Antibiotics: Discussion

Nicolas V. Christou, M.D., PH.D., F.A.C.S.

The antimicrobial agents of choice for various infections (e.g., community-acquired pneumonia 7-9) in
adults are well established [see Table 4 -- omitted], as are their dosages in patients with normal renal
function [see Table 5 -- omitted]. Excellent reviews and practice guidelines have been published. 18,19

Penicillins
Although the original penicillins are still useful against specific bacteria, there are some infections in
which both they and the penicillinase-resistant semisynthetic penicillins are ineffective because of the
emergence of penicillinase-producing staphylococci and methicillin-resistant staphylococci. The
penicillins can be classified by structure, -lactamase susceptibility, and spectrum of action [ see
Figure 1 -- omitted].
The action of the penicillins depends on the presence of a bacterial cell wall containing
peptidoglycans that are accessible to the agent. In actively growing bacteria, interference with
biosynthesis of the peptidoglycan structure-specifically, of the cross-linkages between the peptide
chains-prevents the bacterium from developing its normal structural firmness, and this lack of
firmness leads to lysis.
Natural Penicillins
Aqueous Crystalline Penicillin G. Aqueous crystalline penicillin G is used when a high serum
concentration of the agent is required.36 Its half-life is normally 30 minutes but may be as long as 10
hours in patients with anuria. Approximately 50% of penicillin G is bound to plasma proteins.
Penicillin G sodium contains approximately 2 mEq of sodium per one million units. Therefore, the
potassium salt of penicillin G should be used except in patients with renal insufficiency, who may not
be able to tolerate the 1.7 mEq of potassium contained in each one million units. This agent is
destroyed by gastric acid when given orally.
Penicillin G Benzathine. Penicillin G benzathine, 1.2 to 2.4 million units I.M., is used in the
definitive management of certain infections, such as streptococcal sore throat, and as prophylaxis for
several conditions, such as rheumatic fever, in which reinfection by -hemolytic streptococci is a
constant threat.
Penicillin G Procaine (3 juta iu). Penicillin G procaine is used intramuscularly when a long-acting
preparation is preferred and high blood levels are not required. It is indicated for the treatment of
pneumococcal pneumonia, uncomplicated cases of which are adequately treated by administration of
one or two daily doses of 300,000 units, and for treatment of acute genitourinary gonorrhea, for
which a dose of 4.8 million units is divided and injected at two sites and 1 g of probenecid is given
orally before the injection.
Penicillin V. Phenoxymethyl penicillin, or penicillin V, is resistant to gastric acid and therefore
reaches higher serum concentrations, when given orally, than penicillin G does at similar doses.
Penicillin V should not be substituted for parenterally administered penicillin G when such therapy is
needed, but it can be given orally to treat mild infections of the throat, the respiratory tract, or soft
tissue in doses of 125 to 500 mg given four to six times daily.
Penicillinase-Resistant Penicillins
Methicillin. Methicillin is the least protein-bound of this group (39%); nafcillin (90%), oxacillin
(94%), cloxacillin (95%), and dicloxacillin (98%) all have higher rates of protein binding. Methicillin
was the first of the semisynthetic penicillinase-resistant penicillins. 37 It must be administered
parenterally and is usually given every 4 to 6 hours in a total daily dose of 100 to 300 mg/kg body
weight.
Oxacillin and Nafcillin. Oxacillin seems to be as effective as methicillin against staphylococcal
infections, and it causes interstitial nephritis less often. For parenteral use, oxacillin or nafcillin can be
given in dosages of 100 to 300 mg/kg/day for children and up to 4 to 12 g/day for adults.
Cloxacillin and Dicloxacillin. If penicillinase-producing organisms are identified or suspected and
oral therapy is desired, cloxacillin or dicloxacillin, 1 to 2 g/day, can be given.
Aminopenicillins
Ampicillin ( > 20 kg : 250-500 mg/hr dlm 4 dosis, < 20 kg : 100-200 mg/BB/hr ). Ampicillin is
active against a variety of bacteria, including many strains of Escherichia coli, Proteus mirabilis,
Salmonella, Shigella, Listeria, and Haemophilus influenzae . Most strains of Klebsiella and all strains of
P. aeruginosa are resistant.
Because it is stable in gastric juices, ampicillin is suitable for oral as well as parenteral use. When it is
given orally, peak serum levels are reached in about 2 hours, but they seldom exceed 0.3 g/ml.
When it is given intramuscularly, peak serum levels are achieved in 1 hour, and they are both higher
and more prolonged than the peak levels achieved after oral administration. About 10% of ampicillin
is bound to plasma proteins. The recommended daily dose is 1 to 4 g; parenteral administration of up
to 12 g/day is recommended for major systemic infections.
Amoxicillin ( > 20 kg : 250-500 mg/hr dlm 3 dosis, < 20 kg : 20-40 mg/BB/hr ). Amoxicillin is
closely related to ampicillin, both in chemical structure and in spectrum of antibacterial activity. 38
Amoxicillin, however, is more completely absorbed than ampicillin: approximately 70% of a dose of
amoxicillin is absorbed, compared with approximately 50% of a dose of ampicillin. Consequently, the
blood levels attainable with a given dose of amoxicillin are usually about twice those attainable with a
comparable dose of ampicillin. Amoxicillin is at least as effective as ampicillin in the treatment of
respiratory disorders that are caused by susceptible bacteria, including otitis media, sinusitis, and
bronchitis.
Carboxypenicillins
Carbenicillin. Carbenicillin has an antibacterial range similar to that of ampicillin, with the added
benefit of activity against certain strains of P. aeruginosa,39 indole-positive Proteus species, and
Enterobacter species.40 Because carbenicillin is inactivated by penicillinase, penicillinase-producing S.
aureus is resistant to it. Klebsiella species are resistant to carbenicillin, as are many Serratia
organisms. Carbenicillin is bactericidal and is recoverable from blood, urine, lymph, CSF, and most
body tissues. About 50% of the drug is bound to serum proteins.41
Ticarcillin. The antibacterial spectrum of ticarcillin is similar to that of carbenicillin; however, it is
two to four times more active against P. aeruginosa. It is frequently preferred to carbenicillin in the
treatment of serious gram-negative infections because of its greater potency and the lower incidence
of adverse effects.42 The primary use of ticarcillin is in the treatment of proven or suspected
Pseudomonas infections. The recommended dosage is 16 to 24 g/day.
Ureidopenicillins
Mezlocillin, Azlocillin, and Piperacillin (Tazocin (vial 4.5 gr): Pip 4 gr + Tazobactam 500
mg. > 12 thn 2.25-4.5 gr/8 jam). Mezlocillin, azlocillin, and piperacillin are semisynthetic penicillins
derived from the ampicillin molecule with side-chain adaptations. The ureidopenicillins are generally
bactericidal and act primarily by inhibiting cell wall synthesis in dividing bacteria. In comparison with
the carboxypenicillins carbenicillin and ticarcillin, the ureidopenicillins exhibit less pronounced plasma
protein binding, a shorter serum half-life, and a greater volume of distribution. 43-45 They are minimally
metabolized (10%) and are primarily excreted in an active form by glomerular filtration and tubular
secretion. Unlike carbenicillin and ticarcillin, the ureidopenicillins achieve high concentrations in bile
because of increased biliary excretion.
In vitro, the ureidopenicillins are active against streptococci, enterococci, most Enterobacteriaceae,
Pseudomonas, -lactamase-negative staphylococci, Neisseria, and Haemophilus.46-48-Lactamase-
producing staphylococci and H. influenzae are resistant. The major advantage the ureidopenicillins
have over other penicillins in clinical use is their increased activity against P. aeruginosa and
Klebsiella.
The recommended dosages of the ureidopenicillins are 6 to 16 g/day for mild to moderate infections
and 18 to 24 g/day for severe to life-threatening infections. Small doses may be given
intramuscularly, but large doses must be given intravenously. The dosing interval is usually 4 to 6
hours.

Cephalosporins
Cephalosporium acremonium was discovered in 1948. This fungus was found to produce
cephalosporin C, from which cephalothin, the first cephalosporin to be introduced, was in turn
derived. The basic cephalosporin structure consists of a dihydrothiazine ring fused to a -lactam ring.
Substitutions at the acyl side chain have led to differences in antibacterial spectrum and -lactamase
stability. The side chains substituted at this position interfere with proper stereotactic binding of the
molecule to the -lactamase active site, thus preventing degradation of the cephalosporin. Some of
the side effects involving platelet aggregation that have been observed with the use of moxalactam
can be traced to substitutions at this position.
For convenience, cephalosporins are divided into four generations or groups according to the nature
and extent of their antibacterial spectra. More specifically, the division into generations is based on
the number of gram-negative bacterial species against which each cephalosporin demonstrates
clinical activity. It must be remembered, however, that although the members of each generation are
sufficiently similar to be grouped together, they also are different from one another in a number of
ways [see Table 6 -- omitted].
First-Generation Cephalosporins
First-generation cephalosporins have good activity against aerobic gram-positive cocci such as S.
aureus, group B streptococci, and Streptococcus pneumoniae. In addition, they are effective against
three aerobic gram-negative bacilli-E. coli, K. pneumoniae, and P. mirabilis-although even among
these three, resistance is common, occurring in as many as 30% of cases. First-generation
cephalosporins are also active against most anaerobic cocci and bacilli (other than B. fragilis). They
have little or no activity against Enterobacter, Serratia, Acinetobacter, Pseudomonas, methicillin-
resistant S. aureus, S. epidermidis, and enterococci. They are also inactive against B. fragilis,
Citrobacter, Listeria monocytogenes, Proteus (except for P. mirabilis), and Providencia.
First-generation cephalosporins are used for infections caused by gram-positive cocci, such as skin
infections and osteomyelitis, although penicillins are the agents of choice for all streptococcal
infections and for infections proven by culture to be caused by susceptible staphylococci. The best
use for first-generation cephalosporins is in surgical prophylaxis. For this application, cefazolin sodium
is the preferred agent.
Second-Generation Cephalosporins
Second-generation cephalosporins possess the same spectrum of activity as the first-generation
cephalosporins, with the addition of broader coverage of gram-negative organisms, including H.
influenzae, E. aerogenes, and some Neisseria species. Fewer than 5% of E. coli and Proteus strains
are resistant to second-generation cephalosporins. The activity of second-generation agents against
S. pyogenes and S. pneumoniae is equal to that of the first-generation agents, but their activity
against staphylococci is variable: the MIC ranges from 0.20 to 25 g/ml. Of the second-generation
agents, the most active against staphylococci is cefamandole, which has an MIC of 0.6 g/ml for S.
aureus. Cefotetan and cefoxitin have significant activity against B. fragilis. Cefoxitin is less active
against H. influenzae and E. aerogenes than other second-generation cephalosporins, but it is more
active against Serratia species. Cefoxitin by itself is effective in patients with community-acquired
peritonitis who are unlikely to be infected with Enterobacter or P. aeruginosa.49 Cefuroxime and
cefamandole have been used with some success in empirical therapy for community-acquired
pneumonia.50 Cefotetan, a cephamycin introduced in 1986, has a spectrum of activity very similar to
that of cefoxitin.51 It is as active as cefoxitin against B. fragilis but is less active against other strains
in the B. fragilis group. Unlike cefoxitin, cefotetan is active against H. influenzae. Cefotetan has
proved effective and safe in a variety of clinical situations, including gynecologic infections and
surgical prophylaxis.52
Cefprozil is an oral agent whose spectrum of activity includes gram-positive and gram-negative
pathogens. It has achieved good results in patients with pharyngitis or tonsillitis. 53
Loracarbef is an oral agent of the carbacephem class that is active in vitro against the common
pathogens associated with skin infections, otitis media, sinusitis, bronchopulmonary infections, and
urinary tract infections.54
Third-Generation Cephalosporins
In the third-generation cephalosporins, activity against gram-positive cocci is replaced by broader
gram-negative coverage. This development is illustrated by susceptibility testing done on S. aureus:
the MIC of first-generation cephalosporins is 1 g/ml, that of second-generation cephalosporins is 2
g/ml, and that of third-generation cephalosporins is 3 g/ml. Third-generation cephalosporins are
more active against the enteric gram-negative bacilli covered by first- and second-generation
cephalosporins. Their spectrum of activity includes Serratia and Citrobacter. They are also highly
active against H. influenzae and N. gonorrhoeae and moderately active against P. aeruginosa and
some anaerobes. At first, the third-generation cephalosporins seemed capable of providing the same
spectrum of activity as the aminoglycosides but without their inherent toxicity; however, they have
failed to gain wide popularity in the treatment of high-risk patients or patients with extensive
infections. The reasons for this failure include their incomplete spectra of activity against the range of
organisms likely to be encountered in polymicrobial infections, their unexpected agent-specific
toxicity, their suboptimal pharmacokinetic properties, and their high propensity for inducing
resistance.
Cefixime, an orally absorbed iminomethoxyaminothiazolyl cephalosporin, inhibits 90% of S.
pneumoniae, H. influenzae, and H. parainfluenzae strains, whether they produce -lactamase or not,
at concentrations of less than 0.25 mg/L. It inhibits 90% of Moraxella catarrhalis strains at
concentrations of less than 1 mg/L.
Ceftibuten is an orally active third-generation cephalosporin that possesses increased potency against
members of the Enterobacteriaceae.55 Generally, it is about 16 times more active than cefuroxime,
cefaclor, cephalexin, or amoxicillin-clavulanate; its activity is comparable to that of cefixime.
Ceftibuten is ineffective against staphylococci and only partially effective against S. pneumoniae. H.
influenzae and Neisseria species, however, are highly susceptible to this agent.
Pharmacokinetics. After I.V. administration, third-generation cephalosporins conform to an open,
two-compartment model, characterized by an initial rapid distribution phase followed by a slower
terminal elimination phase. The relatively long elimination half-lives of many of the newer -lactam
antibiotics make less frequent dosing possible. Most third-generation cephalosporins are primarily
eliminated renally, with two exceptions: cefoperazone and ceftriaxone. Cefoperazone is primarily
eliminated unchanged in the bile, and only about 25% of an administered dose is recovered in the
urine after 24 hours.56 Peak biliary concentrations of cefoperazone approach or exceed 2,000 g/ml
after a 2 g I.V. dose.57 Fifty percent of an administered dose of ceftriaxone is eliminated in the bile;
the rest is eliminated renally. Ceftriaxone elimination is decreased to a small extent in end-stage renal
disease; however, because the drug is normally given every 12 to 24 hours, there is little
accumulation and therefore no need to adjust the dose. In general, third-generation cephalosporins
penetrate most tissue and fluid compartments in amounts that, though variable, usually exceed the
MIC for most susceptible pathogens. Sputum concentrations in the range of 0.3 to 6.0 g/ml are
attained with all the agents, and higher concentrations are found in purulent sputum. Ascitic fluid
concentrations ranging from 2.4 g/ml with ceftizoxime to greater than 60 g/ml with cefoperazone
are seen in patients with peritonitis.58
Concentrations in excess of the MIC for susceptible aerobic and anaerobic organisms (except for B.
fragilis) are achieved in female genital tissue with all these agents. 59 These compounds also appear to
penetrate the prostate, the testes, the ureters, and renal tissue in significant amounts. 60
With each of these agents, therapeutic concentrations can be obtained in the gallbladder wall; these
concentrations may be as high as 60 g/g with cefoperazone. Bone-penetration studies reveal
penetration with each of these agents.61
Clinical Utility. Many studies have compared third-generation cephalosporins in an effort to
establish a superior drug or drug combination for life-threatening infections; most have found no
statistically significant differences. It is important to remember that even if there is a difference in
efficacy between two or more antibiotics, that difference may not be apparent if the study group is
not large enough. For example, if one agent fails in 10% of patients and another in only 5%, a study
group of 250 to 500 patients would be required to show a statistical difference. 62,63 Most comparative
antibiotic trials, however, have reported on fewer than 60 patients and thus have not been able to
pinpoint small differences in efficacy between antibiotics.64 Many studies that find no difference
between two regimens are in fact subject to this type of error.
Fourth-Generation Cephalosporins
Cefepime is an extended-spectrum parenteral cephalosporin that provides coverage against both
gram-positive and gram-negative organisms, including S. aureus and P. aeruginosa. Cefepime, which
is a zwitterion, has a net neutral charge that allows it to penetrate the outer membrane of gram-
negative bacteria faster than third-generation cephalosporins. It is more stable against -lactamases
because of the lower affinity of the enzymes for cefepime when compared with third-generation
cephalosporins. In comparison with third-generation cephalosporins, cefepime appears to be less
likely to induce resistance, because of a lower rate of hydrolysis by -lactamases, a low affinity for
these enzymes, and more rapid permeation into the cell. It has been used to treat patients with
pneumonia, with results comparable to those obtained with ceftazidime. 65 Because of its antibacterial
coverage and proven tissue penetration in acute pancreatitis, cefepime should be studied in patients
with severe acute pancreatitis.66 However, it offers poor coverage against Bacteroides and must be
combined with metronidazole or clindamycin. The combination of cefepime and metronidazole was
found to be equivalent to imipenem in a prospective, randomized study of intra-abdominal
infections.67
Adverse Effects
Cephalosporins are associated with a number of adverse side effects. The adverse reactions
associated with their use are similar to those associated with use of other -lactam compounds, such
as local pain and irritation, hypersensitivity reactions, positive Coombs reaction, leukopenia,
thrombocytopenia, transient abnormalities in liver function enzyme levels, and GI disturbances. 68,69
These reactions are usually mild and reversible, except in those rare patients who manifest life-
threatening hypersensitivity reactions. Cephalosporins may be administered to most patients who are
allergic to penicillin, because only 5% to 15% of penicillin-allergic patients react adversely to
cephalosporins.70 An excellent review of cephalosporin allergy and its treatment has been published. 71

Aminoglycosides
Amikacin (Vial 500 mg/2 ml). 15 mg/BB/hari dlm 2 dosis
Dibekacine (Vial 50,100 mg; Ampul 50 mg/ml, 100 mg/2 ml). Dws 100 mg/hari dlm 2 dosis.
Gentamycine (Amp 80 mg/2 ml). 3-5 mg/BB/hari dlm 3 dosis.
Kanamycine (Vial 1 gr). 1 gr/hari dlm 2 dosis
Netilmicin (Vial 50 mg/2 ml, 100 mg/2 ml 150 mg/1.5 ml; Amp 300 mg/1.5 ml). > 50 kg : 150 mg
2x/hari atau 300 mg/hari. < 50 kg : 100 mg 2x/hari atau 200 mg/hari
Streptomycine (Vial 1 gr, 1.5 gr)
Tobramycine (Vial 160 mg/2 ml). 2-3 mg/BB/hari dlm 3 dosis
Aminoglycosides are composed of two or more amino sugars bound by glycosidic linkage to a central
hexose (aminocyclitol) nucleus. Their highly polar, polycationic structure contributes to their poor GI
absorption and their meager ability to penetrate the blood-brain barrier. They bind irreversibly to the
30S bacterial ribosome and interfere with protein synthesis. Aminoglycosides also disturb calcium
homeostasis and induce cell death as a result of efflux of potassium, sodium, and other essential
bacterial constituents. Unlike most other antimicrobial agents that inhibit protein synthesis,
aminoglycosides are bactericidal.
All aminoglycosides share certain pharmacokinetic properties. Because they are poorly absorbed
when given orally, adequate serum concentrations can be obtained only through parenteral
administration. Protein binding is negligible,72 and the volume of distribution approximates the volume
of the extracellular space.73 In adults with normal renal function, the aminoglycosides have a half-life
of about 2 hours, but there is considerable variation between individual patients. 74 In patients with
deteriorating renal function, the half-life of an aminoglycosides increases, often exceeding 24 hours in
patients with end-stage renal disease.75 The prolonged half-lives of aminoglycosides are substantially
shortened during hemodialysis76; these agents are much less efficiently removed by peritoneal
dialysis.77 The aminoglycosides do not penetrate the blood-brain barrier well, even in patients with
meningeal inflammation.78,79 Drug levels in pulmonary secretions are typically 20% to 40% of serum
levels. Low concentrations of aminoglycosides in purulent fluids are probably related to local
inactivation caused by DNA released from leukocytes 80 and by the low regional pH.
The aminoglycosides are rapidly excreted, primarily by glomerular filtration. Urine concentrations may
be 100 times the serum level in patients with normal renal function. The aminoglycosides accumulate
in the renal cortex; sensitive assay techniques can detect them in urine and serum for up to 10 days
after cessation of therapy.
Streptomycin
Widespread resistance among Enterobacteriaceae has limited the usefulness of streptomycin. At
present, streptomycin is almost always employed in combination with other antimicrobial agents.
With penicillin or vancomycin, streptomycin is used to treat infective endocarditis caused by viridans
streptococci or susceptible enterococcal streptococci. It may also be given in conjunction with other
antituberculous drugs to treat mycobacterial diseases and in conjunction with tetracycline to treat
brucellosis. Streptomycin is used alone in the treatment of tularemia and plague.
Kanamycin
Because of widespread resistance among Enterobacteriaceae and P. aeruginosa, kanamycin is rarely
used today. It is occasionally used as a second-line agent in combination with other antibiotics in the
treatment of tuberculosis.
Gentamicin
Gentamicin is used for serious hospital-acquired infections caused by Enterobacteriaceae and most
strains of P. aeruginosa in institutions in which there is minimal background resistance to this agent
(other Pseudomonas species are predictably resistant to aminoglycosides). Gentamicin is given with
penicillin to treat enterococcal endocarditis and with vancomycin plus rifampin to treat prosthetic
valve endocarditis caused by S. epidermidis.
Tobramycin
Tobramycin closely resembles gentamicin with respect to antimicrobial spectrum and
pharmacokinetics. Tobramycin is more active against some strains of A. calcoaceticus but less active
against S. marcescens. Although tobramycin has slightly greater intrinsic activity against P.
aeruginosa, most gentamicin-resistant strains of this organism are also resistant to tobramycin. The
difference in nephrotoxicity between gentamicin and tobramycin is clinically insignificant. 81-83
Amikacin
Amikacin is a semisynthetic derivative of kanamycin. Its major advantage is its resistance to
aminoglycoside-modifying enzymes, the production of which is the principal mechanism of bacterial
resistance to aminoglycosides. Amikacin may therefore be used against gentamicin-resistant
organisms, and it is clearly the aminoglycoside of choice where gentamicin resistance is prevalent.
Fortunately, no substantial increase in amikacin resistance has been noted, even in medical centers
where it has been used extensively.84
Netilmicin and Sisomicin
Netilmicin, a semisynthetic derivative of sisomicin, is not metabolized by most of the aminoglycoside-
modifying enzymes and therefore is active against some strains of Enterobacteriaceae that are
resistant to gentamicin and tobramycin; however, it is less active against P. aeruginosa. Animal
studies suggest that netilmicin may be less nephrotoxic than other aminoglycosides, 82,85 and human
studies suggest that it is somewhat less likely to exert toxic effects on cranial nerve VIII. 82 Sisomicin
is more active than gentamicin against Enterobacteriaceae and P. aeruginosa, but the nephrotoxicity
it has exhibited in animal studies exceeds that of other aminoglycosides. 86
Adverse Effects
Unlike -lactam antibiotics, aminoglycosides, have a narrow range between therapeutic and toxic
levels and are thus more likely to cause side effects. Their ototoxicity is potentially more significant
than their nephrotoxicity because it is often irreversible. Cochlear toxicity has been reported in 8% to
10% of patients and has been clinically evident in as many as 4% of patients treated with
aminoglycosides for various infections.87 Vestibular toxicity, as manifested by electronystagmographic
changes, has been found in 5% to 10% of patients and has been clinically significant in 1% to 5%. 82
Vestibular toxicity is more frequently associated with streptomycin, gentamicin, and tobramycin,
whereas auditory toxicity is more typical of kanamycin and amikacin. Ototoxicity and vestibular
toxicity are difficult to monitor, particularly in hospitalized patients for whom formal audiometry and
caloric testing may be cumbersome or uncomfortable. Because aminoglycoside-associated auditory
toxicity generally affects the higher frequencies, early bedside detection is difficult. Toxic effects on
cranial nerve VIII seem to be related to advanced age, previous aminoglycoside treatment, and
excessive serum levels.
Aminoglycoside Pharmacokinetics
Peak aminoglycoside concentrations higher than 5 g/ml are associated with improved survival in
patients with gram-negative infections.88,89 With gram-negative pulmonary infections, peak
concentrations of 8 to 10 g/ml are necessary because of poor penetration of aminoglycosides into
the lungs.90,91 It has been shown that a loading dose of gentamicin or tobramycin of 2 mg/kg of lean
body weight cannot guarantee adequate peak concentrations in acutely ill patients. The most likely
explanation for the usually low peak serum concentrations of aminoglycosides in acutely ill patients is
an expanded volume of distribution.92-96 Dosage adjustments based on blood levels should be made
as soon as possible after the beginning of therapy and after the steady state has been reached.
Once-Daily Dosing of Aminoglycosides. Efforts to improve the toxic-to-therapeutic ratio of
aminoglycosides include once-daily dosing schedules and reevaluations of the recommended
therapeutic ranges. In conventional administration of aminoglycosides to patients with normal renal
function, divided doses are administered at 8- to 12-hour intervals. In an effort to improve efficacy
and decrease toxicity and cost, once-daily regimens have been compared with conventional
regimens. In most protocols, the total doses were equivalent in the single and divided-dose regimens.
Two meta-analyses of such trials have concluded that once-daily dosing is as effective as divided
dosing and has a lower risk of toxicity in patients with normal renal function. 97,98 Although most trials
evaluated immunocompetent adults, similar trends were noted for children and for patients with
febrile neutropenia. In elderly patients, however, the high peak serumconcentrations that occur with
once-daily dosing may increase the risk of nephrotoxicity,99 probably because of diminished renal
clearance. There are several excellent reviews of the subject in the literature. 100,101

Tetracyclines
The tetracyclines act against microorganisms by inhibiting protein synthesis; their site of action is the
bacterial ribosome. Resistance to the tetracyclines appears slowly and in a stepwise fashion and is
mediated by plasmids. Plasmids impart resistance by coding for proteins that interfere with active
transport of tetracycline through the cytoplasmic membrane. Microorganisms that acquire resistance
to one tetracycline are usually resistant to the other tetracyclines as well.
At appropriate dosages, peak serum concentrations 1 hour after intravenous administration of
tetracycline, doxycycline, or minocycline are typically 10 to 20 g/ml. The newer semisynthetic
tetracyclines-doxycycline, methacycline, and minocycline-have considerably longer serum half-lives
than the older agents.
Tetracyclines are metabolized by the liver and concentrated in the bile. Biliary concentrations of these
agents are, on average, five to 10 times higher than concurrent plasma concentrations. The
tetracyclines penetrate body tissues well and are capable of entering the CSF even in the absence of
inflammation of the meninges. They readily cross the placental barrier, and relatively high
concentrations are found in human milk.
Tetracyclines are useful in the treatment of sexually transmitted diseases. Tetracyclines are also
effective for the treatment of other chlamydial infections, such as lymphogranuloma venereum,
psittacosis, inclusion conjunctivitis, and trachoma. A tetracycline may also be used in the treatment of
gonococcal infections in patients who are unable to tolerate penicillin G. Other sexually transmitted
diseases that may be treated with tetracyclines are chancroid and granuloma inguinale.
A tetracycline or erythromycin is the agent of choice for the treatment of Mycoplasma pneumoniae
infection. Tetracyclines are also effective against rickettsial infections, tularemia, and cholera; in
patients unable to tolerate penicillin, they may be used to treat actinomycosis. Doxycycline is useful
as prophylaxis against traveler's diarrhea caused by toxicogenic strains of E. coli. Unfortunately, the
widespread use of tetracyclines as additives to livestock feed has resulted in increasing bacterial
resistance to these agents.

Macrolides
Erythromycin (Kaps 250 mg, Kapl 500 mg, Sir 200 mg/5 ml)
Erythromycin is a macrolide that contains a many-membered lactone ring to which one or more
deoxy sugars are attached. Erythromycin and other macrolide antibiotics inhibit protein synthesis
through reversible binding to the 50S ribosomal subunits of susceptible microorganisms.
Erythromycin is well absorbed from the GI tract. The presence of food in the stomach reduces
absorption of the drug, except when it is in the estolate form. 102 Erythromycin is excreted primarily in
the bile; only 2% to 5% of a given dose is excreted in the urine. Concentrations in the bile may be
more than 10 times those in plasma. Erythromycin diffuses readily into most tissues, except for the
brain and the CSF.
Erythromycin is the agent of choice for the treatment of M. pneumoniae and Legionella infections. It
is also effective against infections caused by group A -hemolytic streptococci or S. pneumoniae.
Accordingly, it is the agent of choice for the treatment of community-acquired pneumonia in
nonimmunosuppressed patients who do not require hospitalization and who are allergic to
penicillin.103 In addition, erythromycin may be used to treat gonorrhea and syphilis in patients who
are unable to tolerate penicillin G or tetracycline. The incidence of serious erythromycin-related
adverse effects is low.
Clarithromycin (Kapl 250 mg, Tab 500 mg, Sir 125 mg/5 ml). 500 mg 2 x sehari Azithromycin
(Kaps 250 mg, Kapl 500 mg). 500 mg 1 x sehari selama 3 hari
Clarithromycin and azithromycin are new semisynthetic macrolides that are structurally related to
erythromycin. They inhibit protein synthesis in susceptible organisms by binding to the 50S ribosomal
subunit. Clarithromycin and azithromycin are well absorbed and widely distributed, with excellent
cellular and tissue penetration. Both agents have a broader spectrum of activity than erythromycin
does; in addition, they have fewer GI side effects (a major obstacle to compliance with erythromycin
therapy).
Clarithromycin is several times more active against gram-positive organisms in vitro than
erythromycin, whereas azithromycin is two to four times less potent than erythromycin. Azithromycin
has excellent in vitro activity against H. influenzae; clarithromycin, although less active against H.
influenzae according to standard in vitro testing, is metabolized into an active compound with twice
the in vitro activity of the parent drug. Azithromycin and clarithromycin also are active against some
unexpected pathogens (e.g., Borrelia burgdorferi, Toxoplasma gondii, M. avium complex, and M.
leprae). At present, clarithromycin appears to be the more active of the two against atypical
mycobacteria, giving new hope to surgeons faced with what has become a difficult group of
infections to treat.
Superior pharmacodynamic properties distinguish these new macrolides from the prototypical
macrolide, erythromycin. Azithromycin has a large volume of distribution, and although serum
concentrations remain low, it concentrates readily within tissues, demonstrating a tissue half-life of
approximately 3 days; a 5-day course of therapy will provide therapeutic tissue concentrations for at
least 10 days. These properties allow novel dosing schemes. For instance, azithromycin can be given
once daily for 5 days to treat respiratory tract and soft tissue infections, and administration of a
single 1 g dose of azithromycin can effectively treat Chlamydia trachomatis genital infections; these
more convenient dosing schedules improve patient compliance.
Dirithromycin
Dirithromycin is an oral macrolide antibiotic with an antibacterial spectrum similar to that of
erythromycin; it can be administered once daily but has no other advantages over erythromycin. The
drugs produce similar GI side effects, and dirithromycin is substantially more expensive.
Clindamycin (Kaps 150, 300 mg). 150-300 mg/6 jam
Clindamycin is a 7-deoxy-7-chloro derivative of lincomycin that consists of an amino acid attached to
a sulfur-containing octose. Clindamycin binds exclusively to the 50S subunit of bacterial ribosomes
and suppresses the synthesis of protein. Clindamycin, erythromycin, and chloramphenicol all act at
the same site, and the binding of one of these antibiotics to the ribosome may inhibit the binding of
the others. Plasmid-mediated resistance to clindamycin has been reported in B. fragilis; this may be
caused by methylation of bacterial RNA found in the 50S ribosomal subunit. 104 Peak serum
concentrations 1 hour after intravenous administration of a 600 mg dose are approximately 10 to 12
g/ml. Clindamycin is metabolized by the liver and excreted in an inactive form in the urine. It readily
penetrates most body tissues but not the CSF.105
Clindamycin is active against B. fragilis and other anaerobic microorganisms and is useful in the
treatment of patients with intra-abdominal, pelvic, and pulmonary infections. It is associated with a
modest number of adverse effects.

Chloramphenicol
Chloramphenicol is unique among antibiotics in that it contains a nitrobenzene moiety and is a
derivative of dichloroacetic acid. Like clindamycin, it inhibits bacterial protein synthesis by binding
reversibly to the 50S ribosomal subunit, thus keeping the amino acid-containing end of aminoacyl-
transfer RNA (tRNA) from binding to the ribosome. Chloramphenicol is rapidly and completely
absorbed from the GI tract, and absorption is not impaired by concomitant ingestion of food or
administration of antacids. It is inactivated in the liver by glucuronyl transferase. Chloramphenicol
and its metabolites are excreted rapidly in the urine. About 80% to 90% of a dose is excreted in this
way, about 5% to 10% of which is in the biologically active form. The drug penetrates well into all
tissues, including the brain; it also penetrates well into the CSF and the aqueous humor.
Because of the risk of serious or fatal bone marrow toxicity, chloramphenicol should be used only
against those infections for which the benefits of its use outweigh the risks of its potential toxicity. It
still plays a major role in the treatment of typhoid fever, although plasmid-mediated resistance of S.
typhi to chloramphenicol has been reported. Chloramphenicol is effective therapy for bacterial
meningitis and brain abscesses caused by susceptible microorganisms; in conjunction with penicillin,
it is effective empirical therapy for brain abscesses.

Vancomycin (Vial 500 mg). 500 mg/6 jam

Vancomycin is a narrow-spectrum antibiotic derived from Nocardia orientalis. Vancomycin exerts its
bactericidal effect by inhibiting the biosynthesis of the major structural cell wall polymer,
peptidoglycan.106 Vancomycin is about 55% protein bound. Its activity is not significantly affected by
pH values between 6.5 and 8.0. It is poorly absorbed from the GI tract. Because patients invariably
experience pain after intramuscular injections, parenteral administration is limited to the intravenous
route. Vancomycin is primarily excreted by the kidneys; about 80% to 90% of the dose is eliminated
in a 24-hour period. Its half-life is approximately 6 hours in patients with normal renal function. In
anuric patients, the half-life may be prolonged to approximately 7 days. 107 Vancomycin is not
removed by hemodialysis or peritoneal dialysis.
Vancomycin is mainly effective against gram-positive organisms. No cross-resistance has been
demonstrated between vancomycin and other antibiotics, and resistance is uncommon. Vancomycin,
given alone, is the agent of choice in the treatment of methicillin-resistant S. aureus infections.108,109
Some strains of methicillin-resistant S. aureus, however, are resistant to vancomycin. If vancomycin
therapy is ineffective against severe infections caused by such strains, the addition of either an
aminoglycoside or rifampin, or both, should be considered. Several reports have indicated that
vancomycin is not bactericidal for enterococci.110 Vancomycin is indicated for other serious infections
caused by organisms with multiple antibiotic resistance, such as CSF shunt infections and prosthetic
valve infection caused by S. epidermidis or Corynebacterium diphtheriae.111 It is the agent of choice
for infections caused by penicillin-resistant group JK corynebacteria112 and is uniformly active against
rare, multiply resistant strains of S. pneumoniae.113 Given orally, vancomycin is also the agent of
choice for C. difficile-associated enterocolitis,114 although less expensive agents, such as bacitracin115
and metronidazole,116 may be as effective.
Anaphylactoid reactions to vancomycin have been reported since the earliest clinical trials. Such
reactions can occur with the first dose; signs and symptoms range from mild pruritus to dramatic
hypotension and cardiovascular arrest. The rapid intravenous infusion of vancomycin can cause a
peculiar reaction consisting of pruritus; an erythematous or maculopapular rash involving the face,
neck, and upper torso; and possible hypotension.

Metronidazole (Tab 250,500 mg. Lar infus 500 mg/100 ml). Disentri, Abses hati : 750 mg/8 jam
selama 5-10 hari; Inf bakt an aerob : 7.5 mg/BB/6 jam maks 4 gr/hari selama 7-10 hari. Lar infus
15 mg/BB dilanjutkan dgn dosis pemeliharaan 7.5 mg/BB/6 jam maks 4 gr/hari selama 7-10 hari
Metronidazole acts by disrupting bacterial DNA and inhibiting nucleic acid synthesis 117; it is
bactericidal against almost all anaerobic gram-negative bacilli, including B. fragilis, and against most
Clostridium species. Although true anaerobic streptococci are generally susceptible to it,
microaerophilic streptococci as well as Actinomyces and Propionibacterium species are often resistant.
Metronidazole is excellent for anaerobic infections of the abdomen and pelvis. For serious anaerobic
infections, the drug is administered intravenously; a loading dose of 15 mg/kg is given, followed by
7.5 mg/kg every 6 hours until the patient is well enough to take an oral dosage of 7.5 mg/kg every 6
hours. The dosage need not be reduced in azotemic patients, but it should be reduced in patients
with hepatic insufficiency. Because of its bactericidal action and excellent tissue penetration,
intravenous metronidazole may be the treatment of choice for B. fragilis endocarditis and central
nervous system infections, both of which are uncommon. When metronidazole is administered orally,
it is well absorbed and is widely distributed in body tissues, including those of the CNS.
Side effects of metronidazole include dry mouth (associated with a metallic taste) and nausea.
Concurrent use of alcohol may cause a reaction similar to that produced when alcohol is ingested
after taking disulfiram. Neurologic symptoms, including peripheral neuropathy and encephalopathic
reactions, and neutropenia are uncommon. Pancreatitis has been reported, 118 but alternative drugs
are available.

Carbapenems
Imipenem (Vial 500 mg). 1-2 gr/hari dlm 3-4 dosis. Ditingkatkan menjadi 4 gr/hari atau 50
mg/BB/hari
Meropenem (Vial 500 mg, 1 gr). 500 mg - 1 gr/8 jam. Meningitis 2 gr/8 jam
Imipenem and meropenem were the first carbapenems available for clinical use in the United States;
the third, ertapenem, was released in 2002. Like other -lactam antibiotics, they are bactericidal and
act by inhibiting bacterial cell wall synthesis. 119 Three properties account for the extraordinarily broad
antibacterial spectrum of the carbapenems: there is no permeability barrier excluding the drugs from
bacteria; they have high affinity for penicillin-binding protein 2, which is a crucial component of cell
wall structure; and they are extremely resistant to hydrolysis by -lactamases.
Carbapenems are extraordinarily active against gram-negative bacteria. Whereas imipenem tends to
be more active against gram-positive cocci, meropenem appears to be more active against gram-
negative bacilli. Virtually all Enterobacteriaceae are susceptible. Haemophilus and Neisseria species
are also susceptible to carbapenems but at concentrations somewhat higher than those of third-
generation cephalosporins. Acinetobacter, which is resistant to most other -lactam antibiotics, is
susceptible to imipenem and meropenem, as are Serratia, Salmonella, Citrobacter, Yersinia, and
Brucella species. Gram-negative anaerobes, including B. fragilis, are susceptible. P. aeruginosa is also
susceptible, but some resistant strains have emerged during therapy; as a result, imipenem or
meropenem should probably be combined with a second antipseudomonal drug when they are used
to treat serious pseudomonal infections. Certain nosocomial pathogens, such as Stenotrophomonas
maltophilia and P. cepacia, are resistant, as are Flavobacterium species.
Imipenem is extensively degraded in the renal tubule, which results in low urinary levels of the drug.
This drawback can be prevented by using cilastatin, an inhibitor of the brush-border enzyme
dehydropeptidase-1. Cilastatin also appears to prevent the tubular damage that is occasionally
observed in animals given imipenem alone in high doses. For clinical use, imipenem and cilastatin are
administered simultaneously in equal doses.
Meropenem is pharmacologically similar to imipenem except that it is not susceptible to degradation
by dehydropeptidase; as a result, it can be administered without cilastatin. About 70% of both
meropenem and imipenem is excreted in the urine; the dosage should be reduced in azotemic
patients. Like imipenem, meropenem is active against most clinically active gram-positive and gram-
negative bacteria, including anaerobes; however, neither drug is active against methicillin-resistant
staphylococci or E. faecium. Resistant strains of P. aeruginosa have emerged during therapy with
each drug.
The clinical efficacy and toxicity of meropenem are similar to those of imipenem, except that
meropenem appears more likely to be effective in meningitis and less likely to cause seizures.
Because the newest carbapenem, ertapenem, has a longer half-life than the other members of the
group, it can be administered in a single daily intravenous dose. 120 Like the other carbapenems,
ertapenem is excreted in the urine, and the dosage should be reduced in azotemic patients. The
antibacterial spectrum of ertapenem is similar to that of meropenem, except that Pseudomonas and
Acinetobacter strains are less susceptible, and E. faecalis is resistant.121 Ertapenem appears effective
against community-acquired pneumonias, intra-abdominal infections, complicated skin and soft tissue
infections, and complicated urinary tract infections, but experience is limited.
The carbapenems have broader antibacterial spectrums than any other -lactam antibiotics. They are
active against most gram-positive bacteria-both aerobes and anaerobes. Exceptions include some
enterococci; many E. faecalis strains are sensitive to imipenem and meropenem but not ertapenem,
and most E. faecium strains are resistant to all three drugs. Some diphtheroids are resistant.
Although most S. aureus strains are very sensitive, the susceptibility of methicillin-resistant S. aureus
and coagulase-negative staphylococci is highly variable. Methicillin-resistant S. aureus and Listeria
exhibit carbapenem tolerance. Finally, some strains of C. difficile are resistant.
Ertapenem has a spectrum of activity similar to that of meropenem, except that Pseudomonas and
Acinetobacter strains are much less susceptible, and E. faecalis is resistant.
The safety of carbapenems seems comparable to that of other -lactam antibiotics. Nausea and
vomiting, local pain at injection sites, and hypersensitivity are the most common reactions. Seizures,
although unusual, are a potential concern with imipenem; they have been observed in 0.9% of
patients who have received the drug; risk factors for seizure include excessive dosages of the drugs,
preexisting CNS lesions, epilepsy, and renal insufficiency. Meropenem is less likely to provoke
seizures.119 Transient elevations of liver enzymes and leukopenia can occur in patients who are given
carbapenems. Antibiotic-associated pseudomembranous colitis has occurred.
Because the structure of the carbapenems resembles that of the penicillins and cephalosporins, there
is potential for cross-reactivity in patients allergic to other -lactam antibiotics. Clinical experience in
this situation is limited, but it appears prudent to avoid carbapenems in patients with anaphylactic
sensitivity to -lactam drugs and to use them with caution in patients with milder allergies to
penicillins or cephalosporins.122
Carbapenems have been used successfully in patients with pneumonia, intra-abdominal infections,
urinary tract infections, endocarditis, bacteremia, osteomyelitis, cellulitis, and febrile neutropenia. The
broad spectrum and apparent low toxicity of carbapenems is impressive, but they should be used
selectively and with restraint.
Monobactams
The monobactams are monocyclic -lactam antibiotics that lack the thiazolidine ring found in
penicillins and the dihydro-thiazine ring found in cephalosporins. Although there are several
monobactams under investigation, only aztreonam has been approved for clinical use in the United
States. It has been evaluated in open and comparative studies against a number of agents currently
used to treat infections.123,124 It inhibits only aerobic gram-negative species. It can be administered
two or three times daily. It is a poor hapten and has been successfully administered to small numbers
of patients with proven allergy to penicillins and cephalosporins. 125
Aztreonam has been shown to be effective against bacteremia caused by E. coli, K. pneumoniae, P.
mirabilis, S. marcescens, P. aeruginosa, Enterobacter species, Proteus species, and Providencia
species.126,127 It has also been used, alone or in combination with clindamycin, to treat gram-negative
aspiration pneumonia, with results comparable or superior to those obtained with an aminoglycoside-
clindamycin combination.128,129
Aztreonam has been advocated as directed therapy to obviate more toxic drugs. It seems possible
that aztreonam could replace aminoglycosides in many situations in which they are combined with
other agents.
-Lactamase Inhibitors
A novel approach to antibacterial chemotherapy is the use of -lactamase inhibitors with -lactam
agents. Clavulanate has been combined with both amoxicillin and ticarcillin. Because neither
clavulanate nor sulbactam inhibits the -lactamases that function primarily as cephalosporinases in
Enterobacter, Serratia, and P. aeruginosa infections, the addition of clavulanate or sulbactam does
not enhance ticarcillin's activity against Pseudomonas. The principal use of amoxicillin-clavulanate has
been in the treatment of upper respiratory tract infections caused by -lactamase-producing H.
influenzae or M. catarrhalis. Ticarcillin-clavulanate has been used to treat pneumonia caused by P.
aeruginosa and mixed -lactamase-producing flora as well as intra-abdominal infections and
gynecologic infections in which the infecting organisms often possess -lactamases. In febrile
neutropenic patients, its efficacy is comparable to that of other agents, but superinfections may be a
problem.130,131 Because some strains of K. pneumoniae are not adequately inhibited by ticarcillin-
clavulanate, addition of an aminoglycoside would be appropriate in neutropenic patients. Sulbactam
has also been combined with ampicillin.
Clavulanate, sulbactam, and tazobactam have all been combined with piperacillin in an attempt to
enhance the agent's activity against -lactamase-producing bacteria. 132,133 Tazobactam enhances the
spectrum of action and potency of piperacillin to a greater extent than sulbactam does. Although
piperacillin-clavulanate is more potent than piperacillin-tazobactam, the two combinations are
effective against virtually the same spectrum of resistant -lactamase-producing gram-negative
organisms. Piperacillin-tazobactam is more potent than ticarcillin-clavulanate and is effective against
a wider range of gram-negative enteric organisms. Combinations of piperacillin with tazobactam or
clavulanate have a broader spectrum of activity than combinations of piperacillin with sulbactam
against bacteria that produce characterized plasmid-mediated enzymes of clinical significance. In
particular, piperacillin-tazobactam and piperacillin-clavulanate inhibit TEM-1, TEM-2, and SHV-1 -
lactamases, but piperacillin-sulbactam does not. In mice infected with -lactamase-producing E. coli,
K. pneumoniae, P. mirabilis, and S. aureus, both tazobactam and clavulanate have provided greater
enhancement of the therapeutic efficacy of piperacillin than sulbactam has. Reviews of the TEM-type
-lactamases134 and the piperacillin-tazobactam combinations135 have been published.

Quinolones
Moxifloxacin (400 mg). 400 mg/hari
Ciprofloxacin (250,500 mg; Lar infus 200 mg).
Ofloxacin (200,400 mg). 200-600 mg/hari dlm 1-3 dosis terbagi
Levofloxacin (Tab/Vial 250,500mg). 250-500 mg 1 x sehari
Pefloxacin (Tab/Amp/Lar infus 400 mg). 400 mg 2 x sehari
Lincomycin (500 mg). 500 mg 3 x sehari
Gatifloxacin (400 mg). 400 mg/hari
Sparfloxacin (200 mg). 400 mg dosis tunggal lalu 200 mg/hari selama 10 hari
Norfloxacin (400 mg). 200-400 mg 2 x sehari
The addition of a fluorine group and a piperazine substituent to the first quinolones has greatly
improved the antibacterial spectrum of this class of drugs; the addition of a methyl group on the
piperazine ring appears to further enhance the bioavailability of these compounds.
The fluoroquinolones are bactericidal compounds that act by inhibiting DNA gyrase, the bacterial
enzyme responsible for maintaining the supertwisted helical structure of DNA; DNA topoisomerase IV
is a secondary target.136 The fluoroquinolones rapidly kill bacteria, probably by impairing DNA
synthesis and possibly by mechanisms involving the cleaving of bacterial chromosomal DNA. Bacterial
resistance to the fluoroquinolones depends on a change in their DNA gyrase. Bacterial strains that are
resistant to one fluoroquinolone tend to be cross-resistant to related compounds; such resistance is
usually mediated by chromosomes, but plasmid-mediated resistance raises the possibility of
transferable resistance.
The fluoroquinolones are broad-spectrum antimicrobials. Most enteric gram-negative bacilli, including
E. coli, Proteus, Klebsiella, and Enterobacter, are highly susceptible; common GI pathogens, such as
Salmonella, Shigella, and Campylobacter species, are also very sensitive. Other gram-negative
organisms that are killed by low concentrations of the fluoroquinolones are N. gonorrhoeae and N.
meningitidis, H. influenzae, P. multocida, M. catarrhalis, and Y. enterocolitica. Acinetobacter and
Serratia are somewhat less susceptible. P. aeruginosa is susceptible to ciprofloxacin and
trovafloxacin; ofloxacin and levofloxacin are moderately active, but the other quinolones are not
effective. P. cepacia and S. maltophilia are quinolone-resistant. Ciprofloxacin is the drug of choice for
Bacillus anthracis; oflaxacin and levofloxacin are also active in vitro. 137 Among gram-positive cocci,
methicillin-sensitive strains of S. aureus and coagulase-negative staphylococci are usually susceptible
to quinolones, but methicillin-resistant S. aureus and enterococci are not. Lomefloxacin is not active
against pneumococci and other streptococci; ciprofloxacin and ofloxacin are moderately active; and
levofloxacin, sparfloxacin, gatifloxacin, moxifloxacin, and trovafloxacin are highly effective, even
against non-penicillin-sensitive pneumococci. Even fastidious intracellular pathogens can be inhibited
by the quinolones; Chlamydia, Mycoplasma, Listeria, Legionella, and M. tuberculosis are in this
category. Only trovafloxacin is highly active against anaerobes. Levofloxacin, gatifloxacin,
moxifloxacin, and sparfloxacin demonstrate some activity against anaerobes, but the other
quinolones do not. C. difficile is resistant to quinolones.
The fluoroquinolones are rapidly absorbed from the GI tract. Penetration into body fluids and tissues
is generally excellent; therapeutic concentrations are readily achieved in blister fluid, bile, urine,
saliva and sputum, bone, and muscle. Excellent concentrations of these drugs are achieved in the
prostate, and stool levels are extraordinarily high. The fluoroquinolones appear to penetrate the CSF
in the presence of meningeal inflammation, 138 but experience in treating meningitis is scant.
Although serum protein binding is modest, the fluoroquinolones have long serum half-lives, which
range from 3 to 4 hours for ciprofloxacin to 12 hours for moxifloxacin. Most fluoroquinolones are
eliminated by glomerular filtration and tubular secretion, and their dosages should be reduced in the
presence of moderately severe renal failure. Trovafloxacin and moxifloxacin, however, are excreted
chiefly by the liver.
The fluoroquinolones appear to be very well tolerated, with mild GI side effects (nausea, vomiting, or
anorexia), CNS side effects (light-headedness, dizziness, somnolence, or insomnia), or rash occurring
in fewer than 10% of treated patients. Lome-floxacin and sparfloxacin can cause phototoxicity. Less
common side effects include allergic intestinal nephritis, pseudomembranous colitis, and neutropenia.
Sparfloxacin and moxifloxacin may cause QT interval prolongation and should not be used by patients
who have conditions or are using drugs known to prolong the QT interval or predispose to
arrhythmias.139 Tendinitis has been reported; in severe cases, it has resulted in rupture of the
tendons of the shoulder and hand and the Achilles tendon. Crystalluria has been reported after the
use of very large doses. Because fluoroquinolones have caused arthropathy in young animals, these
drugs should be avoided in children and in women who are pregnant or nursing. Ciprofloxacin is safe
in long-term use; there is less long-term experience with the other fluoroquinolones.
The fluoroquinolones have been useful clinically in a variety of infections, including urinary tract,
genital, prostatic, GI, respiratory tract, soft tissue, and bone infections. Because of its excellent
activity against anaerobes, trovafloxacin was considered useful in intra-abdominal and pelvic
infections, but concerns about serious hepatotoxicity have restricted its use to infections deemed life-
or limb-threatening and for patients in whom the benefit of trovafloxacin outweighs its potential risks.
If it must be used, liver function must be monitored carefully.
The fluoroquinolones, administered in various regimens ranging from a single dose to 5 days of
therapy, are effective in preventing and treating traveler's diarrhea and shigellosis. They have been
highly effective in the treatment of typhoid fever. However, prolongation of the carrier state limits
their role in nontyphoidal Salmonella enteritis, and the development of resistance limits their role in
Campylobacter enteritis. The fluoroquinolones may be useful in the empirical treatment of severe
community-acquired gastroenteritis, particularly if treatment is started early.
Because of their extraordinarily broad antimicrobial activity, their favorable pharmacokinetics, and
their low toxicity,140 the fluoroquinolones are extremely valuable new drugs. Like all antimicrobials,
however, fluoroquinolones should be used judiciously, especially in view of new concerns about
resistance141,142 and toxicity and practical considerations about expense.
Adverse Effects
Adverse reactions to the quinolones are estimated to occur in 4% to 8% of cases. 143 Most such
reactions are not severe: cessation of therapy has been necessary in only about 1% to 2% of
patients, and in all cases, the reactions have been reversible. The most common adverse effects are
gastrointestinal-namely, nausea, vomiting, and diarrhea. The next most common are CNS effects,
which include dizziness, headache, insomnia, hallucinations, agitation, and seizures. (The last three
have been attributed to coadministration of enoxacin and theophylline.) Other effects include skin
rash, pruritus, photosensitivity (with ofloxacin and pefloxacin), and mild alterations in hematologic
and biochemical laboratory values.

Streptogramins
Quinupristin and dalfopristin are two structurally distinct streptogramins that bind to separate sites on
the bacterial 50S ribosomal subunit; they thus act synergistically to inhibit protein synthesis. The
drugs are marketed together in a 30:70 ratio as Synercid.144
Although quinupristin-dalfopristin is active against a variety of bacteria, its major use is in the
treatment of serious infections caused by vancomycin-resistant strains of E. faecium. The drugs may
also be useful in occasional vancomycin-intolerant patients with severe infections caused by
methicillin-resistant S. aureus or coagulase-negative staphylococci. Resistance to quinupristin-
dalfopristin is emerging.145
Quinupristin-dalfopristin is administered intravenously; because of a high incidence of phlebitis, a
central line should be used. Other adverse effects include arthralgias and myalgias, which may be
severe, and elevated bilirubin levels. The antibiotic may elevate levels of drugs that are metabolized
by the hepatic enzyme CYP3A4; nifedipine and cyclosporine are examples.
The usual dose of quinupristin-dalfopristin is 7.5 mg/kg given intravenously over 1 hour every 8
hours. The drug is metabolized by the liver, so no dose reduction is required in azotemic patients.
Quinupristin-dalfopristin is extremely expensive.

Oxazolidinones
In 2000, linezolid became the first member of the oxazolidinone class to be approved for clinical use
in the United States.146 Linezolid is a synthetic antibiotic that inhibits protein synthesis by binding to a
site on the bacterial 23S ribosomal RNA of the 50S subunit, thus preventing function of the initiation
complex that is required for ribosomal function.147 Because no other antibiotic acts in this way,
bacteria that have developed resistance to other ribosomally active antimicrobials do not display
cross-resistance to linezolid.
Linezolid is active against nearly all aerobic gram-positive cocci at concentrations of 4 mg/ml or
less,148 including penicillin-resistant pneumococci, methicillin-resistant staphylococci, and vancomycin-
resistant enterococci; however, resistant strains have been isolated. 149 The drug is bacteriostatic
against staphylococci and enterococci, but it is bactericidal against most streptococcal strains.
Linezolid is also active against L. monocytogenes, M. catarrhalis, H. influenzae, N. gonorrhoeae,
Bordetella pertussis, Pasteurella multocida, and Nocardia species. C. difficile, C. perfringens, and
Bacteroides species are susceptible, but enteric gram-negative bacilli and Pseudomonas species are
not.150
Intravenous and oral preparations of linezolid are available; the oral form is absorbed rapidly and
completely with 100% bioavailability that is not affected by meals. Linezolid is widely distributed in
well-perfused tissues. Nonrenal mechanisms account for 65% of the drug's clearance. Patients with
mild to moderate renal or hepatic insufficiency do not appear to require reduced doses; linezolid is
removed by hemodialysis.
Linezolid is well tolerated. Adverse effects have been reported in about 2.8% of all patients 150;
nausea, vomiting, and headaches are the most common side effects, but reversible marrow
suppression, including thrombocytopenia, leukopenia, and anemia, can also occur. Because linezolid
is a reversible inhibitor of monoamine oxidase, patients taking linezolid may experience an
exaggerated hypertensive response to sympathomimetic agents. In addition to avoiding
decongestants, patients taking linezolid should avoid foods or beverages with a high tyramine
content; aged cheeses, air-dried meats, tap beer, red wine, soy sauce, and sauerkraut are examples.
Monoamine oxidase inhibitors and other antidepressants should not be administered during linezolid
therapy.
Linezolid has been used successfully in the therapy of multidrug-resistant gram-positive bacterial
infections.146,147,151 The drug is approved for vancomycin-resistant enterococcal infections and for
pneumonias and skin and soft tissue infections. The usual dosage is 600 mg every 12 hours (p.o. or
I.V.); uncomplicated skin and soft tissue infections may be treated with 400 mg every 12 hours.
Linezolid is a very promising new antimicrobial agent, but clinical experience is still limited. Although
resistance is uncommon, it can develop during therapy. As a result, it may be wise to reserve this
unique antibiotic for serious infections in hospitalized patients; in particular, linezolid should be useful
for infections caused by methicillin-resistant S. aureus or coagulase-negative staphylococci that do
not respond to vancomycin, for penicillin-resistant pneumococcal infections that do not respond to
other agents, and for vancomycin-resistant enterococcal infection. An excellent general review of the
use of linezolid in serious gram-positive infections has been published. 152

Fosfomycin
Fosfomycin is a broad-spectrum antibiotic that inhibits cell wall synthesis in infections caused by E.
coli, S. saprophyticus, and many other common urinary tract pathogens.153 Although it has been used
parenterally in Europe for many years, the drug is approved in the United States only for the single-
dose treatment of uncomplicated urinary tract infections in women. A 3 g dose is generally effective
and well tolerated; diarrhea is the most common side effect. Because of its activity against
vancomycin-resistant enterococci (VRE), fosfomycin may be a useful alternative to linezolid and
quinupristin-dalfopristin in the treatment of VRE infections in certain clinical situations (e.g.,
uncomplicated urinary tract infections). In addition, the use of fosfomycin could limit the use of
newer agents, thus reducing the chance of development of further resistance in the enterococci. 154

Concerns for the Future

Despite a century of often-successful prevention and control efforts, infectious diseases remain an
important global problem in public health, causing over 13 million deaths each year. Changes in
society, technology, and the microorganisms themselves are contributing to the emergence of new
diseases, the reemergence of diseases once controlled, and the development of antimicrobial
resistance. Two areas of special concern in the 21st century are food-borne disease and antimicrobial
resistance. The effective control of infectious diseases in the new millennium will require effective
public health infrastructures that will rapidly recognize and respond to outbreaks and will prevent
emerging problems.
Over the past 40 years, the search for new antibiotics has been largely restricted to well-known
classes of compounds that are active against a standard set of drug targets. Although many effective
compounds have been discovered, insufficient chemical variability has been generated to prevent a
serious escalation in clinical resistance. Recent advances in genomics have provided an opportunity to
expand the range of potential drug targets and have facilitated a fundamental shift from direct
antimicrobial screening programs toward rational target-based strategies. The application of genome-
based technologies such as expression profiling and proteomics will lead to further changes in the
drug discovery paradigm by combining the strengths and advantages of both screening strategies in
a single program.