《传染病学 Infectious Disease》课程教学资源（MBBS）课程参考书籍教材：Infectious Diseases, A Clinical Short Course, Second Edition

ANTI-INFECTIVE THERAPY/ 3 the incidence of serious, immediate immunoglobulin Other less common toxicities are associated with E (IgE)-mediated hypersensitivity reactions is much individual B-lactam antibiotics. Natural penicillins and lower with cephalosporins than with penicillins. imipenem lower the seizure threshold and can result in Approximately 1% to 7% of patients with penicillin grand mal seizures. Ceftriaxone is excreted in high con- sludging and cholecystitis. Antibiotics containing a spe Penicillins are the most allergenic of the B-lactam cific methylthiotetrazole ring(cefamandole, cefopera antibiotics because their breakdown products, partic- zone, cefotetan)can induce hypoprothrombinemia and ularly penicilloyl and penicillanic acid, are able to in combination with poor nutrition, may increase post form amide bonds with serum proteins. The resulting operative bleeding. Cefepime has been associated with antigens increase the probability of a host immune encephalopathy and myoclonus in elderly individuals response. Patients who have been sensitized by previ- All broad-spectrum antibiotics increase the risk of ous exposure to penicillin may develop an immediate pseudomembranous colitis(see Chapter 8). In combi IgE-mediated hypersensitivity reaction that can result nation with aminoglycosides, cephalosporins demon in anaphylaxis and urticaria. In the United States, strate increased nephrotoxicit penicillin-induced allergic reactions result in 400 to 800 fatalities annually. Because of the potential dan- Penicillins ger, patients with a history of an immediate hyperser itivity reaction to penicillin should never be given Tables 1.3 and 1.4, together with Figure 1.5, summarize any B-lactam antibiotic, including a cephalosporin or the characteristics of the various penicillins carbapenem. High levels of immunoglobulin G anti- Penicillins vary in their spectrum of activity. Natural penicillin antibodies can cause serum sickness, a syn- penicillins have a narrow spectrum. The aminopeni drome resulting in fever, arthritis, and arthralgia cillins have an intermediate spectrum, and combined urticaria, and diffuse edema with B-lactamase inhibitors, the carboxy/ureidopeni cillin have a very broad spectrum of activity. NATURAL PENICILLINS KEY POINTS Pharmacokinetics--All natural penicillins are rapidly excreted by the kidneys, resulting in short half-live About B-Lactam Antibiotic Toxicity (Table 1.3). As a consequence, the penicillins must be dosed frequently, and dosing must be adjusted in patients with renal dysfunction. Probenecid slows renal excretion, 1. Allergic reactions are most common toxicity, and this agent can be used to sustain higher serum levels and they include both delayed and immediate ypersensitivity reactions. 2. Allergy to penicillins(PCNs)seen in 1%to 10% of patients: 1% to 3% are allergic to KEY POINTS cephalosporins and carbapenems. 1% to 7% of tients with a pcn allergy are also allergic to ephalosporins and carbapenems. About the natural penicillins imipenem, primarily in patients with renal dys- 1. Very short half-life(15-30 minutes) 2. Excreted renally; adjust for renal dysfunction; 4. Ceftriaxone is excreted in the bile and can crys- probenecid delays excretion. tallize to form biliary sludge. 3. Penetrates most inflamed body cavities. 4. Narrow spectrum Indicated for Streptococcu efamandole, cefoperazone, moxalactam pyogenes, S viridans Gp, mouth flora, Clostridia efotetan )can interfere with vitamin K and meningitidis, Pasteurella increase prothrombin time and spirochetes 6. Pseudomembranous colitis can develop as a result of overgrowth of Clost 5. Recommended for penicillin-sensitive S pneu- moniae [however, penicillin resistant strains are Nephrotoxicity sometimes occurs when now frequent (>30%)]; infections caused by cephalosporins are given in combination with mouth flora; Clostridium perfringens or spiro- aminoglycosides. hetes

the incidence of serious, immediate immunoglobulin E (IgE)–mediated hypersensitivity reactions is much lower with cephalosporins than with penicillins. Approximately 1% to 7% of patients with penicillin allergies also prove to be allergic to cephalosporins and carbapenems. Penicillins are the most allergenic of the
-lactam antibiotics because their breakdown products, partic￾ularly penicilloyl and penicillanic acid, are able to form amide bonds with serum proteins. The resulting antigens increase the probability of a host immune response. Patients who have been sensitized by previ￾ous exposure to penicillin may develop an immediate IgE-mediated hypersensitivity reaction that can result in anaphylaxis and urticaria. In the United States, penicillin-induced allergic reactions result in 400 to 800 fatalities annually. Because of the potential dan￾ger, patients with a history of an immediate hypersen￾sitivity reaction to penicillin should never be given any
-lactam antibiotic, including a cephalosporin or carbapenem. High levels of immunoglobulin G anti￾penicillin antibodies can cause serum sickness, a syn￾drome resulting in fever, arthritis, and arthralgias, urticaria, and diffuse edema. Other less common toxicities are associated with individual
-lactam antibiotics. Natural penicillins and imipenem lower the seizure threshold and can result in grand mal seizures. Ceftriaxone is excreted in high con￾centrations in the bile and can crystallize, causing biliary sludging and cholecystitis. Antibiotics containing a spe￾cific methylthiotetrazole ring (cefamandole, cefopera￾zone, cefotetan) can induce hypoprothrombinemia and, in combination with poor nutrition, may increase post￾operative bleeding. Cefepime has been associated with encephalopathy and myoclonus in elderly individuals. All broad-spectrum antibiotics increase the risk of pseudomembranous colitis (see Chapter 8). In combi￾nation with aminoglycosides, cephalosporins demon￾strate increased nephrotoxicity. Penicillins Tables 1.3 and 1.4, together with Figure 1.5, summarize the characteristics of the various penicillins. Penicillins vary in their spectrum of activity. Natural penicillins have a narrow spectrum. The aminopeni￾cillins have an intermediate spectrum, and combined with
-lactamase inhibitors, the carboxy/ureidopeni￾cillins have a very broad spectrum of activity. NATURAL PENICILLINS Pharmacokinetics—All natural penicillins are rapidly excreted by the kidneys, resulting in short half-lives (Table 1.3). As a consequence, the penicillins must be dosed frequently, and dosing must be adjusted in patients with renal dysfunction. Probenecid slows renal excretion, and this agent can be used to sustain higher serum levels. ANTI-INFECTIVE THERAPY / 13 1. Allergic reactions are most common toxicity, and they include both delayed and immediate hypersensitivity reactions. 2. Allergy to penicillins (PCNs) seen in 1% to 10% of patients; 1% to 3% are allergic to cephalosporins and carbapenems. 1% to 7% of patients with a PCN allergy are also allergic to cephalosporins and carbapenems. 3. Seizures are associated with PCNs and imipenem, primarily in patients with renal dys￾function. 4. Ceftriaxone is excreted in the bile and can crys￾tallize to form biliary sludge. 5. Cephalosporins with methylthiotetrazole rings (cefamandole, cefoperazone, moxalactam, cefotetan) can interfere with vitamin K and increase prothrombin time. 6. Pseudomembranous colitis can develop as a result of overgrowth of Clostridium difficile. 7. Nephrotoxicity sometimes occurs when cephalosporins are given in combination with aminoglycosides. KEY POINTS About
-Lactam Antibiotic Toxicity 1. Very short half-life (15–30 minutes). 2. Excreted renally; adjust for renal dysfunction; probenecid delays excretion. 3. Penetrates most inflamed body cavities. 4. Narrow spectrum. Indicated for Streptococcus pyogenes, S. viridans Gp., mouth flora, Clostridia perfringens, Neisseria meningitidis, Pasteurella, and spirochetes. 5. Recommended for penicillin-sensitive S. pneu￾moniae [however, penicillin resistant strains are now frequent (30%)]; infections caused by mouth flora; Clostridium perfringens or spiro￾chetes. KEY POINTS About the Natural Penicillins

4 CHAPTER 1 Table 1.3. Penicillins: Half-Life, Dosing, Renal Dosing, Cost, and Spectrum Antibiotic Half-life Dose for reduced (trade name creatinine clearance Natural penicillins(PCNs) PCN G <10. Half dose 6-12×10°UMq24h Benzathine pcn g 24×10° U IM weekly PCNV-K 0.5250-500mgPq6-8h Narrow Up to 14 g Iv daily -50:q8h (Omnipen given g4-6h <10q12h Amoxicillin <10:q24h 875 mg q Amoxicillin-clavulanate Same as amoxicillin po SSSs Broad picillin-sulbactam 15-2gq6hⅣ 30-50:q8 ssss Broad <10q12h Penicillinase-resistant PCns 1-2 g q4hI Narrow Prostap Nafcillin 0.5-2gq4hⅣ SSSs Narrow Cloxacillin/dicloxacillin 025-19gq6h rrow Carboxy/ureido-PCNs 3. 1 gq4-6h IV 10-50:3.1gq6-8h5 Very broad Piperacillin-tazobactam 3375gq6h 10-50:225gq6h Very broad osyn) 4.5 g q8h <1025gq8h Intravenous preparations(daily cost dollars): S=20 to 60; $$=61 to 100; $SS=101 to 140; SSSS= 140 to 180; SSSSS =more than treatment ections caused by mouth fora. penicillin intravenously or intramuscularly. Some penicillins have G is also primarily recommended for Clostridium perfrin- been formulated to withstand the acidity of the stomach gens, C. tetani, Erysipelothrix rhusiopathiae, Pasteurella and are absorbed orally. Penicillins are well distributed multocida, and spirochetes including syphilis and Lep- the body and are able to penetrate most inflamed body ospina. This cavities. However, their ability to cross the blood-brain mended therapy for S pneumoniae sensitive to penicillin barrier in the absence of inflammation is poor. In the pres-(MIC 0 1 ug/mL). However, in many areas of the ence of inflammation, therapeutic levels are generally United States, more than 30% of strains are moderately achievable in the cerebrospinal fuid. resistant to penicillin(MIC =0.1-l ug/mL). In these of Activity and Treatment Recommenda- cases, ceftriaxone, cefotaxime, or high-dose penicillin ns--Pencillin G (Table 1. 4)remains the treatment of (12 million units daily) can be used. Moderatel choice for S pyogenes(group A strep")and the S viridans resistant strains of s pneumoniae possess a lower group. It also remains the most effective agent for the affinity PBP, and this defect in binding can be overcome

Depending on the specific drug, penicillins can be given intravenously or intramuscularly. Some penicillins have been formulated to withstand the acidity of the stomach and are absorbed orally. Penicillins are well distributed in the body and are able to penetrate most inflamed body cavities. However, their ability to cross the blood–brain barrier in the absence of inflammation is poor. In the pres￾ence of inflammation, therapeutic levels are generally achievable in the cerebrospinal fluid. Spectrum of Activity and Treatment Recommenda￾tions—Pencillin G (Table 1.4) remains the treatment of choice for S. pyogenes (“group A strep”) and the S. viridans group. It also remains the most effective agent for the treatment of infections caused by mouth flora. Penicillin G is also primarily recommended for Clostridium perfrin￾gens, C. tetani, Erysipelothrix rhusiopathiae, Pasteurella multocida, and spirochetes including syphilis and Lep￾tospira. This antibiotic also remains the primary recom￾mended therapy for S. pneumoniae sensitive to penicillin (MIC < 0.1 g/mL). However, in many areas of the United States, more than 30% of strains are moderately resistant to penicillin (MIC = 0.1–1 g/mL). In these cases, ceftriaxone, cefotaxime, or high-dose penicillin (12 million units daily) can be used. Moderately resistant strains of S. pneumoniae possess a lower￾affinity PBP, and this defect in binding can be overcome 14 / CHAPTER 1 Table 1.3. Penicillins: Half-Life, Dosing, Renal Dosing, Cost, and Spectrum Antibiotic Half-life Dose Dose for reduced Costa Spectrum (trade name) (h) creatinine clearance (mL/min) Natural penicillins (PCNs) PCN G 0.5 24  106 U IV q4h <10: Half dose $ Narrow Procaine PCN G 0.61.2  106 U IM q24h $ Narrow Benzathine PCN G 2.4  106 U IM weekly $ Narrow PCN V–K 0.5 250–500 mg PO q6–8h $ Narrow Aminopenicillins Ampicillin 1 Up to 14 g IV daily, 30–50: q8h $ Moderate (Omnipen) given q4–6h <10: q12h Amoxicillin 1 500 mg PO q8h or <10: q24h $ Moderate (Amoxil) 875 mg q12h Amoxicillin–clavulanate Same as amoxicillin PO Same as $$$$ Broad (Augmentin) amoxicillin Ampicillin–sulbactam 1 1.5–2 g q6h IV 30–50: q8h $$$$ Broad (Unasyn) <10: q12h Penicillinase–resistant PCNs Oxacillin 0.5 1–2 g q4h IV None $ Narrow (Prostaphlin) Nafcillin 0.5 0.5–2 g q4h IV None $$$$ Narrow (Unipen) Cloxacillin/dicloxacillin 0.5 0.25–1 g q6h None $ Narrow (Dynapen) Carboxy/ureido–PCNs Ticarcillin–clavulanate 1 3.1 g q4–6h IV 10–50: 3.1 g q6–8h $ Very broad (Timentin) <10: 2 g q12h Piperacillin–tazobactam 1 3.375 g q6h or 10–50: 2.25 g q6h $$ Very broad (Zosyn) 4.5 g q8h <10: 2.5 g q8h a Intravenous preparations (daily cost dollars):$ = 20 to 60; $$ = 61 to 100; $$$ = 101 to 140; $$$$ = 140 to 180; $$$$$ = more than 180; oral preparations (10-day course cost dollars): $ = 10 to 40; $$ = 41 to 80; $$$ = 81 to 120; $$$$ = 121 to 160; $$$$$ ≥ 160.

ANTI-INFECTIVE THERAPY/ 5 Table 1. 4. Organisms That May Be Susceptible to Penicillins Natural Aminopenicillins Anti-staphylococcal Carboxy/ureidopenicillins penicillins (with or without plus clavulanate or clavulanate) (nafcillin/oxacillin tazobactam Narrower spectrum Covers same S pneumoniae organisms as (increasing numbers of natural penicillins No activity against natural penicillins PCN-resistant strains) plus: Escherichia coli anaerobes, Enterococcus, or plus: MSSA S viridans Proteus gram-negative organisms. E coli PCN- sensitive enterococci N- sensitive enterococci Drug of choice for MSSA. Proteus mirabilis Salmonella spp. Mouth flora including Addition of Capnocytophaga canimorsus, clavulanate ad Enterobacter spp Fusobacterium nucleatum Citrobacter freundii Eikenella corrodens bility to: Serratia Clostridium perfringens H influenzae Clost tetani -lactamase strains Pasteurella multocida Methicillin-sensitive spirochetes Staph. aureus Borrelia burgdorferi, organs eisseria gonorrhoea Neiss. meningitidis Listeria monocytogenes by high serum levels of penicillin in the treatment of Haemophilus influenzae. Aminopenicillins are also pneumonia, but not of meningitis. Infections with high- effective against Shigella flexneri and sensitive strains of level penicillin-resistant s pneumoniae (MiC> nontyphoidal Salmonella. Amoxicillin can be used to 2 ug/mL)require treatment with vancomycin or another treat otitis media and air sinus infections.When alternative antibiotic. combined with a B-lactamase inhibitor (clavulanate or sulbactam), aminopenicillins are also effective against methicillin-sensitive S. aureus (MSSA) Pharmacokinetics--In aminopenicillins, a chemical mod- B-lactamase-producing strains of H. influenzae, and ification of penicillin increases resistance to stomach acid, Moraxella catarrhalis. The latter two organisms are llowing these products to be given orally(Table 1.3). commonly cultured from middle ear and air sinus muscularly or intrav 4. infections(see Chapter 5). However, the superiority of Amoxicillin has excellent oral absorption: 75% as com- amoxicillin-clavulanate over amoxicillin for middle ear pared with 40% for ampicillin. Absorption is not impaired and air sinus infections has not been proven aminopenicillins allow for a longer dosing interval, mak- PENICILLINASE-RESISTANT PENICILLINS a more convenient oral antibiotic than Pharmacokinetics-The penicillinase-resistant peni- cillin. As observed with the natural penicillins, the half-life cillin have the same half-life as penicillin( 30 minutes) is short(I hour)and these drugs are primarily excreted and require dosing at 4-hour intervals or constant unmodified in the urine. intravenous infusion(Table 1.3). Unlike the natural Spectrum of Activity and Treatment Recommenda- penicillins, these agents are cleared hepatically, and tions-The spectrum of activity in the aminopenicillins doses of nafcillin and oxacillin usually do not need to is slightly broader than in the natural llins be adjusted for renal dysfunction. But the efficient (Table 1. 4). Intravenous ampicillin is recommended for hepatic excretion of nafcillin means that the dose treatment of Listeri monocytogenes, sensitive enterococci, needs to be adjusted in patients with significant Proteus mirabilis, and non-B hepatic dysfunction. The liver excretes oxacillin less

by high serum levels of penicillin in the treatment of pneumonia, but not of meningitis. Infections with high￾level penicillin-resistant S. pneumoniae (MIC 2 g/mL) require treatment with vancomycin or another alternative antibiotic. AMINOPENICILLINS Pharmacokinetics—In aminopenicillins, a chemical mod￾ification of penicillin increases resistance to stomach acid, allowing these products to be given orally (Table 1.3). They can also be given intramuscularly or intravenously. Amoxicillin has excellent oral absorption: 75% as com￾pared with 40% for ampicillin. Absorption is not impaired by food. The higher peak levels achievable with aminopenicillins allow for a longer dosing interval, mak￾ing them a more convenient oral antibiotic than ampi￾cillin. As observed with the natural penicillins, the half-life is short (1 hour) and these drugs are primarily excreted unmodified in the urine. Spectrum of Activity and Treatment Recommenda￾tions—The spectrum of activity in the aminopenicillins is slightly broader than in the natural penicillins (Table 1.4). Intravenous ampicillin is recommended for treatment of Listeri monocytogenes, sensitive enterococci, Proteus mirabilis, and non–
-lactamase-producing Haemophilus influenzae. Aminopenicillins are also effective against Shigella flexneri and sensitive strains of nontyphoidal Salmonella. Amoxicillin can be used to treat otitis media and air sinus infections. When combined with a
-lactamase inhibitor (clavulanate or sulbactam), aminopenicillins are also effective against methicillin-sensitive S. aureus (MSSA),
-lactamase-producing strains of H. influenzae, and Moraxella catarrhalis. The latter two organisms are commonly cultured from middle ear and air sinus infections (see Chapter 5). However, the superiority of amoxicillin–clavulanate over amoxicillin for middle ear and air sinus infections has not been proven. PENICILLINASE-RESISTANT PENICILLINS Pharmacokinetics—The penicillinase-resistant peni￾cillins have the same half-life as penicillin (30 minutes) and require dosing at 4-hour intervals or constant intravenous infusion (Table 1.3). Unlike the natural penicillins, these agents are cleared hepatically, and doses of nafcillin and oxacillin usually do not need to be adjusted for renal dysfunction. But the efficient hepatic excretion of nafcillin means that the dose needs to be adjusted in patients with significant hepatic dysfunction. The liver excretes oxacillin less ANTI-INFECTIVE THERAPY / 15 Table 1.4. Organisms That May Be Susceptible to Penicillins Natural Aminopenicillins Anti-staphylococcal Carboxy/ureidopenicillins penicillins (with or without penicillin plus clavulanate or (PCNs) clavulanate) (nafcillin/oxacillin) tazobactam Streptococcus pyogenes S. pneumoniae (increasing numbers of PCN-resistant strains) S. viridans PCN-sensitive enterococci Mouth flora including: Actinomyces israelli, Capnocytophaga canimorsus, Fusobacterium nucleatum, Eikenella corrodens Clostridium perfringens Clost. tetani Pasteurella multocida Erysipelothrix rhusiopathiae Spirochetes: Treponema pallidum, Borrelia burgdorferi, Leptospira interrogans Neisseria gonorrhoeae Neiss. meningitidis Listeria monocytogenes Covers same organisms as natural penicillins plus: Escherichia coli Proteus PCN-sensitive enterococci Salmonella spp. Shigella spp. Addition of clavulanate adds susceptibility to: H. influenzae (
-lactamase strains) Moraxella catarrhalis Methicillin-sensitive Staph. aureus (MSSA) Narrower spectrum than natural penicillins, No activity against anaerobes, Enterococcus, or gram-negative organisms. Drug of choice for MSSA. Covers same organisms as natural penicillins plus: MSSA E. coli Proteus mirabilis Klebsiella pneumoniae Enterobacter spp. Citrobacter freundii Serratia spp. Morganella spp. Pseudomonas aeruginosa Bacteroides fragilis

6/ CHAPTeR 1 dicloxacillin should not be used to treat s. aureus bac- KEY POINTS ieremia. These oral agents are used primarily for mild oft-tissue infectio About the Aminopenicillins 1. Short half-life(1 hour), and dlearance similar to CARBOXYPENICILLINS AND UREIDOPENICILLINS natural penicillin Pharmacokinetics--The half-lives of ticarcillin 2. Slightly broader spectrum of activity. piperacillin are short, and they require frequent 3. Parenteral ampicillin indicated for Listeria Table 1. 3). Sale of ticarcillin and piperacillin alor been discontinued in favor of ticarcillin-clavulanate and monocytogenes, sensitive enterococci, Proteus mirabilis, and non-b-lactamase-producing Haemophilus influenzae Dosing every 6 hours is recommended for 4. Ampicillin plus an aminoglycoside is the treat piperacillin-tazobactam to prevent accumulation of tazobactam. In P aeruginos omonia, the dose ment of choice for enterococci. Whenever possi- ble, vancomycin should be avoided. of piperacillin-tazobactam should be increased from 3.375 g Q6h to 4.5 g Q8h to achieve cidal levels of 5. Amoxicillin has excellent oral absorption; it is the initial drug of choice for otitis media and piperacillin in the sputum. In combination with an bacterial sinusitis aminoglycoside, piperacillin-tazobactam often demon strates synergy against p aeruginosa. However, the 6. Amoxicillin-clavulanate has improved cover- administration of the piperacillin-tazobactam needs to age of Staphylococcus, H influenzae, and mora- xella catarrhalis, but it is expensive and has a be separated from the administration of the aminogly coside by 30 to 60 high incidence of diarrhea. Increased efficacy ompared with amoxicillin is not proven in Spectrum of Activity and Treatment Recommenda titis media. However covers amoxicillin tions-Ticarcillin and piperacillin are able to resist resistant H influenzae, a common pathogen in B-lactamases produced by Pseudomonas, Enterobacter, that disease Morganella, and Proteus-Providencid species. At high doses, ticarcillin and piperacillin can also kill many strains of Bacteroides fragilis and provide effective anaerobic cov- erage. These antibiotics can be used for empiric coverage of moderate to severe intra-abdominal infections. They efficiently, and so dose adjustment is usually not have been combined with a B-lactamase inhibitor(lavu ons- thrum of Activity and Treatment Recomme., tHese agents are reasonable alternatives to nafcillin In negative Cov der it resistant to the B-lactamases produced by erage is als S. aureus reduces the ability f these agents to kill anaerobic mouth flora and Neisseria species(Table 1. 4) These antibiotics are strictly recommended for the treatment of MSSA. They are also used to treat cellulitis KEY POINTS when the most probable pathogens are S. duress a S pyogenes. Because oral preparations result in consid- About Carboxypenicillins and Ureidopenicillins erably lower serum concentration levels, cloxacillin or ffective resista KEY POINTS 2. Carboxypenicillin or ureidopenicillin combined with aminoglycosides demonstrate synergistic killing of Pseudomonas aeruginosa. About Penicillinase-Resistant Penicillins 3. Ticarcillin-clavulanate and piperacillin-tazobac m have excellent broad-spectrum coverage, including methicillin-sensitive Staphylococcus 1. Short half-life, hepatically metabolized ureus and anaerobes. they are also useful for 2. Very narrow spectrum, poor anaerobic activity tra-abdominal infections, acute prostatitis, in 3. Primarily indicated for methicillin-sensitive hospital aspiration pneumonia, and mixed soft Staphylococcus aureus and cellulitis tissue and bone infections

efficiently, and so dose adjustment is usually not required in liver disease. Spectrum of Activity and Treatment Recommenda￾tions–The synthetic modification of penicillin to ren￾der it resistant to the
-lactamases produced by S. aureus reduces the ability of these agents to kill anaerobic mouth flora and Neisseria species (Table 1.4). These antibiotics are strictly recommended for the treatment of MSSA. They are also used to treat cellulitis when the most probable pathogens are S. aureus and S. pyogenes. Because oral preparations result in consid￾erably lower serum concentration levels, cloxacillin or dicloxacillin should not be used to treat S. aureus bac￾teremia. These oral agents are used primarily for mild soft-tissue infections or to complete therapy of a resolv￾ing cellulitis. CARBOXYPENICILLINS AND UREIDOPENICILLINS Pharmacokinetics—The half-lives of ticarcillin and piperacillin are short, and they require frequent dosing (Table 1.3). Sale of ticarcillin and piperacillin alone has been discontinued in favor of ticarcillin–clavulanate and piperacillin–tazobactam. Dosing every 6 hours is recommended for piperacillin–tazobactam to prevent accumulation of tazobactam. In P. aeruginosa pneumonia, the dose of piperacillin–tazobactam should be increased from 3.375 g Q6h to 4.5 g Q8h to achieve cidal levels of piperacillin in the sputum. In combination with an aminoglycoside, piperacillin–tazobactam often demon￾strates synergy against P. aeruginosa. However, the administration of the piperacillin–tazobactam needs to be separated from the administration of the aminogly￾coside by 30 to 60 minutes. Spectrum of Activity and Treatment Recommenda￾tions—Ticarcillin and piperacillin are able to resist
-lactamases produced by Pseudomonas, Enterobacter, Morganella, and Proteus–Providencia species. At high doses, ticarcillin and piperacillin can also kill many strains of Bacteroides fragilis and provide effective anaerobic cov￾erage. These antibiotics can be used for empiric coverage of moderate to severe intra-abdominal infections. They have been combined with a
-lactamase inhibitor (clavu￾lanate or tazobactam) to provide effective killing of MSSA. These agents are reasonable alternatives to nafcillin or oxacillin when gram-negative coverage is also 16 / CHAPTER 1 1. Short half-life (1 hour), and clearance similar to natural penicillins. 2. Slightly broader spectrum of activity. 3. Parenteral ampicillin indicated for Listeria monocytogenes, sensitive enterococci, Proteus mirabilis, and non–b-lactamase-producing Haemophilus influenzae. 4. Ampicillin plus an aminoglycoside is the treat￾ment of choice for enterococci.Whenever possi￾ble, vancomycin should be avoided. 5. Amoxicillin has excellent oral absorption; it is the initial drug of choice for otitis media and bacterial sinusitis. 6. Amoxicillin–clavulanate has improved cover￾age of Staphylococcus, H. influenzae, and Mora￾xella catarrhalis, but it is expensive and has a high incidence of diarrhea. Increased efficacy compared with amoxicillin is not proven in otitis media. However, covers amoxicillin￾resistant H. influenzae, a common pathogen in that disease. KEY POINTS About the Aminopenicillins 1. Short half-life, hepatically metabolized. 2. Very narrow spectrum, poor anaerobic activity. 3. Primarily indicated for methicillin-sensitive Staphylococcus aureus and cellulitis. KEY POINTS About Penicillinase-Resistant Penicillins 1. More effective resistance to gram-negative
-lactamases. 2. Carboxypenicillin or ureidopenicillin combined with aminoglycosides demonstrate synergistic killing of Pseudomonas aeruginosa. 3. Ticarcillin–clavulanate and piperacillin–tazobac￾tam have excellent broad-spectrum coverage, including methicillin-sensitive Staphylococcus aureus and anaerobes. They are also useful for intra-abdominal infections, acute prostatitis, in￾hospital aspiration pneumonia, and mixed soft￾tissue and bone infections. KEY POINTS About Carboxypenicillins and Ureidopenicillins

ANTI-INFECTIVE THERAPY/ 7 Table 1.5. Cephalosporins: Half-Life, Dosing, Renal Dosing, Cost, and Spectrum Antibiotic Dose for reduced Cost Spectrum (trade name creatinine clearance (mL/min) 18 1-1.5gⅣor 10-50:05-1gq8-12h Narrow (Ancef) M g6-8h 0:025-075gq18-24h Po g6-81 Narrow 0.7 s-55 Cefadroxil 1.2 0.5-1 g PO q12h ss-SsSs Narrow 2nd generation Cefoxitin 1-2 g IVor IM q46h,50-80:q8-12h (Mefoxin) not to exceed 0-50:q12-24h broad <10:0.5-1gq12-24h Cefotetan 3.5 1-2 g I or IM ql 5024 <10:q48h Cefuroxime 13 075-15gⅣq8h 10-50:q12h Moderately (Zinacef) <10:075gq24h Cefuroxime-axetil 025-05gP0q12h <10:0.25gq12h Moderately (Ceftin) Cefaclor 025-0.5gPoq8h No change required Moderat (Ceclor) broad 3rd generation Ceftriaxone 1-2gⅣq12-24h No change required Broad (Rocephin 2 gIV q4-8h 10-30:q8-12h Broad (Claforan) (maximum 12 g daily) <10: q12-24h 1-4gⅣq8-12h 10-30:q12h Broad (maximum 12 g daily) <10: q24h Ceftazidime 10-50:1gq12-24h Fortaz <10:0.5q24-48h Cefixime 3.7 400 mg PO q12h 10-30:300mgq24h55oad <10:200mgq2 Cefpodoxime proxetil 2.2 200-400gPoq12h 10-30:×3 weekl Broad antin <10:×1 weekly Cefepime 05-2qⅣq12h 10-30:0.5-1gq24h n sss Very broad 10250-500m9g24hq12h 1-2gⅣq12h 1-2 g IV goh 10-30q12-18h SS-Ssss Narrow (Azactam) <10:q24h Intravenous preparations (daily cost dollars):$=20-70; S$ =71-110; $S$=111-150: S$$= 150-200: SSSSS 2 200; oral preparations(10- day course cost dollars):s=10-50S5=51-100;S55=101-140:5555=141-180;55552180

ANTI-INFECTIVE THERAPY / 17 Table 1.5. Cephalosporins: Half-Life, Dosing, Renal Dosing, Cost, and Spectrum Antibiotic Half-life Dose Dose for reduced Costa Spectrum (trade name) (h) creatinine clearance (mL/min) 1st generation Cefazolin 1.8 1–1.5 g IV or 10–50: 0.5–1 g q8–12h $ Narrow (Ancef ) IM q6–8h <10: 0.25–0.75 g q18–24h Cephalexin 0.9 0.25–1 g PO q6–8h $ Narrow (Keflex) Cephradine 0.7 0.25–1 g PO q6h $–$$ (Velocef ) Cefadroxil 1.2 0.5–1 g PO q12h $$–$$$$ Narrow (Duricef ) 2nd generation Cefoxitin 0.8 1–2 g IV or IM q4–6h, 50–80: q8–12h $$ Moderately (Mefoxin) not to exceed 10–50: q12–24h broad 12 g daily <10: 0.5–1 g q12–24h Cefotetan 3.5 1–2 g IV or IM q12h 10–50: q24h $ Moderately (Cefotan) <10: q48h broad Cefuroxime 1.3 0.75–1.5 g IV q8h 10–50: q12h $ Moderately (Zinacef ) <10: 0.75 g q24h broad Cefuroxime–axetil 1.5 0.25–0.5 g PO q12h <10: 0.25 g q12h $$$$ Moderately (Ceftin) broad Cefaclor 0.8 0.25–0.5 g PO q8h No change required $$$$ Moderately (Ceclor) broad 3rd generation Ceftriaxone 8 1–2 g IV q12–24h No change required $$ Broad (Rocephin) Cefotaxime 1.5 2 g IV q4–8h 10–30: q8–12h $$ Broad (Claforin) (maximum 12 g daily) <10: q12–24h Ceftizoxime 1.7 1–4 g IV q8–12h 10–30: q12h $$ Broad (Cefizox) (maximum 12 g daily) <10: q24h Ceftazidime 1.9 1–3 g IV or IM q8h, 10–50: 1 g q12–24h $$ Broad (Fortaz) up to 8 g daily <10: 0.5 q24–48h Cefixime 3.7 400 mg PO q12h 10–30: 300 mg q24h $$$$ Broad (Suprax) or q24h <10: 200 mg q24h Cefpodoxime proxetil 2.2 200–400 g PO q12h 10–30: 3 weekly $$$ Broad (Vantin) <10: 1 weekly 4th generation Cefepime 2.1 0.5–2 g IV q12h 10–30: 0.5–1 g q24h $–$$ Very broad (Maxipime) <10: 250–500 mg q24h q12h Cefpirome 2 1–2 g IV q12h Same as cefepime $$ Very broad (IV–Cef ) Monobactams Aztreonam 2 1–2 g IV q6h 10–30: q12–18h $$–$$$$ Narrow (Azactam) <10: q24h Intravenous preparations (daily cost dollars): $ = 20–70; $$ = 71–110; $$$ = 111–150; $$$$ = 150–200; $$$$$ ≥ 200; oral preparations (10-day course cost dollars): $ = 10–50; $$ = 51–100; $$$ = 101–140; $$$$ = 141–180; $$$$$ ≥ 180