Document 6493224

How to choose among
the myriad of
antibiotics?
Considerations for the betalactams, aminoglycosides and
fluoroquinolones.
HO Pak Leung 何栢良醫生
MBBS, FACP, MRCP, MRCPath, FRCPA, FHKCPath, FHKAM
Draft as of Aug 2004
www.HoPakLeung.com
We seek to improve the quality of this compendium. If you have
comments or suggestion on this draft, please email to [email protected]
NOTICE
While every effort has been made to ensure the accuracy of the
information contained in the compendium, the possibilities of human
errors or changes in medical practice/knowledge exists. Reader should
therefore check the latest product information of drugs (especially for
new and infrequently used drugs) or tests before they are used. The
most recent recommended clinical practice and normal values of
individual laboratories should also be taken into account.
This publication contains information relating to
general principles of medical care, which should not be
construed as specific instructions for individual patients.
Manufacturers' product information and package inserts
should be reviewed for current information,
including contraindications, dosages and precautions.
3
Contents
1
Beta-lactams
3
2
Aminoglycosides
15
3
Quinolones
26
4
– Beta-lactams –
1
Beta-lactams
INTRODUCTION
β-lactams belong to a group of antibiotics that exert their antibacterial effect by
inhibition of enzymes (transpeptidase and decarboxylase) that are critical for cell
wall synthesis. They have in common a β-lactam ring that form part of the nucleus
of the molecule. Classification of the β-lactams was based traditionally on the
chemical structures and is complex. For practical purposes, the major groups of βlactams include the penicillins, cephalosporins, β-lactam/β-lactamase inhibitor
(BLBLI) and carbapenems. Two other groups, cephamycins (e.g. cefoxitin) and
monobactams (e.g. aztreonam) are used less frequently in Hong Kong.
The bottom line
With few exceptions, efficacy of the agent in question in clinical trials was almost
uniformly “equal” to that of comparators. The question as to whether one βlactam performs better than another remains largely unanswered. Most antibiotic
trials (typically with <500 subjects in each arm) simply lack power to show small
difference in the range of 5−10%.
Overall, the β-lactams have good safety profile. The main factors to be considered
in choosing a β-lactam include the drug’s antibacterial spectrum, pharmacokinetic
(PK) properties, impact on the microbial ecology (i.e. likelihood in selecting
resistant organisms) and cost. All β-lactams exhibit time-dependent mode of
antibacterial activity.[1] Once the drug concentration is higher than the MIC of the
organism, the rate and extent of microbial killing depend on the time of exposure.
Higher concentrations do not kill bacteria faster.
The pharmacology of antibiotic therapy can be divided into two major
components:
Pharmacokinetics (PK): interaction between man and antibiotic, such as
absorption, distribution and elimination of drugs
Pharmacodynamics (PD): interaction between antibiotic and bacteria, such as
concentration-dependent or time-dependent killing.
Accordingly, the application of pharmacodynamics to antibiotic therapy has
generated parameters (commonly known as PK/PD parameters) that are
increasingly considered to be relevant for choosing and using antibiotics.
The “time above MIC” or T>MIC is a PK/PD parameter that measures the time
that serum drug concentration stay higher than the MIC of the organism (Figure).
Many studies have showed that maximal efficacy can be ensured if the T>MIC is
at least 40−60% of the dosing interval (~60% for Gram negative bacteria and ~40%
for Gram positive bacteria). In serious infections or those that were caused by the
5
– Beta-lactams –
less susceptible bacteria, β-lactam dosing that maximizes the T>MIC and hence
the efficacy will be preferred.
Figure. Common antibiotic pharmacokinetic (PK) and minimal inhibitory
concentration (MIC) pharmacodynamic (PD) relationships.
Important note for the β-lactam prescribers:
Over 30 different β-lactam compounds are available in Hong Kong. If you do not
belong to the species of “walking encyclopedia”, it is wise to just remember only
one prototype agent in each group. Try to become familiar with the properties of
only the prototype in a given group and use it properly.
TIPS IN CHOOSING AMONG THE PENICILLINS
Antimicrobial spectrum
Four groups of penicillins can be distinguished according to their spectrum (Table
1).
6
– Beta-lactams –
Table 1. Spectrum of penicillins.
Group
Examples
Streptococci
MSSA
Enterococcus,
Listeria
E. coli
P.
aeruginosa
Antistreptococcal
penicillin
Penicillin
G,
penicillin V
+++
0
++
0
0
Antistaphylococcal
penicillins
Cloxacillin
+
+++
0
0
0
Aminopenicillins
Ampicillin,
amoxicillin
++
0
+++
++
0
Antipseudomonal
penicillins
Ticarcillin,
piperacillin
+ to ++
0
+ to ++
++
++
MSSA, methicillin-sensitive Staphylococcus aureus; Streptococci include S.
pneumoniae, S. pyogenes and other streptococci.
Clinical applications of the PK data
1.
The anti-streptococcal and anti-staphylococal penicillins has very short
half-lives (0.5 h). Serum level of these agents decreased rapidly, even after
high dose. To meet the PK/PD target (i.e achieving T>MIC for 40% dosing
interval), they need to be given at least 4 times daily. For serious
infections (e.g. streptococcal endocarditis), dosing at 4 hourly intervals is
preferred.
2.
The aminopenicillins and anti-pseudomonal penicillins have longer halflives and can be given less frequently. Their serum T½ were: 1.2 h for
ampicillin/amoxicillin; 1.1 h for ticarcillin and 1.2 h for piperacillin. The
pharmacokinetic of piperacillin is dose dependent. The clearance of
piperacillin is non-linear because of saturation of biliary excretion. Serum
T½ of piperacillin increases with large dose and hence allowing longer
dosing intervals. Nonetheless, the MICs of ticarcillin and piperacillin
against P. aeruginosa are 2-4 times higher than that for E. coli. If they are
used for therapy of P. aeruginosa, more frequent dosing (q6h for
piperacillin and q4-6h for ticarcillin) will be required to meet the PK/PD
target (T>MIC for 60% dosing interval).
3.
Where oral administration is appropriate, if higher concentrations are
desired because of difficulty-to-treat infections (e.g. osteomyelitis),
consider the following in IV-to-PO switch:
(a)
IV ampicillin to PO amoxicillin instead of IV ampicillin to PO
ampicillin: potency of ampicillin and amoxicillin can be considered
equivalent. The oral absorption of amoxicillin (80%) double that of
7
– Beta-lactams –
ampcillin (40%). Amoxicillin is the aminopenicillin agent of choice
to be given orally.
(b)
IV cloxacillin to PO flucloxacillin instead of IV cloxacillin to PO
cloxacillin: Three oral anti-staphylococcal penicillins are available
in Hong Kong: cloxacillin (CloxilTM), dicloxacilln (DiclocilTM) and
flucloxacillin (FlucloxilTM). PO cloxacillin is most commonly used
because of the lower cost. If high levels after PO are important, PO
flucloxacillin is preferred because it has the best oral absorption
(oral bioavailability of 60% for flucloxacillin compared to 35% for
cloxacillin).
TIPS IN CHOOSING AMONG THE CEPHALOSPORINS
Antimicrobial spectrum
The cephalosporins are commonly classified into generations, according the their
spectrum of antibacterial activities (Table 2). With the exception of the
cephamycins, all the other cephalosporins do not process clinically useful antianaerobic activity. No cephalosporins are active against the Enterococcus, Listeria,
MRSA. Anti-Gram negative activity increases as one go up the generation
classification tree. “Anti-pseudomonal activity” usually means there is some loss
in the anti-Gram-positive potency. Ceftazidime is poorly active against penicillinnonsusceptible pneumococci and S. aureus (MSSA). Although cefepime is an antipseudomonal cephalosporin with enhanced activity (compared to ceftazidime)
against Gram positive bacteria. The cefotaxime and ceftriaxone are still the agents
with the highest degree of anti-streptococcal activity (e.g. against penicillinnonsusceptible pneumococci).
8
– Beta-lactams –
Table 2. Spectrum of activity of cephalosporins.
Examples of
agents
E. coli,
Klebsiella
CES
P.
aeruginosa
Pen-S
strept,
MSSA
Enterococci,
MRSA
Most
anaerobes,
including
B. fragilis
1GC
Cefazolin
(Cefamazin),
cephalexin
(Keflex)
+
0
0
++
0
0
2GC
Cefuroxime
(Zinnat,
Zincef)
++
0 to +
0
++
0
0
3GC
Cefotaxime
(Claforan),
ceftriaxone
(Rocephin)
+++
+ to
++
0
+++
0
0
Ceftazidime
(Fortun),
eefoperazone
(Cefobid)
++
++
+++
+
0
0
Cefepime
(Maxipime)
+++
+++
+++
++
0
0
4GC
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, methicillinresistant S. aureus.
9
– Beta-lactams –
Clinical applications of the PK data
1.
On the basis of the serum half-lives, cephalosporins can be classified into 3
groups. These data and the usual dosing frequency are showed in Table 3.
2.
Cefazolin is the only first generation cephalosporin with a longer serum
T½. Therapeutic levels are maintained for at least 4 hours after a single 1 g
dose. This property makes it the agent of choice as single dose
preoperative prophylaxis for surgery that lasts <4 hours.
3.
Only the third and fourth 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),
cefoperazone (1.9 h)a, cefepime (2 h)a
3 times daily
>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
(BLBLI) COMBINATION
1.
β-LACTAM/β-LACTAMASE INHIBITOR
Three β-lactamase inhibitors are currently used in combination with a βlactam in five BLBLIs (Table 4). With the exception of sulbactam (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 broadspectrum agents. Some illustrative examples:
(a)
Augmentin (Amoxycillin-clavulanate) is not more effective than
amoxil in the treatment of ampicillin-susceptible Haemophilus
influenzae pneumonia.
(b)
Unasyn (ampicillin-sulbactam) is not more effective than ampicillin
against ampicillin-susceptible Escherichia coli cystitis.
10
– Beta-lactams –
(c)
2.
Be wise in choosing formulation: tips from the β-lactam to β-lactamase
ratio.
(a)
Take amoxicillin-clavulanic acid 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):
(c)
3.
Tazocin (piperacillin-tazobactam) is not more effective than
piperacillin against piperacillin-susceptible P. aeruginosa
bacteraemia.
(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).
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.
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
11
– Beta-lactams –
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.
12
– Beta-lactams –
Table 4.
BLBLI
Trade name
Inhibitor
Preparation
Amount of active βlactam: inhibitor
Amoxycillinclavulanic acid
Augmentin
Clavulanic
acid
IV 1.2 g
1 g : 0.2 g (5:1)
PO 375 mg
250 mg : 125 mg (2:1)
Per 5 ml
syrup PO,
156 mg
125 mg : 31 mg (4:1)
Per 5 ml BD
syrup PO,
457 mg
400 mg : 57 mg (7:1)
PO 1g
875 mg : 125 mg (7:1)
IV 1.5 g
1 g : 0.5 g (2:1)
PO 375 mg
220 mg : 147 mg (1.5:1)
Ampicillin-sulbactam
Unasyn
Sulbactam
Ticarcillin-clavulanic
acid
Timentin
Clavulanic
acid
IV 3.2 g
3 g : 0.2 g (15:1)
Cefoperazonesulbactam
Sulperazon
Sulbactam
IV 1 g
0.5 g : 0.5 g (1:1)
Piperacillintazobactam
Tazocin
Tazobactam
IV 4.5 g
4 g : 0.5 g (8:1)
13
– Beta-lactams –
Table 5.
Unasyn
Augmentin
a Data
Unit dose
Cmaxa
Duration of serum
concentration ≥1 μg/mL
IV 1.5 g (i.e. 1 g
ampicillin)
40−71 (ampicillin),
21−40 (sulbactam)
6−7 h
PO 375 mg (i.e. 250
mg ampicillin)
3−6 (ampicillin)
2−3 h
IV 1.2 g (i.e. 1 g
amoxicillin)
50−100 (amoxicillin), 45
(clavulanic acid)
6−7 h
PO 375 mg (i.e. 250
amoxycillin)
4−5 (amoxicillin), 3.3
(clavulanic acid)
2−3 h
PO 1 g (i.e. 875
amoxicillin)
12.4 (amoxicillin), 3.3
(clavulanic acid)
3−4 h
from package insert/manufacturer brochure.
TIPS IN CHOOSING AMONG CARBAPENEMS
1.
Two carbapenems, imipenem and meropenem 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 (24 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.
14
– Beta-lactams –
3.
4.
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]
Suggestions when a carbapenem 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
15
– Beta-lactams –
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).
16
– Aminoglycosides –
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 vancomycin) 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 Pseudomonas aeruginosa, 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].
17
– Aminoglycosides –
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.
18
– Aminoglycosides –
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
19
– Aminoglycosides –
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, gentamicinresistant 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
20
– Aminoglycosides –
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
21
– Aminoglycosides –
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).
22
– Aminoglycosides –
Result of plotting
Dosing interval for second and
subsequent doses
Level falls in the area
designated q24h
Give the same dose at an interval of every
24h
Level falls in the area
designated q36h
Give the same dose at an interval of every
36h
Level falls in the area
designated q48h
Give the same dose at an interval of every
48h
Level on the line
Choose the longer interval
Level off the normogram at the
given time
Stop the scheduled therapy, obtain serial
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
23
– Aminoglycosides –
Figure. Hartford Hospital once-daily aminoglycoside
normogram for gentamicin and tobramycin.
24
– Aminoglycosides –
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
distribution
Ami1
Gen1
Net1
Tob1
Aqueous
humor
Poor
minimal
minimal
minimal
minimal
Ascitic fluid
Variable
58%
80-100%
79%
Bile
Variable
6-54%
30−60%
10−20%
Bile with
obstruction
Poor
Bone
Poor
30%
13%
CSF (inflamed
meninges)
Poor
15−24%
Peritoneal fluid
Poor
39%
Pleural fluid
Excellent
12-40%
Prostate
Poor
Pulmonary
tissue
Excellent
40-53%
Renal tissue2
Excellent
>100 μg/g
Sputum and
bronchial
secretions
Variable
Synovial fluid
Urine
10−30%
21−26%
14−23%
50%
0-57%
40-69%
11-21%
10%
19%
Excellent
111%
50-80%
89%
Excellent
>10 times
serum
level
>10 times
serum
level
(500−800
μg/ml)
(>100
μg/ml)
>10 times
serum level
(up to
75−100μg/ml)
3-66%
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.
25
– Aminoglycosides –
Table 2. Preparations and recommended dosing
regimens for aminoglycosides.
Agent (generic)
Trade name
Dosage form
(unit cost, HK$)
Usual adult regimen
(daily dose, route,
dosing interval)
Amikacin
Amikin
250 mg vial ($36)
IV 15 mg/kg q24h
(750 mg q24h)a or 7.5
mg/kg q12h
500 mg vial ($56)
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)
200 mg vial ($44.8)
Tobramycin
Nebcin
40 mg/mL 2 ml vial
($18)
IV 4.4 mg/kg q24h
(200 mg q24h)a or IV
2.2 mg/kg q12h
IV 3.6 mg/kg q24h
(180 mg q24h)a or 1.2
mg/kg q8h
Dosage for a typical 50 kg person given. Cost updated as of Feb 2003 in HA.
Once daily administration of aminoglycoside is appropriate for most infection
with the possible exceptions of neutropenic fever, infective endocarditis and in the
presence of severe renal failure.
a
Table 3. Cost comparison of aminoglucosides.
Agent
IV gentamicin 180 mg q24h (3.5 mg/kg/day)
Cost (HK$ per day)
12
IV amikacin 750 mg q24h (15 mg/kg/day)
92
IV tobramycin 180 mg q24h (3.5 mg/kg/day)
54
IV netilmicin 200 mg q24h (4.4 mg/kg/day)
45
(Cost updated as of Feb 2003 in HA. Dosage for a typical 50 kg person.)
26
– Aminoglycosides –
Table 4. Representative MIC (μg/mL) of
aminoglycosides for common pathogens.
Gentamicin
Netilmicin
Tobramycin
Amikacin
Common
Enterobacteriaceae (E.
coli, Klebsiella,
Enterobacter, Proteus
spp.)
0.5−1
0.5−1
0.5−1
2
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
concentration (dose)a
13.7 μg/mL
(3.5mg/kg)
15.4 μg/mL
(4.4mg/kg)
14 μg/mL
(3.5mg/kg)
76 μg/mL
(15mg/kg)
Estimated from known plasma levels after conventional dosing. Values for
plasma levels after conventional dosing were obtained from Physician Desk
Reference 1999.
a
27
– Quinolones –
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
2
3
4
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.
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.
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.
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.
28
– Quinolones –
Table 1. Commonly used quinolone antibiotics.
Year
Agent
Licensed
in HK
Oxoat C4
Piperazinyl
at C7
Fluorine
at C6
1960s
Nalixidic acid
(Wintomylon®)
Yes
+
-
-
1970s
Pipemidic acid
(Urotractin®)
Yes
+
-
-
1980s
Norfloxacin
(Lexinor®)
Yes
+
+
+
Ciprofloxacin
(Ciproxin®)
Yes
+
+
+
Ofloxacin
(Tarivid®)
Yes
+
+
+
Lomefloxacin
(Maxaquin®)
Yes
+
+
+
Levofloxacin
(Cravit®)
Yes
+
+
+
Sparfloxacin
(Zagam®)
Yes
+
+
+
Trovafloxacin
(Trovan®)
Noa
+
+
+
Grepafloxacin
(Raxar®)*
Noa
+
+
+
Moxifloxacin
(Avelox®)
Yes
+
+
+
Gatifloxacin
(Tequin®)
No
+
+
+
Early 1990s
Late
1990s−2000
FREQUENCY AND MECHANISMS OF BACTERIAL RESISTANCE
1
Strains with mutations causing resistance to one FQ are often crossresistant 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
29
– Quinolones –
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. ventilatorassociated 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, pyelonephritis.
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
Respiratory tract infection.
g
Bone and joint infections.
30
– Quinolones –
h
Skin and soft tissue infection.
31
– Quinolones –
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
2
3
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.
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).
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].
32
– Quinolones –
b
4
5
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.
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.
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).
33
– Quinolones –
3
Intracellular concentration >> extracellular concentration (Table 3).
4
Serum level generally low.
5
Low serum protein binding (15−45%).
34
– Quinolones –
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
35
– Quinolones –
Table 4. Pharmacokinetic parameters of selected fluoquinolones.
AUC24
(μg⋅h/mL)
Free drug
AUC24
(μg⋅h/mL)
MIC for 90% of FQsensitive S.
pneumoniae in Hong
Kong
AUIC
1.2
82.4
56
2
28
2.5
1.8
21.3
14.9
2
7.5
4
4.0
2.8
32
22.4
2
11
24−38% (31)
7
5.7
3.9
48
33.1
1
33
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
Dose /
frequency
(mg)
Protein binding
T1/2
(h)
Cmax
ofl
PO 400 BD
32%
7
1.7
cip
PO 500 BD
30%
4
cip
PO 750 BD
30%
levo
PO 500 QD
spar
(μg/mL)
Free drug
Cmax
(μg/mL)
Data sources: drug inserts, Physician Desk Reference 1999 and others [15].
36
– Quinolones –
Table 5. PO vs. IV comparison of pharmacokinetic parameters of
selected FQs.
Dose / route
Cmax
AUC24
(μg⋅h/mL)
Approximate cost
(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
37
– Quinolones –
Safety/side effects profile
Table 6. Fluoroquinolones: comparison of their side effects.
Type of side effects
(frequency of
occurrence, overall %)
Nature
Descending order of
frequency
Gastrointestinal
(2−20%)
Usually minor
spar > cipro ~ levo > nor
Central nervous system
(1−2%)
Headache, dizziness, sleep
disorders, mood changes,
confusion, (rarely
convulsion)
spar > cip > nor > levo
Hepatic (2−3%)
Usually transient rise in
LFT; (rarely cholestatic
jaundice, hepatitis, hepatic
failure)
spar~cip~ofl > levo
Skin (0.5−3%)
Photosensitivity
spar > cip > levo~ofl
Renal (0.2−1.3%)
Azotemia, crystalluria,
haematuria
ofl > cip and others
Musculoskeletal (1%)
Arthropathy (onset in first
few days; weight bearing
joints)
Class effect
Tendon rupture (especially
Achilles tendon; 0.005 to 0.7
per 1000 treated patients)
Probably class effect,
though only reported with
cip, nor, spar
38
(2%) (0.3%)
– Quinolones –
Table 7. Drug interactions.
Drug B
Comment
Drug(s) A
levo
cip
moxi
gati
Antacid, milk, sucralfate,
iron, zinca
+
+
+
+
A class effect, ↓
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
P450
NA
+
Noc
Noc
“+” refers to clinically significant interaction. “−” not clinically significant. NA, no
data available.
a
Give B 2−4 hours before A.
had no effect on excretion of mox, but ↑ T1/2 & AUC of levo (by ~30%),
gati (by ~40%).
b Probenecid
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 pharyngitis.
c
Dental infection, most head and neck infections (anaerobes,
streptococci important).
d
Acute otitis media, acute sinusitis, acute tracheitis, acute bronchitis.
e
Meningitis (inadequate CSF level and limited data).
f
Infective endocarditis (limited data).
39
– Quinolones –
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.
40
– Quinolones –
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41
– Quinolones –
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