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How to Choose Among the Myriad of Antibiotics?

How to Choose Among the Myriad of Antibiotics?

How to choose among the myriad of ?

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.

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Contents

1 Beta-lactams 3

2 Aminoglycosides 15

3 Quinolones 26

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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 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 , , β-lactam/β-lactamase inhibitor (BLBLI) and . Two other groups, (e.g. ) and (e.g. ) 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 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: (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

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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).

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Table 1. Spectrum of penicillins.

Group Examples Strepto- MSSA Enterococcus, E. coli P. cocci Listeria aeruginosa Anti- +++ 0 ++ 0 0 streptococcal G, penicillin penicillin V Anti- + +++ 0 0 0 staphylococcal penicillins , ++ 0 +++ ++ 0 Anti- , + to ++ 0 + to ++ ++ ++ pseudomonal penicillins MSSA, -sensitive ; 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

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ampcillin (40%). Amoxicillin is the agent of choice to be given orally. (b) IV cloxacillin to PO 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 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. is poorly active against penicillin- nonsusceptible pneumococci and S. aureus (MSSA). Although is an anti- pseudomonal with enhanced activity (compared to ceftazidime) against Gram positive bacteria. The and are still the agents with the highest degree of anti-streptococcal activity (e.g. against penicillin- nonsusceptible pneumococci).

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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 + 0 0 ++ 0 0 (Cefamazin), cephalexin (Keflex) 2GC ++ 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.

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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 generation cephalosporins penetrate sufficiently into the CSF to be of therapeutic values. Even then, high dose is required as ratio of the CSF to blood levels is still relatively low: 10% for cefepime, 10% for cefotaxime and 8-16% for ceftriaxone. Table 3. Half lives of cephalosporins

Serum half life Agents (T½) Usual dosing frequency ≤1 hour Cephalexin (1 h) 4 times daily 1−2 hours Cefazolin (1.8 h), cefuroxime (1.7 h), 3 times daily (1.9 h)a, cefepime (2 h)a >5 hours Ceftriaxone (7.3 h) Once daily a Might be given 2 times daily for treatment of infections by highly susceptible organisms. Dosing 3 times daily preferred for serious infections or those that were caused by the less susceptible bacteria.

TIPS IN CHOOSING AMONG β-LACTAM/β-LACTAMASE INHIBITOR (BLBLI) COMBINATION 1. Three β-lactamase inhibitors are currently used in combination with a β- lactam in five BLBLIs (Table 4). With the exception of (which has intrinsic activity against Acinetobacter), the β-lactamase inhibitors themselves has no direct antibacterial activity. They work simply by protecting the active β-lactamase compound from hydrolysis by bacterial enzymes. The issue is resistance. For susceptible organism and when the drugs are given at equivalent doses, BLBLIs are not more potent than the β-lactam on their own. While the BLBLI may be preferred initially as empirical therapy, once a pathogen is identified and sensitivity is known there is little justification to accept the higher cost and increased risk of emergence of resistance associated with the continued use of broad- spectrum agents. Some illustrative examples: (a) Augmentin (Amoxycillin-clavulanate) is not more effective than amoxil in the treatment of ampicillin-susceptible pneumonia. (b) Unasyn (ampicillin-sulbactam) is not more effective than ampicillin against ampicillin-susceptible cystitis.

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(c) Tazocin (piperacillin-) is not more effective than piperacillin against piperacillin-susceptible P. aeruginosa bacteraemia. 2. Be wise in choosing formulation: tips from the β-lactam to β-lactamase ratio. (a) Take amoxicillin- in the treatment of pneumonia as an example: (b) If a dose of 500 mg tds for the amoxicillin component is desired for coverage of penicillin-intermediate S. pneumoniae, depending on the preparation used, the “Augmentin” dose should be (Table 4): (i) PO two 375-tab mg tds (thus giving 750 mg clavulanic acid per day); or (ii) PO 20 mL syrup (i.e. 655mg) tds (thus giving 465 mg clavulanic acid per day); or (iii) PO 571.25 mg or 6.25 mL BD-syrup tds (thus giving 214 clavulanic acid per day). (c) Due to different amoxicillin-to-inhibitor ratio in the different “Augmentin” preparations, the above example illustrate that there can be large variation in the administered dose of the inhibitor, clavulanic acid. It is important to note that only a small dose of clavulanic acid is required to extend the activity of amoxicillin to include β-lactamase-producing H. influenzae and M. catarrhalis. The β-lactamases produced by the latter two bacteria is highly susceptible to inhibition by clavulanic acid (and also by the other 2 inhibitors). Large dosage of clavulanic acid increases the incidence of side effects (e.g. GI upset) and hence is not desirable. On the other hand, higher dose of the amoxicillin component is needed if penicillin nonsusceptible S. pneumoniae is a concern. For this purpose, augmentin tablet can be used in combination with amoxicillin (lower cost). Alternatively, the syrup preparation or the 1g bd tablet should be used. 3. Be wise in using IV vs. PO: tips from oral bioavailability. (a) Given the fact that efficacy depends on achieving drug levels at the site of infection that are above the MIC of the organism (for 40-60% of the dosing interval), and that once this is achieved higher level gives no additional benefits. Oral bioavailability of both PO Unasyn and Augmentin are very high (~80% for both Unasyn and Augmentin) [2;3]. Hence the pharmacokinetics of PO Unasyn and Augmentin closely match those after IV administration. At appropriate dosing, adequate levels can be achieved without the need to resort to IV therapy. (b) PO Unasyn is a prodrug (sultamicillin), which is hydrolyzed to ampicillin and sulbactam after absorption. Peak serum levels of

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ampicillin following sultamicillin are approximately twice that of an equal dose of oral ampicillin. (c) When using Unasyn or Augmentin, early PO or IV-to-PO switch is desirable. Criteria that have been validated are listed below[4]: (i) No clinical indication for IV therapy (e.g. meningitis, endocarditis, neutropenia); (ii) No clinical indication of abnormal gastrointestinal absorption of drugs; (iii) Patient is afebrile for at least 8 hours; (iv) Signs and symptoms related to infection are improving; (v) The WBC count is normalizing.

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Table 4.

BLBLI Trade name Inhibitor Preparation Amount of active β- lactam: inhibitor Amoxycillin- Augmentin Clavulanic IV 1.2 g 1 g : 0.2 g (5:1) clavulanic acid acid PO 375 mg 250 mg : 125 mg (2:1) Per 5 ml 125 mg : 31 mg (4:1) syrup PO, 156 mg Per 5 ml BD 400 mg : 57 mg (7:1) syrup PO, 457 mg PO 1g 875 mg : 125 mg (7:1)

Ampicillin-sulbactam Unasyn Sulbactam IV 1.5 g 1 g : 0.5 g (2:1) PO 375 mg 220 mg : 147 mg (1.5:1)

Ticarcillin-clavulanic Timentin Clavulanic IV 3.2 g 3 g : 0.2 g (15:1) acid acid

Cefoperazone- Sulperazon Sulbactam IV 1 g 0.5 g : 0.5 g (1:1) sulbactam

Piperacillin- Tazocin Tazobactam IV 4.5 g 4 g : 0.5 g (8:1) tazobactam

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Table 5.

a Unit dose Cmax Duration of serum concentration ≥1 μg/mL Unasyn IV 1.5 g (i.e. 1 g 40−71 (ampicillin), 6−7 h ampicillin) 21−40 (sulbactam) PO 375 mg (i.e. 250 3−6 (ampicillin) 2−3 h mg ampicillin) Augmentin IV 1.2 g (i.e. 1 g 50−100 (amoxicillin), 45 6−7 h amoxicillin) (clavulanic acid)

PO 375 mg (i.e. 250 4−5 (amoxicillin), 3.3 2−3 h amoxycillin) (clavulanic acid) PO 1 g (i.e. 875 12.4 (amoxicillin), 3.3 3−4 h amoxicillin) (clavulanic acid) a Data from package insert/manufacturer brochure.

TIPS IN CHOOSING AMONG CARBAPENEMS 1. Two carbapenems, and are currently available in Hong Kong. In general, they should be regarded as reserved antibiotics for treatment of suspected or confirmed infections by multidrug-resistant Gram-negative bacteria (e.g. ESBL-producing Klebsiella pneumoniae). 2. Similarities (a) Imipenem and meropenem are similar in terms of their in vitro activities, except that usually meropenem is slightly more active (2- 4 times) against Gram negative bacteria (e.g. Enterobacteriaceae and P. aeruginosa). MRSA, E. faecium and S. maltophilia are resistant to both carbapenems. Imipenem-resistant organisms are mostly cross-resistant to meropenem and vice versa. (b) Single-drug therapy for serious P. aeruginosa infections has been accompanied by high rates of resistance emergence during treatment. (c) Both carbapenems have some post-antibiotic effect (PAE) against Gram negative bacteria. In contrast, other β-lactams such as penicillins and cephalosporins have no PAE against Gram negative bacteria. (d) Clinical experience with meropenem indicates that it is therapeutically equivalent to imipenem. (e) Both drugs have generally been well tolerated. In patients with penicillin allergy, cross-reactions might occur with both.

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3. Differences (a) Imipenem is formulated as imipenem/cilastatin (TienemTM) for administration. After IV administration, imipenem is readily hydrolyzed by renal dehydropeptidase (DHP-1). This metabolism is a unique phenomenon that occurs only with imipenem but not with other β-lactams. Degradation by DHP-1 results in loss of antibacterial activity in the urine and the formulation of toxic products. This problem is overcome by giving the DHP inhibitor, cilastatin (in a 1:1 ratio to imipenem). Normally, the clearance of imipenem and cilastatin is similar (half-life of both ~1 h). However, in the presence of severe renal impairment, clearance of cilastatin (half-life 16 h) becomes significantly longer than that of imipenem (half-life 3-4 h). Hence, maintaining therapeutic levels of imipenem will inevitably lead to the accumulation of cilastatin. (There is the suspicion that accumulation of cilastatin might increase CNS side effects.) (b) The most serious side effect of imipenem is seizure. This is an infrequent side effect. The manufacturer reports an incidence of 0.4%. In some studies, seizures have occurred in up to 1.5-3% of patients (0.9% considered to be drug-related). This side effect mainly occurs in patients with underlying CNS pathology and in those with renal failure in whom dose adjustment has not been made. Meropenem is less epileptogenic. The overall incidence of seizures during treatment with meropenem was 0.4% (0.05% considered to be drug-related). Of note, the risks of drug-related seizure especially the incidence in patients with CNS disorders were lower. [5] 4. Suggestions when a is indicated (a) Most indications For most patients, either imipenem or meropenem might be used. In terms of daily cost, that for imipenem (HK$ 458 for IV 0.5g Q6H) is ~25% lower than meropenem (HK$ 580 for 1g Q8H). However, this cost difference has to be balanced against differences in dosing frequencies and administration procedures. Meropenem can be given by infusion or by bolus injection over 5 minutes. Imipenem must be administered by infusion over 30-60 minutes. (b) Renal failure In moderate to severe renal impairment or in patients with an increased risk of seizure, meropenem is preferred because of a lower risk of drug-associated seizure. (c) CNS infections In the few situation that a carbapenem is indicated, use meropenem instead of imipenem. Imipenem is not indicated for treatment of meningitis. In patients with inflamed meninges, CSF

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concentrations of meropenem (range 0.9-6.5 μg/mL) after high dose (IV 2g Q8H) are above the MIC of penicillin-susceptible S. pneumoniae (MIC 0.1 μg/ml), susceptible H. influenzae (MIC 0.1 μg/mL) and N. meningitidis (MIC 0.03 μg/mL). (N.B. Package insert of meropenem stated that the efficacy of meropenem in the treatment of meningitis caused by penicillin non-susceptible S. pneumoniae has not been established).

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2 Aminoglycosides

THERAPEUTIC ROLES OF THE AMINOGLYCOSIDES Nowadays, the aminoglycosides are rarely used alone for treatment of bacterial infections because the narrow therapeutic margin of this group of antibiotics and the availability of better alternatives. Instead, the aminoglycosides are usually given with another agent (usually a β-lactam or ) for either or both of the following purposes: 1. To obtain rapid bactericidal effect in an attempt to improve outcome. The antibacterial effect of aminoglycosides and β-lactam/vancomycin combination is synergistic. In serious infections, the bacterial load is high (typically 107–108 bacteria/gram tissue at site of infection) before treatment. In many instances, the risk of mutational resistance is directly proportional to the bacterial load. A theoretical advantage of combination therapy is that by reducing the bacterial load rapidly, the chance of development of resistance is reduced. Furthermore, aminoglycosides bind bacterial endotoxin. There is a theoretical potential of reducing the effect of “sepsis” or “endotoxaemia”. However, it must be emphasized that the latter two points are only theoretical advantages and they have not been proven to be of clinical value. 2. In the case of serious infections caused by the enterococci (e.g. endocarditis), aminoglycoside and β-lactam/vancomycin combination is often used throughout therapy to obtain bactericidal effect. Against the enterococci, either ampicillin or vancomycin given alone is only bacteriostatic. While a bacteriostatic effect may be sufficient for treatment of mild to moderate enterococcal infection, a bactericidal effect is required for serious enterococcal infections. Hence, the aminoglycosides are commonly indicated in the following situations: 1. As part of the empirical treatment in patient with severe sepsis. 2. When serious infection by , S. aureus, Enterococcus or streptococci with reduced susceptibility to the penicillins or vancomycin is suspected or confirmed. With the exception of enterococcal endocarditis, aminoglycosides need not be given for more than 3–5 days in most patients with infections by the other organisms. In fact, two recent reviews of the published literature find no advantage to combination therapy in neutropenic fever and among patients with Gram negative infections or Pseudomonas aeruginosa infections. On the other hand, nephrotoxicity was significantly more common with combination therapy [6;7].

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PHARMACOKINETIC AND PHARMACODYNAMIC ISSUES Pharmacokinetics 1. The apparent volume of distribution of this class of agents is ~25% of the total body weight (0.25-0.3 L/kg), corresponding to the estimated extracellular fluid volume. However, their volume of distribution may be altered significantly in patients who are malnourished, obese, have ascites, or are in an ICU. 2. The aminoglycosides are “extracellular” antibiotics. They do not enter into cells (see exceptions below). 3. Distribution of the aminoglycosides in tissue is shown in table 1. With the exception of the kidney, perilymph of the inner ear, and urine, concentrations of the aminoglycosides attained in tissue and body fluids are lower than that obtained in serum. Levels in bronchial fluid, sputum, pleural fluid, synovial fluid and unobstructed bile are ~20–50% of the serum concentration. While the low aminoglycoside bronchial fluid levels may be considered suboptimal, use of once daily dosing substantial improves drug penetration into this fluid. Penetration of aminoglycosides into CSF and into the vitreous fluid of the eye is inadequate and variable even in the presence of inflammation. 4. The aminoglycosides are not metabolized and biliary excretion is minimal (hence variable and poor bile concentration). The kidneys, via glomerular filtration, are responsible for essentially all aminoglycoside elimination from the body. In subjects with normal renal function, the elimination half life is as follows: 2–3 h (adults and children aged >6 months); 8–12 h (premature and LBW infant and those aged <1 week); 5 h (neonates with birth weight >2 kg). 5. Aminoglycosides can be removed from the systemic circulation by haemodialysis, peritoneal dialysis or continuous haemofiltration techniques. Pharmacodynamics 1. The aminoglycosides kill bacteria in a concentration-dependent manner. Both the rapidity and extent of bacterial killing increases with ascending concentrations of the antibiotic. High peaks are important for efficacy. This anti-bacterial property together with the prolonged post antibiotic effect allows the clinical efficacy to be maintained with once daily dosing. For the vast majority of patients in clinical trials, the once daily dosing regimen is at least equal, if not superior to the conventional thrice-daily regimen with respect to efficacy. 2. Uptake of aminoglycosides by cells of in the inner ear and kidney is more efficient with prolonged and sustained low levels. Clinically, there is at least a tendency towards reduced toxicity for once daily dosing regimen. In many patients, once daily dosing also obviates the need for therapeutic monitoring.

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TWICE DAILY, THRICE DAILY OR ONCE DAILY? More than 100 studies, reviews, and meta analyses have been published on the topic of once daily aminoglycoside dosing. Most of the studies favoured once daily dosing. In most patients, once daily dosing is at least as effective as conventional (twice daily or thrice daily) dosing; and at the same time less toxic.

ADVERSE REACTIONS 1. Nephrotoxicity and ototoxicity related to the aminoglycosides can be delayed in onset, and can progress after cessation of the antibiotics. When symptoms (e.g. creatinine; vertigo; deafness) appear, it might be too late. Incidence of toxicity depends very much on the duration of treatment. Risk increases substantially when treatment is more than 7 days. Therefore, most texts (BNF, Physician Desk Reference) strongly recommended that the aminoglycosides should not be used for more than 7 days, except in rare circumstances. Remember this phrase: whenever possible treatment should not exceed 7 days. It carries medicolegal significance in the case of suspected or confirmed aminoglycoside-related toxicity. [Personally, to avoid inadvertent prolonged therapy and toxicity, I always specify an endpoint whenever I prescribe an aminoglycoside]. This is supported by more recent findings [8;9]. 2. Ototoxicity involves progressive damage to and destruction of nerve cells in the inner ear. Damage is usually irreversible, and may be vertigo, ataxia and loss of balance in the case of vestibular damage, and auditory disturbance/deafness in the case of cochlear damage. 3. Any aminoglycoside may produce both types of effect. Some studies suggest that netilmicin might be less toxic than the other aminoglycosides when they were given multiple times a day. There is no evidence that the small difference is clinically significant. When these agents are administered once daily, any difference between the agents is unlikely to be clinically significant.

WHICH AMINOGLYCOSIDE? 1. There is little clinical evidence to support that one aminoglycoside is better than the other, both in terms of toxicity and clinical efficacy. When the aminoglycosides are given once daily, differences in the relative toxicity (if any) of different agents are likely to be clinically insignificant. Choice of a specific agent is based usually on the likelihood of resistance and cost (tables 2 and 3). 2. Tobramycin is somewhat more active in vitro against Pseudomonas aeruginosa, netilmicin more active against Acinetobacter, and gentamicin more active against Serratia. However, there is no data to ascertain whether these differences are clinically meaningful (table 4). 3. Gentamicin is the aminoglycoside most commonly used. The antimicrobial spectrum/resistance phenotype of gentamicin and

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tobramycin are similar. Amikacin has the widest antimicrobial spectrum and along with netilmicin can be effective in infections with organisms resistant to gentamicin and tobramycin. Netilmicin, while active against a number of gentamicin-resistant Gram negative bacteria, is less active against P. aeruginosa than gentamicin or tobramycin. Overall, resistance of Gram negative bacilli is lowest with amikacin. 4. In the treatment of serious enterococcal infections, sufficient clinical evidence is only available for two aminoglycosides (gentamicin and streptomycin). Among enterococci and staphylococci, resistance to gentamicin is most often due to the ubiquitous bi-functional enzyme AAC(6’)-APH(2’). This enzyme has a broad spectrum (inactivates gentamicin, tobramycin, netilmicin and amikacin). Testing an aminoglycoside other than gentamicin might not accurately detect resistance due to this enzyme. Except with expert advice, gentamicin- resistant enterococci and staphylococci should be regarded as resistant to netilmicin, tobramycin and amikacin. (Testing of these aminoglycosides separately is unnecessary, and can indeed be misleading.) 5. In Gram-negative bacilli, the epidemiology and mechanism of aminoglycoside resistance has become complicated. Generally speaking, gentamicin-susceptible Gram negative bacilli, including P. aeruginosa are usually (but not always) susceptible to netilmicin, tobramycin and amikacin. To avoid the need for testing multiple agents, policies should be set up on the agents that were routinely used, tested and reported. IN Hong Kong, resistance to the aminoglycosides can vary between different institutions. Institution-based susceptibility data should be used to formulate usage strategies.

ONCE DAILY (EXTENDED INTERVAL) REGIMEN 1. There is considerable confusion on the dose and how to monitor serum aminoglycosides levels when using once daily dosing. Currently, the optimal dosage of aminoglycosides in once daily strategy has not been clearly determined. Recommended dosages for gentamicin, tobramycin and netilmicin have ranged from 3–7 mg/kg, and amikacin dosages have ranged from 15–30 mg/kg. 2. The wide variations reflect the uncertainty concerning what peak value is optimal. On the basis of in vitro data, it seems that a target peak concentration of ten times the MIC value of the organism is likely to be very sufficient. When the drug is administered once daily, very high peak concentration (>12 μg/mL for gentamicin and tobramycin) are achieved. These values give Cmax/MIC ratio of >10–20 for almost all Gram negative bacilli. 3. On the basis of local experiences and a recent consensus meeting (IMPACT working group), the following doses are recommended for initial therapy in local Chinese: for gentamicin and tobramycin, 3.5 mg/kg; netilmicin, 4.4 mg/kg and amikacin, 15 mg/kg. The dosage for gentamicin should be adequate for infection by most organisms (in which MIC is less

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than 1 μg/ml, see Table 4). In the case of Pseudomonas aeruginosa (in which is gentamicin MIC is commonly 2 μg/ml, higher dose of gentamicin is indicated or that tobramycin be used) [10]. 4. Calculate dose for individual patient by the actual body weight unless the patient is obese (i.e. 20% over ideal body weight, IBW). In obese patient, use the following equation to work out the appropriate dosing weight. Obese dosing weight = ideal body weight (IBW) + 0.4 (actual body weight - IBW). 5. Like conventional regimens, once daily protocol requires dosing modification for patient with renal dysfunction. A fixed dose (instead of fixed interval) approach is advocated because if reductions are made in the dose as a result of poor renal function, the subsequent serum concentrations would also be lower, resulting in a Cmax: MIC ratio that is less than optimal. If the intended duration of aminoglycosides therapy is less than 3–4 days, then there is no need to routinely monitor serum levels. In patient with impaired renal function, it means that only one or two doses of the aminoglycoside need to be given. In this case, drug level result is unlikely to be clinically useful. The dosing interval for the second dose can usually be worked out by using the following chart (based on the estimated creatinine clearance, CrCl of the patient).

CrCl (mL/min) Initial dosing interval ≥ 60 Q24h 40–60 Q36h 20–40 Q48h < 20 Follow serial levels to determine time of next dose (level <1 μg/mL) In patients with normal renal function who are treated with once daily aminoglycoside, there is no evidence that therapeutic drug monitoring (TDM) contributes to better clinical outcome or a lower incidence of toxicity. Hence, therapeutic drug monitoring (TDM) is not indicated in the following situations: 1. Receiving 24-h dosing regimen. 2. Without concurrently administered nephrotoxic drugs (e.g. vancomycin, amphotericin B, cyclosporin). 3. Without exposure to contrast media. 4. Not quadriplegic or amputee. 5. Not in the ICU. 6. Younger than 60 years of age. 7. Duration of planned therapy less than 5 to 7 days. In practice, if the intended duration of aminoglycoside is only 1 to 3 days then there is no need to request drug levels. If TDM is indicated, obtain a single random serum level after the first dose between 6–14 h after the start of the

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infusion. It is important that the timing of sampling in terms of number of hours after the end of infusion (e.g. 8 hours post dose) be specified in the request because interpretation of the result requires this information. Correct timing is essential as discussed in a recent article that evaluated four normograms [11]. The laboratory should also enter this information (e.g. 8 hours post dose) to the computer record and on the printed report. Plot the serum level on the Hartford normogram (Figure) [12] and work out the appropriate dosing interval using the below chart. This method applies to gentamicin, tobramycin and netilmicin. For once daily amikacin dosing (at 15 mg/kg), halve the measured concentration and plot on the same graph (N.B. there are insufficient data on the use of this method for the following situations: pediatrics, pregnancy, burns (>20%), ascites, dialysis, enterococcal endocarditis).

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Result of plotting Dosing interval for second and subsequent doses Level falls in the area Give the same dose at an interval of every designated q24h 24h Level falls in the area Give the same dose at an interval of every designated q36h 36h Level falls in the area Give the same dose at an interval of every designated q48h 48h Level on the line Choose the longer interval Level off the normogram at the Stop the scheduled therapy, obtain serial given time levels to determine the appropriate time of the next dose

Cockcroft-Gault formula for estimation of creatinine clearance

CrCl (mL/min) = (140 – age) × 1.2 × ideal body weight (kg) /serum creatinine (mmol/L) for males. (Female: 0.85 above value) IBW for male = 50 kg + 0.9 kg for each cm over 152 cm (2.3 kg for each inch over 5 feet) IBW for female = 45.5 kg + 0.9 kg for each cm over 152 cm (2.3 kg for each inch over 5 feet) Conversion to SI unit: for serum creatinine mg/dL × 88.4 = mmol/L

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Figure. Hartford Hospital once-daily aminoglycoside normogram for gentamicin and tobramycin.

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Table 1. Aminoglycoside penetration into various tissues. (N.B. these data were derived primarily from studies that administered aminoglycosides multiple times per day.)

% Serum level Site Extent of Ami1 Gen1 Net1 Tob1 distribution Aqueous Poor minimal minimal minimal minimal humor Ascitic fluid Variable 58% 80-100% 79% Bile Variable 6-54% 30−60% 10−20% Bile with Poor obstruction Bone Poor 30% 13% CSF (inflamed Poor 15−24% 10−30% 21−26% 14−23% meninges) Peritoneal fluid Poor 39% 50% Pleural fluid Excellent 12-40% 0-57% 40-69% Prostate Poor Pulmonary Excellent 40-53% tissue Renal tissue2 Excellent >100 μg/g Sputum and Variable 11-21% 10% 19% 3-66% bronchial secretions Synovial fluid Excellent 111% 50-80% 89% Urine Excellent >10 times >10 times >10 times serum serum serum level level level (up to μ (500−800 (>100 75−100 g/ml) μg/ml) μg/ml) 1Ami = amikacin, Gen = gentamicin, Net = netilmicin, Tob = tobramycin, Kan = kanamycin, Str = streptomycin. 2Unit = micrograms of antibiotic per gram (μg/g) tissue. Source: Mandell’s Principles and Practice of Infectious Diseases 2000; manufacturer’s drug insert.

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Table 2. Preparations and recommended dosing regimens for aminoglycosides.

Agent (generic) Trade name Dosage form Usual adult regimen (unit cost, HK$) (daily dose, route, dosing interval) Amikacin Amikin 250 mg vial ($36) IV 15 mg/kg q24h (750 mg q24h)a or 7.5 500 mg vial ($56) mg/kg q12h Gentamicin Garamycin 20 mg/2 mL ($8) IV 3.6 mg/kg/day q24h (180 mg q24h)a or 40 mg/2 mL ($2) 1.2 mg/kg/dose q8h Netilmicin Netromycin 50 mg vial ($18.5) IV 4.4 mg/kg q24h (200 mg q24h)a or IV 200 mg vial ($44.8) 2.2 mg/kg q12h

Tobramycin Nebcin 40 mg/mL 2 ml vial IV 3.6 mg/kg q24h ($18) (180 mg q24h)a or 1.2 mg/kg q8h a Dosage for a typical 50 kg person given. Cost updated as of Feb 2003 in HA. Once daily administration of aminoglycoside is appropriate for most infection with the possible exceptions of neutropenic fever, infective endocarditis and in the presence of severe renal failure.

Table 3. Cost comparison of aminoglucosides.

Agent Cost (HK$ per day) 12 IV gentamicin 180 mg q24h (3.5 mg/kg/day) 92 IV amikacin 750 mg q24h (15 mg/kg/day) 54 IV tobramycin 180 mg q24h (3.5 mg/kg/day) 45 IV netilmicin 200 mg q24h (4.4 mg/kg/day)

(Cost updated as of Feb 2003 in HA. Dosage for a typical 50 kg person.)

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Table 4. Representative MIC (μg/mL) of aminoglycosides for common pathogens.

Gentamicin Netilmicin Tobramycin Amikacin Common 0.5−1 0.5−1 0.5−1 2 Enterobacteriaceae (E. coli, Klebsiella, Enterobacter, Proteus spp.) Serratia marcescens 0.25 0.5 1 1 P. aeruginosa 2 4 0.5 4 S. aureus 0.25 0.25 0.25 1

Estimated peak serum 13.7 μg/mL 15.4 μg/mL 14 μg/mL 76 μg/mL concentration (dose)a (3.5mg/kg) (4.4mg/kg) (3.5mg/kg) (15mg/kg)

a Estimated from known plasma levels after conventional dosing. Values for plasma levels after conventional dosing were obtained from Physician Desk Reference 1999.

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3 Quinolones

BACKGROUND Quinolones belong to a class of synthetic compounds. On the basis of the core structure, the quinolones can be classified into as fluoroquinolone (nor, ofl, cip, levo, spar, moxi, gati) or naphthyridone (e.g. nalidixic acid, trova, gemi). Quinolones with a fluorine at position C6 are called fluoroquinolones (FQs). All FQs also has a piperazinyl group at C7 (Table 1). The newer agents (e.g. moxifloxacin and gatifloxacin) with enhanced activities against Gram positive cocci and anaerobes have been called “respiratory fluoroquinolones.” Levofloxacin is the active optical isomer of ofloxacin. While levofloxacin is more active against Gram positive cocci than ofloxacin (2 times more active), controversies exist as to whether it should be classified as a new fluoroquinolone. (Abbreviations: gati = gatifloxacin; gemi = gemifloxacin; grepa = grepafloxacin; levo = levofloxacin; moxi = moxifloxacin; nor = norfloxacin; ofl = ofloxacin; spar = sparfloxacin; trova = trovafloxacin)

MECHANISM OF ACTION 1 Inhibitor of DNA gyrase and topoisomerase IV a Both are type II topoisomerases that act by a double-strand DNA break. b Enzymes essential for bacterial DNA replication. 2 DNA gyrase a An A2B2 tetramer with two subunits: gyrase A (gyrA) and B (gyrB). b Essential for initiation of DNA replication and plays a role in elongation, presumably by removing positive supercoils arising from DNA unwinding at the replication fork. 3 Topoisomerase IV a A C2E2 tetramer with two subunits: C (parC) and E (parE) subunits. b Separate interlinked daughter chromosomes to allow their segregation into daughter cells. 4 Quinolones inhibit both enzymes by forming a ternary complex. It is thought that cellular processes acting on the ternary complex result in irreparable double-stranded DNA break, thereby triggering bacterial death.

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Table 1. Commonly used quinolone antibiotics.

Year Agent Licensed Oxo- Piperazinyl Fluorine in HK at C4 at C7 at C6 1960s Nalixidic acid Yes + - - (Wintomylon®) 1970s Pipemidic acid Yes + - - (Urotractin®) 1980s Norfloxacin Yes + + + (Lexinor®) Ciprofloxacin Yes + + + (Ciproxin®) Early 1990s Ofloxacin Yes + + + (Tarivid®) Lomefloxacin Yes + + + (Maxaquin®) Late Levofloxacin Yes + + + 1990s−2000 (Cravit®) Sparfloxacin Yes + + + (Zagam®) Trovafloxacin Noa + + + (Trovan®) Grepafloxacin Noa + + + (Raxar®)* Moxifloxacin Yes + + + (Avelox®) Gatifloxacin No + + + (Tequin®)

FREQUENCY AND MECHANISMS OF BACTERIAL RESISTANCE 1 Strains with mutations causing resistance to one FQ are often cross- resistant to other FQs as well. Most highly resistant clinical isolates have multiple mutations and/or multiple mechanisms of resistance. 2 Target modification Mutation in target genes (DNA gyrase or topoisomerase IV or both) leading to amino acid substitution in the QRDR region and reduced affinity for drug is the most common cause of FQ resistance. 3 Reduced drug permeability or active efflux

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a In Gram negative bacteria: as a result of loss or reduced expression of porin proteins (diffusion channels through which the FQs enters the bacterial cells). Other drugs may use the same porins to enter into the bacterial cells. Therefore, pleiotropic cross-resistance to some β-lactams, imipenem, tetracycline and chloramphenicol can occur. b In S. aureus: increased expression of efflux pumps (e.g. chromosomal norA) in the bacterial cell membrane; thus preventing the accumulation of FQs in the cells. 4 No specific enzymes degrading the FQs have been found in resistant bacteria. 5 Mutation frequency is affected by: a Pharmacokinetic (PK) and pharmacodynamic (PD) considerations: risk ↑ if peak drug concentration to MIC ratio (Cmax: MIC ratio) less than 10. b Organism: highest mutation frequencies with MRSA, Enterococcus, P. aeruginosa. c Increased risk in presence of foreign body: e.g. ventilator- associated pneumonia. d Bacterial persistence: as occur in chronic infection/presence of bacterial biofilm; e.g. osteomyelitis, cystic fibrosis.

FACTORS AFFECTING THE CHOICE OF FLUOROQUINOLONES 1 Clinical efficacy. 2 Spectrum of antimicrobial activity in vitro. 3 Pharmacokinetics/pharmacodynamics (PK/PD). 4 Safety/side effect profile. 5 Potential for selection of resistance. Clinical efficacy 1 Many studies have documented the efficacy of FQs in management of bacterial infections: a UTI, . b Prostatitis. c Gonococcal urethritis, cervicitis; usefulness now limited by high rates of resistance in Hong Kong (>10%). d Chlamydial urethritis. e Enteric fever. f infection. g Bone and joint infections.

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h Skin and soft tissue infection.

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2 Predictors of outcome a Minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) are traditionally used to predict the potency of the drug-organism interactions. However, they are better predictors of failure than response. High MIC value of an antibiotic for a bacterium is usually translated into clinical failure while low MIC value does not always mean there will be good outcome. This is not surprising as MIC/MBC do not take into consideration the pharmcokinetic properties of the drug, nor do they provide information on the rate of bactericidal activity, the effect of increasing concentration and the persistent bactericidal / bacteriostatic effects that occur after exposure to an antibiotic. b Recent data have shown than parameters that take into considerations of the pharmacokinetic (PK) properties and pharmacodynamic (PD) response are better predictors of clinical outcome (2, 3, 6). The PD response of agents exhibiting concentration dependent killing (e.g. aminoglycosides, fluoroquinolones) is described by measuring peak drug concentration (Cmax) to MIC ratio. An additional parameter that integrates both PK and PD principles is the area under the inhibitory curve (AUIC). AUIC is the ratio of the antibiotic under the concentration-time curve (AUC in 24 hours) to the bacterium’s MIC. Outcome is likely to be favorable and selection of resistance deems unlikely if values of >10 for Cmax:MIC and >125 for AUIC are achieved. Spectrum of antimicrobial activity in vitro (Table 2) 1 Highly susceptible Gram negative bacteria: a Enterobacteriaceae such as E. coli, Klebsiella spp. b Enteric pathogens: Salmonella spp., Shigella spp., Vibrio spp. c Fastidious Gram negative bacteria: H. influenzae, M. catarrhalis, N. gonorrhoeae, N. meningitidis, Legionella. 2 Other susceptible Gram negative bacteria (higher MICs): a Non-fermenters such as Pseudomonas aeruginosa, S maltophilia, Acinetobacter. b MIC for P. aeruginosa (from lowest to highest): cip < levo < ofl ~ spar. c MIC for Acinetobacter: spar (0.06-1) < cip (0.25-2). 3 Gram positive cocci: S. aureus, coagulase-negative staphylococci (CoNS), S. pneumoniae, S. pyogenes, enterococci. a FQs with enhanced activity against Gram positive bacteria such as S. pneumoniae: gemi, moxi, gati. It should be point out that in Hong Kong, fluoroquinolone resistance among both invasive and respiratory isolates of pneumococci is emerging [13;14].

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b While more active than ciprofloxacin and levofloxacin against Gram-positive bacteria, the activities of even the newer FQs (e.g. moxi, gati) against most MRSA and methicillin-resistant CoNS are still limited. 4 Other susceptible organisms: a Chlamydia trachomatis and Mycoplasma spp. (most FQs are highly active in vitro). b Mycobacterium tuberculosis (cip and ofl, and recently levo as well were the fluoroquinolones of choice in treatment of tuberculosis as a 2nd line agent. Recent in vitro data suggest that moxifloxacin is more active than cip and ofl against M. tuberculosis). Atypical mycobacteria: M. fortuitum and some strains of M. chelonae also susceptible. 5 Generally resistant: a Anaerobes; except trovafloxacin. b Treponemes.

Table 2. Comparative activity of the FQs against selected organisms.

cip ofl levo spar moxi gati S. pyogenes ± ± + + ++ ++ S. pneumoniae ± ± + + ++ ++ E. faecalis 0/± 0/± + + + + E. faecium 0 0 ± ± ± ± MSSA + + + + +/++ +/++ MRSA 0 0 ± ± + + M. catarrhalis ++ ++ ++ ++ ++ ++ H. influenzae ++ ++ ++ ++ ++ ++ P. aeruginosa ++ ± + 0 + + Enterobacteriaceae ++ + + + + + Atypical respiratory pathogens + + + + ++ ++ Anaerobes 0 0 0 0 + +

Pharmacological properties 1 Excellent oral bioavailibility, >70−90% (Table 4 and 5). 2 Volume of distribution > total body water (due to intracellular concentration).

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3 Intracellular concentration >> extracellular concentration (Table 3). 4 Serum level generally low. 5 Low serum protein binding (15−45%).

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Table 3. Body tissues, fluids, and cells in which quinolone concentrations exceed quinolone concentration in serum.

Site Fold increment (times serum level) Urine 25 to >100 Kidney 2–10 Prostate tissue 1–2 Feces 100–1000 Bile 2–20 Bone 0.3−0.8 Lung tissue 1.6–4 Bronchial mucosa 1.0−45 Saliva 0.3−0.9 CSF (with meningitis) 0.1−0.4 Macrophage and neutrophils 2–14

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Table 4. Pharmacokinetic parameters of selected fluoquinolones.

Dose / Protein binding T1/2 Cmax Free drug AUC24 Free drug MIC for 90% of FQ- AUIC frequency (h) Cmax (μg⋅h/mL) AUC24 sensitive S. (μg/mL) (mg) (μg⋅h/mL) pneumoniae in Hong (μg/mL) Kong ofl PO 400 BD 32% 7 1.7 1.2 82.4 56 2 28 cip PO 500 BD 30% 4 2.5 1.8 21.3 14.9 2 7.5 cip PO 750 BD 30% 4 4.0 2.8 32 22.4 2 11 levo PO 500 QD 24−38% (31) 7 5.7 3.9 48 33.1 1 33 spar PO 400 QD 45% 18 1.6 0.9 32 17.6 0.5 35.2 moxi PO 400 QD 30−45% (37) 12 4.5 2.8 48 30.2 0.19 158.9 gati PO 400 QD 20% 8.4 4.2 3.4 34 27.2 0.25 108.8 gemi PO 320 QD 58% 6.7 1.5 0.6 9.3 3.9 0.03 130

Data sources: drug inserts, Physician Desk Reference 1999 and others [15].

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Table 5. PO vs. IV comparison of pharmacokinetic parameters of selected FQs.

Dose / route Cmax AUC24 Approximate cost (μg⋅h/mL) (HK$) cip 500 mg bd po 2.5 22 19 cip 750 mg bd po 3.5 32 28.5 cip 200 mg bd iv 2.1 12.7 310 cip 400 mg bd iv 4.6 25.4 620

ofl 200 mg bd po 2.1 41.2 14.8 ofl 400 mg bd po 4.6 82.4 29.6 ofl 200 mg bd iv 2.7 43.5 206 ofl 400 mg bd iv 4.0 87 412

levo 500 mg qd po 5.7 48 19.1 levo 500 mg qd iv 6.2 48 240

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Safety/side effects profile Table 6. Fluoroquinolones: comparison of their side effects.

Type of side effects Nature Descending order of (frequency of frequency occurrence, overall %) Gastrointestinal Usually minor spar > cipro ~ levo > nor (2−20%) Central nervous system Headache, dizziness, sleep spar > cip > nor > levo (1−2%) disorders, mood changes, confusion, (rarely convulsion) Hepatic (2−3%) Usually transient rise in spar~cip~ofl > levo LFT; (rarely cholestatic (2%) (0.3%) jaundice, hepatitis, hepatic failure) Skin (0.5−3%) Photosensitivity spar > cip > levo~ofl Renal (0.2−1.3%) Azotemia, crystalluria, ofl > cip and others haematuria Musculoskeletal (1%) Arthropathy (onset in first Class effect few days; weight bearing joints) Tendon rupture (especially Probably class effect, Achilles tendon; 0.005 to 0.7 though only reported with per 1000 treated patients) cip, nor, spar

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Table 7. Drug interactions.

Drug B Comment Drug(s) A levo cip moxi gati Antacid, milk, sucralfate, + + + + A class effect, ↓

iron, zinca absorption of B Theophylline − + − − Monitor level of A (for cip) Warfarin − + − − Cip enhances effect of warfarin Cyclosporin − + − − NSAIDs May ↑ risk of CNS stimulation and convulsion Probenecidb + + − + Inhibition of cytochrome NA + Noc Noc P450 “+” refers to clinically significant interaction. “−” not clinically significant. NA, no data available. a Give B 2−4 hours before A. b had no effect on excretion of mox, but ↑ T1/2 & AUC of levo (by ~30%), gati (by ~40%). c No inhibition of CYP 3A4, 2D6, 2C9, 2C19 or 1A2

Potential for selection of resistance 1 Use of FQs in the following circumstances is not advised: a Most skin and soft tissue infections (S. pyogenes and/or S. aureus are the usual pathogen). b S. pyogenes . c Dental infection, most head and neck infections (anaerobes, streptococci important). d Acute , acute sinusitis, acute tracheitis, acute . e Meningitis (inadequate CSF level and limited data). f Infective endocarditis (limited data).

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2 Reasons a Widespread use encourage emergence/dissemination of resistant mutants (e.g. in normal flora E. coli, staphylococci) b Inadequate coverage as monotherapy c No obvious therapeutic advantage over conventional options; and/or d Limited data.

CONCLUSION: SPECIAL ROLES OF THE FQS 1 Early switch therapy. 2 Oral therapy of P. aeruginosa (ciprofloxacin). 3 Typhoid / enteric fever or serious bacterial gastroenteritis. 4 Multi-drug resistant S. pneumoniae (penicillin MIC ≥4 μg/mL). 5 Some chronic bacterial infection: bone (Gram negative), prostate, tuberculosis (as a second line agent). 6 Prophylaxis in neutropenic patients.

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(2) LOWE MN, LAMB HM. MEROPENEM: AN UPDATED REVIEW OF ITS USE IN THE MANAGEMENT OF INTRA-ABDOMINAL INFECTIONS. DRUGS 2000; 60(3):619-646.

(3) TODD PA, BENFIELD P. AMOXICILLIN/CLAVULANIC ACID. AN UPDATE OF ITS ANTIBACTERIAL ACTIVITY, PHARMACOKINETIC PROPERTIES AND THERAPEUTIC USE. DRUGS 1990; 39(2):264-307.

(4) RAMIREZ JA. SWITCH THERAPY WITH BETA-LACTAM/BETA-LACTAMASE INHIBITORS IN PATIENTS WITH COMMUNITY-ACQUIRED PNEUMONIA. ANN PHARMACOTHER 1998; 32(1):S22-S26.

(5) SCHRANZ J. COMPARISONS OF SEIZURE INCIDENCE AND ADVERSE EXPERIENCES BETWEEN IMIPENEM AND MEROPENEM. CRIT CARE MED 1998; 26(8):1464-1466.

(6) PAUL M, BENURI-SILBIGER I, SOARES-WEISER K, LEIBOVICI L. BETA LACTAM MONOTHERAPY VERSUS BETA LACTAM-AMINOGLYCOSIDE COMBINATION THERAPY FOR SEPSIS IN IMMUNOCOMPETENT PATIENTS: SYSTEMATIC REVIEW AND META-ANALYSIS OF RANDOMISED TRIALS. BMJ 2004; 328(7441):668.

(7) PAUL M, SOARES-WEISER K, LEIBOVICI L. BETA LACTAM MONOTHERAPY VERSUS BETA LACTAM-AMINOGLYCOSIDE COMBINATION THERAPY FOR FEVER WITH NEUTROPENIA: SYSTEMATIC REVIEW AND META-ANALYSIS. BMJ 2003; 326(7399):1111.

(8) ROUGIER F, DUCHER M, MAURIN M, CORVAISIER S, CLAUDE D, JELLIFFE R, MAIRE P. AMINOGLYCOSIDE DOSAGES AND NEPHROTOXICITY: QUANTITATIVE RELATIONSHIPS. CLIN PHARMACOKINET 2003; 42(5):493-500.

(9) BACIEWICZ AM, SOKOS DR, COWAN RI. AMINOGLYCOSIDE-ASSOCIATED NEPHROTOXICITY IN THE ELDERLY. ANN PHARMACOTHER 2003; 37(2):182-186.

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(11) WALLACE AW, JONES M, BERTINO JS, JR. EVALUATION OF FOUR ONCE- DAILY AMINOGLYCOSIDE DOSING NOMOGRAMS. PHARMACOTHERAPY 2002; 22(9):1077-1083.

(12) NICOLAU DP, FREEMAN CD, BELLIVEAU PP, NIGHTINGALE CH, ROSS JW, QUINTILIANI R. EXPERIENCE WITH A ONCE-DAILY AMINOGLYCOSIDE PROGRAM ADMINISTERED TO 2,184 ADULT PATIENTS. ANTIMICROB AGENTS CHEMOTHER 1995; 39(3):650-655.

(13) HO PL, TSE WS, TSANG KWT, KWOK TK, NG TK, CHENG VCC, CHAN RMT. RISK FACTORS FOR ACQUISITION OF LEVOFLOXACIN-RESISTANT

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STREPTOCOCCUS PNEUMONIAE: A CASE-CONTROL STUDY. CLINICAL INFECTIOUS DISEASES 2001; 32(5):701-707.

(14) HO PL, QUE TL, CHIU SS, YUNG RWH, NG TK, TSANG DNC, SETO WH, LAU YL. FLUOROQUINOLONE AND OTHER ANTIMICROBIAL RESISTANCE IN INVASIVE PNEUMOCOCCI, HONG KONG, 1995-2001. EMERGING INFECTIOUS DISEASES 2004; 10(7):1250-1257.

(15) BLONDEAU JM. A REVIEW OF THE COMPARATIVE IN-VITRO ACTIVITIES OF 12 ANTIMICROBIAL AGENTS, WITH A FOCUS ON FIVE NEW RESPIRATORY QUINOLONES'. J ANTIMICROB CHEMOTHER 1999; 43 SUPPL B:1-11.

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