How to choose among the myriad of antibiotics? Considerations for the beta- lactams, aminoglycosides and fluoroquinolones. HO Pak Leung 何栢良醫生 MBBS, FACP, MRCP, MRCPath, FRCPA, FHKCPath, FHKAM Draft as of Aug 2004 www.HoPakLeung.com We seek to improve the quality of this compendium. If you have comments or suggestion on this draft, please email to [email protected] NOTICE While every effort has been made to ensure the accuracy of the information contained in the compendium, the possibilities of human errors or changes in medical practice/knowledge exists. Reader should therefore check the latest product information of drugs (especially for new and infrequently used drugs) or tests before they are used. The most recent recommended clinical practice and normal values of individual laboratories should also be taken into account. This publication contains information relating to general principles of medical care, which should not be construed as specific instructions for individual patients. Manufacturers' product information and package inserts should be reviewed for current information, including contraindications, dosages and precautions. 3 Contents 1 Beta-lactams 3 2 Aminoglycosides 15 3 Quinolones 26 4 – Beta-lactams – 1 Beta-lactams INTRODUCTION β-lactams belong to a group of antibiotics that exert their antibacterial effect by inhibition of enzymes (transpeptidase and decarboxylase) that are critical for cell wall synthesis. They have in common a β-lactam ring that form part of the nucleus of the molecule. Classification of the β-lactams was based traditionally on the chemical structures and is complex. For practical purposes, the major groups of β- lactams include the penicillins, cephalosporins, β-lactam/β-lactamase inhibitor (BLBLI) and carbapenems. Two other groups, cephamycins (e.g. cefoxitin) and monobactams (e.g. aztreonam) are used less frequently in Hong Kong. The bottom line With few exceptions, efficacy of the agent in question in clinical trials was almost uniformly “equal” to that of comparators. The question as to whether one β- lactam performs better than another remains largely unanswered. Most antibiotic trials (typically with <500 subjects in each arm) simply lack power to show small difference in the range of 5−10%. Overall, the β-lactams have good safety profile. The main factors to be considered in choosing a β-lactam include the drug’s antibacterial spectrum, pharmacokinetic (PK) properties, impact on the microbial ecology (i.e. likelihood in selecting resistant organisms) and cost. All β-lactams exhibit time-dependent mode of antibacterial activity.[1] Once the drug concentration is higher than the MIC of the organism, the rate and extent of microbial killing depend on the time of exposure. Higher concentrations do not kill bacteria faster. The pharmacology of antibiotic therapy can be divided into two major components: Pharmacokinetics (PK): interaction between man and antibiotic, such as absorption, distribution and elimination of drugs Pharmacodynamics (PD): interaction between antibiotic and bacteria, such as concentration-dependent or time-dependent killing. Accordingly, the application of pharmacodynamics to antibiotic therapy has generated parameters (commonly known as PK/PD parameters) that are increasingly considered to be relevant for choosing and using antibiotics. The “time above MIC” or T>MIC is a PK/PD parameter that measures the time that serum drug concentration stay higher than the MIC of the organism (Figure). Many studies have showed that maximal efficacy can be ensured if the T>MIC is at least 40−60% of the dosing interval (~60% for Gram negative bacteria and ~40% for Gram positive bacteria). In serious infections or those that were caused by the 5 – Beta-lactams – less susceptible bacteria, β-lactam dosing that maximizes the T>MIC and hence the efficacy will be preferred. Figure. Common antibiotic pharmacokinetic (PK) and minimal inhibitory concentration (MIC) pharmacodynamic (PD) relationships. Important note for the β-lactam prescribers: Over 30 different β-lactam compounds are available in Hong Kong. If you do not belong to the species of “walking encyclopedia”, it is wise to just remember only one prototype agent in each group. Try to become familiar with the properties of only the prototype in a given group and use it properly. TIPS IN CHOOSING AMONG THE PENICILLINS Antimicrobial spectrum Four groups of penicillins can be distinguished according to their spectrum (Table 1). 6 – Beta-lactams – Table 1. Spectrum of penicillins. Group Examples Strepto- MSSA Enterococcus, E. coli P. cocci Listeria aeruginosa Anti- Penicillin +++ 0 ++ 0 0 streptococcal G, penicillin penicillin V Anti- Cloxacillin + +++ 0 0 0 staphylococcal penicillins Aminopenicillins Ampicillin, ++ 0 +++ ++ 0 amoxicillin Anti- Ticarcillin, + to ++ 0 + to ++ ++ ++ pseudomonal piperacillin penicillins MSSA, methicillin-sensitive Staphylococcus aureus; Streptococci include S. pneumoniae, S. pyogenes and other streptococci. Clinical applications of the PK data 1. The anti-streptococcal and anti-staphylococal penicillins has very short half-lives (0.5 h). Serum level of these agents decreased rapidly, even after high dose. To meet the PK/PD target (i.e achieving T>MIC for 40% dosing interval), they need to be given at least 4 times daily. For serious infections (e.g. streptococcal endocarditis), dosing at 4 hourly intervals is preferred. 2. The aminopenicillins and anti-pseudomonal penicillins have longer half- lives and can be given less frequently. Their serum T½ were: 1.2 h for ampicillin/amoxicillin; 1.1 h for ticarcillin and 1.2 h for piperacillin. The pharmacokinetic of piperacillin is dose dependent. The clearance of piperacillin is non-linear because of saturation of biliary excretion. Serum T½ of piperacillin increases with large dose and hence allowing longer dosing intervals. Nonetheless, the MICs of ticarcillin and piperacillin against P. aeruginosa are 2-4 times higher than that for E. coli. If they are used for therapy of P. aeruginosa, more frequent dosing (q6h for piperacillin and q4-6h for ticarcillin) will be required to meet the PK/PD target (T>MIC for 60% dosing interval). 3. Where oral administration is appropriate, if higher concentrations are desired because of difficulty-to-treat infections (e.g. osteomyelitis), consider the following in IV-to-PO switch: (a) IV ampicillin to PO amoxicillin instead of IV ampicillin to PO ampicillin: potency of ampicillin and amoxicillin can be considered equivalent. The oral absorption of amoxicillin (80%) double that of 7 – Beta-lactams – ampcillin (40%). Amoxicillin is the aminopenicillin agent of choice to be given orally. (b) IV cloxacillin to PO flucloxacillin instead of IV cloxacillin to PO cloxacillin: Three oral anti-staphylococcal penicillins are available in Hong Kong: cloxacillin (CloxilTM), dicloxacilln (DiclocilTM) and flucloxacillin (FlucloxilTM). PO cloxacillin is most commonly used because of the lower cost. If high levels after PO are important, PO flucloxacillin is preferred because it has the best oral absorption (oral bioavailability of 60% for flucloxacillin compared to 35% for cloxacillin). TIPS IN CHOOSING AMONG THE CEPHALOSPORINS Antimicrobial spectrum The cephalosporins are commonly classified into generations, according the their spectrum of antibacterial activities (Table 2). With the exception of the cephamycins, all the other cephalosporins do not process clinically useful anti- anaerobic activity. No cephalosporins are active against the Enterococcus, Listeria, MRSA. Anti-Gram negative activity increases as one go up the generation classification tree. “Anti-pseudomonal activity” usually means there is some loss in the anti-Gram-positive potency. Ceftazidime is poorly active against penicillin- nonsusceptible pneumococci and S. aureus (MSSA). Although cefepime is an anti- pseudomonal cephalosporin with enhanced activity (compared to ceftazidime) against Gram positive bacteria. The cefotaxime and ceftriaxone are still the agents with the highest degree of anti-streptococcal activity (e.g. against penicillin- nonsusceptible pneumococci). 8 – Beta-lactams – Table 2. Spectrum of activity of cephalosporins. Examples of E. coli, CES P. Pen-S Enterococci, Most agents Klebsiella aeruginosa strept, MRSA anaerobes, MSSA including B. fragilis 1GC Cefazolin + 0 0 ++ 0 0 (Cefamazin), cephalexin (Keflex) 2GC Cefuroxime ++ 0 to + 0 ++ 0 0 (Zinnat, Zincef) 3GC Cefotaxime +++ + to 0 +++ 0 0 (Claforan), ++ ceftriaxone (Rocephin) Ceftazidime ++ ++ +++ + 0 0 (Fortun), eefoperazone (Cefobid) 4GC Cefepime +++ +++ +++ ++ 0 0 (Maxipime) Number of “+” indicates increasing activity. “0” indicates no activity. 1GC, first generation cephalosporins; 2GC, second generation cephalosporins; 3GC, third generation cephalosporins; 4GC, fourth generation cephalosporins; CES, Citrobacter, Enterobacter and Serratia species; Pen-S Strep, penicillin-sensitive streptococci; MSSA, methicillin-sensitive Staphylococcus aureus; MRSA, methicillin- resistant S. aureus. 9 – Beta-lactams – Clinical applications of the PK data 1. On the basis of the serum half-lives, cephalosporins can be classified into 3 groups. These data and the usual dosing frequency are showed in Table 3. 2. Cefazolin is the only first generation cephalosporin with a longer serum T½. Therapeutic levels are maintained for at least 4 hours after a single 1 g dose. This property makes it the agent of choice as single dose preoperative prophylaxis for surgery that lasts <4 hours. 3. Only the third and fourth