(BQ) Part 2 book The washington manual of medical therapeutics presents the following contents: Antimicrobials; sexually transmitted infections, human immunodeficiency virus, and acquired immunodeficiency syndrome; solid organ transplant medicine; gastrointestinal diseases; liver diseases; liver diseases;... and other content.
15 Antimicrobials David J Ritchie Matthew P Crotty Nigar Kirmani Empiric antimicrobial therapy should be initiated based on expected pathogens for a given infection As microbial resistance is increasing among many pathogens, a review of institutional as well as local, regional, national, and global susceptibility trends can assist in the development of empiric therapy regimens Antimicrobial therapy should be modified, if possible, based on results of culture and sensitivity testing to agent(s) that have the narrowest spectrum possible In some cases, shorter durations of therapy have been shown to be as effective as traditionally longer courses Attention should be paid to the possibility of switching from parenteral to oral therapy where possible, as many oral agents have excellent bioavailability Several antibiotics have major drug interactions or require alternate dosing in renal or hepatic insufficiency, or both For antiretroviral, antiparasitic, and antihepatitis agents, see Chapter 16, Sexually Transmitted Infections, Human Immunodeficiency Virus, and Acquired Immunodeficiency Syndrome; Chapter 14, Treatment of Infectious Diseases; and Chapter 19, Liver Diseases, respectively ANTIBACTERIAL AGENTS Penicillins GENERAL PRINCIPLES Penicillins (PCNs) irreversibly bind PCN-binding proteins in the bacterial cell wall, causing osmotic rupture and death These agents have a diminished role today because of acquired resistance in many bacterial species through alterations in PCN-binding proteins or expression of hydrolytic enzymes PCNs remain among the drugs of choice for syphilis and infections caused by PCN-sensitive streptococci, methicillin-sensitive Staphylococcus aureus (MSSA), Listeria monocytogenes, Pasteurella multocida, and Actinomyces TREATMENT Aqueous PCN G (2-5 million units IV q4h or 12-30 million units daily by continuous infusion) is the IV preparation of PCN G and the drug of choice for most PCN-susceptible streptococcal infections and neurosyphilis Procaine PCN G is an IM repository form of PCN G that can be used as an alternative treatment for neurosyphilis at a dose of 2.4 million units IM daily in combination with probenecid 500 mg PO qid for 1014 days Benzathine PCN is a long-acting IM repository form of PCN G that is commonly used for treating early latent syphilis (1 year [2.4 million units IM weekly for three doses]) It is occasionally given for group A streptococcal pharyngitis and prophylaxis after acute rheumatic fever PCN V (250-500 mg PO q6h) is an oral formulation of PCN that is typically used to treat group A streptococcal pharyngitis Ampicillin (1-3 g IV q4-6h) is the drug of choice for treatment of infections caused by susceptible Enterococcus species or L monocytogenes Oral ampicillin (250-500 mg PO q6h) P.479 may be used for uncomplicated sinusitis, pharyngitis, otitis media, and urinary tract infections (UTIs), but amoxicillin is generally preferred Ampicillin/sulbactam (1.5-3.0 g IV q6h) combines ampicillin with the β-lactamase inhibitor sulbactam, thereby extending the spectrum to include MSSA, anaerobes, and many Enterobacteriaceae The sulbactam component also has unique activity against some strains of Acinetobacter The agent is effective for upper and lower respiratory tract infections; genitourinary tract infections; and abdominal, pelvic, and polymicrobial soft tissue infections, including those due to human or animal bites Amoxicillin (250-1000 mg PO q8h, 875 mg PO q12h, or 775 mg extended-release q24h) is an oral antibiotic similar to ampicillin that is commonly used for uncomplicated sinusitis, pharyngitis, otitis media, community-acquired pneumonia, and UTIs Amoxicillin/clavulanic acid (875 mg PO q12h, 500 mg PO q8h, 90 mg/kg/d divided q12h [Augmentin ES-600 suspension], or 2000 mg PO q12h [Augmentin XR]) is an oral antibiotic similar to ampicillin/sulbactam that combines amoxicillin with the β-lactamase inhibitor clavulanate It is useful for treating complicated sinusitis and otitis media and for prophylaxis of human or animal bites after appropriate local treatment Nafcillin and oxacillin (1-2 g IV q4-6h) are penicillinase-resistant synthetic PCNs that are drugs of choice for treating MSSA infections Dose reduction should be considered in decompensated liver disease Dicloxacillin (250-500 mg PO q6h) is an oral antibiotic with a spectrum of activity similar to that of nafcillin and oxacillin, which is typically used to treat localized skin infections Piperacillin/tazobactam (3.375 g IV q6h or the higher dose of 4.5 g IV q6h for Pseudomonas) combines piperacillin with the β-lactamase inhibitor tazobactam This combination is active against most Enterobacteriaceae, Pseudomonas, MSSA, ampicillin-sensitive enterococci, and anaerobes, making it useful for intra-abdominal and complicated polymicrobial soft tissue infections The addition of an aminoglycoside should be considered for treatment of serious infections caused by Pseudomonas aeruginosa or for nosocomial pneumonia SPECIAL CONSIDERATIONS Adverse events: All PCN derivatives have been rarely associated with anaphylaxis, interstitial nephritis, anemia, and leukopenia Prolonged high-dose therapy (>2 weeks) is typically monitored with weekly serum creatinine and complete blood count (CBC) Liver function tests (LFTs) are also monitored with oxacillin/nafcillin, as these agents can cause hepatitis All patients should be asked about PCN, cephalosporin, or carbapenem allergies These agents should not be used in patients with a reported serious PCN allergy without prior skin testing or desensitization, or both Cephalosporins GENERAL PRINCIPLES Cephalosporins exert their bactericidal effect by interfering with cell wall synthesis by the same mechanism as PCNs These agents are clinically useful because of their broad spectrum of activity and low toxicity profile All cephalosporins are devoid of clinically significant activity against enterococci when used alone Within this class, only ceftaroline is active against methicillin-resistant S aureus (MRSA) P.480 TREATMENT First-generation cephalosporins have activity against staphylococci, streptococci, Escherichia coli , and many Klebsiella and Proteus species These agents have limited activity against other enteric gramnegative bacilli and anaerobes Cefazolin (1-2 g IV/IM q8h) is the most commonly used parenteral preparation, and cephalexin (250-500 mg PO q6h) and cefadroxil (500 mg to g PO q12h) are oral preparations These agents are commonly used for treating skin/soft tissue infections, UTIs, and minor MSSA infections and for surgical prophylaxis (cefazolin) Second-generation cephalosporins have expanded coverage against enteric gram-negative rods and can be divided into above-the-diaphragm and below-the-diaphragm agents Cefuroxime (1.5 g IV/IM q8h) is useful for treatment of infections above the diaphragm This agent has reasonable antistaphylococcal and antistreptococcal activity in addition to an extended spectrum against gram-negative aerobes and can be used for skin/soft tissue infections, complicated UTIs, and some community-acquired respiratory tract infections It does not reliably cover Bacteroides fragilis Cefuroxime axetil (250-500 mg PO q12h), cefprozil (250-500 mg PO q12h), and cefaclor (250-500 mg PO q12h) are oral second-generation cephalosporins typically used for bronchitis, sinusitis, otitis media, UTIs, local soft tissue infections, and oral step-down therapy for pneumonia or cellulitis responsive to parenteral cephalosporins Cefoxitin (1-2 g IV q4-8h) and cefotetan (1-2 g IV q12h) are useful for treatment of infections below the diaphragm These agents have reasonable activity against gram negatives and anaerobes, including B fragilis, and are commonly used for intra-abdominal or gynecologic surgical prophylaxis and infections, including diverticulitis and pelvic inflammatory disease Third-generation cephalosporins have broad coverage against aerobic gram-negative bacilli and retain significant activity against streptococci and MSSA They have moderate anaerobic activity, but generally not against B fragilis Ceftazidime is the only third-generation cephalosporin that is useful for treating serious P aeruginosa infections Some of these agents have substantial central nervous system (CNS) penetration and are useful in treating meningitis (see Chapter 14, Treatment of Infectious Diseases) Third-generation cephalosporins are not reliable for the treatment of serious infections caused by organisms producing AmpC β-lactamases regardless of the results of susceptibility testing These pathogens should be treated empirically with carbapenems, cefepime, or fluoroquinolones Ceftriaxone (1-2 g IV/IM q12-24h) and cefotaxime (1-2 g IV/IM q4-12h) are very similar in spectrum and efficacy They can be used as empiric therapy for pyelonephritis, urosepsis, pneumonia, intraabdominal infections (combined with metronidazole), gonorrhea, and meningitis They can also be used for osteomyelitis, septic arthritis, endocarditis, and soft tissue infections caused by susceptible organisms An emerging therapy is ceftriaxone g IV q12h in combination with ampicillin IV for treatment of ampicillin-sensitive Enterococcus faecalis endocarditis when aminoglycosides need to be avoided Cefpodoxime proxetil (100-400 mg PO q12h), cefdinir (300 mg PO q12h), ceftibuten (400 mg PO q24h), and cefditoren pivoxil (200-400 mg PO q12h) are oral third-generation cephalosporins useful for the treatment of bronchitis and complicated sinusitis, otitis media, and UTIs These agents can also be used as step-down therapy for community-acquired pneumonia Cefixime (400 mg PO once) is no longer recommended as a first-line therapy for gonorrhea but may be used as alternative therapy for gonorrhea with close 7-day test-of-cure follow-up Ceftazidime (1-2 g IV/IM q8h) may be used for treatment of infections caused by susceptible strains of P aeruginosa P.481 The fourth-generation cephalosporin cefepime (500 mg to g IV/IM q8-12h) has excellent aerobic gram-negative coverage, including P aeruginosa and other bacteria producing AmpC β-lactamases Its gram-positive activity is similar to that of ceftriaxone and cefotaxime Cefepime is routinely used for empiric therapy in febrile neutropenic patients It also has a prominent role in treating infections caused by antibiotic-resistant gram-negative bacteria and some infections involving both gram-negative and gram-positive aerobes in most sites Anti-anaerobic coverage should be added where anaerobes are suspected Ceftaroline (600 mg IV q12h) is a cephalosporin with anti-MRSA activity that is US Food and Drug Administration (FDA) approved for acute bacterial skin and skin structure infections and communityacquired bacterial pneumonia Ceftaroline’s unique MRSA activity is due to its affinity for PCN binding protein 2a (PBP2a), the same cell wall component that renders MRSA resistant to all other β-lactams Ceftaroline has similar activity to ceftriaxone against gram-negative pathogens, with virtually no activity against Pseudomonas spp., Acinetobacter, and other organisms producing AmpC β-lactamase, extended-spectrum β-lactamase (ESBL), or Klebsiella pneumoniae carbapenemase (KPC) Like all other cephalosporins, it is relatively inactive against Enterococcus spp Ceftolozane-tazobactam (1 g ceftolozane/0.5 g tazobactam IV q8 h) is a combination product consisting of a cephalosporin and a β-lactamase inhibitor This agent is FDA approved for treatment of complicated intra-abdominal infections and complicated UTIs (cUTIs), including pyelonephritis Ceftolozanetazobactam has activity against many gram-negative bacteria, including some P aeruginosa that are resistant to antipseudomonal carbapenems, antipseudomonal cephalosporins, and piperacillintazobactam Ceftolozane-tazobactam is also active against some ESBL-producing organisms Ceftazidime-avibactam (2 g ceftazidime/0.5 g avibactam IV q8h) is a combination product consisting of ceftazidime plus the novel β-lactamase inhibitor avibactam This agent is FDA approved for treatment of cUTIs and complicated intra-abdominal infections Ceftazidime-avibactam is active against gram-negative bacteria, including some P aeruginosa that are resistant to other antipseudomonal β-lactams This agent is also active against ESBL- and AmpC-producing strains and possesses unique activity against KPCproducing Enterobacteriaceae (but not against metallo-β-lactamases) SPECIAL CONSIDERATIONS Adverse events: All cephalosporins have been rarely associated with anaphylaxis, interstitial nephritis, anemia, and leukopenia PCN-allergic patients have a 5-10% incidence of a cross-hypersensitivity reaction to cephalosporins These agents should not be used in a patient with a reported severe PCN allergy (i.e., anaphylaxis, hives) without prior skin testing or desensitization, or both Prolonged therapy (>2 weeks) is typically monitored with a weekly serum creatinine and CBC Due to its biliary elimination, ceftriaxone may cause biliary sludging Cefepime has been associated with CNS side effects, including delirium and seizures Monobactams GENERAL PRINCIPLES Aztreonam (1-2 g IV/IM q6-12h) is a monobactam that is active only against aerobic gram-negative bacteria, including P aeruginosa It is useful in patients with known serious β-lactam allergy because there is no apparent cross-reactivity P.482 Aztreonam is also available in an inhalational dosage form (75 mg inhaled q8h for 28 days) to improve respiratory symptoms in cystic fibrosis patients infected with P aeruginosa Carbapenems GENERAL PRINCIPLES Imipenem (500 mg to g IV/IM q6-8h), meropenem (1-2 g IV q8h or 500 mg IV q6h), doripenem (500 mg IV q8h), and ertapenem (1 g IV q24h) are the currently available carbapenems Carbapenems exert their bactericidal effect by interfering with cell wall synthesis, similar to PCNs and cephalosporins, and are active against most gram-positive and gram-negative bacteria, including anaerobes They are among the antibiotics of choice for infections caused by organisms producing AmpC or ESBLs TREATMENT Carbapenems are important agents for treatment of many antibiotic-resistant bacterial infections at most body sites These agents are commonly used for severe polymicrobial infections, including Fournier’s gangrene, intra-abdominal catastrophes, and sepsis in immunocompromised hosts Notable bacteria that are resistant to carbapenems include ampicillin-resistant enterococci, MRSA, Stenotrophomonas, and KPC- and metallo-β-lactamase-producing gram-negative organisms In addition, ertapenem does not provide reliable coverage against P aeruginosa, Acinetobacter, or enterococci; therefore, imipenem, doripenem, or meropenem would be preferred for empiric treatment of nosocomial infections when these pathogens are suspected Meropenem is the preferred carbapenem for treatment of CNS infections SPECIAL CONSIDERATIONS Adverse events: Carbapenems can precipitate seizure activity, especially in older patients, individuals with renal insufficiency, and patients with preexisting seizure disorders or other CNS pathology Carbapenems should be avoided in these patients unless no reasonable alternative therapy is available Like cephalosporins, carbapenems have been rarely associated with anaphylaxis, interstitial nephritis, anemia, and leukopenia Patients who are allergic to PCNs/cephalosporins may have a cross-hypersensitivity reaction to carbapenems, and these agents should not be used in a patient with a reported severe PCN allergy without prior skin testing, desensitization, or both Prolonged therapy (>2 weeks) is typically monitored with a weekly serum creatinine, LFTs, and CBC Aminoglycosides GENERAL PRINCIPLES Aminoglycosides exert their bactericidal effect by binding to the bacterial ribosome, causing misreading during translation of bacterial messenger RNA into proteins These drugs are often used in combination with cell wallactive agents (i.e., β-lactams and vancomycin) for treatment of severe infections caused by gram-positive and gram-negative aerobes P.483 Aminoglycosides tend to be synergistic with cell wall-active antibiotics such as PCNs, cephalosporins, and vancomycin However, they not have activity against anaerobes, and their activity is impaired in the low pH/low oxygen environment of abscesses Cross-resistance among aminoglycosides is common, and in cases of serious infections, susceptibility testing with each aminoglycoside is recommended Use of these antibiotics is limited by significant nephrotoxicity and ototoxicity TREATMENT Traditional dosing of aminoglycosides involves daily divided dosing with the upper end of the dosing range reserved for life-threatening infections Peak and trough concentrations should be obtained with the third or fourth dose and then every 3-4 days, along with regular serum creatinine monitoring Increasing serum creatinine or peak/troughs out of the acceptable range requires immediate attention Extended-interval dosing of aminoglycosides is an alternative method of administration and is more convenient than traditional dosing for most indications Extended-interval doses are provided in the following specific drug sections A drug concentration is obtained 6-14 hours after the first dose, and a nomogram (Figure 15-1) is consulted to determine the subsequent dosing interval Monitoring includes obtaining a drug concentration 6-14 hours after the dosage at least every week and a serum creatinine at least three times a week In patients who are not responding to therapy, a 12-hour concentration should be checked, and if that concentration is undetectable, extended-interval dosing should be abandoned in favor of traditional dosing For obese patients (actual weight >20% above ideal body weight [IBW]), an obese dosing weight (IBW + 0.4 × [actual body weight − IBW]) should be used for determining doses for both traditional and extended-interval methods Traditional dosing, rather than extended-interval dosing, should be used for patients with endocarditis, burns that cover more than 20% of the body, anasarca, and creatinine clearance (CrCl) of 90 μg/mL in the acutely intoxicated patient Chronic toxicity usually occurs in patients with a large body burden of theophylline who develop a concurrent illness or are administered a drug that delays the P450 metabolism and theophylline clearance Subtle symptoms such as nausea and anorexia may occur; tachycardia is usually present Severe toxicity may occur at serum levels of 40-60 μg/mL Patients with these serum concentrations may present with seizures Diagnostic Testing Laboratories Therapeutic concentrations are 5-15 μg/mL Acute toxicity is associated with the development of hypokalemia and hyperglycemia In severe cases, expect a metabolic acidosis Obtain a BMP and blood glucose Serial theophylline concentrations should be obtained every 1-2 hours until a downward trend is present; remember, with sustained-release preparations, a peak may not be evident for 16 hours or later after ingestion Calcium, magnesium, and CK should be checked as well Chronic toxicity can occur with lower concentrations than in acute toxicity Many laboratories (e.g., potassium, glucose) may be unremarkable, unless seizures are present, but should still be obtained Serial theophylline concentrations are also warranted in these patients Electrocardiography Adenosine antagonism and increased catecholamines may result in a sinus tachycardia or supraventricular tachycardia (SVT) on the ECG In overdose, premature ventricular contractions (PVCs) may be apparent TREATMENT Patients with theophylline toxicity not require gastric lavage because they tend to vomit Sustainedrelease preparations occasionally form bezoars Severely intoxicated patients require intubation and ventilation Sustained-release formulations should be treated with whole-bowel irrigation Replete potassium and electrolytes as needed Medications Administer AC g/kg Consider MDAC because theophylline clearance is increased by this modality (Clin Pharmacol Ther 1983;33:351) Ensure patients have adequate airway protection because vomiting and aspiration may occur Vomiting should be managed with ondansetron or metoclopramide Phenothiazines are contraindicated because they lower the seizure threshold Seizures are often refractory and should initially be treated with benzodiazepines If this modality fails, consider moving to phenobarbital as a 10 mg/kg loading dose at a rate of 50 mg/min, followed by up to a total of 30 mg/kg at a rate of 50 mg/min, followed by 1-5 mg/kg/d to maintain therapeutic plasma levels Propofol is a reasonable alternative if these fail Monitor for hypotension P.921 Hypotension should be treated with 20 mL/kg bolus of IVF, which may be repeated Direct pressors such as phenylephrine and norepinephrine may be added if fluid boluses are not sufficient Because much of the hypotension is mediated by β2-agonism, avoid epinephrine Consider using short-acting βantagonists such as esmolol, which, although counterintuitive, may reverse β2-mediated vasodilatation Monitor for bronchospasm Arrhythmias should be treated with β-antagonists Use short-acting agents such as esmolol and monitor for bronchospasm Because theophylline is an adenosine antagonist, adenosine may fail to treat SVT Other Nonpharmacologic Therapies Hemoperfusion (charcoal or resin) or hemodialysis is indicated for the following: Intractable seizures or life-threatening cardiovascular complications, regardless of drug level A theophylline level of >100 mg/mL after an acute overdose A theophylline level >60 mg/mL in acute intoxication, with worsening symptoms, or inability to tolerate oral charcoal administration A theophylline level >60 mg/mL in chronic intoxication without life-threatening symptoms A theophylline level >40 mg/mL in a patient with chronic intoxication and CHF, respiratory insufficiency, hepatic failure, or age >60 years (J Emerg Med 1993;11:415) Toxic Alcohol, General GENERAL PRINCIPLES High alcohol concentrations increase the measured plasma osmolality and subsequently widen the osmolar gap A normal gap is 100 mg/dL, toxic methanol manifestations may be delayed; if elevated in presence of acidosis, the acidosis is unlikely to be related to a toxic alcohol ingestion because ethanol blocks the metabolism of the parent compound (unless the toxic alcohol ingestion occurred hours before the ethanol ingestion) Serum methanol concentration: Usually not readily available; therefore, clinically may not be useful TREATMENT ABCs and general supportive care GI decontamination: Nasogastric lavage is only indicated in patients who present