CASE 62-1, QUESTION 7: Serratia marcescens grows from a culture of R.G.’s endotracheal aspirate. How
can it be determined whether an isolate represents a true bacterial infection versus colonization or
A positive culture may represent colonization, contamination, or infection.
Colonization indicates that bacteria are present at the site; however, they are not
actively causing infection. Poor sampling techniques or inappropriate handling of
specimens can result in contamination. Contamination differs from colonization in
that these isolates are not truly at the site in question. The S. marcescens growing
from R.G. could represent infection, colonization, or contamination. If a suction
catheter was used to sample R.G.’s endotracheal aspirate, the infecting organism
likely would be cultured; however, other nonpathogenic flora would also appear in
the culture medium (colonization). Furthermore, if the sample is not handled
aseptically by the clinician or the microbiology laboratory, bacterial contamination is
In summary, culture results do not solely identify true pathogens. In R.G., the
Serratia may be a pathogen, contaminant, or colonizer. Nevertheless, considering the
severity of R.G.’s illness and his associated respiratory symptoms, treatment directed
against this pathogen is necessary.
known allergies. Are there equally effective, less toxic options for this patient?
Adverse Effects and Toxicities
Before antimicrobial therapy is started, it is important to elicit an accurate drug and
allergy history. When “allergy” has been reported by the patient, it is necessary to
determine whether the reaction was intolerance, toxicity, or true allergy. For
example, gastric intolerance caused by oral doxycycline is common; however, this
adverse effect does not represent an allergic manifestation. Although R.G. has no
known allergies, neither imipenem nor gentamicin are optimal choices. Imipenem is
associated with seizures, particularly in patients with renal failure and in doses in
excess of 50 mg/kg/day. Considering R.G.’s acute onset of renal failure and his
history of seizures, other carbapenems, such as meropenem or doripenem, or
alternative classes of antibacterials would be preferable. Gentamicin similarly may
not be a good choice in R.G. His increased age and declining renal function
predispose him to aminoglycoside nephrotoxicity and ototoxicity (cochlear and
21 A reasonable recommendation pending susceptibility results would be
to discontinue imipenem and gentamicin and treat with meropenem or doripenem
with or without a fluoroquinolone. Table 62-8 lists common antibiotics adverse
Antibiotic Adverse Effects and Toxicities
Antibiotics Side Effects Comments
Many patients will have “ampicillin rash” or “β-lactam rash” with
no cross-reactivity with any other penicillins/β-lactams. Most
commonly observed in patients with concomitant EBV disease.
Likelihood of IgE-mediated cross-reactivity between penicillins and
cephalosporins approximately 5%–10%. Most recent data strongly
suggest minimal IgE cross-reactivity between penicillins and
imipenem/meropenem. No IgE cross-reactivity between
Diarrhea Particularly common with ampicillin, augmentin, ceftriaxone.
Antibiotic-associated colitis can occur with most antimicrobials.
Hemolytic anemia more common with higher doses. Antiplatelet
activity (inhibition of platelet aggregation) most common with the
antipseudomonal penicillins and high serum levels of other β-
Hypothrombinemia more often associated with those
cephalosporins with the methyltetrazolethiolside chain
(cefamandole, cefotetan). Reaction preventable and reversible
Hepatitis most common with oxacillin. Biliary sludging and stones
Seizure activity Associated with high levels of β-lactams, particularly penicillins
Potassium load Penicillin G (K+).
Nephritis Occasionally reported for most β-lactams.
Disulfiram reaction Associated with cephalosporins with methyltetrazolethiolside chain
Hypotension, nausea Associated with fast infusion of imipenem.
Nephrotoxicity Average 10%–15% incidence. Generally reversible, usually occurs
after 5–7 days of therapy. Risk factors: dehydration, age, dose,
duration, concurrent nephrotoxins, liver disease.
Ototoxicity 1%–5% incidence, often irreversible. Both cochlear and vestibular
Rare, most common with large doses administered via
intraperitoneal instillation or in patients with myasthenia gravis.
Oral administration. Azithromycin and clarithromycin associated
with less nausea than erythromycin.
Cholestatic jaundice reported for all erythromycin salts, most
Ototoxicity most common with high doses in patients with renal or
Torsades de Pointes and increased risk of cardiac death
associated with increased QT interval.
Severe, sometime fatal hepatotoxicity associated with
Clindamycin Diarrhea Most common adverse effect. High association with antibioticassociated colitis.
Drug Interactions ↓ Oral bioavailability with multivalent cations.” similar to that
stated in the Quinolones section
Avoid in pediatrics (<8 years old), pregnancy, and breastfeeding.
patients with ↓ renal function. Less problematic with
Vestibular Associated with minocycline, particularly high doses.
Associated with rapid infusion of vancomycin. More common
Nephrotoxicity Reversible nephrotoxicity with high doses or in combination with
Ototoxicity Only with receipt of concomitant ototoxins such as
aminoglycosides or macrolides.
Phlebitis Needs large volume dilution.
Dalfopristin/quinupristin Phlebitis Generally requires central line administration.
Myalgia Moderate to severe in many patients.
Daptomycin Myalgia Primarily at high doses and reversible.
Linezolid (Tedizolid) Thrombocytopenia,
with bone marrow suppression and neuropathy.
Sulfonamides GI Nausea, diarrhea.
Hepatic Cholestatic hepatitis, ↑ incidence in HIV.
Exfoliative dermatitis, Stevens–Johnson syndrome. More
Only with trimethoprim (as a component of trimethoprim–
Bone marrow Neutropenia, thrombocytopenia. More common in HIV.
Kernicterus Caused by unbound drug in the neonate. Premature liver cannot
conjugate bilirubin. Sulfonamide displaces bilirubin from protein,
resulting in excessive free bilirubin and kernicterus.
Chloramphenicol Anemia Idiosyncratic irreversible aplastic anemia (rare). Reversible
Gray syndrome Caused by inability of neonates to conjugate chloramphenicol.
Quinolones GI Nausea, vomiting, diarrhea.
Prolonged QT Moxifloxacin; possibly all quinolones as a class.
Drug interactions ↓ Oral bioavailability with multivalent cations.
CNS Altered mentalstatus, confusion, seizures.
Cartilage toxicity Toxic in animal model. Despite this toxicity, appears safe in
children including patients with cystic fibrosis.
Common in elderly, renal failure, concomitant glucocorticoids.
Nephrotoxicity Common. May depend on patient sodium load. Caution with
concomitant nephrotoxins (e.g., aminoglycosides, cyclosporine).
Hypokalemia Predictable. Probably caused by renal tubular excretion of
potassium. More common in patients receiving concomitant
Hypomagnesemia Less commonly observed than hypokalemia.
Anemia Long-term adverse effect. Similar to anemia of chronic disease.
Anidulofungin is reconstituted with alcohol (about the equivalent of
Secondary to metabolism of flucytosine to fluorouracil. More
commonly observed with flucytosine levels >100 mg/mL. More
Hepatitis Usually moderate ↑ in LFT. Rarely clinical hepatitis.
Drug interactions ↓ Oral bioavailability of ketoconazole tablet, and itraconazole
capsules with ↑ gastric pH. Azoles are CYP450 substrates and
also inhibitors of CYP450 3A4 and other CYP isoenzymes.
Voriconazole most likely to be associated with CYP drug
Hepatitis Ranges from mild ↑ in LFT to occasional fatal hepatitis.
More common with high-dose ketoconazole (>400 mg/day). Less
Visual disturbance Unique to voriconazole, particularly first week of therapy.
Antivirals (Excluding Antiretrovirals and Hepatitis Antivirals)
Acyclovir Phlebitis Caused by poor solubility of IV preparation. Reported in 1%–20%
Renal failure Low solubility of acyclovir associated with renal failure.
Dehydrated patients, as well as rapid infusions, predispose to
CNS 1% incidence in AIDS. ↑ Incidence with dose in >10 mg/kg/day.
Foscarnet Nephrotoxicity Occurs in up to 60% of patients. May be prevented with normal
saline bolus before dose. Frequent monitoring of renal function
↑ and ↓ calcium or phosphate may be observed. Hypocalcemia,
hypo- and hyperphosphatemia, hypomagnesemia, hypokalemia. ↑
Risk of cardiomyopathy and seizures.
Anemia Anemia in 33%; usually manageable with transfusions and
↑ Incidence in AIDS. ↑ Incidence with doses in excess of 10
Hepatitis Usually mild to moderate in LFT.
AIDS, acquired immunodeficiency syndrome; CNS, central nervous system; EBV, Epstein–Barr virus; GI,
Concomitant disease states should also be considered in the selection of therapy. As
discussed above, older patients with hearing deficits are poor candidates for
potentially ototoxic aminoglycoside therapy. Diabetic or kidney transplant patients
with candidemia may be better treated with fluconazole or an echinocandin rather
than nephrotoxic amphotericin B products. Patients with a preexisting seizure history
should not receive imipenem if less toxic therapy can be used. In summary, the
toxicologic profile of a drug must be taken into account in the selection of
ANTIMICROBIAL COSTS OF THERAPY
The true cost of antimicrobial therapy is difficult to quantify.
acquisition cost traditionally has been the primary factor in the overall cost of
therapy, drug administration labor costs (i.e., nursing and pharmacy) and the use of
IV sets, piggyback bags, and infusion control devices must be included in the
analysis. As a result, a drug that must be administered several times daily, such as
intravenous penicillin, will incur increased administration costs compared with one,
such as ceftriaxone, that requires once-a-day dosing.
Some drugs, such as aminoglycosides, are associated with increased laboratory
costs (e.g., aminoglycoside serum concentrations, serum creatinine, and audiometry)
that are not required for other agents,
23 such as the third-generation cephalosporins
and quinolones. Similarly, drugs with a high potential for misuse or toxicity can be
associated with increased costs because of monitoring (e.g., medication use
evaluation, pharmacokinetic monitoring). If meropenem with or without ciprofloxacin
had been selected for R.G., this therapy would be expected to be associated with
relatively few laboratory costs. However, the broad spectrum of activity
agents, potential for misuse, and development of resistance might, however, result in
increased monitoring costs and overall cost to society.
Costs that are difficult to quantitate include those associated with failure of
antimicrobial therapy and antimicrobial toxicity. Ineffective or toxic therapy can
prolong hospitalization and may require expensive interventions, such as
23 mechanical ventilation, and intensive care unit admission. The net
effect of these latter costs can be significantly greater than the acquisition and
administration costs of antimicrobial therapy.
In summary, determining the true cost of antimicrobial therapy is complex.
Acquisition cost, IV bags, infusion controllers, and labor must be incorporated into
the analysis. Although they are difficult to estimate, other costs, including antibiotic
toxicity and failure of therapy, should also be included.
CASE 62-1, QUESTION 10: The Serratia was determined to be susceptible to ciprofloxacin. Oral
prescribed. Why is the oral administration of ciprofloxacin reasonable (or unreasonable) in R.G.?
The proper route of antibiotic administration depends on many factors, including
the severity of infection, antimicrobial oral bioavailability, and other patient factors.
In patients who appear “septic,” blood flow often is shunted away from the
mesentery and extremities, resulting in unreliable bioavailability from the
gastrointestinal (GI) tract or muscles. Consequently, hemodynamically unstable
patients should always receive antimicrobials by the IV route to ensure therapeutic
antimicrobial levels. Furthermore, some drug interactions with oral agents can result
in subtherapeutic serum concentrations (e.g., reduced bioavailability associated with
concomitant quinolone and antacid administration and the decreased absorption of
itraconazole with concurrent proton-pump inhibitor [PPI] therapy).
R.G. is clinically septic with a possible Serratia pneumonia. Considering his
unstable state, the bioavailability of oral ciprofloxacin cannot be guaranteed; thus, he
should be treated with IV antimicrobials.
CASE 62-1, QUESTION 11: What dose of IV ciprofloxacin should be given to R.G.? What factors must be
taken into account in determining a proper antimicrobial dose?
The choice of dosing regimen is based on many factors. Table 62-9 provides a
guide for the dosing of more commonly administered antimicrobials. Selection of the
appropriate dosage should be based on evidence confirming the efficacy of the
dosage in the treatment of a specific infection. Patient-specific factors, including
weight, site of infection, and route of elimination, must also be considered in dosage
selection. The patient’s weight is important, particularly for agents with a low
therapeutic index (e.g., aminoglycosides, imipenem, and flucytosine); these drugs
should be dosed on a milligram per kilogram per day basis. Other agents with a more
favorable adverse effect profile, such as cephalosporins, are less likely to require
weight-specific dosing in most disease states.
Site of infection results in different dosage requirements. An uncomplicated urinary
tract infection requires lower doses considering the high urinary drug concentrations
that are achieved with most renally cleared agents. In contrast, a more serious upper
urinary tract infection, such as pyelonephritis, requires increased doses to ensure
therapeutic drug levels in tissue and in serum.
Anatomic and Physiologic Barriers
Anatomic and physiologic barriers must also be considered in evaluating a dosing
regimen. For example, penetration into cerebrospinal fluid requires high doses to
ensure adequate antimicrobial concentrations.
27 are additional sites in which therapeutic antimicrobial concentrations are
Route of elimination must also be considered in the dosage calculation. In general,
antimicrobials are eliminated renally or nonrenally (metabolic or biliary). Renal
function can be estimated via 24-hour urine collection or with equations, such as the
Several anti-infectives are eliminated renally (Table 62-9). Most β-lactams are
eliminated by the kidney. In contrast, ceftriaxone and most antistaphylococcal
penicillins (e.g., nafcillin, oxacillin, and dicloxacillin) are eliminated both renally
and nonrenally. Aminoglycosides, vancomycin, acyclovir, and ganciclovir are
cleared primarily by the kidney. Thus, dosage adjustment is recommended for these
drugs in patients with renal failure (Table 62-9). Because azithromycin, clindamycin,
and metronidazole are primarily eliminated by the liver, no dose reduction is
required in renal failure for these agents. Using the Cockcroft and Gault equation,
R.G.’s age (63 years), weight (70 kg), and current serum creatinine (3.8 mg/dL)
results in a calculated creatinine clearance of 14 mL/minute. R.G. normally would be
given an IV dosage of ciprofloxacin at 400 mg every 12 hours. His increasing
creatinine, however, suggests that his dosage should be decreased to 200 to 300 mg
Adult Antimicrobial Dosing Guidelines for Hospitalized Patients (Selected
mL/minute CrCl 10–50 mL/minute
2 g IV every 6 hours 1 g IV every
Ampicillin/sulbactam 3 g IV every 6 hours 1.5 g IV every 6 hours 1.5 g IV
Aztreonam 2 g IV every 8 hours 2 g IV every 12 hours 1 g IV every
1–2 g IV every 12 hours 1 g IV every
Ceftazidime 2 g IV every 8 hours 2 g IV every 12–24 hours 500 mg IV
1 g IV every 24 hours No change No change No change
Clindamycin 600–900 mg IV every 8
Ertapenem 1 g IV every 24 hours <30 mL/minute
Ethambutol 15–20 mg/kg PO every 24
Imipenem 500 mg IV every 6–8 hours
Isoniazid 300 mg PO every 24 hours No change No change No change
500 mg IV/PO every 8 hours 500 mg
1–2 MU IV every 4–6 hours 1 MU IV
3.375–4.5 g every 6–8 hours 2.25 g every
Pyrazinamide 20–25 mg/kg/day PO
troughs are not recommended in patients in whom anticipated duration of therapy is ≤3 days.
1 For patients with uncomplicated infections requiring vancomycin, trough levels of 10–15 mcg/mL are
ventilator-associated pneumonia, bacteremia, or osteomyelitis), trough levels of 15–20 mcg/mL are
No change No change* No change*
day, then 4 mg/kg/dose every 12 hours.
IV vehicle and is contraindicated in ESRD and hemodialysis. May require dose adjustment in hepatic
SCr (mg/dL) (for females multiply by 0.85). Ideal body weight equation:
Males: IBW = 50 kg + 2.3 kg for each inch over 5 feet.
Females: IBW = 45.5 kg + 2.3 kg for each inch over 5 feet.
Adjusted body weight: ABW = IBW + 0.4 (actual weight - IBW).
Although renal function can be approximated with the use of the Cockcroft and
Gault equation (or a similar equation), hepatic function is more difficult to evaluate.
No standard liver function test (AST, ALT, alkaline phosphatase) has been
demonstrated to correlate well with hepatic drug clearance. Some tests, such as PT,
INR, and albumin, are markers of hepatic function, but even these tests do not clearly
predict drug clearance. Patients receiving hemodialysis or continuous hemofiltration
provide additional dosing challenges. Table 62-9 provides dosing recommendations
in patients receiving hemodialysis or continuous hemofiltration.
It is important to note that most dosing information is derived from a younger,
relatively healthy patient population. It is clear that the very young and the elderly
have a decreased ability to clear drugs; thus, dosage requirements for many agents
are likely to be decreased in neonatal and geriatric patients.
The impact of other factors on the selection of an antimicrobial dose is less clear.
Fever increases and decreases blood flow to mesenteric, hepatic, and renal organ
29 and it can either increase or decrease drug clearance. Inoculum effect has
taken place when higher concentrations of a bacterial inoculum result in an increase
30 As an example, piperacillin may demonstrate an MIC of 8.0 mcg/mL
against P. aeruginosa at a concentration of 10
5 colony-forming units/mL (CFU/mL);
9 CFU/mL, the MIC may increase to 32 to 64 mcg/mL. This
phenomenon is well recognized, particularly with β-lactamase–producing bacteria
abscess, in which extremely high concentrations of bacteria would be expected. As a
result, antimicrobials that are more susceptible to the inoculum effect may require
increased drug dosages for optimal outcome in the treatment of abscesses.
CASE 62-1, QUESTION 12: R.G.’s respiratory status remains unchanged; thus, the ciprofloxacin is
What is the rationale for these approaches, and would either be advantageous for R.G.?
β-Lactams, such as cefepime, are not associated with increased bacterial killing
with increasing drug concentrations. Pharmacodynamic activity with β-lactams best
correlates with the duration of time that antimicrobial levels are maintained above
31 The animal model suggests that β-lactam antimicrobials should be dosed
such that their serum levels exceed the MIC of the pathogen as long as possible.
This observation appears to be most important in the neutropenic model, in which the
use of a constant infusion more reliably inhibits bacterial growth compared with
traditional intermittent dosing. An additional benefit of the use of constant infusions
of β-lactams is that smaller daily doses appear to be as effective as higher doses
administered intermittently. Other than this latter outcome, it is unclear, however,
whether constant infusions have any distinct advantages or disadvantages compared
with usual dosing of β-lactams. The efficacy of quinolones, vancomycin, and
daptomycin best correlates with the peak plasma concentration to MIC ratio or area
under the curve (AUC) to MIC ratio.
In light of this pharmacodynamic principle, it
is possible that ciprofloxacin was underdosed in this patient, contributing to the
therapeutic failure, particularly if the MIC was in the upper range of susceptibility
Aminoglycosides traditionally have been administered every 8 to 12 hours to
achieve peak serum gentamicin levels of 5 to 8 mcg/mL to ensure efficacy in the
treatment of serious gram-negative infection.
33 Gentamicin troughs of greater than 2
mcg/mL have been associated with an increased risk for nephrotoxicity.
studies attempting to correlate efficacy and toxicity with serum levels and the
association of peaks or troughs with clinical outcomes have been questioned.
Vancomycin troughs of 5 to 10 mcg/mL have been traditionally recommended
however, current recommendations suggest higher troughs (10–20 mcg/mL)
depending on the pathogen, site of infection, and severity of illness.
Several antimicrobials (e.g., aminoglycosides) have been associated with a
pharmacodynamic phenomenon known as a post-antibiotic effect (PAE). PAE is
delayed regrowth of bacteria after exposure to an antibiotic
suppression of normal growth in the absence of antibiotic levels above the MIC of
the organism). As an example, if P. aeruginosa is cultured in broth, it will multiply to
9 CFU/mL. If piperacillin is added in a concentration above the
MIC for the organism, a reduction in the bacterial concentration is observed. As
described previously, a β-lactam antibiotic should be present in concentrations
above the MIC to optimize its time-dependent killing. When piperacillin is removed
from the broth, immediate bacterial growth takes place. If the above experiment is
repeated with gentamicin, a reduction in bacterial CFU is observed. In contrast to
that observed with β-lactam antibiotics, if the gentamicin is removed from the system,
a lag period of 2 to 6 hours takes place before characteristic bacterial growth occurs.
This lag period is defined as the PAE. A PAE has also been observed with
quinolones and imipenem against gram-negative bacteria. Although most β-lactam
antibiotics, such as antipseudomonal penicillins or cephalosporins, do not exhibit
PAE with gram-negative organisms, PAE has been demonstrated with β-lactam with
gram-positive pathogens such as S. aureus.
Once-Daily Dosing of Aminoglycosides
As a result of PAE and other pharmacodynamic factors, certain antimicrobials may
be dosed less frequently. The greatest clinical experience has been with the
aminoglycosides in the treatment of gram-negative infection.
suggested that the maximal aminoglycoside peak level to MIC ratio correlates well
with clinical response. Thus, the higher the achievable peak, the greater likelihood of
a favorable outcome. Consequently, greater, less frequent doses of aminoglycosides
should work at least as well as the more traditional lower, more frequent doses.
Once-daily dosing of aminoglycosides in the treatment of gram-negative infection is
as efficacious as traditional multiple daily dosing.
Single daily dosing of aminoglycosides has been investigated primarily in patients
with normal renal function, and few critically ill patients have been treated with this
Thus, patients in septic shock are less clear candidates for once-daily dosing. The
utility and proper timing of serum aminoglycoside concentrations and association
with clinical outcomes are debatable with nontraditional once-daily
In summary, the use of a prolonged IV infusion of cefepime is possible in R.G., but
the benefit of this mode of administration is not clear. Considering the severity of
R.G.’s infection and his elevated serum creatinine level, he is not a candidate for
single daily dosing of aminoglycosides (i.e., 5–6 mg/kg every 24 hours). Independent
of the aminoglycoside-associated PAE, his current renal function requires a reduced
gentamicin dose to treat his infection.
CASE 62-1, QUESTION 13: Ceftriaxone (Rocephin), rather than cefepime, is being considered for the
important in the selection of therapy?
Free (i.e., unbound) rather than total drug levels are best correlated with
41 and the degree of protein binding may have important
clinical consequences in some patients. Chambers et al.
with the highly protein-bound cefonicid (98% protein bound) in patients with
endocarditis caused by S. aureus. Despite achievable serum drug concentrations well
above the MIC of the organism, breakthrough bacteremia occurred in three of four
patients. Although total drug concentrations greatly exceeded the MIC of the
pathogen, free concentrations were consistently below the level necessary to inhibit
bacterial growth. Similar experiences have been reported with daptomycin (90% to
43 Thus, clinical cure appears to be more likely if unbound
antibiotic concentrations exceed the MIC of the infecting organism. Although
ceftriaxone is 85% to 90% protein bound, the free concentrations probably remain
far above the MIC of the Serratia. Therefore, protein-binding considerations are
unlikely to be important in the treatment of R.G.’s infection.
What antibiotic-specific factors may contribute to “antimicrobial failure”?
Antimicrobials may fail for various reasons, including patient-specific host
factors, drug or dosage selection, and concomitant disease states. One of the most
common reasons for antimicrobial failure is drug resistance.
important pathogens have been associated with emergence of resistance during the
past decade, including M. tuberculosis,
50 and others. Of particular concern is the isolation of
glycopeptide-resistant S. aureus,
49 and multidrug-resistant Acinetobacter and
51 Development of resistance during therapy, although less common
than initial intrinsic resistance, may also account for failure to respond to therapy.
Organisms that produce extended-spectrum β-lactamase or amp C β-lactamases may
be unresponsive to β-lactam therapy despite associated in-vitro susceptibility.
Superinfection may also play a role in the unsuccessful treatment of infection.
Superinfection has taken place when a new pathogen resistant to the current
antimicrobial regimen is isolated. If R.G.’s ceftriaxone-treated Serratia pneumonia
subsequently worsens and a tracheal aspirate returns positive for P. aeruginosa, then
supercolonization and, perhaps, superinfection have occurred.
Most infections can be treated with monotherapy (e.g., an E. coli wound infection is
treatable with a cephalosporin). Some infections, however, require two-drug therapy,
including most cases of enterococcal endocarditis and perhaps certain P. aeruginosa
53 studied 200 consecutive patients with P. aeruginosa
bacteremia and demonstrated a 47% mortality in those receiving monotherapy
failure in this specific study.
In contrast to the findings of the previous trial, almost all later investigations do
54–56 An exception to this rule is
bacteremia caused by P. aeruginosa in neutropenic patients.
If two antimicrobials are used in the treatment of infection, one of three sequelae
will result: indifference, synergism, or antagonism.
antimicrobial effect of drug A plus that of drug B equals the anticipated sum activity
of the two drugs. Although numerous definitions exist, synergism generally occurs
when the addition of drug A to drug B results in a total antibiotic activity greater than
the expected sum of the two agents. Antagonism occurs if the addition of drug A to
drug B results in a combined activity less than the sum of drug A plus drug B. An
example of antagonism is the combination of imipenem with a less β-lactamase–
stable β-lactam, such as piperacillin.
If P. aeruginosa is exposed to imipenem and
piperacillin, the imipenem induces the organism to produce increased β-lactamase.
Imipenem is remarkably β-lactamase stable and is not degraded by this β-lactamase.
In direct contrast, piperacillin is easily degraded by the β-lactamase. Thus, imipenem
antagonized the effectiveness of piperacillin. Antagonism is not unique to
antibacterials; itraconazole may antagonize amphotericin B in the treatment of certain
CASE 62-1, QUESTION 15: What pharmacologic or pharmaceutic factors may be implicated in failure of
Subtherapeutic dosing regimens are commonplace, particularly for agents with a
peak gentamicin serum levels are only 3 to 4 mcg/mL.
to 30% of the aminoglycoside penetrates from serum into bronchial secretions, only
0.5 to 1.0 mcg/mL may exist at the site of infection,
60 a level that may be inadequate
to treat pneumonia. Another example of dosing contributing to antimicrobial failure
centers on the use of loading doses. Aminoglycosides or vancomycin should be
initiated with a loading dose, particularly in patients with renal failure. If the
clinician neglects to use a loading dose, it may take several days before a therapeutic
level is achieved. As described previously, yet another reason for subtherapeutic
antimicrobial levels and potential drug failure is reduced oral absorption secondary
to drug interactions (e.g., concomitant oral ciprofloxacin with antacids or iron).
An emerging problem relates to the use of vancomycin in the treatment of serious
methicillin-resistant S. aureus (MRSA) infection. By CLSI standards, an isolate of
MRSA with an MIC of 2 mcg/mL is considered susceptible. Current vancomycin
dosing schemes are designed to achieve an AUC/MIC ratio of ≥400 to ensure
maximal efficacy. However, a meta-analysis of patients with S. aureus bacteremia
demonstrated no differences in the risk of death when comparing patients with S.
aureus exhibiting high-vancomycin MIC (≥1.5 mg/L) to those with low-vancomycin
61 The infection site also potentially contributes to antimicrobial
failure. Most antimicrobials concentrate in the urine, resulting in therapeutic levels
even with low doses. In some infections, such as meningitis, prostatitis, and
endophthalmitis, antimicrobial penetration to the site of infection may be inadequate.
Agents that penetrate well into these sites are associated with a more favorable
Another potential reason for antimicrobial failure is inadequate therapy duration.
A woman with a first-time uncomplicated cystitis may respond adequately to a 3-day
course of an antibiotic. In contrast, patients with recurrent urinary tract infections are
not candidates for this short course of therapy, however, and failure would be
expected with only 3 days of therapy.
CASE 62-1, QUESTION 16: What host factors may contribute to the failure of antimicrobial therapy?
Several host factors may limit the ability of an antibiotic to cure infection.
Infection of prosthetic material (e.g., IV catheters, orthopedic prostheses, mechanical
cardiac valves, and vascular grafts) is difficult to eradicate without removal of the
hardware. In most cases, surgical intervention is necessary. To treat R.G.’s IV
catheter infection adequately, removal of his central intravenous catheter would be
optimal. Similar to removal of prostheses, large undrained abscesses are difficult, if
not impossible, to treat with antimicrobial therapy. These infections generally require
surgical drainage for successful outcome.
Diabetic foot ulcer cellulitis may not respond adequately to antimicrobial therapy.
Reasons for antimicrobial failure in patients with diabetes include poor wound
healing and reduced delivery of antibiotics to the infection site.
Immune status, particularly neutropenia or lymphocytopenia, also affects the
outcome in the treatment of infection. Profoundly, neutropenic patients with
disseminated Aspergillus infections are unlikely to respond to even the most
appropriate antifungal therapy. Similarly, patients with AIDS, who have low CD4
lymphocyte counts, cannot eradicate various infections, including those caused by
cytomegalovirus, atypical mycobacteria, and cryptococci.
Once these factors have been eliminated as causes for antimicrobial failure,
noninfectious sources must be ruled out. As discussed, malignancy, autoimmune
disease, drug fever, and other diseases must be evaluated.
can be considered in this patient with septic shock?
The 2013 Surviving Sepsis Campaign: International Guidelines for Management of
Severe Sepsis and Septic Shock consultants developed key recommendations toward
the early goal-directed resuscitation of the septic patient.
include the use of “sepsis bundles”, i.e., multiple interventions taking place at the
same time. Key recommended adjuncts include administration of broad-spectrum
antibiotics within 1 hour of diagnosis of septic shock, administration of either
crystalloid or colloid fluid resuscitation, and norepinephrine or dopamine to maintain
mean arterial pressure of at least 65 mm Hg. In addition, stress-dose steroid therapy
can be given to those patients whose blood pressure is poorly responsive to fluid
resuscitation and vasopressors. While one might expect improved survival with
adherence to such guidelines, the results have been mixed. A large meta-analysis
evaluated the influence of performance improvement programs regarding compliance
with sepsis bundles. These programs have been found to be associated with
increased adherence to resuscitation and management sepsis bundles and with
reduced mortality in patients with sepsis, severe sepsis, or septic shock.
in patients with septic shock who were identified early and received intravenous
antibiotics and adequate fluid resuscitation, hemodynamic management according to a
strict early goal-directed therapy protocol did not lead to an improvement in
A full list of references for this chapter can be found at
http://thepoint.lww.com/AT11e. Below are the key references and websites for this
chapter, with the corresponding reference number in this chapter found in parentheses
Angus DC, van der Poll T. Severe sepsis and septic shock. N EnglJ Med. 2013;369(9):840. (3)
Boucher HW et al. Bad bugs, no drugs: No ESKAPE! An update from the Infectious Diseases Society of
America. Clin Infect Dis. 2009;48(1):1. (44)
shock. Intensive Care Med. 2013;39(2):165. (62)
with Staphylococcus aureus bloodstream infections: a systematic review and meta-analysis. JAMA.
management of community-acquired pneumonia in adults. Clin Infect Dis. 2007;44(Suppl 2):S27. (15)
Rybak MJ et al. Vancomycin therapeutic guidelines: a summary of consensus recommendations from the
Infectious Diseases Pharmacists. Clin Infect Dis. 2009;49(3):325. (37)
correction appears in Clin Infect Dis. 2010;50(12):1695]. Clin Infect Dis. 2010;50(2):133. (13)
Vincent JL et al. Evolving concepts in sepsis definitions. Crit Care Clin. 2009;25(4):665, vii. (1)
Infect Dis. 2013;13(5):426. (4)
COMPLETE REFERENCES CHAPTER 62 PRINCIPLES OF
Vincent JL et al. Evolving concepts in sepsis definitions. Crit Care Clin. 2009;25(4):665, vii.
Lee WL, Slutsky AS. Sepsis and endothelial permeability. N EnglJ Med. 2010;363(7):689.
Angus DC, van der Poll T. Severe sepsis and septic shock. N EnglJ Med. 2013;369(9):840.
Am J Respir Crit Care Med. 2009;179(3):220.
Zarrouk V et al. Evaluation of the management of postoperative aseptic meningitis. Clin Infect Dis.
Lee BE, Davies HD. Aseptic meningitis. Curr Opin Infect Dis. 2007;20(3):272.
Kayoko H et al. Fever of unknown origin: an evidence-based review. Am J Med Sci. 2012;344(4):307.
Horowitz HW. Fever of unknown origin or fever of too many origins? N EnglJ Med. 2013;368(3):197.
Patel RA, Gallagher JC. Drug fever. Pharmacotherapy. 2010;30(1):57.
correction appears in Clin Infect Dis. 2010;50(12):1695]. Clin Infect Dis. 2010;50(2):133.
a systematic review and meta-analysis. Clin Infect Dis. 2014;58(3):330
the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007;44(Suppl 2):S27.
Philadelphia, PA: Elsevier Saunders; 2015.
Testing; Twenty-fifth Informational Supplement. CLSI Document M100-S25. Wayne, PA: CLSI; 2015.
Rev Anti Infect Ther. 2009;7(1):107.
Clin Microbiol. 2009;47(10):3142.
stay, and health care costs. Clin Infect Dis. 2006;42(Suppl 2): S82.
the Infectious Diseases Society of America. Clin Infect Dis. 2008;46(2):155.
Lipsky BA et al. Treatment of bacterial prostatitis. Clin Infect Dis. 2010;50(12):1641.
Mackowiak PA. Influence of fever on pharmacokinetics. Rev Infect Dis. 1989;11(5):804.
Brook I. Inoculum effect. Rev Infect Dis. 1989;11(3):361.
Czock D et al. Pharmacokinetics and pharmacodynamics of antimicrobial drugs. Expert Opin Drug Metab
Mattie H et al. Determinants of efficacy and toxicity of aminoglycosides. J Antimicrob Chemother.
Matske GR et al. Controlled comparison of gentamicin and tobramycin nephrotoxicity. Am J Nephrol.
Rybak MJ et al. Vancomycin therapeutic guidelines: a summary of consensus recommendations from the
of Infectious Diseases Pharmacists. Clin Infect Dis. 2009;49(3):325.
review. Clin Infect Dis. 1997;24(5):810.
Am J Health Syst Pharm. 1996;53(10):1141.
Agents Chemother. 2008;52(11):3994.
Chambers HF et al. Failure of a once-daily regimen of cefonicid for treatment of endocarditis due to
Staphylococcus aureus. Rev Infect Dis. 1984;6(Suppl 4):S870.
endocarditis: impact of protein binding? Ann Pharmacother. 2008;42(2):289.
Boucher HW et al. Bad bugs, no drugs: No ESKAPE! An update from the Infectious Diseases Society of
America. Clin Infect Dis. 2009;48(1):1.
Jassal M, Bishai WR. Extensively drug-resistant tuberculosis. Lancet Infect Dis. 2009;9(1):19.
Comments
Post a Comment
اكتب تعليق حول الموضوع