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Cephalosporins are semisynthetic derivatives of cephalosporin C produced by the fungus Acremonium, previously called Cephalosporium. Cephalosporins have a ring structure similar to that of penicillins and are generally divided into first, second, third, fourth, and fifth generations based on their antimicrobial spectrum. First generation cephalosporins include cefadroxil, cefazolin, cephalexin, cephapirin, and cephradine. Second generation cephalosporins include cefaclor, cefamandole, cefonicid, cefotetan, cefoxitin, cefprozil, and cefuroxime. Third generation cephalosporins include cefdinir, ceftazidime, cefixime, ceftibuten, cefoperazone, ceftizoxime, cefotaxime, ceftriaxone, and cefpodoxime. The fourth generation cephalosporin is cefepime and the fifth generation cephalosporin is ceftaroline.
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Effects occurring after acute overdose of cephalosporins resemble those occurring with penicillins. Some cephalosporins also have epileptogenic potential similar to penicillin.244 Case reports demonstrate seizures after inadvertent intraventricular administration.34,129,252 Management of cephalosporin overdose is similar to that of penicillin overdose. Table 57–1 lists the pharmacologic mechanism of cephalosporins.
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Adverse Effects Associated with Therapeutic Use.
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Cephalosporins rarely cause an immune-mediated acute hemolytic crisis.70 Cefaclor is the cephalosporin most commonly reported to cause systemic immune complex hypersensitivity or serum sickness, although this can occur with other cephalosporins.119,140 Also like penicillins, first-generation cephalosporins are associated with chronic toxicity, including interstitial nephritis and hepatitis.249 Cefepime is reported to cause reversible coma and seizures.1,218
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Cross-Hypersensitivity.
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The cephalosporins contain a six-member dihydrithiazine ring instead of the five-member thiazolidine penicillin ring. The extent of cross-reactivity between penicillins and cephalosporins in an individual patient is largely determined by the type of penicillin allergic response experienced by the patient. The incidence of anaphylaxis to cephalosporins is between 0.0001% and 0.1%, with a threefold increase in patients with previous penicillin allergy.120 The overall cross-reactivity rate is approximately 1% between penicillin and a first- or second-generation cephalosporin. Cross-reactivity between penicillin and third-, fourth-, or fifth-generation cephalosporins is likely to be negligible due to a dissimilar antigenic side chain.43 In fact, IgE directed against a methylene substituent linking the side chain to the penicillin molecule is identified.95 These determinants are quite distinct among cephalosporins, which cause the pattern of cross-hypersensitivity among cephalosporins to be much less well defined than among the penicillins. Caution should be used when considering first- or second-generation cephalosporins in penicillin- or cephalosporin-allergic patients; however, if a risk-to-benefit analysis demonstrates a clear benefit to the patient without equivalent alternatives, the cephalosporin should be given.
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N-methylthiotetrazole Side-Chain Effects.
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Cephalosporins containing an N-methylthiotetrazole (nMTT) side chain (moxalactam, cefazolin, cefoperazone, cefmetazole, cefamandole, cefotetan) have toxic effects unique to their group structure. As these cephalosporins undergo metabolism, they release free nMTT, which is responsible for their effects (Fig. 57–2).148 Free nMTT inhibits the enzyme aldehyde dehydrogenase and, in conjunction with ethanol, can cause a disulfiramlike reaction (Chaps. 79 and 80).38
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The nMTT side chain is also associated with hypoprothrombinemia, although a causal relationship is controversial.91 It is thought that nMTT depletes vitamin K-dependent clotting factors by inhibition of vitamin K epoxide reductase.167 In a study of children one month to one year of age who were maintained on a prolonged antibiotic regimen, a significant degree of vitamin K–depletion was found.22 Treatment of patients suspected of hypoprothrombinemia caused by these cephalosporins consists of fresh frozen plasma, if bleeding is evident, and vitamin K1 in doses required to resynthesize vitamin K cofactors (Chap. 60 and Antidotes in Depth: A15).
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Other β-Lactam Antimicrobials
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Included in this group are monobactams such as aztreonam and carbapenems such as imipenem and meropenem. Table 57–1 lists the pharmacologic mechanism of these xenobiotics.
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Effects occurring after acute overdose of other β-lactam antimicrobials resemble those occurring after penicillin exposure. Imipenem has epileptogenic potential in both overdose and therapeutic dosing (see Adverse Effects Associated With Therapeutic Use).42,131 Management guidelines for other β-lactam overdoses are similar to those for penicillin overdoses.
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Adverse Effects Associated with Therapeutic Use.
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The risk factors for imipenem-related seizures include central nervous system disease, prior seizure disorders, and abnormal kidney function.173 The mechanism for seizures appears to be GABA antagonism (similar to the penicillins) in conjunction with enhanced activity of excitatory amino acids.62,224
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Cross-Hypersensitivity.
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Aztreonam is a monobactam that does not contain the antigenic components required for cross-allergy with penicillins, and generalized cross-allergenicity is not expected.202 However, aztreonam cross-reacts in vitro with ceftriaxone, thought to be the result of the similarity in their side-chain structure.175 Skin test manifested cross-allergenicity has also been noted between imipenem and penicillin, although the clinical incidence of adverse reactions is yet to be determined.201
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Trimethoprim-Sulfamethoxazole
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Trimethoprim and sulfamethoxazole work as antibacterials in tandem effectively preventing tetrahydrofolic acid synthesis in bacterial cells. Significant toxicity after acute overdose is not expected; however, a myriad of effects occur after chronic therapeutic use. Hyperkalemia can result due to the ability of trimethoprim to competitively inhibit sodium channels in the distal nephron causing impairment in renal potassium excretion. Clinically significant hyperkalemia is reported in patients concurrently on other xenobiotics that increase potassium and among those with CKD.68,164 Other effects commonly reported after use of trimethoprim/sulfamethoxazole combinations include cutaneous allergic reactions, hematologic disorders, methemoglobinemia, hypoglycemia, rhabdomyolysis, and psychosis.
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Trimethoprim also inhibits the renal tubular secretion of creatinine resulting in an increase in serum creatinine measurement.59 This effect is thought to be dose related and ranges from 13% to 35% in patients with CKD. The rise in creatinine is independent of glomerular filtration rate and resolves upon drug discontinuation.
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Chloramphenicol was originally derived from Streptomyces venezuelae and is now synthetically produced. Antimicrobial activity is demonstrated against many Gram-positive and Gram-negative aerobes and anaerobes. Table 57–1 lists the pharmacologic mechanism of chloramphenicol.
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Acute overdose of chloramphenicol commonly causes nausea and vomiting. Chloramphenicol inhibits protein synthesis in rapidly proliferating cells. Metabolic acidosis occurs as a result of the inhibition of mitochondrial enzymes, oxidative phosphorylation, and mitochondrial biogenesis.81 Infrequently, sudden cardiovascular collapse can occur 5 to 12 hours after acute overdoses. Cardiovascular compromise is more frequent in patients with serum concentrations higher than 50 µg/mL.81,154,231 Because concentrations are not readily available, all poisoned patients should be closely observed for at least 12 hours after exposure. Orogastric lavage may be useful for recent ingestions when the patient has not vomited, and activated charcoal 1 g/kg should be orally given.
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Extracorporeal means of eliminating chloramphenicol are not usually required because of its rapid metabolism. However, both hemodialysis and charcoal hemoperfusion decrease serum chloramphenicol concentrations and may be of benefit in patients with large overdoses, or in patients with severe hepatic or renal dysfunction.80,150,215 Exchange transfusion also lowers serum chloramphenicol concentrations in neonates.223 Surviving patients should be closely monitored for signs of bone marrow suppression, which is usually dose dependent.
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Adverse Effects Associated with Therapeutic Use.
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Chronic toxicity of chloramphenicol is similar to that which occurs following acute poisoning. The classic description of chronic chloramphenicol toxicity is the “gray baby syndrome.”154 Children with this syndrome exhibit vomiting, anorexia, respiratory distress, abdominal distension, green stools, lethargy, cyanosis, ashen color, metabolic acidosis, hypotension, and cardiovascular collapse.
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Approximately 90% of systemic chloramphenicol is metabolized via glucuronyl transferase, forming a glucuronide conjugate. The remainder is excreted renally unchanged. Infants, in particular, are predisposed to the gray baby syndrome because they have a limited capacity to form a glucuronide conjugate of chloramphenicol and, concomitantly, a limited ability to excrete unconjugated chloramphenicol in the urine.88,248
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There are two types of bone marrow suppression that occur after use of chloramphenicol. The most common type is dose dependent and occurs with high serum concentrations of chloramphenicol.106,107,208 Clinical manifestations usually occur within several weeks of therapy and include anemia, thrombocytopenia, leukopenia, and, very rarely, aplastic anemia. Bone marrow suppression is generally reversible on discontinuation of therapy. A second type occurs through inhibition of protein synthesis in the mitochondria of marrow cell lines.157 This type causes the development of aplastic anemia, which is not dose related, generally occurs in susceptible patients within 5 months of treatment and has an approximately 50% mortality rate (Chap. 22).69,255 The dehydro and nitroso bacterial metabolites of chloramphenicol injure human bone marrow cells through inhibition of myeloid colony growth, inhibition of DNA synthesis, and inhibition of mitochondrial protein synthesis.115
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Other adverse effects associated with chloramphenicol include peripheral neuropathy, neurologic abnormalities (eg, confusion, delirium), optic neuritis, nonlymphocytic leukemia, and contact dermatitis.52,124,133,180,213
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The fluoroquinolones are a structurally similar, synthetically derived group of antimicrobials that have diverse antimicrobial activities. They include balofloxacin, ciprofloxacin, clinafloxacin, enoxacin, fleroxacin, gatifloxacin, gemifloxacin, grepafloxacin, levofloxacin, lomefloxacin, moxifloxacin, nadifloxacin, nalidixic acid, norfloxacin, ofloxacin, pefloxacin, rufloxacin, sparfloxacin, temafloxacin, and tosufloxacin. Like other antimicrobials, the fluoroquinolones rarely produce life-threatening effects following acute overdose, and most patients can be safely managed with minimal intervention.11Table 57–1 lists the pharmacologic mechanism of fluoroquinolones.
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Rarely, acute overdose of a fluoroquinolone results in AKI or seizures.127 The mechanism of AKI after fluoroquinolone exposure is controversial. In animals, ciprofloxacin and norfloxacin are nephrotoxic, especially in the setting of neutral or alkaline urine.54,205 In humans, AKI is reported after both acute and chronic exposure to fluoroquinolones. A hypersensitivity reaction is postulated to explain pathologic changes consistent with interstitial nephritis.104,187 Treatment includes discontinuation of the fluoroquinolone and supportive care. Improvement in kidney function usually occurs within several days.
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Seizures are reported with ciprofloxacin and may be a result of the inhibition of GABA or elevation of neuronal glutamate.2,216,235 Others postulate that seizures result from the ability of fluoroquinolones to bind efficiently to cations, particularly magnesium. This hypothesis is related to the inhibitory role of magnesium at the excitatory NMDA-gated ion channel (Chap. 14).63 Treatment is supportive, using benzodiazepines and, if necessary, barbiturates to increase inhibitory tone.
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Adverse Effects Associated with Therapeutic Use.
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Several fluoroquinolones are substrates and/or inhibitors of cytochrome CYP enzymes. This can result in xenobiotic interactions, which are especially important with xenobiotics that have a narrow therapeutic index.
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Serious adverse effects related to fluoroquinolone use consist of central nervous system toxicity, as discussed, cardiovascular toxicity, hepatotoxicity, and notable musculoskeletal toxicity.
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Fluoroquinolones cause prolongation of the QT interval, and they may also cause torsade de pointes.195 Prolongation is due to the ability of fluoroquinolones to block the rapid component of the delayed rectifier potassium current (IKr). Treatment of patients presenting with QT prolongation is supportive.
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Fluoroquinolones also rarely result in potentially fatal hepatotoxicity.136 This adverse effect is most notable with trovafloxacin, which was withdrawn from the US market.
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Fluoroquinolones should be used with caution in children and pregnant women because of their potential adverse effects on developing cartilage and bone.118 Damage is more common to fluoroquinolones with fleroxacin, pefloxacin, levofloxacin, and ofloxacin due to a substitution at the R-7 position of the quinolone core structure. There are very limited data regarding damage to articular cartilage as a result of using fluoroquinolones in humans; however, children given ciprofloxacin on a compassionate basis developed complaints of swollen, painful, and stiff joints after 3 weeks of therapy.114 All signs and symptoms abated within 2 weeks of discontinuation of therapy. However, 29 additional children treated with ofloxacin or ciprofloxacin showed no differences with respect to cartilage thickness, cartilage structure, edema, cartilage-bone borderline, or synovial fluid.57 Women who received quinolones during pregnancy had larger babies and more caesarean deliveries because of fetal distress than did controls.19
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Fluoroquinolones are implicated as a cause of tendon rupture, which is reported to occur for months to one year after the start of treatment as well as after the discontinuation of therapy.174,219 The fluoroquinolone should be discontinued in patients, particularly in athletes who complain of symptoms consistent with painful and swollen tendons.
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Other adverse effects include acute psychosis, hyperglycemia, hypoglycemia, rash, tinnitus, eosinophilia, serum sickness, and photosensitivity .39,92,155,172,222
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Macrolides and Ketolides
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The macrolide antimicrobials include various forms of erythromycin (base, ethylsuccinate, gluceptate, lactobionate, stearate), azithromycin, clarithromycin, dirithromycin, fidaxomicin, and troleandomycin. Ketolides are similar in pharmacology to macrolides; telithromycin is the only available agent at this time. Table 57–1 lists the pharmacologic mechanism of macrolides and ketolides.
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Acute oral overdoses of macrolide antimicrobials are not life threatening and symptoms, which are generally confined to the gastrointestinal tract, include nausea, vomiting, and diarrhea. However, intravenous overdoses can cause dysrhythmias.228
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Intravenous and oral therapeutic use of macrolides cause QT interval prolongation and dysrhythmias. The QT interval prolongation seen occurs due to blockade of delayed rectifier potassium currents (IKr; Chaps. 16 and 64).194 Erythromycin lactobionate causes QT interval prolongation and torsade de pointes after intravenous use.168 Oral erythromycin is also implicated in causing prolongation of the QT interval and torsade de pointes, especially in patients concurrently taking cytochrome (CYP3A4) inhibitors, in women, and in those with underlying heart disease.66,94,181 Oral use of azithromycin use is associated with an increased risk of cardiovascular death with several case reports of QT interval prolongation, torsade de pointes, and polymorphic ventricular tachycardia.180 In children, intravenous overdoses of azithromycin result in similar findings.
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Although there are no acute overdose data regarding ketolide antimicrobials, effects are expected to be similar to macrolide antimicrobials. Therapeutic use of telithromycin is reported to result in QT interval prolongation, hepatotoxicity, toxic epidermal necrolysis, and anaphylaxis.35
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Adverse Events Associated with Interactions with Xenobiotics.
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Erythromycin is the prototypical macrolide and, as such, has received the most attention with respect to potential and documented xenobiotic interactions. Clarithromycin, erythromycin, and troleandomycin are all potent inhibitors of the CYP3A4 enzyme system; azithromycin does not inhibit this enzyme.56 Erythromycin inhibits cytochrome P450 after metabolism to a nitroso intermediate, which then forms an inactive complex with the iron (II) of cytochrome P450. The appendix to Chap. 13 lists substrates for the CYP3A4 system. Clinically significant interactions occur with erythromycin and warfarin, carbamazepine, or cyclosporine.40,99,178 Inhibition of cisapride metabolism results in increased concentrations of the parent xenobiotic, which is capable of causing prolongation of the QT interval and causing torsade de pointes.29 Cases of carbamazepine toxicity are documented when combined with the use of erythromycin.99 Erythromycin also inhibits CYP1A2, producing clinically significant interactions with clozapine, theophylline, and warfarin.190
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Macrolides may also interact with the absorption and renal excretion of xenobiotics that are amenable to intestinal P-glycoprotein excretion, or interfere with normal gut flora responsible for metabolism. This may be part of the underlying mechanism of cases of macrolide-induced digoxin toxicity (Chap. 65).166
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The most common toxic effect of macrolides after chronic use is hepatitis, which may be immune mediated.44 Erythromycin estolate is the macrolide most frequently implicated in causing cholestatic hepatitis.87,111
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Large doses (> 4 g/day) of macrolide antimicrobials are also associated with reversible high-frequency sensorineural hearing loss.36 Renal impairment may be a risk factor.198,225 There are rare case reports in which ototoxicity did not resolve following discontinuation of therapy.132 Other, rare toxic effects associated with macrolides include cataracts after clarithromycin use in animals and acute pancreatitis in humans.75,239 Allergy is rare and reported at a rate of 0.4% to 3%.60 Telithromycin contains a carbamate side chain that may interfere with the normal function of neuronal cholinesterase. It should be used cautiously in patients with myasthenia gravis, particularly patients receiving pyridostigmine because of the risk of cholinergic crisis.229
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Clindamycin is a lincosamide with similar structure and clinical effects to macrolides. Clindamycin phosphate is commonly used topically while clindamycin hydrochloride is available for intravenous use. Data regarding acute overdose are limited and most cases of chronic toxicity occur after use of systemic doses of clindamycin phosphate. The most consequential toxicity is gastrointestinal resulting in esophageal ulcers, diarrhea, and C. difficile mediated enterocolitis.188
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Sulfonamides antagonize para-aminobenzoic acid or paraaminobenzyl glutamic acid, which are required for the biosynthesis of folic acid. Table 57–1 lists the pharmacologic mechanism of sulfonamides. Acute oral overdoses of sulfonamides are usually not life threatening, and symptoms are generally confined to nausea, although allergy and methemoglobinemia occur rarely.79 Treatment is similar to acute oral penicillin overdoses.
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Adverse Effects Associated with Therapeutic Use.
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The most common adverse effects associated with sulfonamide therapy are nausea and cutaneous hypersensitivity reactions. Hypersensitivity reactions are thought to be caused by the formation of hapten sulfamethoxazole metabolites, N-hydroxy-sulfamethoxazole and nitroso-sulfamethoxazole. The degree of hapten binding is mitigated in vitro by cysteine and glutathione.158 The incidence of adverse reactions to sulfonamides, including allergy, is increased in HIV-positive patients and is positively correlated to the number of previous opportunistic infections experienced by the patient.130 This may be caused by a decrease in the mechanisms available for detoxification of free radical formation, as cysteine and glutathione concentrations are low in these patients.246 Whether supplementation with a glutathione precursor such as N-acetylcysteine will reduce the incidence of these reactions is unknown.4
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Methemoglobinemia and hemolysis occur rarely.67,159 The mechanism for adverse reactions is not entirely clear. However, when sulfamethoxazole is exposed to ultraviolet B radiation in vitro, free radicals are formed that can participate in the development of tissue peroxidation and hemolysis.255 This finding may be of particular importance in treating patients with glucose-6-phosphate dehydrogenase deficiency associated with decreased in reducing capabilities.5
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The sulfonamides are associated with many chronic adverse effects. Bone marrow suppression is rare, but the incidence is increased in patients with folic acid or vitamin B12 deficiency, and in children, pregnant women, alcoholics, dialysis patients, and immunocompromised patients, as well as in patients who are receiving other folate antagonists. Other adverse effects include hypersensitivity pneumonitis, stomatitis, aseptic meningitis, hepatotoxicity, renal toxicity, and central nervous system toxicity.25
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Tetracyclines are derivatives of Streptomyces cultures. Currently available tetracyclines include demeclocycline, doxycycline, methacycline, minocycline, oxytetracycline, and tetracycline. Table 57–1 lists the pharmacologic mechanism of tetracyclines. Significant toxicity after acute overdose of tetracyclines is unlikely. Gastrointestinal effects consisting of nausea, vomiting, and epigastric pain have been reported.37
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Adverse Effects Associated with Therapeutic Use.
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Tetracycline should not be used in children during the first 6 to 8 years of life or by pregnant women after the 12th week of pregnancy because of the risk of development of secondary tooth discoloration in children or developing children in utero. Tooth discoloration can be effectively removed using topical application of carbamide peroxide whitening treatments.234 Other effects associated with tetracyclines include nephrotoxicity, hepatotoxicity, skin hyperpigmentation in sun-exposed areas, and hypersensitivity reactions.44,90,109,227 More severe hypersensitivity reactions, xenobiotic-induced lupus, and pneumonitis are reported after minocycline use, as are cases of necrotizing vasculitis of the skin and uterine cervix, and lymphadenopathy with eosinophilia.143,207,212 Demeclocycline rarely causes nephrogenic diabetes insipidus (Chaps. 19 and 28).45
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Vancomycin is obtained from cultures of Nocardia orientalis and is a tricyclic glycopeptide. Vancomycin is biologically active against numerous Gram-positive organisms. Table 57–1 lists the pharmacologic mechanism of vancomycin.
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Acute oral overdoses of vancomycin rarely cause significant toxicity and most cases can be treated with supportive care alone. After large iatrogenic rapidly infused intravenous overdoses, AKI can occur in patients with preexisting kidney disease due to sustained high serum concentrations. In these patients, multiple doses of activated charcoal and potentially high-flux hemodialysis can be considered to enhance clearance.125,238
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Adverse Effects Associated with Therapeutic Use.
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Patients who receive intravenous vancomycin may develop the “red man syndrome” through an anaphylactoid (non–IgE-mediated) mechanism.84 Symptoms include chest pain, dyspnea, pruritus, urticaria, flushing, and angioedema.193 Signs and symptoms spontaneously resolve, typically within 15 minutes. Other symptoms attributable to “red man syndrome” include hypotension, cardiovascular collapse, and seizures.13,162
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The incidence of red man syndrome appears to be related to the rate of infusion and is approximately 14% when 1 g is given over 10 minutes, and falls dramatically to only 3.4% when given over 1 hour.162,169 A trial in 11 healthy persons studied the relationship between intradermal skin hypersensitivity and the development of red man syndrome. Each of the 11 study participants underwent skin testing that was followed one week later by an intravenous dose of vancomycin 15 mg/kg over 60 minutes. Following intravenous vancomycin, all participants developed dermal flare responses and erythema, and 10 of 11 participants developed pruritus within 20 to 45 minutes. After the infusion was terminated, symptoms resolved within 60 minutes.176
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The signs and symptoms of this syndrome are related to the rise and fall of histamine concentrations.134,200 Tachyphylaxis occurs in patients given multiple doses of vancomycin.97,245 Animal models demonstrated a direct myocardial depressant and vasodilatory effect of vancomycin.53 More serious reactions result when vancomycin is given via intravenous bolus, further supporting a rate-related anaphylactoid mechanism.21
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Patients most often experience red man syndrome after vancomycin is administered intravenously. In rare cases, oral administration of vancomycin can also result in the syndrome.18 Treatment includes increasing the dilution of vancomycin and slowing intravenous administration. Antihistamines may be useful as pretreatment, especially prior to the first dose.183 A placebo-controlled trial in adult patients studied the incidence of these symptoms in patients given 1 g of vancomycin over one hour, as well as the effect of diphenhydramine in the prevention of the syndrome.245 There was a 47% incidence of reaction without diphenhydramine and a 0% incidence with diphenhydramine.
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Chronic use of vancomycin may cause reversible nephrotoxicity, particularly in patients with prolonged excessive steady-state serum concentrations.10,186 Concomitant administration of aminoglycoside antimicrobials may increase the risk of nephrotoxicity.196 Vancomycin also causes, though rarely, thrombocytopenia and neutropenia.50,51,65