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 presence of inflammation, therapeutic levels are generally achievable in the cerebrospinal fluid. Spectrum of Activity and Treatment Recommendations—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 perfringens, C. tetani, Erysipelothrix rhusiopathiae, Pasteurella multocida, and spirochetes including syphilis and Leptospira. This antibiotic also remains the primary recommended 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 loweraffinity 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 highlevel penicillin-resistant S. pneumoniae (MIC 2 g/mL) require treatment with vancomycin or another alternative antibiotic. AMINOPENICILLINS Pharmacokinetics—In aminopenicillins, a chemical modification 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 compared with 40% for ampicillin. Absorption is not impaired by food. The higher peak levels achievable with aminopenicillins allow for a longer dosing interval, making them a more convenient oral antibiotic than ampicillin. 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 Recommendations—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 penicillins 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 Recommendations–The synthetic modification of penicillin to render 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 considerably lower serum concentration levels, cloxacillin or dicloxacillin should not be used to treat S. aureus bacteremia. These oral agents are used primarily for mild soft-tissue infections or to complete therapy of a resolving 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 demonstrates synergy against P. aeruginosa. However, the administration of the piperacillin–tazobactam needs to be separated from the administration of the aminoglycoside by 30 to 60 minutes. Spectrum of Activity and Treatment Recommendations—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 coverage. These antibiotics can be used for empiric coverage of moderate to severe intra-abdominal infections. They have been combined with a -lactamase inhibitor (clavulanate 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 treatment of choice for enterococci.Whenever possible, 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 coverage of Staphylococcus, H. influenzae, and Moraxella 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 amoxicillinresistant 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–tazobactam have excellent broad-spectrum coverage, including methicillin-sensitive Staphylococcus aureus and anaerobes. They are also useful for intra-abdominal infections, acute prostatitis, inhospital aspiration pneumonia, and mixed softtissue 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
CHAPTER 1 Table 1.6. Organisms That May Be Susceptible to Cephalosporin 1st generation 2nd generation 3rd generation 4th generation (cefazolin) (cefoxitin, cefotetan) (ceftriaxone, cefotaxime) (cefepime) Methicillin-sensitive Covers same organisms Covers same organisms Covers same organisms Staphylococcus aureus as cefazolin but as cefazolin and ceftriaxon eaker gram-positive often weaker gram Excellent gram-positive and Streptococcus pyogenes positive and gram-negative activity Penicillin(PCN)-sensitive Also covers stronger gram-negative Also covers. Haemophilus influenzae activity S pneumoniae Intermediate Moraxella catarrhalis Also covers. Escherichia coli PCN-resistant (some species) H influenzae M catarrhalis Bacteroides fragilis N gonorrhoeae (some strains N. meningitidis (some species Morganella spp nigella spp required. Both agents can be used for in-hospital that, for many infections, earlier-generation, narrower aspiration pneumonia to cover for mouth flora and spectrum cephalosporins are preferred to the more serious intra-abdominal, gynecologic, and acute prostate nfections. They have been used for skin and bone infec FIRST-GENERATION CEPHALOSPORINS tions thought to be caused by a combination of gram- Pharmacokinetics--Cefazolin, the preferred parenteral egative and gram-positive organisms first-generation cephalosporin, has a longer half-life than penicillin, and it is primarily excreted by the Cephalosporins kidneys(Table 1.5). The first-generation cephalosporins penetrate most body cavities, but they fail to cross the the characteristics of the ner with Figure 1.5, summarize blood-brain barrier. Oral preparations ( cephalexin Tables 1.5 and 1.6, togetl Is cephalosporins cephradine, cefadroxil)are very well absorbed, achieving In an attempt to create some semblance of order, the excellent peak serum concentrations(0.5 g cephalexin cephalosporins have been classified into generations results in a 18 ug/mL peak). Absorption is not affected based on spectrum of activity(Table 1.5).Fi generation cephalosporins are predominantly effective against gram-positive cocci. Second-generation cepha rins demonstrate increased activity against aerobic KEY POINTS d anaerobic gram-negative bacilli, but have variable activity against gram-positive cocci. The third-genera- About First-Generation Cephalosporins tion cephalosporins demonstrate even greater activity gainst gram-negative bacilli, but only limited activity against gram-positive cocci. Finally, the fourth-genera- 1. Excellent gram-positive coverage, some gram- tion cephalosporins demonstrate the broadest specs.e of activity, being effective against both gram-positiy 2. Do not cross the blood-brain barrier occi and gram-negative baci 3. Inexpensive. of the cephalosporins by generation nat- 4. Useful for treating soft-tissue infections and for urally leads to the assumption that newer, later rgical prophylaxis Can often be used as an eneration cephalosporins are better than the older alternative to oxacillin or nafcillin cephalosporins. However, it is important to keep in mind
required. Both agents can be used for in-hospital aspiration pneumonia to cover for mouth flora and gram-negative rods alike, and they can also be used for serious intra-abdominal, gynecologic,and acute prostate infections. They have been used for skin and bone infections thought to be caused by a combination of gramnegative and gram-positive organisms. Cephalosporins Tables 1.5 and 1.6, together with Figure 1.5, summarize the characteristics of the various cephalosporins. In an attempt to create some semblance of order, the cephalosporins have been classified into generations based on spectrum of activity (Table 1.5). Firstgeneration cephalosporins are predominantly effective against gram-positive cocci. Second-generation cephalosporins demonstrate increased activity against aerobic and anaerobic gram-negative bacilli, but have variable activity against gram-positive cocci. The third-generation cephalosporins demonstrate even greater activity against gram-negative bacilli, but only limited activity against gram-positive cocci. Finally, the fourth-generation cephalosporins demonstrate the broadest spectrum of activity, being effective against both gram-positive cocci and gram-negative bacilli. Classification of the cephalosporins by generation naturally leads to the assumption that newer, latergeneration cephalosporins are better than the older cephalosporins. However, it is important to keep in mind that, for many infections, earlier-generation, narrowerspectrum cephalosporins are preferred to the more recently developed broader-spectrum cephalosporins. FIRST-GENERATION CEPHALOSPORINS Pharmacokinetics—Cefazolin, the preferred parenteral first-generation cephalosporin, has a longer half-life than penicillin, and it is primarily excreted by the kidneys (Table 1.5). The first-generation cephalosporins penetrate most body cavities, but they fail to cross the blood–brain barrier. Oral preparations (cephalexin, cephradine, cefadroxil) are very well absorbed, achieving excellent peak serum concentrations (0.5 g cephalexin results in a 18 g/mL peak). Absorption is not affected 18 / CHAPTER 1 Table 1.6. Organisms That May Be Susceptible to Cephalosporins 1st generation 2nd generation 3rd generation 4th generation (cefazolin) (cefoxitin, cefotetan) (ceftriaxone, cefotaxime) (cefepime) Methicillin-sensitive Staphylococcus aureus (best activity) Streptococcus pyogenes Penicillin (PCN)–sensitive S. pneumoniae Escherichia coli (some species) Klebsiella pneumoniae (some species) Proteus mirabilis (some species) Covers same organisms as cefazolin, but weaker gram-positive activity. Also covers: Haemophilus influenzae Moraxella catarrhalis Neisseria gonorrhoeae N. meningitidis Bacteroides fragilis (some strains) Covers same organisms as cefazolin, but often weaker grampositive and stronger gram-negative activity. Also covers: H. influenzae M. catarrhalis N. gonorrhoeae N. meningitidis Citrobacter freundii Morganella spp. Salmonella spp. Shigella spp. Covers same organisms as cefazolin and ceftriaxone. Excellent gram-positive and gram-negative activity. Also covers: Intermediate PCN-resistant S. pneumoniae Enterobacter spp. Pseudomonas aeruginosa Serratia spp. 1. Excellent gram-positive coverage, some gramnegative coverage. 2. Do not cross the blood–brain barrier. 3. Inexpensive. 4. Useful for treating soft-tissue infections and for surgical prophylaxis. Can often be used as an alternative to oxacillin or nafcillin. KEY POINTS About First-Generation Cephalosporins