ANTIBIOTIC SIDE EFFECTS

Transcription

1 ANTIBIOTIC THERAPY, PART I /01 $ OO ANTIBIOTIC SIDE EFFECTS Burke A. Cunha, MD Antimicrobial side effects present as adverse drug reactions involving one or more organ systems. Although most antibiotics are safe considering their volume of use, some antimicrobials have the potential for life-threatening side effects. In general, p-lactams have the least frequent and least severe side effects. Although any antibiotic is capable of causing side effects, specific agents from each antibiotic class are more likely to do so than others. Clinicians should be familiar with the sideeffect potential of individual antibiotics as well as the likelihood of specific agents being involved in an adverse reaction and should be familiar with the spectrum of organ involvement associated with particular antimicrobials. Clinicians have a vast armamentarium of antimicrobials effective against a wide variety of pathogens. Most antimicrobials have a good safety profile. Physicians should consider the frequency and severity of potential adverse effects of antimicrobials when selecting agents for therapy* INDIVIDUAL VERSUS CLASS SIDE EFFECTS Most antibiotic-related adverse events are related to specific antimicrobial agents and are not related to antimicrobial classes. Clinicians often are misled by considering class side effects of antimicrobials instead of assessing the possibility of individual agents being responsible for the adverse reaction. For example, photosensitizing reactions are From the State University of New York School of Medicine, Stony Brook, and the Infectious Disease Division, Winthrop-University Hospital, Mineola, New York MEDICAL CLINICS OF NORTH AMERICA VOLUME 85 - NUMBER 1 * JANUARY

2 150 CUNHA common with tetracycline but are rare with minocycline or doxycycline. Similarly, sparfloxacin is associated with photosensitivity reactions among the quinolones, but other quinolones do not have this problem. In some cases, class side effects, such as drug fevers among the p-lactam antibiotics, have clinical relevance, but even with p-lactams there are important differences. In a patient with a penicillin allergy, cross-reactivity with a cephalosporin is least likely if cefoxitin or cefoperazone is used. When class side effects exist (e.g., drug fewers with quinolones), there is great variety within the class of antibiotics (e.g., ciprofloxacin and trovafloxacin are most likely to be associated with drug fevers, although any member of the class may be responsible). Although clinicians should consider class side effects, they need to be more familiar with specific side effects associated with individual agents and be familiar with the probability that such side effects may occur (Tables 1 and 2). HEMATOLOGIC SIDE EFFECTS Leukopenia and Thrombocytopenia Hematologic side effects are common with a wide variety of antimicrobial agents. Isolated cytopenias occur frequently in clinical practice and may present as neutropenia, anemia, and thrombocytopenia. Leukopenia and thrombocytopenia are the most common hematologic side effects related to antimicrobial therapy.34 p-lactam antibiotics and the sulfamethoxazole component of trimethoprim-sulfamethoxazole (TMP- SMX) are the two most common causes of isolated leukopenia or thrombocytopenia.ls4, ls6, ls8 Anemia and pancytopenia are less common.9, 68, 82, Io7 Table 1. ANTIBIOTIC CLASS SIDE EFFECTS Antibiotic Class P-Lactams Sulfonamides Quinolones HIV protease inhibitors Macrolides Aminoglycosides Aminoglycosides P-Lactams Anti-Pseudomonas penicillins Side Effects Drug fever, drug rash Lipid abnormalities, lipodystrophy Nausea, vomiting, abdominal discomfort, diarrhea Ototoxic potential Nephrotoxic potential t Prothrombin time/inr Impaired platelet aggregation HIV = human immunodeficiency virus; INR = international normalized ratio

3 ANTIBIOTIC SIDE EFFECTS 151 Table 2. AGENT-SPECIFIC NOT CLASS-SPECIFIC SIDE EFFECTS Side Effects Specific Agent Other Antibiotics in Same Class SeiZUreS Imipenem Not meropenem Ciprofloxacin Not ofloxacin Trovaflovacin Not levofloxacin Not gatifloxacin Not moxifloxacin Photosensitivity reactions Tetracycline Sparfloxacin Not doxycycline Not minocyclie Not ciprofloxacin QTc interval prolongation (23 msec) Tendinitis, tendon rupture Ciprofloxacin Not ofloxacin Not levofloxacin Not gatifloxacin Not moxifloxacin Not levofloxacin Not ciprofloxacin Not ofloxacin Not gatifloxacin Not ofloxacin Hepatitis ( t SGOT/SGPT) Trovafloxacin Grepafloxacin INH Not levofloxacin Not gatifloxacin Not moxifloxacin Not ciprofloxacin Not ofloxacin Not levofloxacin Not gatifloxacin Not moxifloxacin Not ethambutol Acute pancreatitis Trovafloxacin Not rifampin Not cycloserine Not ethionamide Not pyrazinamide Not ciprofloxacin Not ofloxacin Not levofloxacin Not gatifloxacin Not moxifloxacin Interstitial nephritis OxaciUin Not nafcillin t Prothrombin time/inr Trovafloxacin Not ciprofloxacin Temafloxacin Not ofloxacin Clinical bleeding Non-C. djqicik diarrhea Moxalactam Trovafloxacin Not levofloxacin Not gatifloxacin Not moxifloxacin Not cefotaxime Not ceftizoxime Not cefoperazone Not ceftazidime Not cefepime Not ciprofloxacin Not ofloxacin Not levofloxacin Not gatifloxacin Not moxifloxacin Anaphylactic reactions to p-lactams Not aztreonam** penicillin Not imipenemt Not meropenemt *Rifampin may potentiate increased INH-induced elevations in serum transaminases. A monobactam; not a p-lactam in terms of cross allergenicity. tcarbapenems; not p-lactams in terms of cross allergenicity. SGOT/SGPT = Serum glutamic-oxaloacetic transaminase/senun glutamic-pyruvic transaminase; INH = isoniazid; INR = international normalized ratio.

4 152 CUNHA Anemia The mechanism of antibiotic-related anemia varies according to the antibiotic being used." For example, p-lactams may cause autoimmune hemolytic anemia. TMP-SMX may be associated with folate deficiency, which may result in a megaloblastic anemia.63 Eosinophilia may be associated with any antibiotic causing a drug fever but may occur with fosfomycin in the absence of drug fever. Chloramphenicol rarely may cause irreversible aplastic anemia. Aplastic anemia is an idiosyncratic reaction to chloramphenicol and is not dose related. Serial hemograms are useful to monitor dose-related, reversible bone marrow suppression but are of no value in predicting or preventing chloramphenicol-induced aplastic anemia?, 13, 151, 152 Chloramphenicol-related aplastic anemia occurs with oral, rectal, topical, or intramuscular administration but does not occur if given intravenously. Immune Platelet Dysfunction Although certain antimicrobials may decrease the platelet count, others may interfere with platelet function. Impaired platelet aggregation occurs most commonly in association with the antipseudomonal penicillin~.~~ Antipseudomonal penicillin problems with platelet aggregation are a dose-related side effect.25* 92 The effect on platelets is greatest with the antipseudomonal penicillins used in high doses (e.g., carbenicillin, usual dose, 30 g/d). Antipseudomonal penicillins used in lower doses (e.g., azlocillin, mezlocillin, piperacillin, usual dose, 18 g/d) have less potential for platelet aggregati~n.~~ Excluding carbenicillin, the antipseudomonal penicillins have little potential for clinical bleeding unless given to patients with an underlying bleeding diathe~is.~~, 90 Clinical Bleeding Moxalactam has been associated with clinical bleeding by interfering with the synthesis of vitamin K-dependent clotting factors and impairing platelet aggregation. Many antibiotics, particularly the p-lactams, may increase the international normalized ratio (INR) or prothrombin time (PT) by interfering with the synthesis of vitamin K-dependent clotting Trovafloxacin, among the quinolones, frequently increases the PT or INR; other quinolones do not show this effect. Formerly, it was thought thaf the methyltetrathiozole (MTT) side chain was a structural marker of bleeding potential among p-lactam antibiotics. Cephalosporins with a MTT side chain include cefamandole, cefoperazone, and cefotetan, but antibiotics with a MTT side chain have not caused clinical bleeding. Elevations of the INR or PT normalize rapidly after discontinuation of the antibiotic or the administration of intramuscular vitamin K by weekly intramuscular injection. Clinical bleeding

5 ANTIBIOTIC SIDE EFFECTS 153 relates to the severity of the clinical illness, not to the MTT side chain (no MTT side chain). In a study in the intensive care setting, cefoxitin was associated most frequently with clinical bleeding. The authors concluded that the potential for bleeding is related to severity of illness and not to any particular structural component of the antibiotic (e.g., the MTT side chain). Based on this study and the experience of others, most clinicians give intensive care unit (ICU) patients prophylactic intramuscular injections of vitamin K on a weekly basis to minimize potential bleeding problems (Table 3). HYPERSENSITIVITY SIDE EFFECTS Drug Fever Drug fevers are the most common antibiotic-mediated hypersensitivity side effect. Drug fevers account for 10% to 15% of unexplained fevers in hospitalized patients in the United States. Drug fevers may occur with any antibiotic but are particularly common with p-lactams and sulfonamides and may occur with any antiviral, antifungal, or antiparasitic medication.l, 155 Drug fevers are defined as hypersensitivity reactions to medications whose primary clinical expression is that of fever without rash. Drug fevers are febrile reactions to medications that are mediated in the liver. Transient mild elevations of the serum transaminases are regular clinical features of drug fevers.54 It is a common misconception that most drug fevers are antibiotic related. Most drug fevers are caused by nonantibiotics and are particularly common with diuretics, stool softeners, antiseizure medications, antiarrhythmics, sedatives, antihypertensives, and pain medications. If the clinician can exclude nonantibiotic medications, antibiotics should be considered, keeping in mind the relative frequency of individual antimicrobial agents causing drug fever. Laboratory abnormalities associated with drug fever may suggest an infectious process in the airway (e.g., the white blood cell count often is elevated with a left shift). Eosinophils usually are present in the peripheral smear of patients with drug fevers, but eosinophilia is less common. The diagnosis of drug fevers should be entertained in patients with obscure fevers with negative blood cultures, after other explanations for the fever have been excluded. Drug fever is a syndromic diagnosis characterized by temperatures greater than or equal to 102 F (usual range, 102 F to 106 F) and relative bradycardia in patients not on P-blocker therapy, with arrhythmias or with a pacemaker. Relative bradycardia is a constant finding in patients with drug fevers greater than or equal to 102 F. Such patients also look relatively well for the degree of fever and do not have shaking chills unless they have been given antipyretics.88 Transient elevations of the serum transaminases accompanied by eosinophils in the peripheral smear in a patient with negative blood cultures, excluding contaminants, are suggestive of drug fever. The diagnosis of drug fever is confirmed by observing a decrease in the

6 CI i2 Table 3. HEMATOLOGIC SIDE EFFECTS Neutropenia Side Effects Common Uncommon Comments Anemia Nonhemolytic anemia P-Lactams Flucytosine Pyrimethamine TMP-SMX AZT Vancomycin Dapsone Chloramphenicol Amphotericin B Quinolones P-Lactams and anti-hiv drugs are the most common Indinavir cause of neutropenia. WBCs rapidly return to Lamivudine (3TC) normal after the causative drug is discontinued ddi Penicillins more commonly cause leukopenia than ddc cephalosporins Ganciclovir Griseofulvin Capreomycin Chloramphenicol Aztreonam Imipenem Amantadine Piperacillin/ Tazobactam AZT Ganciclovir Indinavir Ribavirin Adefovir Anemia secondary to chloramphenicol is dose related. Anemia is the first sign of chloramphenicol marrow depression, is readily reversible when chloramphenicol is discontinued, and is not a precursor of aplastic anemia Anemia secondary to amphotericin B is due to inhibition of erythropoietin Clinically, rarely due to cephalosporins Autoimmune hemolytic anemia P-Lactams G6PD hemolytic anemia Sulfonamides Nalidixic acid Sideroblastic anemia INH TMP-SMX INH Indinavir Ceftriaxone Primaauine DapsoAe Th4P-SMX Nitrofurantoin P-Lactams Pyrazinamide

7 mezlocillin, or uiueracillin, that are used in lower Megaloblastic anemia Aplastic anemia Eosinophilia Thrombocytopenia Pancytopenia Impaired platelet aggregation TMP-SMX Chloramphenicol TMP-SMX P-Lactams P-Lactams TMP-SMX Flucytosine Linezolid Chloramphenicol Antipseudomonal penicillins Moxalactam TMP is a folate antagonist, and TMP may result in megaloblastic anemia Chloramphenicol aplastic anemia may occur after only 1 dose. Does not occur with intravenous chloramphenicol but may occur with oral, intramuscular, rectal, or topical ocular Fosfomycin cells (anemia) followed by white cells (leukopenia) and lastly platelets (thrombocytopenia). Pancytopenia is a dose-related reversible effect of prolonged chloramphenicol use Dose-dependent side effect with antipseudomonal penicillins (e.g., carbenicillin 30 g/d). Usually, clinically unimportant with newer antipseudomonal penicillins, ticarcillin, azlocillin, administration Any antibiotic causing drug fever (except Nevirapine pentamidine) may also cause eosinophilia Pyrimethamine Platelet counts rapidly revert to normal after Ganciclovir offending agent is discontinued. A clue to drug- AZT induced thrombocytopenia is the reactive Chloramphenicol thrombocytosis after platelet counts return to TMP-SMX normal Chloramphenicol-associated, dose-related bone ddi marrow suppression sequentially depresses red Cef triaxone Clinical bleeding Moxalactam Temafloxacin Car b e ni c ill in dosage (e.g., 18 &d) Clinical bleeding is not related to the MTT side chain. No blegding with cefamandole, cefoperazone, or cefotetan Clinical bleeding is related to the severitv of illness (e.g., ICU pativents on cefoxitin) INR/urothrombin time Trovafloxacin ' Anv B-Lactam 2. t INR/hmothrombinemia most common with trovaflokacin, cefoperazone, and cefotetan TMP-SMX = Trimethoprim-sulfamethoxazole; AZT = azidothymidine; ddi = dideoxyinosine; ddc = dideoxycytidine; HIV = human immunodeficiency virus; WBCs = white blood cells; INH = isoniazid; GGPD = glucose-6-phosphate dehydrogenase; INR = international normalized ratio. CI m

8 156 CUNHA Drug Fever Clinical Features History Many individuals are atopic May have been on sensitizing medication for days or years Signs Low-grade to high-grade fevers (102 F 2 106"F, but usually 102 OF-1 04 F) Relative bradycardia with temperatures 2102 F Appear inappropriately well for degree of fever Determination of relative bradycardia Inclusive criteria Adult with temperature 2102 F Pulse must be taken simultaneously with the temperature Exclusive criteria Patient must not be on p-blocker medications Patient has no arrhythmia, second-degree or third-degree heart block, or pacemaker rhythm Exclude other disorders associated with relative bradycardia (e.g., Legionella, psittacosis, Q fever, typhoid fever, typhus, malaria, babesiosis, leptospirosis, yellow fever, dengue fever, Rocky Mountain spotted fever, central nervous system lesions, lymphomas, and factitious fever) Normal temperature-pulse relationships Temperature and appropriate pulse response (beatslmin) 106 F (41.1"C) F (395 C) F (40.6%) F (38.9%) F (40.0"C) 130 Laboratory tests Elevated white blood cell count (usually with left shift) Eosinophils almost always present in peripheral blood, but eosinophilia (low grade) is uncommon (520%) Elevated erythrocyte sedimentation rate is present in most cases (may be 2100 mmlh) but usually in the range of mmlh) Transient, mild elevations of serum transaminases (approximately 90%) usually 52 x normal occur early Drugs Implicated in Drug Fever Common Common Uncommon Asparaginase Barbiturates Methyldopa Penicillins Cephalosporins Phenytoin Procainamide Quinidine Sulfonamides (including sulfacontaining laxatives) Diuretics Narcotics Sleep medications Allopurinol Azathioprine Hydralazine Iodides lsoniazid Nonsteroidal antiinflammatory drugs p-blockers Calcium channel blockers Angiotensin-converting enzyme inhibitors Aminoglycosides Macrolides Tetracyclines Clindamycin Chloramphenicol Quinolones Vancomycin Linezolid

9 ANTIBIOTIC SIDE EFFECTS 157 temperature after the offending medication is withdrawn. The temperature with drug fever decreases to near normal within 72 hours after the sensitizing medication is discontinued if a rash is not present. If a hypersensitivity reaction causing the drug fever is allowed to continue without discontinuing the medication, the patient may develop a drug rash.88 The accompanying box presents information on clinical drug fever. Drug Rash Drug rash may be caused by any of the medications causing drug fever but is particularly common with p-lactams or the sulfamethoxazole component of TMP-SMX.28, 63 Drug rashes are a cutaneous manifestation of a drug hypersensitivity reaction.127, lz8 Nonantibiotic medications are common causes of drug rash and should be sought before considering an antimicrobial explanation for the rash. Acute drug rashes usually are accompanied by all of the clinical and laboratory features of drug fever. Drug fever rashes involve the entire body and may involve the palms and the soles. The spectrum of cutaneous manifestations range from maculopapular eruptions to the Stevens-Johnson syndrome. Drug rashes most frequently are maculopapular but may have a petechial component. Virtually all drug rashes are pruritic at some stage. Drug-induced exanthems may be differentiated from the maculopapular rash of contact dermatitis by the distribution of the rash.31 Patients with contact dermatitis do not have any of the features of a drug fever or rash and have a rash that is limited to certain areas and does not involve most of the body.lo, 19,20,22, 54,141 Red neck or red man syndrome is a histamine-mediated reaction to the rapid infusion of vancomycin and does not represent a true allergic reaction to vancomycin.l, 13, 34, 65* 115, l5o, 153 Vancomycin may be given safely to patients with red man or red neck syndrome. This reaction to vancomycin may be eliminated or minimized if the drug is given slowly intravenously. Anaphylactic Reactions Among antimicrobials, p-lactams most frequently are associated with anaphylactoid reactions.s, 86 The sulfamethoxazole component of TMP-SMX also is a common cause of antibiotic-induced anaphylaxis. Although structurally similar to p-lactams, monobactams and carbapenems should not be considered as p-lactams." Aztreonam, imipenem, and meropenem may be used safely in patients with anaphylactoid reactions to penicillin (Table 4).lL ,87, 113,125,134,135

10 Quinolones are an uncommon cause of Patients with allergic reactions to cephalosporins are least likely to cross-react with cefoperazone or cefoxitin among the cephalosporins Aztreonam, imipenem, and meropenem may be used safely in penicillin allergies Table 4. HYPERSENSITIVITY SIDE EFFECTS Side Effects Common Uncommon Comments Drug fever P-Lactams Antivirals The TMP component of TMP-SMX Sulfonamides (TMP-SMX) Antifungals never is responsible for allergic reactions with TMP-SMX; it is Antiparasitics Quinolones - always related to the sulfa component-smx Drug rash Efavirenz P-Lactams Q u in o 1 ones Sulfonamides (TMP-SMX) Delavirdine Nevirapine drug fever; however, among the quinolones, ciprofloxacin and trovafloxacin most often cause drug fevers Cutaneous drug reactions to p-lactams often have a raised papular component Cutaneous sulfa rashes usually are morbilliform

11 Aztreonam, imipenem, and meropenem do not cross-react with p-lactams and may be used in patients with anaphylactic reactions to p-lactams Sulfonamides are the most common antibiotic cause of E. rnultiforrne Drug-induced SLE does not affect the central nervous system or kidneys Doxycycline and minocycline rarely cause photosensitivity reactions Phototoxicity reactions to sparfloxacin may occur days after the drug is discontinued Usually occurs approximately 2 weeks after drug is discontinued Serum sickness reactions are characterized by fever and arthralgias Anaphylaxis P-Lactams TMP-SMX E. rnultiforrne, Stevens-Johnson syndrome Drug-induced SLE Phototoxicity reactions Serum sickness Sulfonamides (TMP-SMX) Delavirdine Grieseofulvin Chloroquine P-Lactams Efavirenz INH Nevirapine Nitrofurantoin Minocycline Grieseofulvin Tetracycline Pyrazinamide Sparfloxacin Pefloxacin Lomefloxacin P-Lactams Primaquine Any antibiotic SLE = Systemic lupus erythematosus.

12 160 CUNHA Serum Sickness Serum sickness reactions may occur with any medication and when associated with antimicrobial therapy usually are due to p-lactams. Serum sickness symptoms usually occur 2 weeks after exposure to the causative medication and are accompanied by nonspecific systemic findings that include low-grade fevers and arthralgias and myalgias. Serum sickness should be suspected in patients with low-grade fevers and arthralgias occurring 2 weeks after antimicrobial therapy and may be confirmed by showing a decrease in the serum complement in such patients after other disorders have been excluded.77, 90, lz4 Photosensitivity Reactions Photosensitizing reactions commonly occur with tetracycline and sparfloxacin. Photosensitivity reactions are rare with doxycycline and minocycline as well as the other fluoroquinolones. Less commonly, perfloxacin and lomefloxacin have been associated with photosensitizing reactions. The photosensitizing reactions that occur with sparfloxacin may occur for 1 week after cessation of the medication. If sparfloxacin is used, patients are advised to use sunscreens or to avoid direct sunlight for at least 1 week after sparfloxacin therapy.18, 40, 90, 143 Drug-Induced Systemic Lupus Erythematosus Many medications may induce a systemic lupus erythematosus-like syndrome. Antibiotics are a rare cause of drug-related systemic lupus erythematosus. Antibiotics implicated in drug-induced systemic lupus erythematosus include minocycline, isoniazid (INH), nitrofurantoin, and griseofulvin. NEUROLOGIC SIDE EFFECTS Antimicrobials are responsible for a wide spectrum of neurologic adverse reactions. The most serious neurologic side effects include encephalitis, seizures, neuromuscular blockage, and muscular spasticity. Encephalopathy Encephalopathy is a frequent side effect of trovafloxacin therapy and has been reported in association with clarithromycin. As with nonantimicrobial medications, the antibiotic-induced encephalopathy clears rapidly after the medication is dis~ontinued.'~, 16, 58, lo5

13 ANTIBIOTIC SIDE EFFECTS 161 Seizures Antibiotic-induced seizures usually are due to ciprofloxacin, imipenem, or trovafloxacin.lo5 A wide variety of medications have been implicated in seizures but less c~mmonly.~o,~~ The ability of an antimicrobial to induce seizures depends on the seizure threshold of the patient and the neuroexcitatory effect of the medication on central nervous system receptors.30, 14*, Although ciprofloxacin, imipenem, and trovafloxacin do not cross the blood-brain barrier in high concentrations, they have been implicated in antibiotic-induced seiz~reses.9~~ Seizures usually resolve promptly after the offending medication is withdrawnz6, 90, lol Levofloxacin and meropenem do not predispose to or cause seizures.", 55, 57 Neuromuscular Blockade Neuromuscular blockade may occur after aminoglycoside therapy if large amounts of the aminoglycoside are absorbed (e.g., aerosolized instillation into the lungs or when used for peritoneal lavage). Clindamycin, when used in peritoneal lavage, may induce transient respiratory arrest. Such patients should receive ventilatory support until neuromuscular transmission returns to normal and the patient resumes unassisted ventilation. Peripheral Neuropathy Peripheral neuropathy most commonly is associated with INH toxicity but may occur with griseofulvin or cycloserine. Pyridoxine should be given along with INH in antituberculous regimens to prevent INHinduced peripheral neuropathy. Long-term high-dose nitrofurantoin therapy in patients with renal insufficiency also may result in peripheral ne~ropathy.'~, Muscular Tremors and Myalgias Muscular tremors and spasticity traditionally have been associated with amantadine therapy. The parkinsonian-like symptoms of amantadine are most common in the elderly and may be prevented or eliminated by decreasing the dose in elderly patients?o Trovafloxacin may cause isolated muscular tremors or spasticity involving the entire body.105, lz9 Painful myalgias has been an infrequent, but disturbing, side effect of quinupristin/dalfopristin.

14 162 CUNHA Ototoxicity Ototoxicity is seen most commonly with aminoglycosides or parenteral erythromycin therapy. Ototoxicity may be cochlear or vestibular, but only aminoglycosides have been associated most commonly with both types of toxicity. Deafness resulting from cochlear toxicity may be irreversible and is associated with prolonged, highly elevated aminoglycoside serum levels. Deafness may follow rapid infusions of intravenous erythromycin. In contrast, dizziness or vestibular toxicity is associated with minocycline. Minocycline's vestibular toxicity is due to high lipid solubility, which results in high minocycline concentrations in the cells of the vestibular apparatus. Symptoms resulting from minocycline-induced dizziness usually clear within a few days after minocycline is discontinued. Blindness Blindness resulting from antimicrobials is unusual. Ethambutol most commonly is associated with a decrease in visual acuity, which may lead to blindness. Ethambutol's ocular toxicity may occur in patients receiving greater than or equal to 25 mg/kg of ethambutol as part of an antituberculous regimen but does not occur if mg/kg is used. Serial ophthalmologic examinations usually are not needed in patients receiving ethambutol unless they have pre-existing eye disease. Patients can screen for visual toxicity by noticing a change in visual acuity when reading books or newspapers and report this to their physician. Patients experiencing such changes should be referred to a neurologist for ophthalmologic evaluation (Table 5).13, 90 PULMONARY SIDE EFFECTS Pulmonary drug reactions are an uncommon side effect of antimicrobial therapy. The presence of drug-induced pulmonary side effects should suggest a nonantimicrobial explanation. Acute Pulmonary Reactions The most common pulmonary side effects resulting from antibiotics are a flulike illness often seen early after the initiation of rifampin the rap^.^ The other antimicrobial reactions directly involving the lung most frequently are due to nitrofurantoin. Nitrofurantoin pulmonary reactions may be acute or chronic, and these clinical manifestations are dissimilar. Acute pulmonary reactions resulting from nitrofurantoin usually result in fever accompanied by pulmonary infiltrates with varying degrees of respiratory insufficiency, pleural effusions, and peripheral

15 ANTIBIOTIC SIDE EFFECTS 163 eosinophilia. Acute nitrofurantoin pulmonary reactions are transient and are readily reversible when the antimicrobial is discontinued. Chronic Pulmonary Reactions Chronic pulmonary reactions secondary to nitrofurantoin may result in pulmonary fibrosis, which is irreversible. Chronic pulmonary reactions secondary to nitrofurantoin are not characterized by fever, peripheral eosinophilia, or pleural effusions but are a chronic, slowly progressive inflammatory process. Chronic pulmonary nitrofurantoin toxicity occurs in patients with renal insufficiency receiving prolonged high doses of nitrofurantoin. Such patients should never receive nitrofurantoin in the presence of renal insufficiency and should not be given the medication over prolonged periods without dosing modifications. Given the volume of use for nitrofurantoin, acute pulmonary reactions are relatively uncommon, and chronic reactions are rare.12 Chronic pulmonary toxicity secondary to nitrofurantoin may be avoided by using nitrofurantoin only for short courses of therapy in patients with advanced renal insufficiency, then using a reduced dose commensurate with the patient s renal function (Table 6).13 CARDIAC SIDE EFFECTS Prolonged QT, Interval Ventricular arrhythmias may occur by direct effect of the drug on myocardial irritability. A prolonged QTc interval may result in ventricular arrhythmias (e.g., torsades de pointes)jl The antimicrobials most commonly associated with prolongation of the QT, interval include IV erythromycin, terbinafine, and some quinolones. QTc prolongation occurs rapidly after an antibiotic is administered, and normalization of the QT, interval occurs after the drug is withdrawn.149 Quinolones that prolong the QT, interval 2 3 msec should not be used together with other medications that cause QTc prolongation or in patients with cardiac arrhythmias of conduction abnormalities. Heart block is an unusual manifestation of antimicrobial therapy, and if present, a nonantimicrobial explanation should be sought. Myocarditis is a rare complication of nevirapine therapy. Hypotension Antimicrobial-induced hypotension commonly occurs with pentamidine. Trovafloxacin and amphotericin B also may induce hypotension (Table 7). Trovafloxacin-induced hypotension may be prolonged (i.e., 12 to 24 hours) and require fluids and pressors to maintain blood pressure organ perfusion until trovafloxacin is metabolized and eliminated.96 Text continued on page 170

16 Trovafloxacin may cause muscle spasms of the neck (meningismus) mimicking meningitis Trovafloxacin central nervous system side effects include mental confusion and encephalopathy, which clear when trovafloxacin is discontinued Table 5. NEUROLOGIC SIDE EFFECTS Side Effects TMP-SMX may or aseptic Common Uncommon Comments Headache TMP-SMX Erythromycin cause headache Cycloserine Aseptic meningitis TMP-SMX Clarithromycin meningitis Itr aconazole Az i thro m y c in Griseofulvin Delavirdine Saquinavir Abacavir Efavirenz Foscamet Polymyxin B Trovafloxacin TMP-SMX often is overlooked as a cause of aseptic meningitis Encephalopathy Trovafloxacin Clarithromycin Cycloserine Foscamet Ethambutol Amantadine Ethionamide Ganciclovir Polymyxin B

17 Neuroexcitatory effects may be minimized by taking antibiotics with neuroexcitatory effects in the morning rather than in the evening Most common causes of antibiotic-related seizures are ciprofloxacin, imipenem, and trovafloxacin Levofloxacin and meropenem do not cause seizures Disappears after drug withdrawal May occur with aminoglycosides/polymyxin B administered to the lungs by aerolizer or with aminoglycoside/clindamycin by peritoneal lavage Disappears after drug withdrawal Neuromuscular blockage may follow massively absorbed quantities of drug interfering with neuromuscular transmission Disappears after drug withdrawal Table continued on following page Neuroexcitatory symptoms Ciprofloxacin C ycloserine Ofloxacin Seizures Cerebellar ataxia Myasthenic syndrome, neuromuscular blockade Ciprofloxacin Imipenem Trovafloxacin Cycloserine Acyclovir Valc yclovir Famciclovir Metronidazole Amantadine Aminogl ycosides Capreomycin Am ant ad in e Rifampin Foscamet Ganciclovir Metronidazole TMP-SMX Nalidixic acid Erythromycin TMP-SMX Nitrofurantoin Nalidixic acid Polymyxin B Polymyxin B Clindamycin Erythromycin Depression C ycloserine Ethionamide

18 Table 5. NEUROLOGIC SIDE EFFECTS (Continued) Side Effects Common Uncommon Comments Psychosis Foscarnet E thio n ami d e Efavirenz Pseudotumor cerebri (benign Tetracycline intercranial HT) Peripheral neuropathy INH Griseofulvin Cycloserine Trovafloxacin Muscular tremors, spasticity Severe myalgias Amantadine Trovafloxacin Trovafloxacin Amprenavir Nitrofurantoin Ethionamide Polymyxin B Ethambutol Metronidazole Foscamet d4t Lamivudine (3TC) ddc dd1 AZT Ganciclovir Disappears after drug withdrawal INH-induced peripheral neuropathy may be prevented by concomitant administration of p yridixine Peripheral neuropathy owing to nitrofurantoin is associated with prolonged high-dose therapy in patients with renal insufficiency and may be permanent Parkinsonian symptoms reversible when drug is discontinued Although severe myalgias are uncommon, they are prolonged/very painful when they occur

19 daily doses of 4 5 mg/kg Ethambutol may cause central scotoma Dysphagia Indinavir Amprenavir Circumoral paresthesias Amprenavir Reversible when drug is discontinued Ototoxicity Deafness (cochlear) Aminogl ycosides Erythromycin Vancomycin Capreomycin rapid intravenous infusion is usually irreversible Aminoglycoside deafness may occur after prolonged, highly elevated peak serum concentrations Vestibular toxicity from minocycline is due to Deafness from erythromycin may follow Viomycin Aminoglycoside-associated cochlear deafness Dizziness (vestibular) h4inocycline Streptomycin Aminoglycoside Efavirenz its high lipid solubility and concentration in Abacavir vestibular cells Among the aminoglycosides, streptomycin Blindness Ethambutol Chloroquine Ganciclovir has the greatest otologic potential Ganciclovir may cause retinal detachment Ethambutol causes red-green color blindness Ethambutol causes dose-dependent visual acuity in high doses; does not occur with NSAIDs = Nonsteroidal anti-inflammatory drugs.

20 Amphotericin B may cause acute pulmonary infiltrates in leukopenic patients Prolonged high-dose nitrofurantoin in patients with renal insufficiency rarely may cause pulmonary fibrosis Chronic nitrofurantoin pulmonary toxicity may be irreversible. Fever, peripheral eosinophilia, and pleural effusions are not features of chronic nitrofurantoin pulmonary reactions Promptly disappears when rifampin is discontinued Any antibiotic causing drug-induced systemic lupus erythematosus may cause pleural effusions Pleural effusions are a feature of acute nitrofurantoin pulmonary reactions that clear rapidly when the drug is discontinued Table 6. PULMONARY SIDE EFFECTS Side Effects Common Uncommon Comments Acute pulmonary reactions Pulmonary infiltrates, acute respiratory insufficiency Nitrofurantoin Amphotericin B Acute lung reactions are more common than chronic and are characterized by fever, pleural effusion, and migratory pulmonary and peripheral eosinophilia. Acute pulmonary effects promptly disappear when drug is discontinued Chronic pulmonary reactions Pulmonary fibrosis Nitrofurantoin Sulfonamides Flu-like illness Pleural effusions Rifampin Nitrofurantoin Abacavir Efavirenz

21 Table 7. CARDIAC SIDE EFFECTS Side Effects Common Uncommon Comments Ventricular arrhythmias AZT Erythromycin Prolonged QT, interval Erythromycin (23 msec) Terbinafine Sparfloxacin Grepafloxacin M o x iflo x a cin Heart block ddi Quinine Hypotension Pentamidine Trovafloxacin Amphotericin B Indinavir Penicillins Vancomycin Amphotericin B I tr a c o n a z o 1 e Amphotericin B Vancomycin Antiparasitics Miconazole Hypertension Amphotericin B lipid formulations Myocarditis Nevirapine Efavirenz Amphotericin B and vancomycin are rare causes of cardiac arrest Rapid intravenous infusion of penicillins with high potassium contact may result in hyperkalemia-induced arrhythmias Sparfloxacin causes the greatest QT, interval prolongation Heart block reverses when drug is discontinued Pentamidine-induced and amphotericin B-induced hypotension is transient and corrects after the infusion is terminated Trovafloxacin-induced hypotension may occur after a single dose and may be prolonged (approximately 24 h) and require intravenous fluids and pressors to restore blood pressure May occur as part of DRESS syndrome (drug rash, eosinophilia, and systemic symptoms)

22 GASTROINTESTINAL SIDE EFFECTS Nausea and Vomiting Many drugs are associated with nausea and vomiting, and antimicrobials are no exception. As a group, antiretrovirals commonly are associated with nausea, vomiting, or abdominal discomfort, which may be so severe as to lead to cessation of the medication. Among antibiotics, the macrolides are the least well tolerated when given by the oral route. Clarithromycin is associated with gastric discomfort and taste perversion (i.e., metallic taste). The new formulations of clarithromycin (Biaxin XL) and amoxicillin/clavulanate have minimal gastrointestinal side ef- fects.15 69,83,157 Tetracyclines usually are well tolerated when administered orally, but doxycycline and minocycline may cause gastrointestinal upset if given on an empty stomach. Although tetracycline should be administered without food (i.e., 1 hour before or 2 hours after a meal), doxycycline and minocycline always should be administered with food. Giving doxycycline using the tablet formulation with food all but eliminates gastrointestinal problems in most patients.49, 50 Non-Clostridium difficile Diarrhea Antibiotic-induced diarrhea may be due to a variety of mechanisms. C. dzjicile diarrhea should be viewed as being an irritative diarrhea and is caused by change in the colonic flora, by having a high osmotic load, or by being irritative to the colon in high concentrations.35 Usually orally administered antibiotics that are absorbed (i.e., 290%) in the proximal gastrointestinal tract are not associated with nausea or vomiting or diarrhea (irritative diarrheas). Antibiotic-induced non-c. dijicile diarrhea is associated most commonly with the macrolides Non-C. dificile diarrhea also commonly may accompany therapy with ampicillin, amoxicillin-clavulanic acid, ceftriaxone, macrolides, or trovafloxacin.80, 83, 117 Ampicillin causes diarrhea by being irritative to the colon in high concentration because it is not absorbed efficiently from the proximal gastrointestinal tract. Amoxicillin is well tolerated by the proximal gastrointestinal tract and is not associated with irritative diarrheas? Non-C. dificile antibiotic-associated diarrheas are frequently accompanied by Cundidu infection of the throat, urine, or vagina as a result of disruption of the colonic microflora. Among the cephalosporins, ceftriaxone induces the most substantial changes in the colonic microflora, often resulting in diarrhea., 11* Ceftriaxone-induced non-c. dificile diarrhea is not due to the high intraluminal concentrations of ceftriaxone or ceftriaxone s enterohepatic biliary Other antibiotic drugs with an enterohepatic circulation with high intracolonic concentrations

23 ANTIBIOTIC SIDE EFFECTS 171 (nonirritative) include nafcillin and do~ycycline.~~, 49 These antibiotics do not cause non-c. dificile irritative diarrheas. The incidence of ceftriaxone diarrhea in children is approximately 50% but is much less in adults. Closfridium difficile Diarrhea Some but not all antibiotics may cause C. difficile diarrhea. The p- lactams are the most important antibiotic class causing this adverse event. Antibiotic-associated C. dificile diarrhea may occur weeks after the antibiotic exposure. Quinolones Doxycycline, and Meropenem are rare causes of C. difficile diarrhea.15, 148 Acute Pancreatitis Acute chemical or clinical pancreatitis has been associated with pentamidine Alternately, antiretrovirals and TMP-SMX have been implicated as a cause of antimicrobial-induced pancreatitka, 90 Trovafloxacin may induce chemical or clinical acute pancreatitis. (Table 8):7, 71 HEPATIC SIDE EFFECTS Drug-Induced Hepatitis Elevations in the serum transaminases traditionally have been associated with INH in antituberculous therapy. Mild and transient elevations of serum transaminases are common with a wide variety of drugs and are particularly common with antiretroviral therapy.lz6 Oxacillin is the most common p-lactam associated with antibiotic-induced hepatitis, but nafcillin, even with an enterohepatic circulation, is a rare cause of antibiotic-induced hepatitis. Elevations in the serum transaminases secondary to trovafloxacin may occur after a single oral or intravenous dose. Patients receiving trovafloxacin should be monitored with daily transaminase determinations to detect these abrupt elevations in the serum transaminases. If trovafloxacin is discontinued, serum transaminase elevations return to normal rapidly in most patients, but in patients with pre-existing liver disease, trovafloxacin-induced elevations of se- 133, 13*, 139 rum transaminases take days to weeks to normalize.59, Cholestasis Cholestasis is more common with nonantimicrobial medications. Among antimicrobials, erythromycin, nitrofurantoin, and thiabendazole are the most common causes of antimicrobial-induced cholestasis. Tetra-

24 Table 8. GASTROINTESTINAL SIDE EFFECTS Side Effects Common Uncommon Comments Nausea, vomiting N e 1 fina v i r TMP-SMX Protease inhibitors, nucleoside analogue, and macrolides, Ritonavir Metronidazole particularly clarithromycin, are the most common Ribavirin Dox yc ycline causes of antibiotic-associated or antiviral-associated Delavirdine Itraconazole nausea, vomiting, and abdominal discomfort Foscamet Ketoconazole Rapid intravenous infusion of imipenem may cause In d in a v i r Ganciclovir nausea and vomiting Saquinavir Terbinafine Quinupristin-dalfopristin causes T SGPT and less Abacavir Methenamine salts commonly SGOT Etionamide Fosfomycin AZT ddi d4t 3TC Clarithromycin Erythromycin Azithromycin Diarrhea Non-C. dzfficile diarrhea Clarithromycin Erythromycin Az i thr o m y c in Ampicillin Amoxicillii-clavulanic acid Ceftriaxone Trovafloxacin Tetracyclines Clindamycin Flucytosine Because amoxicillin and doxycycline are well absorbed in the proximal gastrointestinal tract, they do not cause irritative diarrheas owing to high intraluminal concentrations of antibiotics Ceftriaxone causes non-c. dificile diarrhea by inducing profound changes in the intestinal flora. Non-C. dificile ceftriaxone diarrhea occurs in approximately 50% of children and is less common in adults C. difficile diarrhea P-Lactams Acute pancreatitis Trova floxacin Pentamidine Trova floxacin TMP-SMX Nitrofurantoin ddc lipase with abdominal pain) Lamivudine (3TC) ddi d4t May occur weeks after antibiotic exposure Trovafloxacin-induced pancreatitis may be chemical (e.g., t amylase and lipase) or clinical ( t amylase and Linezolid may cause T lipase or amylase, causing chemical but not clinical pancreatitis

25 ANTIBIOTIC SIDE EFFECTS 173 cycline is hepatotoxic in pregnancy and is dose related. Tetracycline hepatotoxicity occurs with doses greater than or equal to 2 g/d. Doxycycline and minocycline are not hepatotoxic since their usual daily dose is much less than 2 g/d (i.e., 200 to 400 mg/d).13,23,47,89,99 Hepatic Necrosis Acute hepatic necrosis and liver failure may occur in association with PAS, ketoconazole, or trovafloxacin therapy?o Fatal hepatic necrosis secondary to trovafloxacin appears to be due to an idiosyncratic (i.e., not dose related) hypersensitivity rea~tion.~ 48 Trovafloxacin liver failure has necessitated liver transplantation and has resulted in death in several cases?8 Because of the potential of fatal hepatic necrosis, trovafloxacin should not be used.q 139 Nitrofurantoin rarely causes chronic active hepatitis (Table 9).60, NEPHROTOXIC SIDE EFFECTS Nephrotoxicity Nephrotoxicity may be manifested as glomerular or tubular toxicity and may be due to a variety of anti-infectious agents.3, 7, 44, ~4, 147 Tubular toxicity is more common and has been associated with multipledose aminoglycoside therapy. Nephrotoxic potential is similar among aminoglycosides and varies according to the frequency of intravenous admini~tration.~~ Aminoglycosides are potentially toxic to the tubules of the nephron. After intravenous administration, aminoglycosides saturate tubular cells. Intracellular aminoglycosides are subsequently pumped out of the tubular cells, reducing potentially toxic intracellular concentrations.17, 56 Intravenous administration of aminoglycosides by multidose regimens usually does not permit sufficient time for the tubular cells to eliminate intracellular aminoglycoside concentrations before the next dose.112 Once-daily intravenous aminoglycoside regimens have virtually eliminated the nephrotoxic potential of aminoglycosides.lo8 Once-daily aminoglycoside therapy should be used whenever intravenous aminoglycosides are As with multidose regimens, intravenous aminoglycoside single-dose regimens should be dosed based on creatinine clearance.7o, n, loo, Io2 Aminoglycoside-induced tubular dysfunction is best assessed by urinary cast excretion counts, not by monitoring the serum creatinine. The serum creatinine is increased for a variety of reasons in many hospitalized patients and is not a good indicator of tubular function. Serum creatinine is related to lean body mass in the elderly and is an indicator of glomerular rather than tubular function. Aminoglycoside tubular-induced dysfunction usually occurs after about 2 weeks of intravenous aminoglycoside therapy with multiple daily dose regimens.

26 CI 2 Table 9. HEPATIC SIDE EFFECTS Side Effects Common Uncommon Comments Drug-induced hepatitis INH ( t serum transaminases) Trovafloxacin 0 x a c ill in Hyperbilirubinemia Ceftriaxone Tema floxacin Cholestasis Erythromycin Nitrofurantoin Trovafloxacin Thiabendazole Chronic active hepatitis Nitrofurantoin Hepatic necrosis, liver Trova floxacin failure Ketoconazole PAS Rifampin Chloramphenicol Ketoconazole Ethionamide Flucytosine Delavirdine Abacavir Adefovir S a q u in a v ir Indinavir ddi d4t ddc Nevirapine Crixivan Abacavir Adefovir Linezolid Chloramphenicol Tetracycline F 1 u c o n a z o 1 e Nitrofurantoin ddi ddc Most causes of INH hepatitis occur in rapid acetylators during the first month of antituberculosis therapy Most t serum transaminases resulting from INH revert to normal when INH is discontinued. INH should be discontinued if serum transaminases t 210 X normal Trovafloxacin may t serum transaminases to IU/L after a single dose. Usually serum transaminases 1 rapidly after trovafloxacin is discontinued Normalization of t serum transaminases after trovafloxacin may take days or weeks in patients with pre-existing liver disease Nafcillin rarely causes drug-induced hepatitis Ceftizoxime in the neonate may result in kemicterus Erythromycin estolate most common cause of cholestasis, but other erythromycin formulations also cause cholestasis Tetracycline hepatoxicity is dose related (e.g., 22 g/d) Doxycycline and minocycline are not hepatoxic Trovafloxacin may cause fatal hepatic necrosis Trovafloxacin hepatic necrosis is idiosyncratic hypersensitivity reaction

27 ANTIBIOTIC SIDE EFFECTS 175 There are few reasons to use aminoglycosides for longer than a 2- week period. If aminoglycoside therapy is minimized to 2 weeks and if administered by using a once-daily regimen, aminoglycoside nephrotoxic potential is extremely low. Vancomycin has little or no nephrotoxic p~tential.'"~ In patients receiving intravenous vancomycin with increasing serum creatinine, an explanation should be sought for the elevated serum creatinine. Other medications being given concurrently with the vancomycin usually are the cause, but the elevation in the serum creatinine in hospital patients may be due to a variety of non-drug-related causes (e.g., hypovolemia). Interstitial Nephritis Interstitial nephritis may occur with a wide variety of antimicrobials but is associated most closely with p-lactam therapy.13, 90 Acute interstitial nephritis should not be confused with the nephrotoxic reactions described earlier and are hypersensitivity reactions. Eosinophiluria is a cardinal finding in antibiotic-induced, acute allergic interstitial nephritis. Hansen's stain of the urinary sediment is useful diagnostically to show eosinophiluria. Usually renal function returns after the offending antibiotic is discontinued. Other renal adverse events associated with antimicrobials include crystal formation and are associated most commonly with acyclovir or indinavir (Table 10).7,s,13 METABOLIC SIDE EFFECTS Many antibiotics may cause metabolic abnormalities. Commonly recognized side effects include gonadal and adrenal dysfunction induced by ketoconazole. Lactic acidosis may accompany abacavir therapy. Hyperglycemia frequently is associated with pentamidine administration. Gynecomastia, lipodystrophy, and other lipid abnormalities are particularly associated with indinavir but may occur with other protease inhibitors. Pathophysiology of lipid abnormalities associated with indinavir is not clear because patients have a redistribution of body fat that may be sufficiently disturbing to the patient to result in cessation of antiretroviral therapy. Triglyceride elevations may occur secondary to AZT or ddi therapy. Itraconazole may increase serum triglycerides and decrease serum aldosterone levels (Table ll)?7 MISCELLANEOUS SIDE EFFECTS A variety of other side effects have been ascribed to antimicrobials (Table 12).* Adverse reactions are important from a differential diagnostic and pharmacoeconomic standpoint. *References 103, 104, 106, 110, 111, 116, ,123, , 140, 146.

28 Table 10. NEPHROTOXICITY SIDE EFFECTS Side Effects Common Uncommon Comments Glomerular toxicity. Capreomycin Tubular toxicity Aminoglycosides Polymyxin B Pentamidine Crystal formation Acyclovir Indinavir Interstitial nephritis P-Lactams ATN Aminoglycosides ATN = Acute tubular necrosis. Foscamet Tetracycline Capreomycin Adefovir Sulfonamides (TMP-SMX) TMP-SMX Erythromycin Ciprofloxacin Nevirapine Temafloxacin Foscamet causes nephrogenic diabetes insipidus Vancomycin is not nephrotoxic Nephrotoxicity occurring with other nephrotoxic drugs (e.g., vancomycin plus aminoglycoside combinations) is due to the nonvancomycin component Increased fluid intake decreases potential crystal formation Hansen s stain of urine (eosinophiluria) is diagnostic Common with oxacillin but not nafcillin Temafloxacin-induced ATN is secondary to autoimmune hemolysis Aminoglycoside-induced ATN is reversible

29 ANTIBIOTIC SIDE EFFECTS 177 Phlebitis Phlebitis or phlebitis-like local reactions most commonly are associated with erythromycin, trovafloxacin, and quinupristin/dalfopristin. Local intravenous site reactions subside rapidly after drug infusion is terminated. Arthropathy Previously, it was thought that quinolones interfered with cartilage formation with resultant arthropathy in children. It has been shown that for short courses of quinolone therapy (i.e., 2 to 4 weeks), quinolones do not cause cartilage dysgenesis or arthropathy. Quinolones may be used safely in young children.ls, 137 Tendinitis and Tendon Rupture Tendinitis or tendon rupture has been associated with ciprofloxacin and is not a quinolone class side effect (see Table 12).137 Skin Discoloration Skin discoloration may occur after prolonged minocycline use and may not reverse after discontinuation of t~eatment.3~ SUMMARY Antibiotic side effects are approached best from an individual agent perspective rather than from a class-related standpoint. As this article indicates, with the exception of drug fevers and drug rashes, most antibiotic side effects are related to individual agents and not class side effects., 76 Clinicians should view antimicrobial side effects as related to each organ system and be aware that more often a nonmicrobial medication is the explanation for the drug side effect rather than the antimicrobial. Nonantimicrobial medications are the most common cause of drug fever; among antimicrobials, p-lactams and sulfonamides are the most common causes of drug-induced fevers. Antimicrobial side effects have important implications for the patient, legal and economic implications for the hospital, and medicolegal implications for the physician. Antibiotic side effects that prolong hospitalization in today s managed care environment have important economic implications. Clinicians should be familiar with the most common side effects of the most frequently used antimicrobials, to minimize the potential of having adverse reactions occur in patients q

30 Table 11. METABOLIC SIDE EFFECTS Side Effects Gonadal function. Lactic acidosis H yperglycemia J, Cortisol production Gynecomastia Lipodystrophy, lipid abnormalities Myositis Hyperuricemia T CPK CpK = Creatine phosphokinase. ~ ~ ~~ Common Uncommon Comments Ketoconazole Abacavir Pentamidine Ketoconazole Indinavir Indinavir AZT AZT ddi Ritonavir Stavudine Decreased gonadal function may occur with prolonged ketoconazole use Reversible when drug is discontinued Transient effect that disappears after infusion Itraconazole Lipodystrophy may occur with protease inhibitors but is most common with indinavir Ethambutol Adefovir t Triglycerides and J, aldosterone may occur with itraconazole t Triglycerides may occur with AZT and ddi Minimize with increased fluid intake and allopurinol Ethambutol is the only antituberculosis medication that is not hepatically inactivated or eliminated

31 Table 12. OTHER SIDE EFFECTS Side Effects Common Uncommon Comments Hyperpigmentation Discolored nails Alopecia Flushing Fever (nondrug fever) Local intravenous site reactions Metallic taste Tendinitis, tendon rupture Glossitis, stomatitis Arthralgias, myalgias Rhabdomyolysis Oral ulcers Conjunctivitis Lymphadenopathy Minoc ycline Minoc ycline Tetracycline Ethionamide Vancomycin Amphotericin B Erythromycin Trovafloxacin Clarithromycin Metronidazole Ciprofloxacin Griseofulvin Quinupristin-dalfopristin AZT Foscamet Ribavirin TMP-SMX Nevirapine Nalidixic acid AZT Lamivudine (3TC) Quinupristindalfopristin Ethambutol Capreomycin Etionamide TMP-SMX ddc Aztreonam ddc Sulfonamides Efavirenz Minocycline discoloration may be permanent Minocycline discoloration may be permanent. Tetracyclines cause nail discoloration in young children, not adults Usually reversible after drug is discontinued Usually reversible after drug is discontinued Red neck or red man syndrome is a transient drug histamine reaction Amphotericin B regularly causes fever when infused; fever abates after infusion completed Local reactions subside after drug infusions Clarithromycin tastes like aluminum sand in addition to causing taste perversion Oral metronidazole frequently is associated with taste perversion Nearly all quinolone-related tendinitis and tendon ruptures are due to ciprofloxacin Heals slowly after drug is discontinued May be severe, may be related to dose/dosing interval Any antibiotic causing serum sickness or drug-induced SLE can cause arthralgias or myalgias Common with AZT; rare with aztreonam Heals slowly after drug is discontinued Sulfonamides cause conjunctivitis as part of Stevens-Johnson syndrome May occur as part of DRESS syndrome (drug rash, eosinophilia, and systemic syndromes) CI U \o SLE = Systemic lupus erythematosus.

32 180 CUNHA Most adverse events related to antimicrobials are reversible rapidly on cessation of the medication. Irreversible toxicities include aminoglycoside-induced ototoxicity, Stevens-Johnson syndrome, and toxicity secondary to nitrofurantoin. The most common acute fatal drug reactions include hypersensitivity reactions resulting in anaphylaxis or the Stevens-Johnson syndrome and fatal hepatic necrosis secondary to trovafloxacin. Clinicians should eliminate the use of drugs associated with chronic or fatal toxicities because multiple therapeutic alternatives exist for virtually every potential infection. References 1. Ackerman BH, Bradsher RW Vancomycin and red necks. Ann Intem Med 102:724, Adam D, Von Rosenstiel N Adverse reactions to quinolones, potential toxicities, drug interactions, and metabolic effects. Infect Dis Clin Pract 3(suppl 3):S177, Albert CA, Rho JP: Amphotericin B associated nephrotoxicity. Antibiotics for Clinicians 2114, Alvarez-Elcoro S, Enzler MJ: The macrolides: Erythromycin, clarithromycin, and azithromycin. Mayo Clin Proc 74:613, Aminimanizani A, Rho JP: Hematological toxicities of chloramphenicol. Antibiotics for Clinicians 2:89, Appel GB: A decade of pencillin related acute interstitial nephritis-more questions than answers. Clin Nepthrol 13:151, Appel GB, Neu HC: The nephrotoxicity of antimicrobial agents. N Engl J Med :722. ~~, Appel GB, Neu HC: The nephrotoxicity of antimicrobial agents. N Engl J Med ,1977 Aquinas SM, Allan WGL, Horsfall PAL, et a1 Adverse reactions to daily and intermittent rifampicin regimens for pulmonary tuberculosis in Hong Kong. BMJ 1:765, 1972 Amdt KA, Jick H: Rates of cutaneous reactions to drugs. JAMA 235:918, 1976 Austen KF: Current concepts: Systemic anaphylaxis in the human being. N Engl J Med 291:661, 1974 Back 0, Lundgren R, Wiman L-G: Nitrofurantoin-induced pulmonary fibrosis and lupus syndrome. Lancet 1:930, 1974 Ball AP: Toxicity. In OGrady F, Finch RG, Lambert HP, et a1 (eds): Antibiotic and Chemotherapy, ed 7. New York, Churchill Livingstone, 1997, p 108 Ball P: Adverse reactions and interactions of fluoroquinolones. Clin Invest Med 12:28, 1989 Bartlett JG: Antibiotic-associated diarrhea. J Infect Dis 15:573, 1992 Bedikian A, Rho JP: Neurological side effects. Antibiotics for Clinicians 1:75, 1997 Begg EJ, Barclay ML Aminoglycosides-50 years on. Br J Clin Pharmacol39:597,1995 Bethel HJN Photo-onycholysis caused by demethylchlortetracycline. BMJ 2:96, 1977 Beveridge J, Harris M, Wise G, et a1 Long acting sulphonamides associated with Stevens-Johnson syndrome. Lancet 2:593, 1964 Bigby M, lick S, Jich H, et al: Drug-induced cutaneous reactions. JAMA ,1986 Blum MD, Graham DJ, McCloskey CA. Temafloxacin syndrome: Review of 95 cases. Clin Infect Dis 18:946, 1994 Bossi P, Colin D, Bricaire F, et al: Hypersensitivity syndrome associated with efavirenz therapy. Clin Infect Dis 30: ,2000 Braun P: Hepatoxicity of erythromycin. J Infect Dis 119:300, 1969 Brogden RN, Heel RC: Aztreonam: A review of its antibacterial activity, pharmacokinetic properties and therapeutic use. Drugs 31:96, 1986

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