and have a bacteriostatic effect. They have a broad spectrum of action. Aminoglycosides induce the binding of wrong amino acyl-tRNA complexes, resulting in the synthesis of false proteins. These agents are bactericidal and act mainly against gram-negative pathogens. Chloramphenicol inhibits the enzyme peptide synthetase, which prevents growth of the peptide chain. It is bacteriostatic against a broad spectrum of pathogens. Macrolides prevent the ribosome from moving along the mRNA to “read” it. They are bacteriostatic against mainly gram-positive pathogens.

image

— These drugs are widely distributed in the body (but reach only low concentrations in CSF, even when the meninges are inflamed) and penetrate well into bone.

– Both drugs are metabolized extensively and excreted primarily in bile and feces.

– Clindamycin is a more potent antimicrobial agent than lincomycin.

Uses

– Lincomycin is seldom used clinically.

– Clindamycin is useful for therapy of anaerobic infections, including those caused by B. fragilis. It is potentially useful as a penicillin substitute but is more toxic than erythromycin.

Side effects

– Diarrhea is the most common adverse effect. Clindamycin is the antibiotic that most frequently causes antibiotic-associated pseudomembranous colitis (see call-out box on page 295).

– Skin rashes and reversible changes in hepatic enzymes in serum may also occur.

Tetracyclines

Tetracycline, Oxytetracycline, Doxycycline, Demeclocycline, Methacycline, and Minocycline

Mechanism of action. Tetracyclines preferentially bind to the 30S subunit of the microbial ribosome, interfere with binding of amino acyl-tRNA, and inhibit chain termination (Fig. 29.6). Tetracyclines are usually bacteriostatic.

Spectrum. Tetracyclines are broad-spectrum agents.

– Effective against gram-positive and gram-negative bacteria, Rickettsia, Chlamydia, spirochetes, and amebiasis

Pharmacokinetics

– Most tetracyclines are incompletely absorbed after oral administration. Absorption is further delayed by food, calcium salts, and aluminum salts (Fig. 29.7). An exception to this is the oral absorption of doxycycline, which is superior to other tetracyclines and is virtually unaffected by food.

– They are distributed in total body water.

– They are usually excreted in the urine; thus, renal function should be considered for dosage determinations. However, doxycycline is excreted primarily into the bile, and demeclocycline is metabolized in the liver.

– Tetracycline and oxytetracycline are rapidly eliminated.

– Demeclocycline and methacycline are more slowly eliminated.

– Doxycycline and minocycline are long acting.

– No penetration into CSF

Uses

– Rickettsial infections, chlamydial infections, sexually transmitted diseases, acne, and brucellosis

– Used as alternate therapy in penicillin-allergic patients

Side effects

– GI disturbances

– Superinfections

– Damage to developing teeth and bones, liver damage (particularly in pregnant women who receive the drug intravenously)

— Photosensitization (particularly with demeclocycline)

– Parenteral forms are irritating.

Tetracycline staining of teeth

Tetracycline that is ingested is incorporated into developing enamel, causing intrinsic tooth discoloration. It appears as a yellow-brown band on the teeth that were forming at the time of the tetracycline therapy. It is not harmful to teeth but is unsightly and typically camouflaged by porcelain veneers.

 

Cholera

Cholera is an infectious disease caused by Vibrio cholerae, a gram-negative bacteria. It is spread via the fecal–oral route. Vibrio cholerae toxin increases cAMP concentrations in intestinal mucosal cells, causing the opening of Clchannels and massive secretion of Cl. This results in the production of a profuse amount of watery diarrhea which, in turn, causes severe dehydration. This can lead to kidney failure, shock, coma, and death. Treatment requires rapid replacement of lost body fluids with oral or IV solutions containing salts and sugar. Tetracycline reduces fluid loss and diminishes transmission of the bacteria.

 

Aminoglycosides

Streptomycin, Neomycin, Kanamycin, Gentamicin, and Amikacin

– Amikacin is a derivative of kanamycin.

Mechanism of action. All aminoglycosides inhibit bacterial protein synthesis. Streptomycin binds to a specific site on the 30S ribosomal subunit, but other aminoglycosides bind to sites on both the 30S and 50S ribosomal subunits. The antibacterial action is usually attributed to inhibition of protein synthesis, but disruption of cell membrane function caused by transport of the antibiotics across the bacterial cell membranes may also be involved (Fig. 29.6). Amikacin resists inactivation by many bacterial enzymes. These agents are bactericidal.

Spectrum. Aminoglycosides are broad-spectrum agents.

– Active against gram-positive and gram-negative bacteria

– Because aminoglycosides are actively transported into a bacterial cell by an oxygen-dependent enzyme system, only aerobic bacteria are sensitive to these drugs.

Pharmacokinetics

– Aminoglycosides are not absorbed from the GI tract but are readily absorbed from intramuscular or subcutaneous sites (Fig. 29.8).

– They are distributed to extracellular water, but penetrate CSF poorly, even when the meninges are inflamed.

Fig. 29.7 image Aspects of the therapeutic use of tetracyclines and chloramphenicol.

Tetracyclines are absorbed to varying degrees in the gastrointestinal (GI) tract. They tend to cause irritation to mucous membranes, and they alter the natural flora of the gut, which allows pathogenic bacteria to proliferate. These factors account for the GI upset that often accompanies tetracycline use. Tetracyclines also form insoluble complexes with cations, such as Ca2+ and Al3+, which cause them to be unable to be absorbed, to be unable to exert their antibacterial effects, and to lose their irritant properties. Chloramphenicol is completely absorbed following oral administration and shows high penetrability into tissues, including through the blood–brain barrier. Its toxicity to bone marrow severely limits its use.

image

— They are excreted in the urine after glomerular filtration of the parent compound.

– Neomycin is the most toxic agent.

Uses

– Tuberculosis (TB), bacterial endocarditis, plague, and tularemia (streptomycin)

– Gut sterilization (oral or topical neomycin)

Gentamicin, tobramycin, and netilmicin are essentially comparable agents for systemic use in serious infections. There may be slight differences in bacterial sensitivity or in their potential for renal or auditory toxicity.

Many infectious disease specialists feel that amikacin should be reserved for susceptible infections resistant to other aminoglycosides.

Kanamycin is an older agent that is seldom used.

Side effects

– Renal toxicity

– Ototoxicity (agents may damage both vestibular and auditory functions of the vestibulocochlear nerve)

– Allergic reactions occasionally occur.

Other Inhibitors of Protein Synthesis

Chloramphenicol

Mechanism of action. Chloramphenicol attaches at P sites of the 50S subunit of microbial ribosomes and inhibits functional attachment of the amino acyl end of amino acyl-tRNA to the 50S subunit. It is bacteriostatic.

Spectrum. Chloramphenicol is a broad-spectrum agent.

– Chloramphenicol is more effective than tetracyclines against typhoid fever and other Salmonella infections.

– There is good activity against many anaerobic bacteria and Rickettsia.

Notifiable diseases

Certain diseases must be reported by clinicians to the National Notifiable Diseases Surveillance System (NNDSS), operated by the Centers for Disease Control and Prevention (CDC). Examples of such diseases are human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDs), measles, mumps, pertussis, hepatitis C, meningococcal disease, typhoid fever, TB, polio, rubella, malaria, syphilis, and gonorrhea.

 

Pharmacokinetics

– Chloramphenicol is well absorbed after oral administration and is distributed into total body water. Its high lipid solubility results in excellent penetration into CSF, ocular fluids, and joint fluids (Fig. 29.7).

– It is rapidly excreted in urine, 10% as chloramphenicol and 90% as the glucuronide conjugate.

Uses. Chloramphenicol's broad spectrum and penetration into CSF makes it useful in meningitis, rickettsial infections, anaerobic infections, and Salmonella infections.

Side effects

– Irreversible aplastic anemia is a rare but serious effect. The risk of aplastic anemia limits its application to situations in which safer drugs are not likely to be effective.

– Reversible bone marrow depression

– “Gray baby” syndrome in neonates is due to deficient glucuronidation of the drug and its subsequent accumulation in the infant's body.

– Superinfection

Spectinomycin

This agent is chemically related to the aminoglycosides.

Fig. 29.8 image Aspects of the therapeutic use of aminoglycosides.

Aminoglycosides consist of glycoside-linked amino sugars. They contain numerous hydroxyl and amino groups that can bind protons; hence, they are highly polar. This renders them unable to diffuse through membranes, and thus unable to be adsorbed enterally. This lack of absorption is used by giving neomycin orally to eradicate intestinal bacteria (e.g., prior to bowel surgery) or to reduce NH3 formation by gut bacteria in hepatic coma. Otherwise, aminoglycosides are given by injection for serious infections. Aminoglycosides gain access to the bacterial interior via bacterial transport systems. In the kidney, they enter the proximal tubule via an uptake system for oligopeptides and cause damage to tubular cells. They can also cause damage to the vestibular apparatus and organ of Corti in the ear.

image

Mechanism of action. Spectinomycin binds at the 30S subunit of the microbial ribosome, but at a site different from that of streptomycin. The drug seems to be bacteriostatic rather than bactericidal because of reversible binding.

Pharmacokinetics

– Spectinomycin is not absorbed orally and is given intramuscularly.

– No penetration into CSF

Uses

– Used exclusively for one-shot treatment of gonorrhea

– Ineffective against syphilis

29.3 Inhibitors of Nucleic Acid Metabolism

Gyrase Inhibitors: Fluoroquinolones (Quinolones)

Ciprofloxacin, Gemifloxacin, Levofloxacin, Moxifloxacin, Norfloxacin, and Ofloxacin

Fluoroquinolones are chemically derived from the urinary antiseptic nalidixic acid and are all fluorinated compounds.

Mechanism of action. Fluoroquinolones inhibit bacterial DNA gyrase, an enzyme involved in DNA nicking and supercoiling, and are bactericidal drugs (Fig. 29.9).

Spectrum. Fluoroquinolones are broad-spectrum agents.

– Active against a wide variety of gram-negative bacteria, but gram-positive organisms are usually less susceptible

– Ciprofloxacin is highly active against Pseudomonas species.

– Anaerobic bacteria respond poorly to the fluoroquinolones.

Pharmacokinetics

– Well-absorbed after oral administration and widely distributed in the body, but highest concentrations accumulate in urine

– Renal excretion involves both glomerular filtration and active secretion.

– Fluoroquinolone metabolites have less antimicrobial activity than the parent drug.

– Their relatively long half-life allows twice-daily dosing.

– These agents penetrate CSF but are not approved for use in meningitis.

Uses

– Complicated infections of the genitourinary tract

– Abdominal, respiratory, skin, and soft tissue infections that are resistant to other agents

– Gram-negative bone infections

– Prophylaxis and treatment of anthrax

Side effects

– Fluoroquinolones are usually well tolerated.

– Irreversible damage to developing cartilage has been observed in studies with young animals; therefore, fluoroquinolones are not recommended for patients younger than 18 years or for use in pregnancy.

29.4 Inhibitors of Folate Metabolism (Antimetabolites)

Antimetabolites are substances that have structural similarity to substrates used in intermediary metabolism of the cell and that compete for enzymatic binding sites. Examples include purine and pyrimidine analogs used in cancer or antiviral chemotherapy, as well as the sulfonamide antibacterial drugs that are discussed in this section. The ultimate effects of these antimetabolites may be exerted on nucleic acids, proteins, and cell walls.

Sulfonamides (Sulfas)

Sulfacytine, Sulfadiazine, Sulfamethizole, Sulfisoxazole, and Sulfamethoxazole

Mechanism of action. Sulfonamides are structurally similar to p-aminobenzoic acid (PABA). They inhibit the synthesis of dihydrofolic acid in microbes that must synthesize dihydrofolic acid from PABA (Fig. 29.10). Dihydrofolic acid is then reduced to form tetrahydrofolic acid by dihydrofolate reductase. This is required for the synthesis of purines and pyrimidines and amino acids. They are bacteriostatic at concentrations achieved in most body tissues and fluids, but bactericidal concentrations may be found in the urine.

Spectrum. The sulfonamides are broad-spectrum agents.

– Effective against most gram-positive bacteria, many gram-negative bacteria, Nocardia, Actinomyces, Chlamydia, and Plasmodium

Pharmacokinetics

– Sulfonamides are readily absorbed after oral administration.

– Sodium salts may be given intravenously, but they are strongly alkaline and cause pain and tissue sloughing if extravasated (i.e., if the drug leaks into surrounding tissue).

Fig. 29.9 image Antibacterial drugs acting on DNA.

Antibacterial drugs act on bacterial DNA, preventing the reading of the genetic information at the DNA template, thus damaging the regulatory center of cell metabolism. Gyrase (topoisomerase II) catalyzes the supercoiling of DNA strands. It does this by opening, underwinding, and closing the DNA strand such that the full loop need not be rotated. Gyrase inhibitors (green portion of ofloxacin formula) seem to act to prevent the resealing of opened strands. Metronidazole damages DNA by complex formation or strand breakage. Anaerobic bacteria are able to convert metronidazole to reactive metabolites that attack DNA; thus; it is effective only in this group of bacteria. Rifampin inhibits DNA-dependent RNA polymerase, the enzyme that catalyzes RNA transcription from the DNA template.

image

— Sulfonamides are 20 to 90% bound to plasma albumin, depending on the sulfonamide and its concentration. Free (unbound) drug is distributed to total body water.

– Sulfonamides are eliminated in the urine by glomerular filtration and tubular secretion.

– Metabolites include acetylated and glucuronide conjugates, along with oxidized products.

– Sulfacytine, sulfadiazine, sulfamethizole, and sulfisoxazole are short-acting sulfonamides that are rapidly absorbed and excreted into the urine, giving high urinary concentrations. They are usually given four times daily.

– Sulfamethoxazole is an intermediate-acting sulfonamide. Its longer half-life allows dosing at 8- to 12-hour intervals.

– No penetration into CSF

Uses

– Sulfonamides are used primarily in urinary tract infections, but they have been useful in tularemia, nocardia, actinomycosis, and resistant falciparum malaria.

– Burns (mafenide [not a true sulfonamide] and silver sulfadiazine)

– Trisulfapyrimidine: contains equal amounts of sulfadiazine, sulfamerazine, and sulfamethazine; an old “triple sulfa” formulation for additive antibacterial effects but less chance of crystalluria

Side effects

– Sulfonamides may precipitate in acidic urine and cause renal damage.

– Drug allergy

– Toxicity to the hematopoietic system (acute hemolytic anemia, thrombocytopenia, etc.)

Resistance. Resistance has developed in many bacterial strains to sulfonamides.

29.5 Miscellaneous Antibacterial Drugs

Polymyxin B and Colistin

Mechanism of action. These are polypeptide antibiotics that damage the bacterial cytoplasmic membrane and are bactericidal.

Spectrum. Polymyxin B and colistin are primarily active against gram-negative organisms, particularly Pseudomonas.

Pharmacokinetics. These agents do not penetrate CSF but can be used topically or intravenously for meningitis (inflamed meninges allow penetration).

Uses. They may be used systemically in life-threatening infections resistant to safer antibiotics.

Polymyxin is available in combination with neomycin and hydrocortisone for topical treatment of eye and ear infections.

Side effects. Renal damage and various neurologic changes limit the usefulness of these drugs to topical applications.

Metronidazole

Mechanism of action. Metronidazole has a cytotoxic effect on bacteria by damaging DNA, but the precise mechanism of action is unclear (Fig. 29.9).

Spectrum. Active against amebic infections and many anaerobic bacteria, including C. difficile and B. fragilis.

Pharmacokinetics. Well absorbed after oral administration

Side effects

– Neurologic effects, disulfiram-like inhibition of aldehyde dehydrogenase, Na+ retention, and various GI symptoms

Anaerobic bacteria

The mucosal surfaces of the upper respiratory tract, GI tract, and genitourinary tract are colonized with a large number of anaerobic microbes. The infections are usually not transmissible and are polymicrobic, (they involve several different species). Infections with nonspore-forming anaerobes lead to necrosis and abscess formation and are chronic. Specific clinical syndromes include skin and soft tissue infections, gynecologic infections, respiratory tract infections, brain abscesses, bacteremia, and intra-abdominal infections.

 

Anaerobic infections

Clues for anaerobic infection are as follows:

– Clinical setting influence (i.e., infection following bowel surgery)

– Proximity to a mucosal surface

– Infectious discharge that is foul-smelling

– Presence of gas in tissue (palpable masses that move may be gas)

– Dead and necrotic tissue, or the presence of intestinal pseudomembrane

– Bite wound infections from humans or animals

– Malignancy-associated infections

– Presence of septic thrombophlebitis

– Infections that are slow to respond to antibiotics

– Presence of sulfur granules (actinomycosis)

– Laboratory cultures that are negative under aerobic culture

– Polymicrobial Gram stain assessment

 

Fig. 29.10 image Inhibitors of tetrahydrofolate synthesis.

Bacteria, unlike humans, are able to synthesize dihydrofolic acid (DHF), which is converted to tetrahydrofolic acid (THF) by the enzyme dihydrofolate reductase. THF is then used to synthesize purines and thymidine. Sulfonamides structurally resemble p-aminobenzoic acid (PABA), a precursor in DHF synthesis. They act as a false substrate and so competitively inhibit the utilization of PABA, and hence DHF synthesis. Trimethoprim inhibits bacterial DHF-reductase. The human enzyme is less sensitive to this than the bacterial one, so it is relatively selectively toxic for bacteria. Co-trimoxazole is a combination of trimethoprim and sulfamethoxazole, so THF synthesis is inhibited on two fronts. Sulfasalazine, a drug used in inflammatory bowel disease (e.g., Crohn disease and ulcerative colitis), is cleaved by intestinal bacteria to mesalamine and sulfapyridine. Mesalamine exerts its antiinflammatory effects on the gut mucosa when present in high concentrations. Coupling to sulfonamide prevents premature absorption in the upper small bowel, but it can be absorbed following cleavage, and may exert typical adverse effects.

image

Fig. 29.11 image Drugs used to treat infections with mycobacteria (1. tuberculosis, 2. leprosy).

Antitubercular drugs of choice are shown (1). Their mechanisms of action are unclear, but isoniazid is converted to isonicotinic acid in the bacterium. This substance is unable to diffuse through cell membranes and so accumulates intracellularly. Antileprotic drugs shown (2) are frequently combined with rifampin. Dapsone inhibits dihydrofolate (DHF) synthesis. Clofazimine is a dye with bactericidal effects against M. leprae. CNS, central nervous system.

image

Table 29.2 provides a summary of common bacteria, the antimicrobial agents of choice to treat infections, and secondary agents that may be used if the primary agent is unsuccessful.

  Table 29.2 image Summary of the Treatment of Microorganisms

Microorganisms

Primary Antimicrobial Drugs

Secondary Antimicrobial Drugs

Gram-positive cocci

Staphylococcus aureus or S. epidermidis

Penicillinase-resistant penicillins: naficillin, oxacillin, cloxicillin, dicloxicillin, or methicillin

Vancomycin ± gentamicin

Enterococcus

Penicillin G + gentamicin

Vancomycin + gentamycin

Streptococcus

Penicillin G or penicillin V

Clindamycin or erythromycin

Penicillin-resistant S. pneumonia

Vancomycin + third-generation cephalosporin

 

Gram-positive bacilli

Bacillus cereus

Vancomycin

 

Bacillus anthracis

Fluoroquinolone

 

Listeria

Ampicillin ± gentamicin

 

Clostridium difficile

Metronidazole or vancomycin

 

Gram-negative cocci

Neisseria gonorrhoeae

Ceftriaxone

 

Neisseria meningitides

Penicillin G

 

Gram-negative bacilli

Enterobacteriaceae

   

Escherichia

Third-generation cephalosporin

 

Yersinia pestis

Streptomycin or tetracycline

 

Proteus mirabilis

Ampicillin

 

Proteus vulgaris

Third- or fourth-generation cephalosporin

 

Salmonella

Ceftriaxone or a fluoroquinolone

 

Shigella

Fluoroquinolone

 

Enterobacter

Imipenem

 

Klebsiella

Third- or fourth-generation cephalosporin

 

Campylobacter jejuni

Erythromycin

 

Legionella

Azithromycin or a fluoroquinolone ± rifampin

 

Vibrio cholera

Tetracycline

 

Helicobacter pylori

Amoxicillin + clarithromycin + omeprazole or tetracycline + metronidazole + bismuth subsalicylate

 

Bacteroides

Metronidazole

 

Miscellaneous

Mycobacterium tuberculosis

Isoniazid + rifampin + pyrazinamide ± ethambutol

 

Mycobacterium leprae

Dapsone + rifampin ± clofazimine

 

Spirochetes

Treponema pallidum

Penicillin G

 

Leptospira

Penicillin G

 

Borrelia burgdorferi

Doxycycline

 

Mycoplasma

Macrolide or fluoroquinolone

 

Chlamydia

Doxycycline

 

Rickettsia

Doxycycline

 

29.6 Antimycobacterial Drugs

Tuberculosis (TB) is an infection spread by inhalation of Mycobacterium tuberculosis that mainly affects the lungs. Most infected individuals have asymptomatic latent infections. Active TB occurs in ~10% of untreated individuals with latent infections, particularly in response to decreased immune function caused by stress, malnutrition, or other diseases. Most cases (75%) are pulmonary, with a chronic cough accompanied by malaise, anorexia, fever, chills, and night sweats. When the infection moves outside the lungs, it is denoted extrapulmonary TB.

Antimycobacterial drugs are used to treat TB, caused by M. tuberculosisM. avium-intracellulare complex, caused by M. avium-intracellulare; and Hansen disease (leprosy), caused by Mycobacterium leprae. Therapy for active mycobacterial infections includes at least two drugs to prevent failure due to emergence of resistant strains and continues for at least 6 months.

Antituberculosis Drugs

Isoniazid (Isonicotine Hydrazine [INH])

Mechanism of action. Isoniazid, or isonicotine hydrazine (INH), inhibits cell wall synthesis. It can be either tuberculostatic or tuberculocidal, depending on its concentration (Fig. 29.11).

Spectrum. INH is effective only against mycobacteria.

Pharmacokinetics

– INH is readily absorbed after oral administration and is widely distributed in the body, including into CSF and tissues.

– Fast acetylators metabolize the drug more rapidly than slow acetylators.

Uses

– Used for prophylaxis as well as for treatment of active mycobacterial infections

Side effects

– INH reacts chemically with pyridoxal and causes peripheral neuritis (adults) and convulsions (children). However, co-administration of vitamin B6 prevents these symptoms.

– Some patients may develop isoniazid-induced hepatitis during the first 3 months of therapy. Risk is higher in older patients. Ten to 20% of patients have asymptomatic minor elevations of transaminases that often resolve with continued therapy. Otherwise, INH is usually well-tolerated in most patients.

Ethambutol

Mechanism of action. Ethambutol is a bacteriostatic agent that inhibits bacterial cell wall synthesis.

Pharmacokinetics

– Given orally

Uses

– Combination therapy of TB (M. tuberculosis) and M. avium-intracellulare

Side effects. Ethambutol is usually well tolerated, but retrobulbar neuritis is seen occasionally at high doses.

Resistance

– Develops slowly

Retrobulbar neuritis

Retrobulbar neuritis is a form of optic neuritis in which the optic nerve becomes inflamed behind the eyeball. It is most commonly caused by drugs, multiple sclerosis, meningitis, syphilis, and tumors. Symptoms include pain on moving the eyes, blurred vision or loss of vision, and tenderness of the eye to pressure. This condition may resolve without the need for treatment, or prednisone may be required.

 

Rifampin

Mechanism of action. Rifampin inhibits DNA-directed RNA synthesis. It may be bacterio-static or bactericidal, depending on the concentration (Fig. 29.2).

Spectrum

– Active against M. tuberculosis and other microbes

Pharmacokinetics

– Orally effective

Resistance. Resistance develops rapidly and limits its usefulness.

Uses

– Primarily used to treat TB

– Prevention of Haemophilus influenzae type B (HiB) infection

Side effects

– Gives a harmless orange color to body fluids, including contact lenses

– Induces most P-450 enzymes, which enhances elimination of warfarin, phenytoin, estrogen, and other drugs

Antibiotics and the contraceptive pill

Antibiotics are thought to reduce the efficacy of the contraceptive pill, although the extent to which they do this is subject to debate. Rifampin and griseofulvin are known to induce hepatic enzymes and hasten the metabolism of the contraceptive pill. Other broad-spectrum antibiotics affect the absorption of estrogen from the gut by eradicating the bacterial flora responsible for this. Patients are advised to use barrier methods of contraception, in addition to using the contraceptive pill, while taking antibiotics and for 1 week after.

 

Pyrazinamide

Mechanism of action. The mechanism of action is uncertain.

Pharmacokinetics

– Orally effective

Uses

– TB

Side effects. Patients must be monitored for signs of hepatotoxicity.

Table 29.3 lists the protocols for the treatment of TB.

  Table 29.3 image Protocol for the Treatment of Tuberculosis

Treatment Type

Antimicrobial Protocol

 

Standard treatment

Combination therapy with isoniazid, rifampin, and pyrazin-amide for 6 months

 

Prototype therapy for active TB

First 2 months: isoniazid, rifampin, pyrazinamide, and ethambutol (can be stopped if bacterial isolates test negative for resistance). This combination may be extended an additional 3 months if culture remains positive at end of first 2 months

Next 4 months: isoniazid, rifampin

 

Prototype therapy for quiescent, previously untreated pulmonary TB (positive skin test with fibrotic upper lobe lesions)

Isoniazid alone for 1 year, or isoniazid, rifampin, and pyrazin-amide for 3 months until cultures are negative and chest radiograph is stable

 

29.7 Antileprotic Drugs

Dapsone (Diaminophenylsulfone [DDS])

Mechanism of action. Dapsone's mechanism of action is similar to that of sulfonamides. It is bactericidal.

Pharmacokinetics. Its long half-life permits once-weekly administration.

Uses

– Leprosy

– DDS is sometimes used in the treatment of chloroquine-resistant malaria.

Side effects

– Hemolysis is a serious side effect.

– Exacerbation of lepromatous leprosy may occur.

Clofazimine

Mechanism of action. Clofazimine's mechanism is uncertain. However, clofazimine has antiinflammatory properties combined with slow antibacterial effects.

Uses

– Leprosy

29.8 Antiseptics and Disinfectants

Urinary Antiseptics

Urinary antiseptics are defined as substances that can be given orally but provide significant antibacterial effects only in the urine.

Trimethoprim

Mechanism of action. Trimethoprim causes selective inhibition of bacterial dihydrofolate reductase. It may be bacteriostatic or bactericidal.

Uses

– The only approved indication as a sole agent is for uncomplicated urinary tract infections caused by susceptible organisms.

– It is most often used in combination with sulfamethoxazole.

Urinary tract infections

Urinary tract infections (UTIs) are common, especially in women due to the proximity of the urethra to the vagina (allowing easier spread of sexually transmitted infections and diseases) and due to the relative length of the urethra compared to men (men have longer urethras). UTIs present with any of the following symptoms: frequency of urination, urgency, strangury (frequent, painful expulsion of small amounts of urine despite urgency), hematuria (blood in the urine), cloudy urine, incontinence, fever with diarrhea and vomiting, and pain (usually suprapubic pain in women and anal pain in men). Trimethoprim with sulfamethoxazole is given to treat uncomplicated UTIs caused by susceptible bacteria (E. coliStaphylococci, Streptococci, Pseudomonas, and Proteus). In addition, patients are advised to drink plenty of fluids and urinate often.

 

Nitrofurantoin

Mechanism of action. This agent has bacteriostatic activity against several urinary tract pathogens. It appears to work by affecting the bacterial metabolism of the drug, which results in the formation of reactive metabolites that attack DNA.

Uses

– Urinary tract infections

Side effects. Hypersensitivity reactions, nausea, and vomiting are limitations to its usefulness, but a crystalline form of nitrofurantoin has a reduced incidence of GI intolerance.

Resistance

– Rarely develops

External Antiseptics and Disinfectants

Germicides that are too toxic for internal use but that may be effective for removal of microbes from the skin (disinfectants) or surgical instruments (antiseptics) have important roles in medicine or dentistry. Some examples are included in Table 29.4.

  Table 29.4 image External Antiseptics and Disinfectants

Class of Substance

Examples

 

Detergents

Anionic: ordinary soaps

Cationic: benzalkonium chloride

 

Phenols (probably also act as detergents)

Phenol: hexylresorcinol

Cresol: hexachlorophene

 

Alcohols

Ethanol and isopropyl alcohol

 

Halogens

Chlorine, chloramines, and iodine

 

Metals

Silver (used in combination with sulfadiazine) and mercury (thimerosal)

 

Oxidants

Hydrogen peroxide, permanganate, sodium peroxide, and perborate