ACIDS, ALKALIS, GLUCOSE. PLASMA SUBSTITUTES. SOLUTIONS FOR PARENTERAL NUTRITION. (Acidum salicilicum, Acidum benzoicum, acidum dehydrochloricum delutum, Natrii hydrocarbonas, Magnesii oxydum, Solutio Ammonii caustici, Aluminii hydroxidum, Kalii chloridum, Asparcam (Pananginum), Magnesii sulfas, Calcii chloridum, Calcii gluconas, Natrii chloridum, Solutio Ringer-Lokka, Trisol, Lipofundinum, Glucosa, Albuminum, Natrii carbonas, Trisaminum, Reopolyglukin, Gelatynolum, Neohemodes)
Plasma substitutes
de la glucosa poco soluble
History: Plasma volume expanders are used for treatment of circulatory shock. They restore vascular volume thereby stabilizing circulatory hemodynamics and maintaining tissue perfusion. Two general categories of volume expanders exist: crystalloids and colloids. The crystalloids most commonly used in clinical practice are normal saline (0.9% NaCl) or lactated Ringer’s (LR) solutions, although many others are available. Colloids include the naturally occuring plasma substances (albumin, plasma protein fractions) and synthetic colloids (dextran, hetastarch). Debate regarding the preferred general type of volume expander has been ongoing.
Albumin is normally present in the blood and constitutes 50-60% of the plasma proteins and 80-85% of the oncotic pressure. Plasma protein fraction consists of 88% albumin and 12% globulins. Plasma protein fraction is effective in maintaining blood volume, but it does not maintain an increased oncotic pressure. Albumin and plasma protein fraction are derived from pooled human blood, plasma, serum, or placentas. Because of the source of these products, there may be risks for hypotension (secondary to naturally occuring prekallikrein activators) and hepatitis. The purification process used in the preparation of these products reduces this risk.
Albumin has been available since 1942, but the high cost of albumin still makes its use in clinical practice somewhat prohibitive. A recombinant form is due to begin clinical trials in 1995.
Dextran and hetastarch are synthetic colloidal volume expanders. Dextran was first described by a German chemist Schleibler and was approved in 1951 as a 6% solution. Dextran 70/75 was approved by the FDA in 1953 and Dextran
Mechanism of Action: Albumin, dextran, and hetastarch produce volume expansion by increasing the oncotic pressure within the intravascular space. Dextran 70, dextran 75 and hetastarch all exert osmotic effects similar to those of albumin. Administration of volume expander products causes water to move from interstitial spaces into the intravascular space, thereby increasing the circulating blood volume. This increased volume causes an increase in central venous pressure, cardiac output, stroke volume, blood pressure, urinary output, and capillary perfusion, and a decrease in heart rate, peripheral resistance, and blood viscosity. In dehydrated patients, albumin has little or clinical effect on circulating blood volume. Administration of a volume of 25% albumin solution causes 3.5 times the administered volume to be drawn into the circulation within 15 minutes. Following a single infusion of dextran circulating blood volume is increased maximally within a few minutes following infusion of dextran 40 and within 1 hour after dextran 70 or 75. Hetastarch produces a volume expansion that is slightly greater than the administered volume, with maximum expansion occurring within minutes. The duration of volume expansion usually lasts for approximately 24 hours for all of these products. Dextran 40, unlike the higher MW dextran products, also improves microcirculation independently of its volume-expanding effects. The exact mechanism of this activity is unknown, but it is believed to occur by minimizing erythrocyte aggregation and/or decreasing blood viscosity.
Dextran 40 is also believed to coat erythrocytes, which maintains erythrocyte electronegativity and, in turn, decreases the attraction between erythrocytes and reduces erythrocyte rigidity which aids in passage through capillaries. Dextran is used clinically in the prophylaxis of venous thrombosis and pulmonary embolism in patients undergoing surgery that carries a high risk of thromboembolic complications (e.g., hip surgery).
Distinguishing Features: Albumin is a low-molecular-weight protein derived from pooled human blood, plasma, serum, or placentas. Commercially available albumin human solutions have no blood-clotting factors, no effective Rh factor, or other antibodies. Dextran is a branched polysaccharide formed by a bacterium, Leuconostoc mesenteroides. Hetastarch is a synthetic polymer, available as a colloidal solution. Albumin is also responsible for the transport of a variety of substances including bilirubin, calcium, and many drugs. Hetastarch has no oxygen-carrying capacity. Albumin is also used in combination with loop diuretics in the treatment of nephrotic syndrome, and in combination with exchange transfusions to bind bilirubin in patients with hyperbilirubinemia and erythroblastosis fetalis. Albumin is also used to replace protein in patients with hypoproteinemia until the cause of the deficiency can be determined.
Dextran
is available in various molecular weights, and these products exhibit different osmotic and pharmacologic properties. Dextran 40 contains molecules of molecular weight (MW) 40,000 daltons while dextran 70 contains molecules of 70,000 daltons.
Both types of products contain molecules of varying molecular weights, some lower and some higher than the stated label. Hetastarch causes an increase in the erythrocyte sedimentation rate (ESR) when added to whole blood and is used to facilitate the collection of granulocytes in leukopheresis. Compared with dextran 75, hetastarch causes a greater increase in the ESR. Some clinicians have strong opinions regarding the pros and cons of using a crystalloid-type versus a colloid-type plasma expander. In a study of 26 patients with hypovolemia and septic shock, the hemodynamic and respiratory effects of NS, albumin, and hetastarch were compared. Patients were administered enough plasma volume expander to reach a target central venous pressure (CVP). Approximately 2 to 4 times greater fluid volume was needed using NS compared to albumin and hetastarch. The only hemodynamic differences included a greater increase in cardiac output and cardiac index in the albumin and hetastarch groups compared to the NS group. Colloid osmotic pressure decreased below baseline in the NS group, resulting in a significantly higher incidence of pulmonary edema in the NS group compared to the albumin and hetastarch groups. Both albumin and hetastarch groups maintained or increased the colloid osmotic pressure compared to baseline. In general there were no significant differences between the albumin and hetastarch groups.
Adverse Reactions: Anaphylactoid reactions can occur with hetastarch, albumin, or any of the dextran preparations. Dextran is formed by a bacterium, Leuconostoc mesenteroides, which contributes to its antigenicity; however, due to improved preparation techniques, the incidence of hypersensitivity reactions is reduced. Of the dextran products, dextran 40 has less potential for causing these adverse reactions. The risk of antigenicity is less with hetastarch compared to dextran. High doses or repeat administration of albumin is more likely to produce anaphylactoid reactions than low doses of albumin. Close observation during the first few minutes of administration of these products is essential. Allergic reactions include urticaria, nasal congestion, wheezing, tightness of the chest, nausea and vomiting, periorbital edema, and hypotension, which can be mild or severe. Volume expander therapy should be stopped at the first sign of allergic reactions. Because substances with a molecular weight of 50,000 or less can be filtered by the glomerulus, dextran 40 could cause renal injury if tubular flow is decreased. Dextran 40 undergoes rapid urinary excretion, increasing the viscosity and specific gravity of urine. Patients with a reduced flow of urine are especially susceptible to tubular stasis and blocking. Adequate hydration is essential during therapy with dextran 40. Dextran 70 contains molecules of roughly 70,000 daltons. Renal failure does not occur with dextran 70 or 75 because of its limited renal clearance.
Aluminum has been detected as a contaminate of albumin products. There have been reports of accumulation of the aluminum ions, with subsequent toxicity (e.g. encephalopathy, osteodystrophy). Aluminum toxicity is more likely to occur in patients with impaired renal function receiving human albumin (e.g. via plasmaphoresis procedures). Volume overload may lead to cardiovascular effects. Excessive administration of albumin, dextran or hetastarch can precipitate cardiac failure, pulmonary edema, peripheral edema of the lower extremities, hypertension, or tachycardia. Hypotension following administration of albumin and plasma protein fraction can occur. Hypotension is due to prekallikrein activators (Hageman-factor fragments) which are found in very low concentrations in albumin products. Prekallikrein activators are found in higher concentrations in plasma protein fraction, causing a higher incidence of hypotension.Bleeding is a major concern with hetastarch therapy. Hetastarch appears to affect total platelet count, and hemodilution can exacerbate this. A prolonged bleeding time, partial thromboplastin time and prothrombin time can result as a temporary adverse effect. Effects on coagulation are minor, however, at volumes of less than 1500 ml or 20 ml/kg.Adverse GI effects have been reported from use of dextran 70 or 75 and hetastarch, including abdominal pain, parotid gland enlargement, nausea, and vomiting.
Beta-Lactam Antibiotics & Other Inhibitors of Cell Wall Synthesis
Beta-Lactam Compounds
Penicillins
The penicillins are classified as -lactam drugs because of their unique four-membered lactam ring. They share features of chemistry, mechanism of action, pharmacologic and clinical effects, and immunologic characteristics with cephalosporins, monobactams, carbapenems, and –lactamase inhibitors, which also
are – lactam compounds
.
Chemistry
All penicillins have the basic structure shown in Figure 43–1. A thiazolidine ring (A) is attached to a -lactam ring (B) that carries a secondary amino group (RNH–). Substituents (R; examples shown in Figure 43–2) can be attached to the amino group. Structural integrity of the 6-aminopenicillanic acid nucleus is essential for the biologic activity of these compounds. If the -lactam ring is enzymatically cleaved by bacterial -lactamases, the resulting product, penicilloic acid, lacks antibacterial activity.
The attachment of different substitutents to 6-aminopenicillanic acid determines the essential pharmacologic and antibacterial properties of the resulting molecules. Penicillins can be assigned to one of three groups (below). Within each of these groups are compounds that are relatively stable to gastric acid and suitable for oral administration, eg, penicillin V, dicloxacillin, and amoxicillin. The side chains of some representatives of each group are shown in Figure 43–2, with a few distinguishing characteristics. Penicillins (eg, penicillin G).
These have the greatest activity against gram-positive organisms, gram-negative cocci, and non- – lactamase-producing anaerobes. However, they have little activity against gram-negative rods.
They are susceptible to hydrolysis by lactamases.
These drugs retain the antibacterial spectrum of penicillin and have improved activity against gramnegative organisms, but they are destroyed by lactamases.
Figure 43–1.
Penicillin Units and Formulations
The activity of penicillin G was originally defined in units. Crystalline sodium penicillin G contains approximately 1600 units/mg (1 unit =
Semisynthetic penicillins are prescribed by weight rather than units. The minimum inhibitory concentration (MIC) of any penicillin (or other antimicrobial) is usually given in g/mL.
Most penicillins are dispensed as the sodium or potassium salt of the free acid. Potassium penicillin G contains about 1.7 meq of K+ per million units of penicillin (2.8 meq/g). Nafcillin contains Na+, 2.8 meq/g. Procaine salts and benzathine salts of penicillin G provide repository forms for intramuscular injection. In dry crystalline form, penicillin salts are stable for long periods (eg, for years at
Mechanism of Action
Penicillins, like all -lactam antibiotics, inhibit bacterial growth by interfering with a specific step in bacterial cell wall synthesis. The cell wall is a rigid outer layer that is not found in animal cells. It completely surrounds the cytoplasmic membrane (Figure 43–3), maintaining the shape of the cell and preventing cell lysis from high osmotic pressure. The cell wall is composed of a complex crosslinked polymer, peptidoglycan (murein, mucopeptide), consisting of polysaccharides and polypeptides. The polysaccharide contains alternating amino sugars, N-acetylglucosamine and Nacetylmuramic acid (Figure 43–4). A five-amino-acid peptide is linked to the N-acetylmuramic acid sugar. This peptide terminates in D-alanyl-D-alanine. Penicillin-binding proteins (PBPs) catalyze the
transpeptidase reaction that removes the terminal alanine to form a crosslink with a nearby peptide, which gives cell wall its structural rigidity. -Lactam antibiotics are structural analogs of the natural D-Ala-D-Ala substrate and they are covalently bound by PBPs at the active site. After a –lactam antibiotic has attached to the PBP, the transpeptidation reaction is inhibited (Figure 43–5), peptidoglycan synthesis is blocked, and the cell dies. The exact mechanism responsible for cell death is not completely understood, but autolysins, bacterial enzymes that remodel and break down cell wall, are involved.
Penicillins and cephalosporins are bactericidal only if cells are actively growing and synthesizing cell wall.
Cephalosporins & Cephamycins
Cephalosporins and cephamycins are similar to penicillins chemically, in mechanism of action, and in toxicity. Cephalosporins are more stable than penicillins to many bacterial -lactamases and therefore usually have a broader spectrum of activity. Cephalosporins are not active against enterococci and Listeria monocytogenes.
Chemistry
The nucleus of the cephalosporins, 7-aminocephalosporanic acid (Figure 43–6), bears a close resemblance to 6-aminopenicillanic acid (Figure 43–1). The intrinsic antimicrobial activity of natural cephalosporins is low, but the attachment of various R1 and R2 groups has yielded drugs of good therapeutic activity and low toxicity (Figure 43–6). The cephalosporins have molecular weights of 400–450. They are soluble in water and relatively stable to pH and temperature changes. Cephalosporins can be classified into four major groups or generations, depending mainly on the spectrum of antimicrobial activity. As a general rule, first-generation compounds have better activity against gram-positive organisms and the later compounds exhibit improved activity against gram-negative aerobic organisms. Other Beta Lactam Drugs
Monobactams
These are drugs with a monocyclic -lactam ring (Figure 43–1)
They are relatively resistant to lactamases and active against gram-negative rods (including pseudomonas and serratia). They have no activity against gram-positive bacteria or anaerobes.
Aztreonam is the only monobactam available in the
100 g/mL. The half-life is 1–2 hours and is greatly prolonged in renal failure.
Penicillin-allergic patients tolerate aztreonam without reaction. Occasional skin rashes and elevations of serum aminotransferases occur during administration of aztreonam, but major toxicity has not yet been reported. The clinical usefulness of aztreonam has not been fully defined.
Beta-Lactamase Inhibitors (Clavulanic Acid, Sulbactam, & Tazobactam)
These substances resemble -lactam molecules (Figure 43–7) but themselves have very weak antibacterial action. They are potent inhibitors of many but not all bacterial lactamases and can protect hydrolyzable penicillins from inactivation by these enzymes. -Lactamase inhibitors are most active against Ambler class A lactamases (plasmid-encoded transposable element [TEM] – lactamases in particular) such as those produced by staphylococci, H influenzae, N gonorrhoeae,
salmonella, shigella, E coli, and K pneumoniae. They are not good inhibitors of class C – lactamases, which typically are chromosomally encoded and inducible, produced by enterobacter, citrobacter, serratia, and pseudomonas, but they do inhibit chromosomal lactamases of legionella, bacteroides, and branhamella. The three inhibitors differ slightly with respect to pharmacology, stability, potency, and activity, but these differences are of little therapeutic significance. -Lactamase inhibitors are available only in fixed combinations with specific penicillins. The antibacterial spectrum of the combination is determined by the companion penicillin, not the -lactamase inhibitor. (The fixed combinations available in the
The indications for penicillin- -lactamase inhibitor combinations are empirical therapy for infections caused by a wide range of potential pathogens in both immunocompromised and immunocompetent patients and treatment of mixed aerobic and anaerobic infections, such as intraabdominal infections.
Figure 43–6.
Doses are the same as those used for the single agents except that the recommended dosage of piperacillin in the piperacillin-tazobactam combination is
Adjustments for renal insufficiency are made based on the penicillin component.
Carbapenems
The carbapenems are structurally related to -lactam antibiotics (Figure 43–1). Ertapenem, imipenem, and meropenem are licensed for use in the
Enterococcus faecium, methicillin-resistant strains of staphylococci, Clostridium difficile, Burkholderia cepacia, and Stenotrophomonas maltophilia are resistant. Imipenem is inactivated by dehydropeptidases in renal tubules, resulting in low urinary concentrations. Consequently, it is administered together with an inhibitor of renal dehydropeptidase, cilastatin, for clinical use.
Meropenem is similar to imipenem but has slightly greater activity against gram-negative aerobes and slightly less activity against gram-positives. It is not significantly degraded by renal dehydropeptidase and does not require an inhibitor. Ertapenem is less active than meropenem or imipenem against Pseudomonas aeruginosa and acinetobacter species. It is not degraded by renal dehydropeptidase.
Carbapenems penetrate body tissues and fluids well, including the cerebrospinal fluid. All are cleared renally, and the dose must be reduced in patients with renal insufficiency. The usual dose of imipenem is 0.25–0.5 g given intravenously every 6–8 hours (half-life 1 hour). The usual adult dose of meropenem is
Carbapenems are active against many highly penicillin-resistant strains of pneumococci.
A carbapenem is the – lactam antibiotic of choice for treatment of enterobacter infections, since it is resistant to destruction by the lactamase produced by these organisms.
Strains of Pseudomonas aeruginosa may rapidly
develop resistance to imipenem or meropenem, so simultaneous use of an aminoglycoside is recommended for infections caused by those organisms. Ertapenem is insufficiently active against P
aeruginosa and should not be used to treat infections caused by that organism. Imipenem or meropenem with or without an aminoglycoside may be effective treatment for febrile neutropenic patients.
The most common adverse effects of carbapenems—which tend to be more common with imipenem—are nausea, vomiting, diarrhea, skin rashes, and reactions at the infusion sites.
Excessive levels of imipenem in patients with renal failure may lead to seizures. Meropenem and ertapenem are less likely to cause seizures than imipenem. Patients allergic to penicillins may be allergic to carbapenems as well.
Other Inhibitors of Cell Wall Synthesis
Vancomycin
Vancomycin is an antibiotic produced by Streptococcus orientalis. With the single exception of flavobacterium, it is active only against gram-positive bacteria, particularly staphylococci.
Vancomycin is a glycopeptide of molecular weight 1500. It is water-soluble and quite stable.
Mechanisms of Action & Basis of Resistance
Vancomycin inhibits cell wall synthesis by binding firmly to the D-Ala-D-Ala terminus of nascent peptidoglycan pentapeptide (Figure 43–5). This inhibits the transglycosylase, preventing further elongation of peptidoglycan and cross-linking. The peptidoglycan is thus weakened and the cell becomes susceptible to lysis. The cell membrane is also damaged, which contributes to the antibacterial effect. Resistance to vancomycin in enterococci is due to modification of the D-Ala-D-Ala binding site of the peptidoglycan building block in which the terminal D-Ala is replaced by D-lactate. This results in the loss of a critical hydrogen bond that facilitates high-affinity binding of vancomycin to its target and loss of activity. This mechanism is also present in vancomycin-resistant S aureus strains (MIC 32 g/mL), which have acquired the enterococcal resistance determinants. The mechanism for reduced vancomycin susceptibility of vancomycin-intermediate strains (MICs = 8–16 g/mL) is not known.
Antibacterial Activity
Vancomycin is bactericidal for gram-positive bacteria in concentrations of 0.5–10 g/mL. Most pathogenic staphylococci, including those producing lactamase and those resistant to nafcillin and methicillin, are killed by 4 g/mL or less. Vancomycin kills staphylococci relatively slowly and only if cells are actively dividing; the rate is less than that of the penicillins both in vitro and in vivo. Vancomycin is synergistic with gentamicin and streptomycin against E faecium and E faecalis strains that do not exhibit high levels of aminoglycoside resistance.
Pharmacokinetics
Vancomycin is poorly absorbed from the intestinal tract and is administered orally only for the treatment of antibiotic-associated enterocolitis caused by Clostridium difficile. Parenteral doses must be administered intravenously.
A 1 hour intravenous infusion of
Vancomycin in combination with gentamicin• Pharyngitis, tonsillitis
is an alternative regimen for treatment of enterococcal endocarditis in a patient with serious penicillin allergy.
Vancomycin (in combination with cefotaxime, ceftriaxone, or rifampin) is also recommended for treatment of meningitis suspected or known to be caused by a highly penicillin-resistant strain of pneumococcus (ie, MIC > 1 g/mL). The recommended dosage is 30 mg/kg/d in two or three divided doses. A typical dosing regimen for most infections in adults with normal renal function is
40 mg/kg/d in three or four divided doses. Clearance of vancomycin is directly proportionate to creatinine clearance, and the dose is reduced accordingly in patients with renal insufficiency should have serum concentrations checked. Recommended peak serum concentrations are 20–50 g/mL, and trough concentrations are 5–15 g/mL.
Oral vancomycin, 0.125–0.25 g every 6 hours, is used to treat antibiotic-associated enterocolitis caused by Clostridium difficile. However, because of the emergence of vancomycin-resistant enterococci and the strong selective pressure of oral vancomycin for these resistant organisms, metronidazole is strongly preferred as initial therapy and vancomycin should be reserved for treatment of refractory cases.
Adverse Reactions
Adverse reactions are encountered in about 10% of cases. Most reactions are minor. Vancomycin is irritating to tissue, resulting in phlebitis at the site of injection. Chills and fever may occur. Ototoxicity is rare and nephrotoxicity uncommon with current preparations. However, administration with another ototoxic or nephrotoxic drug, such as an aminoglycoside, increases the risk of these toxicities. Ototoxicity can be minimized by maintaining peak serum concentrations below 60 g/mL. Among the more common reactions is the so-called “red man” or “red neck” syndrome. This infusion-related flushing is caused by release of histamine. It can be largely prevented by prolonging the infusion period to 1–2 hours or increasing the dosing interval.
Teicoplanin
Teicoplanin is a glycopeptide antibiotic that is very similar to vancomycin in mechanism of action and antibacterial spectrum. Unlike vancomycin, it can be given intramuscularly as well as intravenously. Teicoplanin has a long half-life (45–70 hours), permitting once-daily dosing. This drug is available in Europe but has not been approved for use in the
Fosfomycin
Fosfomycin trometamol, a stable salt of fosfomycin (phosphonomycin), inhibits a very early stage of bacterial cell wall synthesis (Figure 43–5). An analog of phosphoenolpyruvate, it is structurally unrelated to any other antimicrobial agent. It inhibits the cytoplasmic enzyme enolpyruvate transferase by covalently binding to the cysteine residue of the active site and blocking the addition of phosphoenolpyruvate to UDP-N-acetylglucosamine. This reaction is the first step in the formation of UDP-N-acetylmuramic acid, the precursor of N-acetylmuramic acid, which is found only in bacterial cell walls. The drug is transported into the bacterial cell by glycerophosphate or glucose 6-phosphate transport systems. Resistance is due to inadequate transport of drug into the cell.
Fosfomycin is active against both gram-positive and gram-negative organisms at concentrations 125 g/mL. Susceptibility tests should be performed in growth medium supplemented with glucose 6-phosphate to minimize false-positive indications of resistance. In vitro synergism occurs when fosfomycin is combined with -lactam antibiotics, aminoglycosides, or fluoroquinolones.
Fosfomycin trometamol is available in both oral and parenteral formulations, though only the oral preparation is approved for use in the
Fosfomycin is approved for use as a single
The drug appears to be safe for use in pregnancy.
Bacitracin
Bacitracin is a cyclic peptide mixture first obtained from the
Bacitracin is markedly nephrotoxic if administered systemically, producing proteinuria, hematuria, and nitrogen retention. Hypersensitivity reactions (eg, skin rashes) are rare. Because of its marked toxicity when used systemically, it is limited to topical use. Bacitracin is poorly absorbed. Topical application results in local antibacterial activity without significant systemic toxicity. The small amounts of bacitracin that are absorbed are excreted by glomerular filtration.
Bacitracin, 500 units/g in an ointment base (often combined with polymyxin or neomycin), is useful for the suppression of mixed bacterial flora in surface lesions of the skin, in wounds, or on mucous membranes. Solutions of bacitracin containing 100–200 units/mL in saline can be employed for irrigation of joints, wounds, or the pleural cavity.
Cycloserine
Cycloserine is an antibiotic produced by Streptomyces orchidaceus. It is water-soluble and very unstable at acid pH. Cycloserine inhibits many gram-positive and gram-negative organisms, but it is used almost exclusively to treat tuberculosis caused by strains of M tuberculosis resistant to firstline agents. Cycloserine is a structural analog of D-alanine and inhibits the incorporation of Dalanine into peptidoglycan pentapeptide by inhibiting alanine racemase, which converts L-alanine to D-alanine, and D-alanyl-D-alanine ligase (Figure 43–5). After ingestion of
doses. Testing penicillin
Cycloserine causes serious dose-related central nervous system toxicity with headaches, tremors, acute psychosis, and convulsions. If oral dosages are maintained below 0.75 g/d, such effects can usually be avoided.
Amoxicillin (generic, Amoxil, others)
Oral: 125, 200, 250, 400 mg chewable tablets; 500, 875 mg tablets; 250, 500 mg capsules; powder
to reconstitute for 50, 125, 200, 250, 400 mg/mL solution
Amoxicillin/potassium clavulanate (generic, Augmentin)*
* Clavulanate content varies with the formulation; see package insert.
Oral: 250, 500, 875 mg tablets; 125, 200, 250, 400 mg chewable tablets; 1000 mg extended release
tablet powder to reconstitute for 125, 200, 250 mg/5 mL suspension
Ampicillin (generic)
Oral: 250, 500 mg capsules; powder to reconstitute for 125, 250 mg suspensions
Parenteral: powder to reconstitute for injection (125, 250, 500 mg, 1,
Ampicillin/sulbactam sodium (generic, Unasyn)
Sulbactam content is half the ampicillin content.
Parenteral: 1,
Carbenicillin (Geocillin)
Oral: 382 mg tablets
Dicloxacillin (generic)
Oral: 250, 500 mg capsules
Mezlocillin (Mezlin)
Parenteral: powder to reconstitute for injection (in 1, 2, 3,
Nafcillin (generic)
Oral: 250 mg capsules
Parenteral: 1,
Oxacillin (generic)
Oral: 250, 500 mg capsules; powder to reconstitute for 250 mg/5 mL solution
Parenteral: powder to reconstitute for injection (0.5, 1, 2,
Penicillin G (generic, Pentids, Pfizerpen)
Oral: 0.2, 0.25, 0.4, 0.5, 0.8 million unit tablets; powder to reconstitute 400,000 units/5 mL
suspension
Parenteral: powder to reconstitute for injection (1, 2, 3, 5, 10, 20 million units)
Penicillin G benzathine (Permapen, Bicillin)
Parenteral: 0.6, 1.2, 2.4 million units per dose
Penicillin G procaine (generic)
Parenteral: 0.6, 1.2 million units/mL for IM injection only
Penicillin V (generic, V-Cillin, Pen-Vee K, others)
Oral: 250, 500 mg tablets; powder to reconstitute for 125, 250 mg/5 mL solution
Piperacillin (Pipracil)
Parenteral: powder to reconstitute for injection (2, 3,
Piperacillin and tazobactam sodium (Zosyn)‡
‡ Tazobactam content is 12.5% of the piperacillin content.
Parenteral: 2, 3,
Ticarcillin (Ticar)
Parenteral: powder to reconstitute for injection (1, 3,
Ticarcillin/clavulanate potassium (Timentin)§
§ Clavulanate content
Parenteral:
Cephalosporins & Other Beta-Lactam Drugs
Narrow Spectrum (First-Generation) Cephalo-sporins
Cefadroxil (generic, Duricef)
Oral: 500 mg capsules;
Cefazolin (generic, Ancef, Kefzol)
Parenteral: powder to reconstitute for injection (0.25, 0.5,
Cephalexin (generic, Keflex, others)
Oral: 250, 500 mg capsules and tablets;
Cephalothin (generic, Keflin)¶
¶Not available in the
Parenteral: powder to reconstitute for injection and solution for injection (
pack)
Cephapirin (Cefadyl)
Parenteral: powder to reconstitute for injection (
Cephradine (generic, Velosef)
Oral: 250, 500 mg capsules; 125, 250 mg/5 mL suspension
Parenteral: powder to reconstitute for injection (0.25, 0.5, 1,
Intermediate Spectrum (Second-Generation) Cephalosporins
Cefaclor (generic, Ceclor)
Oral: 250, 500 mg capsules; 375, 500 mg extended-release tablets; powder to reconstitute for 125,
187, 250, 375 mg/5 mL suspension
Cefamandole (Mandol)
Parenteral: 1,
Cefmetazole (Zefazone)
Parenteral: 1,
Cefonicid (Monocid)
Parenteral: powder to reconstitute for injection (1,
Cefotetan (Cefotan)
Parenteral: powder to reconstitute for injection (1, 2,
Cefoxitin (Mefoxin)
Parenteral: powder to reconstitute for injection (1, 2,
Cefprozil (Cefzil)
Oral: 250, 500 mg tablets; powder to reconstitute 125, 250 mg/5 mL suspension
Cefuroxime (generic, Ceftin, Kefurox, Zinacef)
Oral: 125, 250, 500 mg tablets; 125, 250 mg/5 mL suspension
Parenteral: powder to reconstitute for injection (0.75, 1.5,
Loracarbef (Lorabid)
Oral: 200, 400 mg capsules; powder for 100, 200 mg/5 mL suspension
Broad-Spectrum (Third- & Fourth-Generation) Cephalosporins
Cefdinir (Omnicef)
Oral: 300 mg capsules; 125 mg/5 mL suspension
Cefditoren (Spectracef)
Oral: 200 mg tablets
Cefepime (Maxipime)
Parenteral: powder for injection 0.5, 1,
Cefixime (Suprax)
Oral: 200, 400 mg tablets; powder for oral suspension, 100 mg/5 mL
Cefoperazone (Cefobid)
Parenteral: powder to reconstitute for injection (1,
Cefotaxime (Claforan)
Parenteral: powder to reconstitute for injection (0.5, 1,
Cefpodoxime proxetil (Vantin)
Oral: 100, 200 mg tablets; 50, 100 mg granules for suspension in 5 mL
Ceftazidime (generic, Fortaz, Tazidime)
Parenteral: powder to reconstitute for injection (0.5, 1,
Ceftibuten (Cedax)
Oral: 400 mg capsules; 90, 180 mg/5 mL powder for oral suspension
Ceftizoxime (Cefizox)
Parenteral: powder to reconstitute for injection and solution for injection (0.5, 1,
Ceftriaxone (Rocephin)
Parenteral: powder to reconstitute for injection (0.25, 0.5, 1, 2,
Carbapenems & Monobactam
Aztreonam (Azactam)
Parenteral: powder to reconstitute for injection (0.5, 1,
Ertapenem (Invanz)
Parenteral:
lidocaine diluent) injection
Imipenem/cilastatin (Primaxin)
Parenteral: powder to reconstitute for injection (250, 500, 750 mg imipenem per vial)
Meropenem (Merrem IV)
Parenteral: powder for injection (0.5,
Other Drugs Discussed in This Chapter
Cycloserine (Seromycin Pulvules)
Oral: 250 mg capsules
Fosfomycin (Monurol)
Oral:
Vancomycin (generic, Vancocin, Vancoled)
Oral: 125, 250 mg Pulvules; powder to reconstitute for 250 mg/5 mL, 500 mg/6 mL solution
Parenteral: 0.5, 1, 5,
Chloramphenicol, Tetracyclines, Macrolides, Clindamycin, Streptogramins
Chloramphenicol
Crystalline chloramphenicol is a neutral, stable compound with the following structure:
It is soluble in alcohol but poorly soluble in water. Chloramphenicol succinate, which is used for parenteral administration, is highly water-soluble. It is hydrolyzed in vivo with liberation of free chloramphenicol.
Antimicrobial Activity
Chloramphenicol is a potent inhibitor of microbial protein synthesis. It binds reversibly to the 50S subunit of the bacterial ribosome (Figure 44–1). It inhibits the peptidyl transferase step of protein synthesis. Chloramphenicol is a bacteriostatic broad-spectrum antibiotic that is active against both aerobic and anaerobic gram-positive and gram-negative organisms. It is active also against rickettsiae but not chlamydiae. Most gram-positive bacteria are inhibited at concentrations of 1–10 g/mL, and many gram-negative bacteria are inhibited by concentrations of 0.2–5 g/mL.
Figure 44–1.
Haemophilus influenzae, Neisseria meningitidis, and some strains of bacteroides are highly susceptible, and for them chloramphenicol may be bactericidal.
Low-level resistance may emerge from large populations of chloramphenicol-susceptible cells by selection of mutants that are less permeable to the drug. Clinically significant resistance is due to production of chloramphenicol acetyltransferase, a plasmid-encoded enzyme that inactivates the drug.
Pharmacokinetics
The usual dosage of chloramphenicol is 50–100 mg/kg/d. After oral administration, crystalline chloramphenicol is rapidly and completely absorbed. A
cell membranes readily. Most of the drug is inactivated either by conjugation with glucuronic acid (principally in the liver) or by reduction to inactive aryl amines.
Excretion of active
chloramphenicol (about 10% of the total dose administered) and of inactive degradation products (about 90% of the total) occurs by way of the urine. A small amount of active drug is excreted into bile or feces. The systemic dosage of chloramphenicol need not be altered in renal insufficiency, but it must be reduced markedly in hepatic failure. Newborns less than a week old and premature infants also clear chloramphenicol less well, and the dosage should be reduced to 25 mg/kg/d.
Clinical Uses
Because of potential toxicity, bacterial resistance, and the availability of other effective drugs (eg, cephalosporins), chloramphenicol is all but obsolete as a systemic drug. It may be considered for treatment of serious rickettsial infections, such as typhus or Rocky Mountain spotted fever, in children for whom tetracyclines are contraindicated, ie, those under 8 years of age.
It is an alternative to a -lactam antibiotic for treatment of meningococcal meningitis occurring in patients who have major hypersensitivity reactions to penicillin or bacterial meningitis caused by penicillinresistant strains of pneumococci. The dosage is 50–100 mg/kg/d in four divided doses. Chloramphenicol is occasionally used topically in the treatment of eye infections because of its wide antibacterial spectrum and its penetration of ocular tissues and the aqueous humor. It is ineffective for chlamydial infections.
Adverse Reactions
Gastrointestinal Disturbances
Adults occasionally develop nausea, vomiting, and diarrhea. This is rare in children. Oral or vaginal candidiasis may occur as a result of alteration of normal microbial flora. Bone Marrow Disturbances
Chloramphenicol commonly causes a dose-related reversible suppression of red cell production at dosages exceeding 50 mg/kg/d after 1–2 weeks. Aplastic anemia is a rare consequence of chloramphenicol administration by any route. It is an idiosyncratic reaction unrelated to dose, though it occurs more frequently with prolonged use. It tends to be irreversible and can be fatal. Aplastic anemia probably develops in one of every 24,000–40,000 patients who have taken chloramphenicol.
Toxicity for Newborn Infants
Newborn infants lack an effective glucuronic acid conjugation mechanism for the degradation and detoxification of chloramphenicol. Consequently, when infants are given dosages above 50 mg/kg/d, the drug may accumulate, resulting in the gray baby syndrome, with vomiting, flaccidity, hypothermia, gray color, shock, and collapse. To avoid this toxic effect, chloramphenicol should be used with caution in infants and the dosage limited to 50 mg/kg/d or less (during the first week of life) in full-term infants and 25 mg/kg/d in premature infants.
Interaction with Other Drugs
Chloramphenicol inhibits hepatic microsomal enzymes that metabolize several drugs. Half-lives are prolonged, and the serum concentrations of phenytoin, tolbutamide, chlorpropamide, and warfarin are increased. Like other bacteriostatic inhibitors of microbial protein synthesis, chloramphenicol can antagonize bactericidal drugs such as penicillins or aminoglycosides.
Tetracyclines
All of the tetracyclines have the basic structure shown below:
Free tetracyclines are crystalline amphoteric substances of low solubility. They are available as hydrochlorides, which are more soluble. Such solutions are acid and, with the exception of chlortetracycline, fairly stable. Tetracyclines chelate divalent metal ions, which can interfere with their absorption and activity.
Antimicrobial Activity
Tetracyclines are broad-spectrum bacteriostatic antibiotics that inhibit protein synthesis. They are active against many gram-positive and gram-negative bacteria, including anaerobes, rickettsiae, chlamydiae, mycoplasmas, and L forms; and against some protozoa, eg, amebas. The antibacterial activities of most tetracyclines are similar except that tetracycline-resistant strains may remain susceptible to doxycycline or minocycline, drugs that are less rapidly transported by the pump that is responsible for resistance (see Resistance). Differences in clinical efficacy are minor and attributable largely to features of absorption, distribution, and excretion of individual drugs.
Tetracyclines enter microorganisms in part by passive diffusion and in part by an energy-dependent process of active transport. Susceptible cells concentrate the drug intracellularly. Once inside the cell, tetracyclines bind reversibly to the 30S subunit of the bacterial ribosome, blocking the binding of aminoacyl-tRNA to the acceptor site on the mRNA-ribosome complex (Figure 44–1). This prevents addition of amino acids to the growing peptide.
Resistance
Three mechanisms of resistance to tetracycline have been described: (1) decreased intracellular accumulation due to either impaired influx or increased efflux by an active transport protein pump; (2) ribosome protection due to production of proteins that interfere with tetracycline binding to the ribosome; and (3) enzymatic inactivation of tetracyclines. The most important of these is production of an efflux pump. The pump protein is encoded on a plasmid and may be transmitted by transduction or by conjugation. Because these plasmids commonly encode resistance genes for other drugs, eg, aminoglycosides, sulfonamides, and chloramphenicol, tetracycline resistance is a marker for resistance to multiple drugs.
Pharmacokinetics
Tetracyclines mainly differ in their absorption after oral administration and their elimination. Absorption after oral administration is approximately 30% for chlortetracycline; 60–70% for tetracycline, oxytetracycline, demeclocycline, and methacycline; and 95–100% for doxycycline and minocycline. A portion of an orally administered dose of tetracycline remains in the gut lumen, modifies intestinal flora, and is excreted in the feces. Absorption occurs mainly in the upper small intestine and is impaired by food (except doxycycline and minocycline); by divalent cations (Ca2+, Mg2+, Fe2+) or Al3+; by dairy products and antacids, which contain multivalent cations; and by alkaline pH. Specially buffered tetracycline solutions are formulated for intravenous administration.
Tetracyclines are 40–80% bound by serum proteins. Oral dosages of 500 mg every 6 hours of tetracycline hydrochloride or oxytetracycline produce peak blood levels of 4–6 g/mL. Peak levels of 2–4 g/mL are achieved with a 200 mg dose of doxycycline or minocycline. Intravenously injected tetracyclines give somewhat higher levels only temporarily. Tetracyclines are distributed widely to tissues and body fluids except for cerebrospinal fluid, where concentrations are 10–25%
of those in serum. Minocycline reaches very high concentrations in tears and saliva, which makes it useful for eradication of the meningococcal carrier state.
Tetracyclines cross the placenta to reach the fetus and are also excreted in milk. As a result of chelation with calcium, tetracyclines are bound to—and damage—growing bones and teeth.
Carbamazepine, phenytoin, barbiturates, and chronic alcohol ingestion may shorten the half-life of doxycycline 50% by induction of hepatic enzymes that metabolize the drug.
Tetracyclines are excreted mainly in bile and urine. Concentrations in bile exceed those in serum tenfold. Some of the drug excreted in bile is reabsorbed from the intestine (enterohepatic circulation) and contributes to maintenance of serum levels. Ten to 50 percent of various tetracyclines is excreted into the urine, mainly by glomerular filtration. Ten to 40 percent of the drug in the body is excreted in feces. Doxycycline, in contrast to other tetracyclines, is eliminated by nonrenal mechanisms, does not accumulate significantly in renal failure, and requires no dosage adjustment, making it the tetracycline of choice for use in the setting of renal insufficiency.
Tetracyclines are classified as short-acting (chlortetracycline, tetracycline, oxytetracycline), intermediate-acting (demeclocycline and methacycline), or long-acting (doxycycline and minocycline) based on serum half-lives of 6–8 hours, 12 hours, and 16–18 hours, respectively. The almost complete absorption and slow excretion of doxycycline and minocycline allow for oncedaily dosing.
Clinical Uses
A tetracycline is the drug of choice in infections with Mycoplasma pneumoniae, chlamydiae, rickettsiae, and some spirochetes. They are used in combination regimens to treat gastric and duodenal ulcer disease caused by Helicobacter pylori. They may be employed in various grampositive and gram-negative bacterial infections, including vibrio infections, provided the organism is not resistant. In cholera, tetracyclines rapidly stop the shedding of vibrios, but tetracycline resistance has appeared during epidemics. Tetracyclines remain effective in most chlamydial infections, including sexually transmitted diseases. Tetracyclines are no longer recommended for treatment of gonococcal disease because of resistance. A tetracycline—usually in combination with an aminoglycoside—is indicated for plague, tularemia, and brucellosis. Tetracyclines are sometimes employed in the treatment of protozoal infections, eg, those due to Entamoeba histolytica or
Plasmodium falciparum. Other uses include treatment of acne, exacerbations of bronchitis, community-acquired pneumonia, Lyme disease, relapsing fever, leptospirosis, and some nontuberculous mycobacterial infections (eg, Mycobacterium marinum). Tetracyclines formerly were used for a variety of common infections, including bacterial gastroenteritis, pneumonia (other than mycoplasmal or chlamydial pneumonia), and urinary tract infections. However, many strains of bacteria causing these infections now are resistant, and other agents have largely supplanted tetracyclines.
Minocycline, 200 mg orally daily for 5 days, can eradicate the meningococcal carrier state, but because of side-effects and resistance of many meningococcal strains, rifampin is preferred.
Demeclocycline inhibits the action of ADH in the renal tubule and has been used in the treatment of inappropriate secretion of ADH or similar peptides by certain tumors.
Oral Dosage
The oral dosage for rapidly excreted tetracyclines, equivalent to tetracycline hydrochloride, is 0.25–
Parenteral Dosage
Several tetracyclines are available for intravenous injection in doses of 0.1–0.5 g every 6–12 hours (similar to oral doses), depending on the agent. Intramuscular injection is not recommended because of pain and inflammation at the injection site. Doxycycline is the preferred agent, at a dosage of 100 mg every 12–24 hours.
Adverse Reactions
Hypersensitivity reactions (drug fever, skin rashes) to tetracyclines are uncommon. Most adverse
effects are due to direct toxicity of the drug or to alteration of microbial flora. Gastrointestinal Adverse Effects Nausea, vomiting, and diarrhea are the most common reasons for discontinuing tetracycline medication. These effects are attributable to direct local irritation of the intestinal tract. Nausea, anorexia, and diarrhea can usually be controlled by administering the drug with food or carboxymethylcellulose, reducing drug dosage, or discontinuing the drug.
Tetracyclines modify the normal flora, with suppression of susceptible coliform organisms and overgrowth of pseudomonas, proteus, staphylococci, resistant coliforms, clostridia, and candida. This can result in intestinal functional disturbances, anal pruritus, vaginal or oral candidiasis, or enterocolitis with shock and death. Pseudomembranous enterocolitis associated with Clostridium difficile should be treated with metronidazole.
Bony Structures and Teeth
Tetracyclines are readily bound to calcium deposited iewly formed bone or teeth in young children. When the drug is given during pregnancy, it can be deposited in the fetal teeth, leading to fluorescence, discoloration, and enamel dysplasia; it can also be deposited in bone, where it may cause deformity or growth inhibition. If the drug is given for long periods to children under 8 years of age, similar changes can result.
Liver Toxicity
Tetracyclines can probably impair hepatic function, especially during pregnancy, in patients with preexisting hepatic insufficiency and when high doses are given intravenously. Hepatic necrosis has been reported with daily doses of
Kidney Toxicity
Renal tubular acidosis and other renal injury resulting iitrogen retention have been attributed to the administration of outdated tetracycline preparations. Tetracyclines given along with diuretics may produce nitrogen retention. Tetracyclines other than doxycycline may accumulate to toxic levels in patients with impaired kidney function.
Local Tissue Toxicity
Intravenous injection can lead to venous thrombosis. Intramuscular injection produces painful local irritation and should be avoided.
Photosensitization
Systemic tetracycline administration, especially of demeclocycline, can induce sensitivity to sunlight or ultraviolet light, particularly in fair-skinned persons.
Vestibular Reactions
Dizziness, vertigo, nausea, and vomiting have been particularly noted with doxycycline at doses above 100 mg. With dosages of 200–400 mg/d of minocycline, 35–70% of patients will have these reactions.
Medical & Social Implications of Overuse
Tetracyclines have been extensively used in animal feeds to enhance growth. This practice has contributed to the spread of tetracycline resistance among enteric bacteria and of plasmids that encode tetracycline resistance genes.
Chloramphenicol, Tetracyclines, Macrolides, Clindamycin, Streptogramins
Macrolides
The macrolides are a group of closely related compounds characterized by a macrocyclic lactone ring (usually containing 14 or 16 atoms) to which deoxy sugars are attached. The prototype drug, erythromycin, which consists of two sugar moieties attached to a 14-atom lactone ring, was obtained in 1952 from Streptomyces erythreus. Clarithromycin and azithromycin are semisynthetic derivatives of erythromycin.
Erythromycin
Chemistry
The general structure of erythromycin is shown above with the macrolide ring and the sugars desosamine and cladinose.
It is poorly soluble in water (0.1%) but dissolves readily in organic solvents. Solutions are fairly stable at
Antimicrobial Activity
Erythromycin is effective against gram-positive organisms, especially pneumococci, streptococci, staphylococci, and corynebacteria, in plasma concentrations of 0.02–2 g/mL. Mycoplasma, legionella, Chlamydia trachomatis, C psittaci, C pneumoniae, helicobacter, listeria, and certain mycobacteria (Mycobacterium kansasii, Mycobacterium scrofulaceum) are also susceptible. Gramnegative organisms such as neisseria species, Bordetella pertussis, Bartonella henselae, and B quintana (etiologic agents of cat-scratch disease and bacillary angiomatosis), some rickettsia species, Treponema pallidum, and campylobacter species are susceptible. Haemophilus influenzae is somewhat less susceptible.
The antibacterial action of erythromycin may be inhibitory or bactericidal, particularly at higher concentrations, for susceptible organisms. Activity is enhanced at alkaline pH. Inhibition of protein synthesis occurs via binding to the 50S ribosomal RNA. Protein synthesis is inhibited because aminoacyl translocation reactions and the formation of initiation complexes are blocked (Figure 44–1).
Resistance
Resistance to erythromycin is usually plasmid-encoded. Three mechanisms have been identified: (1) reduced permeability of the cell membrane or active efflux; (2) production (by Enterobacteriaceae) of esterases that hydrolyze macrolides; and (3) modification of the ribosomal binding site (so-called ribosomal protection) by chromosomal mutation or by a macrolide-inducible or constitutive
methylase. Efflux and methylase production account for the vast majority of cases of resistance in gram-positive organisms. Cross-resistance is complete between erythromycin and the other macrolides. Constitutive methylase production also confers resistance to structurally unrelated but mechanistically similar compounds such as clindamycin and streptogramin B (so-called macrolidelincosamide
streptogramin, or MLS-type B, resistance), which share the same ribosomal binding site. Because nonmacrolides are poor inducers of the methylase, strains expressing an inducible methylase will appear susceptible in vitro. However, constitutive mutants that are resistant can be selected out and emerge during therapy with clindamycin.
Pharmacokinetics
Erythromycin base is destroyed by stomach acid and must be administered with enteric coating. Food interferes with absorption. Stearates and esters are fairly acid-resistant and somewhat better absorbed. The lauryl salt of the propionyl ester of erythromycin (erythromycin estolate) is the bestabsorbed oral preparation. Oral dosage of 2 g/d results in serum erythromycin base and ester concentrations of approximately 2 g/mL. However, only the base is microbiologically active, and
its concentration tends to be similar regardless of the formulation. A 500 mg intravenous dose of erythromycin lactobionate produces serum concentrations of 10 g/mL 1 hour after dosing. The serum half-life is approximately 1.5 h normally and 5 hours in patients with anuria. Adjustment for renal failure is not necessary. Erythromycin is not removed by dialysis. Large amounts of an administered dose are excreted in the bile and lost in feces, and only 5% is excreted in the urine. Absorbed drug is distributed widely except to the brain and cerebrospinal fluid. Erythromycin is taken up by polymorphonuclear leukocytes and macrophages. It traverses the placenta and reaches the fetus.
Clinical Uses
An erythromycin is the drug of choice in corynebacterial infections (diphtheria, corynebacterial sepsis, erythrasma); in respiratory, neonatal, ocular, or genital chlamydial infections; and in treatment of community-acquired pneumonia because its spectrum of activity includes the pneumococcus, mycoplasma, and legionella. Erythromycin is also useful as a penicillin substitute in penicillin-allergic individuals with infections caused by staphylococci (assuming that the isolate is susceptible), streptococci, or pneumococci. Emergence of erythromycin resistance in strains of group A streptococci and pneumococci (penicillin-resistant pneumococci in particular) has made macrolides less attractive as first-line agents for treatment of pharyngitis, skin and soft tissue infections, and pneumonia. Erythromycin has been recommended as prophylaxis against endocarditis during dental procedures in individuals with valvular heart disease, though clindamycin, which is better tolerated, has largely replaced it. Although erythromycin estolate is the best-absorbed salt, it imposes the greatest risk of adverse reactions. Therefore, the stearate or succinate salt may be preferred.
The oral dosage of erythromycin base, stearate, or estolate is 0.25–0.5 g every 6 hours (for children, 40 mg/kg/d). The dosage of erythromycin ethylsuccinate is 0.4–0.6 g every 6 hours. Oral erythromycin base (
Adverse Reactions
Gastrointestinal Effects
Anorexia, nausea, vomiting, and diarrhea occasionally accompany oral administration. Gastrointestinal intolerance, which is due to a direct stimulation of gut motility, is the most frequent reason for discontinuing erythromycin and substituting another antibiotic.
Liver Toxicity
Erythromycins, particularly the estolate, can produce acute cholestatic hepatitis (fever, jaundice, impaired liver function), probably as a hypersensitivity reaction. Most patients recover from this, but hepatitis recurs if the drug is readministered. Other allergic reactions include fever, eosinophilia, and rashes.
Drug Interactions
Erythromycin metabolites can inhibit cytochrome P450 enzymes and thus increase the serum concentrations of numerous drugs, including theophylline, oral anticoagulants, cyclosporine, and methylprednisolone. Erythromycin increases serum concentrations of oral digoxin by increasing its bioavailability.
Clarithromycin
Clarithromycin is derived from erythromycin by addition of a methyl group and has improved acid stability and oral absorption compared with erythromycin. Its mechanism of action is the same as that of erythromycin. Clarithromycin and erythromycin are virtually identical with respect to antibacterial activity except that clarithromycin is more active against Mycobacterium avium Complex leprae and Toxoplasma gondii. Erythromycin-resistant streptococci and staphylococci are also
resistant to clarithromycin. A 500 mg dose produces serum concentrations of 2–3 g/mL. The longer half-life of clarithromycin (6 hours) compared with erythromycin permits twice-daily dosing. The recommended dosage is
250–500 mg twice daily. Clarithromycin penetrates most tissues well, with concentrations equal to or exceeding serum concentrations.
Clarithromycin is metabolized in the liver. The major metabolite is 14-hydroxyclarithromycin, which also has antibacterial activity. A portion of active drug and this major metabolite is eliminated in the urine, and dosage reduction (eg, a 500 mg loading dose, then 250 mg once or twice daily) is recommended for patients with creatinine clearances less than 30 mL/min.
Clarithromycin has drug interactions similar to those described for erythromycin. The advantages of clarithromycin compared with erythromycin are lower frequency of gastrointestinal intolerance and less frequent dosing. Except for the specific organisms noted above, the two drugs are otherwise therapeutically very similar, and the choice of one over the other usually turns on issues of cost (clarithromycin being much more expensive) and tolerability.
Azithromycin
Azithromycin, a 15-atom lactone macrolide ring compound, is derived from erythromycin by addition of a methylated nitrogen into the lactone ring of erythromycin. Its spectrum of activity and clinical uses are virtually identical to those of clarithromycin. Azithromycin is active against M avium complex and T gondii. Azithromycin is slightly less active than erythromycin and clarithromycin against staphylococci and streptococci and slightly more active against H influenzae. Azithromycin is highly active against chlamydia. Azithromycin differs from erythromycin and clarithromycin mainly in pharmacokinetic properties.
A 500 mg dose of azithromycin produces relatively low serum concentrations of approximately 0.4 g/mL. However, azithromycin penetrates into most tissues (except cerebrospinal fluid) and phagocytic cells extremely well, with tissue concentrations exceeding serum concentrations by 10- to 100-fold. The drug is slowly released from tissues (tissue half-life of 2–4 days) to produce an elimination half-life approaching 3 days. These unique properties permit once-daily dosing and
shortening of the duration of treatment in many cases. For example, a single
azithromycin is as effective as a 7-day course of doxycycline for chlamydial cervicitis and urethritis. Community-acquired pneumonia can be treated with azithromycin given as a 500 mg loading dose, followed by a 250 mg single daily dose for the next 4 days.
Azithromycin is rapidly absorbed and well tolerated orally. It should be administered 1 hour before or 2 hours after meals. Aluminum and magnesium antacids do not alter bioavailability but delay absorption and reduce peak serum concentrations. Because it has a 15-member (not 14-member) lactone ring, azithromycin does not inactivate cytochrome P450 enzymes and therefore is free of the drug interactions that occur with erythromycin and clarithromycin.
Clindamycin penetrates well into most tissues, with brain and cerebrospinal fluid being important exceptions. It penetrates well into abscesses and is actively taken up and concentrated by phagocytic cells. Clindamycin is metabolized by the liver, and both active drug and active metabolites are excreted in bile. The half-life is about 2.5 hours iormal individuals, increasing to 6 hours in patients with anuria. No dosage adjustment is required for renal failure.
Clinical Uses
Clindamycin is indicated for treatment of severe anaerobic infection caused by bacteroides and other anaerobes that often participate in mixed infections. Clindamycin, sometimes in combination with an aminoglycoside or cephalosporin, is used to treat penetrating wounds of the abdomen and the gut; infections originating in the female genital tract, eg, septic abortion and pelvic abscesses; or
aspiration pneumonia. Clindamycin is now recommended instead of erythromycin for prophylaxis of endocarditis in patients with valvular heart disease who are undergoing certain dental procedures.
Clindamycin plus primaquine is an effective alternative to trimethoprim-sulfamethoxazole for moderate to moderately severe Pneumocystis carinii pneumonia in AIDS patients. It is also used in combination with pyrimethamine for AIDS-related toxoplasmosis of the brain.
Adverse Effects
Common adverse effects are diarrhea, nausea, and skin rashes. Impaired liver function (with or without jaundice) and neutropenia sometimes occur. Severe diarrhea and enterocolitis have followed clindamycin administration. Antibiotic-associated colitis that has followed administration of clindamycin and other drugs is caused by toxigenic C difficile. This potentially fatal complication must be recognized promptly and treated with metronidazole, 500 mg orally or intravenously three times a day (the preferred therapy), or vancomycin, 125 mg orally four times a day (less desirable given the increasing prevalence of vancomycin-resistant enterococci). Relapse may occur. Variations in the local prevalence of C difficile may account for the great differences in incidence of antibiotic-associated colitis. For unknown reasons, neonates given clindamycin may become colonized with toxigenic C difficile but do not develop colitis.
Aminoglycosides Spectinomycin
Aminoglycosides
Aminoglycosides are a group of bactericidal antibiotics originally obtained from various streptomyces species and sharing chemical, antimicrobial, pharmacologic, and toxic characteristics.
The group includes streptomycin, neomycin, kanamycin, amikacin, gentamicin, tobramycin, sisomicin, netilmicin, and others.
Aminoglycosides are used most widely against gram-negative enteric bacteria, especially in bacteremia and sepsis, in combination with vancomycin or a penicillin for endocarditis, and for treatment of tuberculosis. Streptomycin is the oldest and best-studied of the aminoglycosides. Gentamicin, tobramycin, and amikacin are the most widely employed aminoglycosides at present. Neomycin and kanamycin are now largely limited to topical or oral use.
General Properties of Aminoglycosides
Physical and Chemical Properties
Aminoglycosides have a hexose ring, either streptidine (in streptomycin) or 2-deoxystreptamine (other aminoglycosides), to which various amino sugars are attached by glycosidic linkages (Figures 45–1 and 45–2). They are water-soluble, stable in solution, and more active at alkaline than at acid pH. Aminoglycosides frequently exhibit synergism with -lactams or vancomycin in vitro.
In combination they eradicate organisms more rapidly than would be predicted from the activity of either single agent. However, at high concentrations aminoglycosides may complex with –lactam drugs, resulting in loss of activity, and they should not be mixed together for administration.
Figure 45–1.
Spectinomycin
Spectinomycin is an aminocyclitol antibiotic that is structurally related to aminoglycosides. It lacks amino sugars and glycosidic bonds.
While active in vitro against many gram-positive and gram-negative organisms, spectinomycin is used almost solely as an alternative treatment for gonorrhea in patients who are allergic to penicillin or whose gonococci are resistant to other drugs. The vast majority of gonococcal isolates are inhibited by 6 g/mL of spectinomycin.
Strains of gonococci may be resistant to spectinomycin, but there is no cross-resistance with other drugs used in gonorrhea. Spectinomycin is rapidly absorbed after intramuscular injection. A single dose of 40 mg/kg up to a maximum of
Preparations Available
Amikacin(generic, Amikin)
Parenteral: 50, 250 mg (in vials) for IM, IV injection
Gentamicin(generic, Garamycin)
Parenteral: 10, 40 mg/mL vials for IM, IV injection
Kanamycin(Kantrex)
Oral: 500 mg capsules
Parenteral: 500, 1000 mg for IM, IV injection; 75 mg for pediatric injection
Neomycin(generic, Mycifradin)
Oral: 500 mg tablets; 125 mg/5 mL solution
Netilmicin (Netromycin)
Parenteral: 100 mg/mL for IM, IV injection
Paromomycin(Humatin)
Oral: 250 mg capsules
Spectinomycin(Trobicin)
Parenteral:
Streptomycin (generic)
Parenteral: 400 mg/mL for IM injection
Tobramycin(generic, Nebcin)
Parenteral: 10, 40 mg/mL for IM, IV injection; powder to reconstitute for injection
Antibacterial Drugs
Drugs for Treating Bacterial Infections
When bacteria overcome the cutaneous or mucosal barriers and penetrate body tissues, a bacterial infection is present. Frequently the body succeeds in removing the invaders, without outward signs of disease, by mounting an immune response. If bacteria multiply faster than the body’s defenses can destroy them, infectious disease develops with inflammatory signs, e.g., purulent wound infection or urinary tract infection. Appropriate treatment employs substances that injure bacteria and thereby prevent their further multiplication, without harming cells of the host organism (1).
Apropos nomenclature: antibiotics are produced by microorganisms (fungi, bacteria) and are directed “against life” at any phylogenetic level (prokaryotes, eukaryotes). Chemotherapeutic agents originate from chemical synthesis. This distinction has been lost in current usage.
Specific damage to bacteria is particularly practicable when a substance interferes with a metabolic process that occurs in bacterial but not in host cells.
Clearly this applies to inhibitors of cell wall synthesis, because human and animal cells lack a cell wall. The points of attack of antibacterial agents are schematically illustrated in a grossly simplified bacterial cell, as depicted in (2).
In the following sections, polymyxins and tyrothricin are not considered further. These polypeptide antibiotics enhance cell membrane permeability. Due to their poor tolerability, they are prescribed in humans only for topical use.
The effect of antibacterial drugs can be observed in vitro (3). Bacteria multiply in a growth medium under control conditions. If the medium contains an antibacterial drug, two results can be discerned: 1. bacteria are killed—bactericidal effect; 2. bacteria survive, but do not multiply—bacteriostatic effect. Although variations may occur under therapeutic conditions, different drugs can be classified according to their respective primary mode of action (color tone in 2 and 3). When bacterial growth remains unaffected by an antibacterial drug, bacterial resistance is present. This may occur because of certain metabolic characteristics that confer a natural insensitivity to the drug on a particular strain of bacteria (natural resistance). Depending on whether a drug affects only a few or numerous types of bacteria, the terms narrow-spectrum (e.g., penicillin G) or broad-spectrum (e.g., tetracyclines) antibiotic are applied. Naturally susceptible bacterial strains can be transformed under the influence of antibacterial drugs into resistant ones (acquired resistance), when a random genetic alteration (mutation) gives rise to a resistant bacterium. Under the influence of the drug, the susceptible bacteria die off, whereas the mutant multiplies unimpeded. The more frequently a given drug is applied, the more probable the emergence of resistant strains (e.g., hospital strains with multiple resistance)!
Resistance can also be acquired when DNA responsible for nonsusceptibility (so-called resistance plasmid) is passed on from other resistant bacteria
by conjugation or transduction.
Inhibitors of Cell Wall Synthesis
In most bacteria, a cell wall surrounds the cell like a rigid shell that protects against noxious outside influences and prevents rupture of the plasma membrane from a high internal osmotic pressure. The structural stability of the cell wall is due mainly to the murein (peptidoglycan) lattice. This consists of basic building blocks linked together to form a large macromolecule. Each basic unit contains the two linked aminosugars N-acetylglucosamine and N-acetylmuramyl acid; the latter bears a peptide chain. The building blocks are synthesized in the bacterium, transported outward through the cell membrane, and assembled as illustrated schematically. The enzyme transpeptidase cross-links the peptide chains of adjacent aminosugar chains.
Inhibitors of cell wall synthesis are suitable antibacterial agents, because animal and human cells lack a cell wall. They exert a bactericidal action on growing or multiplying germs. Members of this class include -lactam antibiotics such as the penicillins and cephalosporins, in addition to bacitracin and vancomycin.
Penicillins (A). The parent substance of this group is penicillin G (benzylpenicillin). It is obtained from cultures of mold fungi, originally from Penicillium notatum. Penicillin G contains the basic structure common to all penicillins, 6-amino-penicillanic acid (p. 271, 6-APA), comprised of a thiazolidine and a 4-membered -lactam ring. 6- APA itself lacks antibacterial activity.
Penicillins disrupt cell wall synthesis by inhibiting transpeptidase. When bacteria are in their growth and replication phase, penicillins are bactericidal; due to cell wall defects, the bacteria swell and burst.
Penicillins are generally well tolerated; with penicillin G, the daily dose can range from approx.
up to 5%), with manifestations ranging from skin eruptions to anaphylactic shock (in less than 0.05% of patients). Known penicillin allergy is a contraindication for these drugs. Because of an increased risk of sensitization, penicillins must not be used locally.
Neurotoxic effects, mostly convulsions due to GABA antagonism, may occur if the brain is exposed to extremely high concentrations, e.g., after rapid i.v. injection of a large dose or intrathecal injection. Penicillin G undergoes rapid renal elimination mainly in unchanged form (plasma t1/2 ~ 0.5 h). The duration of the effect can be prolonged by:
1. Use of higher doses, enabling plasma levels to remain above the minimally effective antibacterial concentration;
2. Combination with probenecid. Renal elimination of penicillin occurs chiefly via the anion (acid)-secretory system of the proximal tubule (-COOH of 6-APA). The acid probenecid (p. 316) competes for this route and thus retards penicillin elimination;
3. Intramuscular administration in depot form. In its anionic form (-COO-) penicillin G forms poorly water-soluble salts with substances containing a positively charged amino group. Depending on the substance, release of penicillin from the depot occurs over a variable interval.
Although very well tolerated, penicillin G has disadvantages (A) that limit its therapeutic usefulness: (1) It is inactivated by gastric acid, which cleaves the -lactam ring, necessitating parenteral administration. (2) The -lactam ring can also be opened by bacterial enzymes (-lactamases); in particular, penicillinase, which can be produced by staphylococcal strains, renders them resistant to penicillin G. (3) The antibacterial spectrum is narrow; although it encompasses many gram-positive bacteria, gram-negative cocci, and spirochetes, many gram-negative pathogens are unaffected.
Derivatives with a different substituent on 6-APA possess advantages (B): (1) Acid resistance permits oral administration, provided that enteral absorption is possible. All derivatives shown in (B) can be given orally. Penicillin V (phenoxymethylpenicillin) exhibits antibacterial properties similar to those of penicillin G. (2) Due to their penicillinase resistance, isoxazolylpenicillins caused penicillinaseproducing staphylococci. (3) Activity spectrum: The aminopenicillin
amoxicillin is active against many gramnegative organisms, e.g., coli bacteria or Salmonella typhi. It can be protected from destruction by penicillinase by combination with inhibitors of penicillinase (clavulanic acid, sulbactam, tazobactam).
The structurally close congener ampicillin (no 4-hydroxy group) has a similar activity spectrum. However, because it is poorly absorbed (<50%) and therefore causes more extensive damage to the gut microbial flora (side effect: diarrhea), it should be given only by injection. A still broader spectrum (including Pseudomonas bacteria) is shown by carboxypenicillins (carbenicillin, ticarcillin) and acylaminopenicillins (mezclocillin, azlocillin, piperacillin). These substances are neither acid stable nor penicillinase resistant.
Cephalosporins (C). These -lactam antibiotics are also fungal products and have bactericidal activity due to inhibition of transpeptidase.
Their shared basic structure is 7-aminocephalosporanic acid, as exemplified by cephalexin (gray rectangle). Cephalosporins are acid stable, but many are poorly absorbed. Because they must be given parenterally, most—including those with high activity—are used only in clinical settings. A few, e.g., cephalexin, are suitable for oral use.
Cephalosporins are penicillinase-resistant, but cephalosporinase-forming organisms do exist. Some derivatives are, however, also resistant to this -lactamase.
Cephalosporins are broad-spectrum antibacterials. Newer derivatives (e.g., cefotaxime, cefmenoxin, cefoperazone, ceftriaxone, ceftazidime, moxalactam) are also effective against pathogens resistant to various other antibacterials. Cephalosporins are mostly well tolerated. All can cause allergic reactions, some also renal injury, alcohol intolerance, and bleeding (vitamin K antagonism).
Other inhibitors of cell wall synthesis.
Bacitracin and vancomycin interfere with the transport of peptidoglycans through the cytoplasmic membrane and are active only against gram-positive bacteria.
Bacitracin is a polypeptide mixture, markedly nephrotoxic and used only topically.
Vancomycin is a glycopeptide and the drug of choice for the (oral) treatment of bowel inflammations occurring as a complication of antibiotic therapy (pseudomembranous enterocolitis caused by Clostridium difficile). It is not absorbed.
Inhibitors of Tetrahydrofolate Synthesis
Tetrahydrofolic acid (THF) is a co-enzyme in the synthesis of purine bases and thymidine. These are constituents of DNA and RNA and required for cell growth and replication. Lack of THF leads to inhibition of cell proliferation. Formation of THF from dihydrofolate (DHF) is catalyzed by the enzyme dihydrofolate reductase. DHF is made from folic acid, a vitamin that cannot be synthesized in the body, but must be taken up from exogenous sources. Most bacteria do not have a requirement for folate, because they are capable of synthesizing folate, more precisely DHF, from precursors. Selective interference with bacterial biosynthesis of THF can be achieved with sulfonamides and trimethoprim.
Sulfonamides structurally resemble p-aminobenzoic acid (PABA), a precursor in bacterial DHF synthesis. As false substrates, sulfonamides competitively inhibit utilization of PABA, hence DHF synthesis. Because most bacteria cannot take up exogenous folate, they are depleted of DHF. Sulfonamides thus possess bacteriostatic activity against a broad spectrum of pathogens. Sulfonamides are produced by chemical synthesis. The basic structure is shown in (A). Residue R determines the pharmacokinetic properties of a given sulfonamide.
Most sulfonamides are well absorbed via the enteral route. They are metabolized to varying degrees and eliminated through the kidney. Rates of elimination, hence duration of effect, may vary widely. Some members are poorly absorbed from the gut and are thus suitable for the treatment of bacterial bowel infections. Adverse effects may include, among others, allergic reactions, sometimes with severe skin
damage, displacement of other plasma protein-bound drugs or bilirubin ieonates
(danger of kernicterus, hence contraindication for the last weeks of gestation and in the neonate). Because of the frequent emergence of resistant bacteria, sulfonamides are now rarely used.
Introduced in 1935, they were the first broad-spectrum chemotherapeutics. Trimethoprim inhibits bacterial DHF reductase, the human enzyme being significantly less sensitive than the bacterial one (rarely bone marrow depression). A 2,4-diaminopyrimidine, trimethoprim, has bacteriostatic activity against a broad spectrum of pathogens. It is used mostly as a component of cotrimoxazole. Co-trimoxazole is a combination of trimethoprim and the sulfonamide sulfamethoxazole. Since THF synthesis is inhibited at two successive steps, the antibacterial effect of co-trimoxazole is better than that of the individual components. Resistant pathogens are infrequent; a bactericidal effect may occur.
Adverse effects correspond to those of the components. Although initially developed as anantirheumatic agent, sulfasalazine (salazosulfapyridine) is used mainly in the treatment of inflammatory bowel disease (ulcerative colitis and terminal ileitis or Crohn’s disease). Gut bacteria split this compound into the sulfonamide sulfapyridine and mesalamine (5-aminosalicylic acid). The latter is probably the anti-inflammatory agent (inhibition of synthesis of chemotactic signals for granulocytes, and of H2O2 formation in mucosa), but must be present on the gut mucosa in high concentrations. Coupling to the sulfonamide prevents premature absorption in upper small bowel segments. The cleaved-off sulfonamide can be absorbed and may produce typical adverse effects (see above).
Dapsone (p. 280) has several therapeutic uses: besides treatment of leprosy, it is used for prevention/prophylaxis of malaria, toxoplasmosis, and actinomycosis.
Inhibitors of DNA Function
Deoxyribonucleic acid (DNA) serves as a template for the synthesis of nucleic acids. Ribonucleic acid (RNA) executes protein synthesis and thus permits cell growth. Synthesis of new DNA is a prerequisite for cell division. Substances that inhibit reading of genetic information at the DNA template damage the regulatory center of cell metabolism. The substances listed below are useful as antibacterial drugs because they do not affect human cells.
Gyrase inhibitors. The enzyme gyrase (topoisomerase II) permits the orderly accommodation of a ~1000 µmlong bacterial chromosome in a bacterial cell of ~1 µm. Within the chromosomal strand, double-stranded DNA has a double helical configuration. The former, in turn, is arranged in loops that are shortened by supercoiling. The gyrase catalyzes this operation, as illustrated, by opening, underwinding, and closing the DNA double strand such that the full loop need not be rotated.
Derivatives of 4-quinolone-3-carboxylic acid (green portion of ofloxacin formula) are inhibitors of bacterial gyrases.
They appear to prevent specifically the resealing of opened strands and thereby act bactericidally. These agents are absorbed after oral ingestion. The older drug, nalidixic acid, affects exclusively gram-negative bacteria and attains effective concentrations only in urine; it is used as a urinary tract antiseptic.
Norfloxacin has a broader spectrum. Ofloxacin, ciprofloxacin, and enoxacin, and others, also yield systemically effective concentrations and are used for infections of internal organs. Besides gastrointestinal problems and allergy, adverse effects particularly involve the CNS (confusion, hallucinations, seizures). Since they can damage epiphyseal chondrocytes and joint cartilages in laboratory animals, gyrase inhibitors should not be used during pregnancy, lactation, and periods of growth.
Azomycin (nitroimidazole) derivatives, such as metronidazole, damage DNA by complex formation or strand breakage. This occurs in obligate anaerobes, i.e., bacteria growing under O2 exclusion. Under these conditions, conversion to reactive metabolites that attack DNA takes place (e.g., the hydroxylamine shown). The effect is bactericidal. A similar mechanism is involved in the antiprotozoal action on Trichomonas vaginalis (causative agent of vaginitis and urethritis) and Entamoeba histolytica (causative agent of large bowel inflammation, amebic dysentery, and hepatic abscesses). Metronidazole is well absorbed via the enteral route; it is also given i.v. or topically (vaginal insert). Because metronidazole is
considered potentially mutagenic, carcinogenic, and teratogenic in the human, it should not be used longer than 10 d, if possible, and be avoided during pregnancy and lactation. Timidazole may be considered equivalent to metronidazole.
1. http://www.youtube.com/watch?v=RedO6rLNQ2o&feature=related
2. 2 http://www.youtube.com/watch?v=SqRVLIPof90&feature=related
3. http://www.youtube.com/watch?v=sMp-y8qx9D0&feature=related
4. http://www.youtube.com/watch?v=yG2PWCJnX2Q&feature=related
5. http://www.apchute.com/moa.htm