Antibiotics are grouped into categories on the basis of their
mechanisms of action. These categories include cell-wall active
antibiotics, ribosomal active antibiotics, RNA active antibiotics,
DNA active antibiotics, antimetabolites, and the reducing compounds.
The cell-wall active antibiotics include penicillins, β-lactamase
inhibitors, cephalosporins, other β-lactam antibiotics, and
vancomycin. β-lactamase inhibitors are combined with
the penicillins to enhance the antibiotic activity against β-lactamase-producing
organisms.
Penicillins
The penicillin class of antibiotics is frequently used for the
treatment of musculoskeletal infections. The penicillins can be
divided into general groups on the basis of their antibacterial
activity. The major penicillin groups of interest to an orthopaedic surgeon
are natural penicillins, aminopenicillins, penicillinase-resistant
penicillins, antipseudomonal penicillins (carboxypenicillins), and
extended spectrum penicillins (ureidopenicillins). There is overlap
among these groups; the differences are usually pharmacological
in nature.
The major side effects of all of the penicillins are hypersensitivity reactions
that range in severity from a rash to anaphylaxis1.
Immediate hypersensitivity reactions have been reported to occur
in 0.0004% to 0.15% of patients2.
Of those patients, urticaria occurs in 1% to 5% and
a rash occurs in 2% to 9%. Hemolytic anemia and central
nervous system toxicities can also occur with penicillin administration.
Serum sickness rarely occurs with penicillins. Additionally, exfoliative
dermatitis and erythema multiforme are rare forms of allergic reactions
to penicillin.
Penicillin G is the major natural penicillin. Although penicillin
G has a half-life of thirty to sixty minutes, it can be combined
with procaine or benzathine to produce a repository penicillin.
Penicillin is the drug of choice for the treatment of Streptococcus
pyogenes, Streptococcus agalactiae, and Clostridium
perfringens. In addition, penicillin has a good anaerobic
spectrum of activity except for the Bacteroides fragilis group. Streptococcus
pneumoniae continues to become more resistant to penicillin.
Currently, Streptococcus pneumoniae has an intermediate
resistance to penicillin in 15% of cases and a high-level
resistance to penicillin in 15%.
The major side effects of the natural penicillins are immediate
hypersensitivity reactions, including anaphylaxis, bronchospasm,
and hives, as well as delayed reactions, including skin rashes3. Other potential side effects are renal
failure, Coombs-positive hemolytic anemia, and seizure activity,
which usually occurs with aqueous penicillin doses of >20 ¥ 106 U/day.
The parenteral penicillinase-resistant penicillins are methicillin, nafcillin,
and the isoxazolyl penicillins (including oxacillin, cloxacillin, dicloxacillin,
and flucloxacillin). The most active parenteral semisynthetic penicillins
are nafcillin and oxacillin. These drugs are resistant to Staphylococcal β-lactamase
and are used when methicillin-sensitive Staphylococcus aureus is
present or suspected. The semisynthetic penicillins are also active against Streptococcus
pyogenes and Streptococcus pneumoniae.
However, they have no activity against Enterococcus species or gram-negative
bacilli.
Methicillin is associated with the greatest potential for producing interstitial
nephritis4. Nafcillin and oxacillin
may cause interstitial nephritis, leukopenia, and reversible hepatic
dysfunction5,6. Cloxacillin and
dicloxacillin are the oral semisynthetic penicillins of choice in
the United States, and they have fewer side effects than the parenteral
semisynthetic penicillins.
The major aminopenicillins include ampicillin and amoxicillin.
Ampicillin may be given parenterally or orally, whereas amoxicillin
may be given only orally. The antibacterial activities of the aminopenicillins are
similar. They are the antibiotics of choice for the treatment of
sensitive Enterococcus species (Enterococcus faecalis and Enterococcus
faecium)7. The aminopenicillins
are also active against many highly susceptible gram-negative rods,
such as Escherichia coli and Proteus mirabilis.
They are not stable to β-lactamase and are less active
than penicillin G against Streptococcus pyogenes and Streptococcus
agalactiae. While the aminopenicillins may cause skin rashes,
an idiosyncratic rubella-form rash occurs in 99% of patients
who have mononucleosis and are given the aminopenicillins.
Ticarcillin (carboxypenicillin) is an antipseudomonal penicillin.
Ticarcillin has a β-lactam ring and is susceptible
to β-lactamase of both gram-positive and gram-negative
organisms. Ticarcillin has a gram-negative spectrum of activity
similar to ampicillin but is more active than ampicillin against Pseudomonas
species, Enterobacter species, Serratia species, and certain strains
of the Bacteroides fragilis group. Ticarcillin
has poor activity against Klebsiella species8.
The side effects of this class of penicillins include sodium-loading and
bleeding problems secondary to platelet dysfunction9.
The extended spectrum penicillins (ureidopenicillins) include
mezlocillin and piperacillin. They have an antibacterial spectrum
similar to that of ticarcillin. In vitro, these
antibiotics are active against Enterococcus species and Streptococcus
species, and they inhibit the majority of Klebsiella species. They are
also more active than ticarcillin against Haemophilus influenzae and
the Bacteroides fragilis group10,11.
These drugs act in synergy with the aminoglycosides against Pseudomonas
aeruginosa and most of the Enterobacteriaceae. They have
the same side effects as ticarcillin, except they cause less sodium-loading
and bleeding dysfunction.
Penicillins as a group have a number of drug interactions. However, these
interactions are generally uncommon. The carboxypenicillins and
ureidopenicillins inactivate the aminoglycosides12,13.
This drug interaction is seen in patients who have underlying renal dysfunction14,15. Probenecid inhibits tubular
secretion of the penicillins and increases the drug half-life of
these agents16.
b-lactamase Inhibitors
β-lactamase of gram-positive species is an exoenzyme.
Clavulanic acid, sulbactam, and tazobactam are potent inhibitors
of β-lactamase produced by gram-positive and gram-negative
organisms17. Clavulanic acid,
sulbactam, and tazobactam have been shown to inhibit β-lactamase
for a number of clinically important gram-positive organisms, including Staphylococcus
aureus and Staphylococcus epidermidis18. β-lactamase
of both gram-negative and most anaerobic organisms is situated in
the periplasmic space and is chromosome and plasmid-induced19. Clavulanic acid, sulbactam, and tazobactam
inhibit β-lactamase of many gram-negative organisms,
including Escherichia coli, and most Klebsiella
and Bacteroides species. Currently, clavulanic acid is commercially
available with amoxicillin (Augmentin; SmithKline Beecham Pharmaceuticals,
Philadelphia, Pennsylvania) and ticarcillin (Timentin; SmithKline
Beecham Pharmaceuticals). Sulbactam is available with ampicillin
(Unasyn; Pfizer, New York, NY). Tazobactam is combined with piperacillin (Zosyn;
Lederle, Pearl River, New York). The β-lactam inhibitors enhance
the gram-positive coverage and, to a lesser extent, the gram-negative
spectrum of these antibiotics. The side effects are the same as those
of the penicillin class of antibiotics.
Cephalosporins
The cephalosporins have been divided into first, second, third,
and fourth-generation agents. The first-generation cephalosporins
include cephalothin, cephapirin, cephradine, and cefazolin and are
active against Staphylococcus aureus, Staphylococcus epidermidis, and
Streptococcus species. They have limited gram-negative activity but
are active against Escherichia coli, Klebsiella
species, and Proteus mirabilis. The first-generation
cephalosporins are safe antibiotics but are occasionally associated
with allergic reactions, drug eruptions, phlebitis, and diarrhea.
Cefazolin is the first-generation cephalosporin used by the orthopaedic
community for the treatment of staphylococcal infections, including
osteomyelitis. The large amounts of β-lactamase produced
by Staphylococcus aureus (109 organisms
per gram of tissue) inactivate cefazolin20.
However, high numbers of Staphylococcus aureus are
not the norm in staphylococcal osteomyelitis; £105 organisms per gram of bone are usually
found. Cefazolin has a longer half-life and higher serum concentration
than the other first-generation cephalosporins21.
The remainder of the first-generation cephalosporins are comparable.
They are all more stable to β-lactamase than cefazolin
is.
There are many second-generation cephalosporins, but the major parenteral
ones are cefamandole, cefoxitin, cefotetan, and cefuroxime. The
major oral cephalosporins are cefuroxime, cefprozil, and loracarbef.
The second-generation cephalosporins are somewhat more active against
gram-negative organisms than are the first-generation agents, but
they are less active than the third-generation agents. Cefoxitin and
cefotetan are more active against the anaerobes, especially the Bacteroides
fragilis group, than are the first-generation or the other
second-generation cephalosporins22.
The second-generation cephalosporins have the same toxicity potential
as the first-generation cephalosporins with the exception of those
that have a methylthiotetrazole side chain.
The major third-generation cephalosporins are cefotaxime, ceftriaxone,
ceftizoxime, cefoperazone, and ceftazidime. Compared with the first-generation
cephalosporins, the third-generation cephalosporins are generally
less active against gram-positive organisms but are more active
against the Enterobacteriaceae23.
Cefotaxime, ceftriaxone, and ceftizoxime are third-generation cephalosporins
with similar antibacterial activity. They are highly resistant to β-lactamase,
and they have activity against gram-positive organisms with the
exception of the Enterococcus species. They have good activity against
most gram-negative organisms except for Pseudomonas aeruginosa.
Cefotaxime, ceftizoxime, and ceftriaxone have half-lives of 1.1, 1.7,
and 8.0 hours, respectively.
Ceftazidime is similar to cefotaxime, ceftizoxime, and ceftriaxone
with regard to activity against the Enterobacteriaceae, but it has superior
activity against Pseudomonas aeruginosa24. For serious Pseudomonas
aeruginosa infections, it should be combined with an aminoglycoside25. The activity of ceftazidime against gram-positive
organisms is half that of cefotaxime, ceftizoxime, and ceftriaxone.
The fourth-generation cephalosporins are represented by cefepime. Cefepime
has excellent activity against aerobic gram-positive organisms,
including methicillin-sensitive Staphylococcus aureus, and
gram-negative organisms, including Pseudomonas aeruginosa.
In vitro data have suggested increased activity of cefepime
against multiresistant Enterobacter species. Like other cephalosporins,
cefepime has no activity against Enterococcus species.
In general, the cephalosporins have a low prevalence of adverse
reactions. A cross-reactivity occurs in 3% to 7% of
patients with an allergy to penicillin. This may be a true cross-reactivity
(allergy) or those patients may be more allergic. The allergic reactions
to the cephalosporins include a type-I immediate hypersensitivity
reaction, including bronchospasm, hives, and skin rashes, occurring
three to five days after the initiation of therapy. Fever, lymphadenopathy,
eosinophilia, and serum-sickness reactions may also occur. The cephalosporins
cause a Coombs-positive anemia in approximately 3% of patients.
Neutropenia occurs in approximately 1% of patients, usually
after three weeks of the therapy. Liver function abnormalities,
with elevation of liver enzyme levels, occur in 1% to 7% of patients.
Antibiotic-associated colitis is associated with cephalosporin administration
as well.
Some second and third-generation cephalosporins, including cefotetan and
cefamandole (second generation) as well as moxalactam and cefoperazone
(third generation), have the methylthiotetrazole side chain. Antibiotics
with the methylthiotetrazole side chain can cause a disulfiram reaction
when a patient drinks alcohol26-30,
and they are also associated with hypoprothrombinemia31-35. The cephalosporins have very
few reported drug-drug and drug-food interactions.
Other b-lactam Antibiotics
Aztreonam is a monocyclic β-lactam antibiotic,
which is active against most Enterobacteriaceae and Pseudomonas
aeruginosa36. Aztreonam
has no appreciable antibacterial activity against aerobic gram-positive
or anaerobic bacteria. The drug must be given parenterally. No major
adverse reactions have been reported with this antibiotic37,38. Minor reactions to aztreonam include
nausea, vomiting, and diarrhea. On occasion, the drug may cause
elevated levels of liver transaminases. Aztreonam has a low probability
of cross-reactivity (allergy) in patients allergic to penicillin
or cephalosporin.
Imipenem is an antimicrobial agent belonging to the β-lactam class
of antibiotics. Biochemically, it is a carbapenem. Imipenem also has
excellent in vitro activity against aerobic gram-positive
organisms, including Staphylococcus aureus, Staphylococcus
epidermidis, and Streptococcal species. Imipenem also has
excellent activity against gram-negative organisms, including the
Enterobacteriaceae and Pseudomonas aeruginosa.
In addition, imipenem inhibits most anaerobic species, including the Bacteroides
fragilis group39. Some
patients have nausea, vomiting, and diarrhea with imipenem therapy.
Penicillin cross-reactivity occurs with imipenem. Grand
mal seizures occur in 1% to 4% of patients
receiving this antibiotic. The prevalence of seizures is increased
in patients with renal dysfunction40,41 and/or
a history of seizure activity. Finally, resistance to Pseudomonas
aeruginosa and fungal superinfection may develop during
therapy.
Vancomycin
Vancomycin has excellent activity against Staphylococcus
aureus, Staphylococcus epidermidis, and Enterococcus species.
It is the antibiotic of choice for individuals who are unable to
tolerate either the penicillins or the cephalosporins42. Vancomycin is also the antibiotic of
choice for the treatment of methicillin-resistant Staphylococcus
aureus43 and coagulase-negative
Staphylococcus species44. Recent
reports on vancomycin-resistant Enterococcus species have dictated
increased vigilance and caution45,46.
When used as monotherapy, the end organ toxicity of vancomycin
is minimal. The "red man syndrome"47,48 may be observed with vancomycin therapy.
This syndrome includes flushing of the head, neck, and upper torso
and is often associated with hypotension. It occurs in 5% to 13% of
patients, especially when the infusion is given over less than one
hour. Allergic reactions rarely occur with vancomycin therapy. Vancomycin
may be associated with nephrotoxicity49-52 or
ototoxicity, especially when given concurrently with an aminoglycoside.
Vancomycin may also cause neutropenia53,54 and
thrombocytopenia55,56.
The ribosomal active antibiotics include clindamycin, macrolides, quinupristin/dalfopristin,
tetracyclines, oxazolidinones, and aminoglycosides.
Clindamycin
Clindamycin is one of the antibiotics most active against clinically important
anaerobic bacteria, particularly the Bacteroides fragilis group.
However, clindamycin is ineffective against clostridial species,
other than Clostridium perfringens, in 10% to
20% of cases57. In addition
to its anaerobic activity, clindamycin is also effective against Staphylococcus
aureus, coagulase-negative Staphylococcus species, and
the Streptococcus species. Clindamycin has a half-life of 2.4 hours
and is ideally given every eight hours. Clindamycin demonstrates
good penetration into most tissues, including bone58,59, and penetrates well into abscesses.
Clindamycin is relatively nontoxic but causes diarrhea and pseudomembranous
colitis in approximately 8% of patients60.
In 10% of patients who have antibiotic-associated diarrhea, pseudomembranous
colitis develops secondary to toxins produced by the overgrowth
of Clostridium difficile. Hypersensitivity reactions,
including rashes, urticaria, and erythema multiforme, may occur
with clindamycin administration. Clindamycin drug interactions are
rare, but clindamycin may potentiate the action of neuromuscular
blocking agents61-63.
Macrolides
Erythromycin is the prototype of the macrolide class of antibiotics64. These agents work at the ribosomal
level and are bacteriostatic. Erythromycin has in vitro activity
against Streptococcus species, Listeria monocytogenes, Moraxella
catarrhalis, Mycoplasma pneumoniae,Legionella
pneumophila, and Chlamydia pneumoniae.
The new macrolides (clarithromycin and azithromycin) can inhibit Mycoplasma
pneumoniae, Legionella species, and Chlamydia pneumoniae at
lower concentrations. They are also more active against Haemophilus
influenzae, Mycobacterium avium-intracellulare, and other
atypical mycobacteria. The new macrolides are active against the
agent of Lyme disease, Borrelia burgdorferi. Because
of its high intracellular concentration, azithromycin is more active
against Chlamydia trachomatis and Toxoplasma
gondii and clarithromycin is very active against Helicobacter
pylori. The macrolides are indicated for the treatment
of upper and lower respiratory tract infections and skin structure
infections. The new macrolides are the agents of choice for Mycobacterium
avium-intracellulare infections.
The macrolides are generally considered to be very safe drugs.
They cause gastrointestinal reactions, including nausea, vomiting,
and abdominal cramps, in approximately 20% of patients.
These problems are less frequent with newer erythromycins such as
azithromycin and clarithromycin. The macrolides have a number of
drug interactions. They stimulate hepatic microsomal activity with
cytochrome P-450 complexes. This stimulation causes increased levels
of theophylline, warfarin, cyclosporin, carbamazepine, and cisapride.
Azithromycin has the least drug-interaction potential of the macrolides.
Quinupristin/Dalfopristin
Quinupristin/dalfopristin (Synercid; Aventis, Parsippany,
New Jersey) is a fixed combination of two streptogramins in a ratio
of 30:70. This antibiotic produces in vitro inhibitory
and bactericidal activity against most gram-positive organisms,
including vancomycin-resistant Enterococcus faecium65. Quinupristin/dalfopristin
also has a role in the treatment of methicillin-resistant Staphylococcus
aureus and coagulase-negative Staphylococcus species infections
in patients who cannot tolerate vancomycin therapy. Adverse reactions66 to quinupristin/dalfopristin
appear to be mild and include self-limited local reactions such
as itching, pain, and burning as well as vomiting and diarrhea67. Major side effects are phlebitis, especially
in the smaller veins. The antibiotic should be given through a central
line. In a recent study68, the
drug caused severe myalgia in approximately 15% to 20% of thirty-two
patients who received it.
Tetracyclines
The tetracyclines are divided into three groups: the short-acting
compounds (chlortetracycline, oxytetracycline, and tetracycline),
an intermediate group (demeclocycline), and the more recently developed
longer-acting group (doxycycline and minocycline). The tetracyclines
are primarily bacteriostatic. They are useful drugs for the treatment
of relatively uncommon diseases, including brucellosis and granuloma
inguinale. Tetracyclines are also active against mycoplasma, rickettsia,
and Lyme disease (Borrelia burgdorferi). In addition,
they also are useful in the treatment of chlamydial diseases, including
lymphogranuloma venereum, psittacosis, and trachoma. Minocycline
is the most active drug of the tetracycline class against Staphylococcus
aureus. Minocycline is often used in combination with rifampin
for the oral treatment of methicillin-resistant Staphylococcus
aureus and coagulase-negative Staphylococcus species.
The tetracyclines have excellent tissue distribution probably
because of their high lipid solubility. Minocycline is the most
lipid-soluble tetracycline. The high lipid solubility and diffusion
make it useful for the treatment of metabolically inactive organisms.
Tetracyclines accumulate in bone.
The tetracyclines have major side effects, including anorexia,
nausea, vomiting, and diarrhea. Tetracyclines also cause hepatotoxicity, especially
in pregnant women. They should not be given to children less than
twelve years of age, as they cause gray-brown-yellowish discoloration
of teeth and may impair bone growth in this age-group. Tetracyclines
are catabolic and aggravate preexisting renal failure. They have
a propensity to cause major photosensitivity reactions. Other side
effects include esophageal ulcers and hypersensitivity reactions.
Minocycline causes vestibular toxicity in some patients.
Tetracycline antibiotics have a number of drug interactions.
Divalent metals, including calcium, magnesium, and aluminum (antacids)69-71, when given concurrently, lead
to decreased absorption of the tetracyclines. A number of drugs
increase hepatic metabolism of the tetracyclines, which causes a
decreased half-life of this class of antibiotics.
Oxazolidinones
The oxazolidinones72,73 are
a new synthetic class of antimicrobials. These agents have bacteriostatic
activity against a number of important organisms, including methicillin-resistant Staphylococcus
aureus, penicillin-resistant Streptococcus pneumoniae, and
vancomycin-resistant Enterococcus species74.
They have efficacy when administered either parenterally or orally. Side
effects include tongue discoloration, a folliculitis type of rash, nausea,
vomiting, and diarrhea.
Aminoglycosides
The aminoglycosides, which include gentamicin, tobramycin, amikacin, and
netilmicin, are the standard against which other antibiotics are measured
for the treatment of aerobic gram-negative infections. The aminoglycosides
generally have poor activity against gram-positive organisms. Initially,
they may be used for the treatment of Staphylococcus aureus, but
resistance may develop rapidly75,76.
They have no effect against the Streptococcus species or anaerobes, but
they have excellent activity against the Enterobacteriaceae and Pseudomonas
aeruginosa. The aminoglycosides may be inactivated by enzymatic
modification. Amikacin has fewer available sites than the other
aminoglycosides for enzymatic inactivation. Consequently, the percentage
of strains susceptible to amikacin is greater than that susceptible
to tobramycin, gentamicin, or netilmicin77.
There is no evidence that establishes whether amikacin has greater or
lesser activity than the other aminoglycosides.
The aminoglycosides can cause nephrotoxicity and ototoxicity.
Ototoxicity reactions include hearing loss, tinnitus, ear fullness,
and vestibular problems such as nausea, vomiting, vertigo, nystagmus,
and difficulty with gait. Other aminoglycoside toxicities include
neuromuscular blockade and hypersensitivity reactions.
The aminoglycosides have some drug interactions. There is increased
nephrotoxicity and ototoxicity when cyclosporin, vancomycin, amphotericin
B, ethacrynic acid, neuromuscular blocking agents, nonsteroidal
anti-inflammatory drugs, or radiographic contrast agents are given
concurrently with the aminoglycosides.
Rifampin exhibits bactericidal activity against a wide variety
of gram-positive and gram-negative organisms. Rifampin is the most active
antistaphylococcal agent known78.
However, it is less active against most gram-negative bacteria than are
the aminoglycosides. When rifampin is used alone for the treatment
of bacterial infections, a rifampin-resistant subpopulation rapidly
develops79. Expression of rifampin
resistance can be lessened by the addition of a second effective
antibiotic. Rifampin in combination with a semisynthetic penicillin
has been used to treat osteomyelitis caused by methicillin-sensitive
Staphylococcus species. Trimethoprim-sulfamethoxazole or minocycline
and rifampin have been used to treat osteomyelitis caused by methicillin-resistant
Staphylococcus species.
Side effects of rifampin include orange-red discoloration of
body fluids, gastrointestinal symptoms, hepatitis, and possibly
mild immunosuppression. There are a number of rifampin drug interactions80-82. The co-administration of rifampin with
INH (isoniazid) leads to a higher rate of hepatotoxicity83. Co-administration of rifampin with ketoconazole84 can result in a failure of either drug.
Food interferes with the absorption of rifampin, and this antibiotic
must be taken on an empty stomach. Rifampin induces hepatic microsomal
enzymes and can decrease the level of certain drugs (Table I). Patients
taking these medications must be carefully monitored, and their
drug doses must be adjusted when indicated.
There are four generations of quinolones. The first generation,
nalidixic acid, is used to treat urinary tract infections. The second,
third, and fourth-generation quinolones may be used to treat musculoskeletal infections,
including osteomyelitis85.
The second-generation quinolones include ciprofloxacin and ofloxacin, which
provide adequate serum, tissue, and urine concentrations and have
efficacy against most gram-negative organisms. Most streptococcal
strains and anaerobic organisms are resistant to ciprofloxacin and
ofloxacin. Reports of resistance by some Staphylococcus
aureus and Staphylococcus epidermidis strains
dictate caution. Ciprofloxacin is advantageous in the treatment of
gram-negative bone infections, which previously required prolonged
parenteral antibiotic therapy85.
The third-generation quinolones include levofloxacin and sparfloxacin,
which provide higher serum levels than do either ciprofloxacin or
ofloxacin. These agents have excellent activity against Streptococcus
species, including penicillin-intermediate strains and resistant Streptococcus
pneumoniae. They are also active against atypical respiratory
pathogens (Mycoplasma pneumoniae, Legionella species,
and Chlamydia pneumoniae). They have efficacy against
most gram-negative organisms as well.
The fourth-generation (trovafloxacin) quinolones have aerobic
gram-positive and gram-negative organism coverage similar to that
of the third-generation quinolones, but, unlike the third-generation
quinolones, the fourth-generation quinolones have excellent anaerobic organism
coverage86,87. In a small number
of patients, trovafloxacin has been associated with serious liver
injury leading to liver transplant and/or death. While
this problem has been reported with both short and long-term therapy, treatment
for more than two weeks is associated with an increased risk of
liver injury. Currently, trovafloxacin may be used only for serious life
or limb-threatening infections in a hospital or nursing-care facility.
None of the quinolones have reliable Enterococcus species coverage88. The current quinolones have variable Staphylococcus
aureus and Staphylococcus epidermidis coverage,
and resistance to the second and third-generation quinolones is
increasing89.
Although second, third, and fourth-generation quinolones are
formulated for parenteral administration, oral administration provides
excellent serum concentrations and is associated with a decreased
duration of hospitalization and reduced treatment costs. In most
cases, treatment with quinolone is begun parenterally and, after
one to two days, is switched to oral therapy unless that is contraindicated.
Patients who have not completed puberty should not be treated
with the quinolone class of antibiotics because altered bone growth
has been found in studies on young beagles90.
Overall, the toxicity of the quinolones is low91.
Gastrointestinal disturbances consisting of nausea, vomiting, and/or dyspepsia
occur in 2% to 5% of patients. Central nervous
system reactions, including headache, dizziness, tiredness, and
insomnia, occur in 1% to 2% of patients. The quinolones
may cause hypersensitivity reactions, including skin rashes. Moderate-to-severe
phototoxicity may be caused by some of the quinolones, especially
lomefloxacin and sparfloxacin. The quinolones may also cause tendinitis
and a predisposition to rupture of the Achilles tendon, and, rarely,
this class of antibiotic may cause acute interstitial nephritis.
While all quinolones cause mild toxicity, individual quinolones
have the propensity for certain side effects. Sparfloxacin, for
example, causes prolongation of the Q-T interval (Table II). The quinolones
also have multiple drug-drug interactions92.
Antacids, including sucralfate, iron, zinc, and calcium, decrease the
absorption and the efficacy of most quinolones. Certain quinolones
have specific drug-drug interactions (Table III).
The antimetabolites include the sulfonamides and trimethoprim-sulfamethoxazole.
Trimethoprim-Sulfamethoxazole
Trimethoprim-sulfamethoxazole is a fixed combination of a trimethoprim and
sulfonamide. In vitro, these agents are more active together
than either agent is alone93.
Aerobic gram-negative bacteria, including Escherichia coli,
Proteus mirabilis, Haemophilus influenzae, and Stenotrophomonas
maltophilia, are consistently susceptible. In addition, Klebsiella
pneumoniae, Enterobacter species, Serratia marcescens, indole-positive
Proteus, and nonaeruginosa Pseudomonas are frequently susceptible.
The principal targets of trimethoprim-sulfamethoxazole are aerobic
gram-negative organisms, but some gram-positive bacteria such as Staphylococcus
aureus, Streptococcus pneumoniae, and Streptococcus
pyogenes are often susceptible94.
In some hospitals, the combination of trimethoprim-sulfamethoxazole and
rifampin may be effective for the oral treatment of methicillin-resistant Staphylococcus
aureus and Staphylococcus epidermidis95. Trimethoprim-sulfamethoxazole may
be given either parenterally or orally. The combination is useful
as suppressive therapy for osteomyelitis.
All of the sulfonamides, including trimethoprim-sulfamethoxazole, have
multiple side effects, including gastrointestinal disturbances.
Other side effects include blood dyscrasias such as acute hemolytic
anemia, glucose-6-phosphate dehydrogenase deficiency problems, agranulocytosis,
aplastic anemia, and thrombocytopenia. Hypersensitivity reactions
include erythema multiforme, urticaria, and erythema nodosum. The
sulfonamides may cause a focal or diffuse hepatitis and neurologic
symptoms consisting of headache, confusion, and peripheral neuropathy.
A serum-sickness-like syndrome can occur with the sulfonamides,
and a drug fever occurs in 3% of patients taking these
drugs. The sulfonamides have also been reported to cause nephrotoxicity
and pruritus without a rash. Trimethoprim-sulfamethoxazole should
not be administered during the last month of pregnancy.
The sulfonamides have a number of drug interactions, which include increased
anticoagulation effects of warfarin96,97 and
increased levels of phenytoin98.
They also potentiate the hypoglycemic effects of the sulfonylurea compounds99-102. Finally, the sulfonamides potentiate
the bone-marrow suppression by methotrexate103.
Metronidazole is a useful and inexpensive antibiotic for the
treatment of anaerobic organisms. This antibiotic is a reducing
compound that leads to the formation of toxic oxygen radicals. Toxic
oxygen radicals are lethal for strict anaerobic organisms, since
they lack the protective enzymes superoxide dismutase and catalase.
Metronidazole is active against all anaerobic organisms except for
actinomycetes and microaerophilic streptococci104.
The drug is absorbed well and penetrates into tissues and abscesses.
Side effects are rare but can include metallic taste, seizures,
cerebellar dysfunction, disulfiram reaction with alcohol, and pseudomembranous
colitis. Metronidazole may also have gastrointestinal side effects,
including anorexia, nausea, vomiting, diarrhea, abdominal pain, and
pancreatitis.
In selecting specific antibiotics for the treatment of musculoskeletal infections,
the type of infection, hospital sensitivity patterns, and risk of adverse
reactions must be appraised. Once the infecting organism or organisms
are isolated and the sensitivities are established, the initial
antibiotic regimen should be modified, if indicated. The initial choices
of antibiotics for gram-positive, gram-negative, and anaerobic organisms
are shown in Tables IV, V, and VI. The initial antibiotic regimen
is modified, if necessary, on the basis of culture and sensitivity
results.
Sensitivity Testing
Once the organism or organisms are isolated, the specific antibacterial
activity of a variety of antibiotics can be determined by appropriate
sensitivity techniques. The disk diffusion method is commonly used
for susceptibility testing for fastidious and slow-growing organisms.
The diameter of a zone of inhibition around an antimicrobial-impregnated
paper disk relates approximately linearly to the antibiotic’s
log2 mean inhibitory concentration. Inhibition diameters are interpreted
as signifying susceptibility, intermediate susceptibility, or resistance
to each antimicrobial agent tested according to published criteria105. Quantitative data are provided
by methods that incorporate serial dilution of antibiotics in agar-containing
or broth culture media.
Quantitative sensitivity testing by macrodilution or microdilution techniques
is a prerequisite for the determination of the lowest concentration
of the antibiotic required to inhibit (mean inhibitory concentration)
and kill (mean bactericidal concentration) the isolated organism
or organisms106. Clinical prejudice
demands selection of an antibiotic or antibiotic combination with
a low mean inhibitory concentration-to-mean bactericidal concentration
ratio relative to its expected serum concentration. Most clinical
laboratories report only mean inhibitory concentrations.
Serum-cidal Concentrations
Peak and trough serum bacteriostatic and bactericidal levels,
as described by Schlicter and MacLean107,
are often employed to assess the bacteriostatic and bactericidal capabilities
of the treatment antibiotic or antibiotics. Initially, serum samples
are obtained from the patient after administration of a dose of
the antibiotic in order to obtain the peak and trough serum levels.
The serum samples are then serially diluted, and the dilution fractions
are tested against an inoculum of the infecting bacterial species.
With use of this method, one can estimate the antibiotic dose necessary
to obtain adequate serum inhibitory and bactericidal antibiotic
levels. These results are expressed as minimum inhibitory dilutions
and minimum serum bactericidal dilutions. The interpretation criteria
and importance of the data vary among different laboratories108-110. Most investigators strive
for a peak minimum serum bactericidal dilution of 1:8 (that is,
an eightfold or higher dilution of a patient’s serum has
a bactericidal effect on the infecting bacterial species or strain)111. In children with osteomyelitis, minimum
serum bactericidal dilutions have been utilized to ensure the adequacy
of oral antibiotic therapy112.
In a typical patient with osteomyelitis for whom optimal antibiotics are
selected by mean inhibitory concentration testing, the likelihood of
success is governed by the adequacy of débridement rather
than by the adequacy of serum-cidal levels.
Antibiotics in Pregnancy
All antibiotics must be used with caution in pregnancy113. Antibiotics that have the best safety
record include penicillins, cephalosporins, and erythromycin. Other
antibiotics can cause problems; the aminoglycosides, for instance,
can cause deafness. The sulfonamides, when given in the third trimester,
displace bilirubin from albumin leading to kernicterus. The tetracyclines
alter bone growth in the baby and can cause pancreatitis and liver
dysfunction in the mother. Metronidazole is carcinogenic in rats.
The quinolones alter cartilage growth in juvenile animals. Rifampin,
trimethoprim, and clarithromycin are either teratogenic in rodents
or cause adverse outcomes in nonhuman primates.
Antibiotics in Nursing Mothers
Many antibiotics, such as sulfonamides, quinolones, and chloramphenicol,
appear in breast milk when administered to lactating women and can
have adverse effects on infants. It is prudent for the mother to
discontinue breast-feeding temporarily during antibiotic therapy,
while maintaining milk flow by means of a breast pump. If there
is any question concerning a specific antibiotic, specific references
or specialists should be consulted114.
The duration of antibiotic therapy varies according to the type
of musculoskeletal infection (cellulitis, erysipelas, septic arthritis,
or osteomyelitis in a long bone or a diabetic foot).
Cellulitis and Erysipelas
Among the musculoskeletal infections, cellulitis and erysipelas
need the shortest duration of antibiotic therapy (ten to fourteen
days)115. Parenteral therapy can
be changed to oral therapy when the patient is clinically stable.
Erysipelas has a higher relapse rate, and a longer course of parenteral
therapy is usually recommended for this specific soft-tissue infection.
Septic Arthritis
Septic arthritis is treated with parenteral antibiotic therapy,
usually for two to three weeks after aspiration or arthroscopic
or open débridement116,117.
A two-week course can be given when the septic arthritis is caused by
organisms that are very susceptible to antibiotic therapy, including Haemophilus
influenzae, Streptococcus species, and Neisseria
gonorrhoeae. For the more resistant organisms, including Staphylococcus
aureus and gram-negative bacilli, three weeks of parenteral
antibiotic therapy is usually given.
Osteomyelitis
Osteomyelitis is traditionally treated with parenteral antibiotic therapy,
usually for four to eight weeks after the last major débridement.
Many open-label studies but few randomized studies have justified
the current duration of osteomyelitis treatment. The best data on this
subject come from animal models. With use of an experimental Staphylococcus
aureus osteomyelitis model, Norden and Dickens treated
groups of animals with cephaloridine for two, four, or six weeks118. The longer that the animals were treated
with cephaloridine, the better the treatment results. The animal model
used in that study is not amenable to surgery; antibiotics alone must
eradicate the infection. Parenteral antibiotic therapy has been
investigated in eight randomized studies119-125.
The arrest rates associated with four to eight weeks of parenteral antibiotic
therapy in those studies ranged from 50% to 100%.
The optimal duration of antibiotic therapy has not been clearly
determined.
Streamlining from parenteral to oral therapy may be an effective alternative
strategy for the treatment of osteomyelitis. In a historical control
study by Swiontkowski et al.126,
ninety-three patients were managed with five to seven days of parenteral
therapy followed by six weeks of oral therapy. Treatment was successful
in 91% (seventy-nine) of the eighty-seven who were able
to be followed. In a randomized study of the treatment of long-bone
osteomyelitis, Shirtliff et al.127 compared
four weeks of parenteral antibiotic therapy with two weeks of parenteral
therapy followed by four weeks of oral antibiotic therapy. The arrest
rate was 84.3% in the group that received parenteral antibiotic
therapy and 89.5% in the group managed with parenteral antibiotic
therapy followed by oral antibiotic therapy.
The current recommendation for the duration of antibiotic therapy
in the treatment of long-bone osteomyelitis is four to six weeks.
Children are given two weeks of parenteral therapy followed by four
weeks of oral therapy. The traditional treatment for adults is four
to six weeks of parenteral therapy. However, many centers use two
weeks of parenteral therapy followed by four to six weeks of oral
therapy.
Osteomyelitis in the Diabetic Foot
The duration of antibiotic treatment of osteomyelitis in the
diabetic foot is usually based on the type of surgical therapy128. When surgical therapy is not possible
or is unacceptable, the patient can be treated with long-term oral antibiotic
suppressive therapy. When osteomyelitis is in a bone that is amenable
to débridement, the infection may be debrided and four to
six weeks of antibiotic therapy should be administered after surgery.
When the patient is managed with ablative therapy and the entire bone
containing the osteomyelitis is removed, antibiotics are given for two
weeks in order to treat any residual soft-tissue infection. When the
infected bone is transected, the patient is given four to six weeks
of culture-directed antibiotic therapy. Finally, when amputation
is performed remote to the site of infection, the patient is treated
with a short course of antibiotic therapy, which is usually less
than three days. Occasionally, a diabetic patient with osteomyelitis
of the foot is treated with long-term oral antibiotic therapy for
eradication of the infection. This is possible only for the treatment
of osteitis (involvement of the outer cortex of the bone). Eradication
of full-thickness osteomyelitis with long-term antibiotic therapy
probably is not possible.
Note: The authors thank Kristi Overgaard, Melinda Stevens, Donna
Milner Mader, JD, and the late Stephen C. Bergquist, MS, for their
assistance in the research and preparation of this manuscript.
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