Antimicrobial Treatment of Chronic Osteomyelitis - Lippincott ...

CLINICAL ORTHOPAEDICS AND RELATED RESEARCH 

Number 360, pp 47-65 

0 1999 Lippincott Williams & Wilkins, Inc. 

Antimicrobial Treatment of 

Chronic Osteomyelitis 

Jon T. Mader, MD*j**>P$; Mark E. Shirtliff, BS**j$; 

Stephen C. Bergquist, MSIk and Jason Calhoun, MDY 

Chronic osteomyelitis has been a difficult 

problem for patients and the treating physicians. 

Appropriate antibiotic therapy is necessary 

to arrest osteomyelitis along with adequate 

surgical therapy. Factors involved in 

choosing the appropriate antibiotic(s) include 

infection type, infecting organism, sensitivity 

results, host factors, and antibiotic characteristics. 

Initially, antibiotics are chosen on the 

basis of the organisms that are suspected to be 

causing the infection. Once the infecting organism(s) 

is isolated and sensitivities are established, 

the initial antibiotic(s) may be modified. 

In selecting specific antibiotics for the 

treatment of osteomyelitis, the type of infection, 

current hospital sensitivity resistance 

patterns, and the risk of adverse reactions 

must be strongly appraised. Antibiotic classes 

used in the treatment of osteomyelitis include 

penicillins, p-lactamase inhibitors, cephalosporins, 

other p-lactams (aztreonam and imipenem), 

vancomycin, clindamycin, rifampin, 

aminoglycosides, fluoroquinolones, trimethoprim-sulfamethoxazole, 

metronidazole, and 

new investigational agents including teicoplanin, 

quinupristiddalfopristin, and oxazolidinones. 

Traditional treatments have used operative 

procedures followed by 4 to 6 weeks of 

From the Divisions of *Infectious Diseases and **Marine 

Medicine, Marine Biomedical Institute, Departments 

of $Internal Medicine, §Microbiology and Immunology, 

IIPharmacy, and 9Orthopaedic Surgery, 

University of Texas Medical Branch, Galveston, TX. 

Reprint requests to Jon T. Mader, MD, Surgical Infectious 

Diseases Hyperbaric Facility, New Trauma Building, 

University of Texas Medical Branch, Galveston, 

TX 77555-1 115. 

parenteral antibiotics. Adjunctive therapy for 

treating chronic osteomyelitis may be achieved 

by using beads, spacers, or coated implants to 

deliver local antibiotic therapy andlor by using 

hyperbaric oxygen therapy (once per day for 

90-120 minutes at two to three atmospheres at 

100% oxygen). 

Based on etiologic considerations, bone infections 

traditionally have been classified as 

either hematogenous osteomyelitis, osteomyelitis 

secondary to a contiguous focus 

of infection, or chronic osteomyelitis.g* Contiguous 

focus osteomyelitis has been subdivided 

further into osteomyelitis in patients 

having normal vascularity and those having 

generalized vascular insufficiency. All etiologic 

classes of osteomyelitis may progress 

to a chronic disease process. 

Appropriate antibiotic therapy is necessary 

to arrest osteomyelitis along with adequate 

surgical therapy. Factors involved in 

choosing the appropriate antibiotic(s) include 

infection type, infecting organism, 

sensitivity results, host factors, and antibiotic 

characteristics. Initially, antibiotics are 

chosen on the basis of the organisms that are 

suspected to be causing the infection. Later, 

when an infecting organism is isolated and 

sensitivities are established, the initial antibiotic(s) 

may be modified. 

In hematogenous osteomyelitis one organism 

usually is responsible for the infec- 

47

48 Maderetal 

tion with Staphylococcus aureus being the 

most common isolate. In contrast to 

hematogenous osteomyelitis, more than one 

pathogen usually is isolated in contiguous 

focus osteomyelitis and chronic osteomyelitis. 

In contiguous focus osteomyelitis, 

Staphylococcus aureus is the 

most commonly isolated pathogen, but aerobic 

Gram negative rods and anaerobic organisms 

often are found. 

BACTERIAL ANTIBIOTIC 

RESISTANCE 

Beta-lactamase production primarily is mediated 

by plasmids. This enzyme is responsible 

for the resistance approximately 90% of 

Staphylococcus aureus isolates to penicillin. 

Of the penicillins, the penicillinase resistant 

semisynthetic penicillins have become the antistaphylococcal 

drugs of choice because of 

their stability in the presence of Staphylococcus 

aureus P-lactamase. 

Intrinsic resistance is chromosomally mediated 

and heterogeneous. This type of resistance 

is present in only a small percentage of a 

given Staphylococcus aureus inoculum. Methicillin 

resistant Staphylococcus aureus and 

Staphylococcus epidermidis are the significant 

examples of intrinsic resistance. These 

isolates are resistant to the semisynthetic 

penicillins and to the cephalosporins. The expression 

of this intrinsically resistant subpopulation 

can be enhanced by altering several 

cultural conditions such as the use of agar 

containing high salt concentrations and incubation 

at 30" C.77 Methicillin resistant Staphylococcus 

aureus and methicillin resistant 

Staphylococcus epidermidis are isolated frequently 

in large tertiary care hospitals and 

nursing homes.85 

Tolerance of organisms to antibiotics is understood 

poorly. It is an in vitro phenomenon 

characterized by resistance to the lethal action 

of a normally bactericidal drug. There is a 

marked discrepancy between the mean inhibitory 

concentration and mean bactericidal 

concentration of the bactericidal antibiotic to 

Clinical Orthopaedics 

and Related Research 

the organism. A functional definition of tolerance 

is a mean bactericidal concentration that 

is 32-fold or greater than the mean inhibitory 

concentration.76 The clinical significance of 

tolerance is still controversial. One study suggested 

that seriously ill patients who are 

treated with an antimicrobial to which the infecting 

organism was tolerant did less well 

than patients treated with bactericidal therapy.53 

The existence of tolerance is another 

reason to perform mean inhibitory concentration 

and mean bactericidal concentration testing 

on all pathogens isolated from infected 

bone. 

Chronic osteomyelitis or infected joints 

with replacements are treated for 4 to 6 weeks 

or more. 1.6,29,36,38-41,45 These lengthy antibiotic 

regimens become even more problematic 

when the patient is infected with methicillin 

resistant Staphylococcus aureus, vancomycin 

resistant enterococcus, or other multiresistant 

bacterial species. In particular, because some 

methicillin resistant Staphylococcus aureus 

strains are resistant to all current antibiotics 

except vancomycin, these infections must be 

resolved with parenteral vancomycin treatment 

with its associated clinical toxi~ity.55,~~ 

Also, it has been shown in the laboratory that 

the vancomycin resistance gene cluster found 

in Enterococcus faecalis can be transferred to 

Staphylococcus aureus via conjugation and 

can express high level resistance.53 Vancomycin 

resistance also has been seen in serial 

passaged Staphylococcus aureus laboratory 

isolates and has been found in the clinical 

setting in Japan, New Jersey, and Oregon. 

Therefore, vancomycin, the last chance antimicrobial 

for many strains of methicillin resistant 

Staphylococcus aureus, soon may become 

ineffective because of the development 

of resistant strains. 

SENSITIVITY TESTING 

Once the organism(s) is isolated, the specific 

antibacterial activity of various antibiotics 

can be determined by appropriate sensitivity 

techniques. The disk diffusion method is the

Number 360 

March, 1999 Antimicrobial Treatment of Osteomyelitis 49 

most commonly used method for susceptibility 

testing. The diameter of a zone of inhibition 

around an antimicrobial impregnated paper 

disk relates approximately linearly to the 

antibiotic’s log, mean inhibitory concentration. 

Inhibition diameters are interpreted as 

signifying susceptibility, intermediate susceptibility, 

or resistance to each antimicrobial 

agent tested according to published criteria.54 

Standard procedures must be followed for 

these criteria to retain their validity. The interpretive 

criteria only apply to organisms that 

grow rapidly. The disk diffusion method is 

simple to perform and relatively inexpensive. 

However, the method provides only semiquantitative 

or qualitative data about the susceptibility 

of a given organism to a given antibiotic. 

Nonetheless, if the test is done 

carefully, it provides information that is clinically 

useful. Quantitative data are provided by 

methods that incorporate serial dilution of antibiotics 

in agar containing or broth culture 

media. Quantitative sensitivity testing by 

macro or microdilution techniques is a prerequisite 

for the determination of the least concentration 

of the antibiotic required to inhibit 

(mean inhibitory concentration) and kill 

(mean bactericidal concentration) the isolated 

organisms.14 Clinical prejudice demands selection 

of an antibiotic or antibiotic combination 

having a low mean inhibitory concentration 

and mean bactericidal concentration 

activity relative to its expected serum concentration. 

Quantitative testing is useful for selecting 

antibiotics for difficult aerobic infections 

and/or where therapy will be prolonged. 

Selection of the best antibiotic or antibiotic 

combination is crucial in these situations. It is 

reasonable to use quantitative testing to determine 

the best antibiotic therapy for osteomyelitis, 

septic joint infections, and prosthetic 

joint infections. Quantitative testing of 

anaerobic organisms is not yet standardized. 

BACTERICIDAL LEVELS 

Peak and trough serum bacteriostatic and 

bactericidal levels described by Schlicter 

and MacLean** often are used to assess the 

bacteriostatic and bactericidal capabilities of 

the treatment antibiotic(s). Initially, patient 

serum samples are obtained after dosing to 

obtain the peak and trough serum levels. The 

serum samples then are diluted serially and 

the dilution fractions are tested against an inoculum 

of the infecting bacterial species. 

Using this method, one can obtain an estimation 

of the antibiotic dose necessary to obtain 

adequate serum inhibitory and bactericidal 

antibiotic levels. These results are expressed 

as minimal inhibitory dilutions and minimum 

serum bactericidal dilutions. The interpretation 

criteria and significance of the data 

vary for different laboratories and a standard 

uniform system for minimal inhibitory dilutions 

and minimum serum bactericidal dilutions 

studies currently is needed.68J1.90 Most 

investigators strive for a peak minimum 

serum bactericidal dilution of 1:8 or greater 

(eightfold or higher dilution of patient’s 

serum still is capable of having a bactericidal 

effect on the infecting bacterial species or 

strain).74 In patients with osteomyelitis, 

serum bactericidal concentrations have been 

used to verify the likelihood of treatment 

success, especially when second choice antibiotics 

are necessary for treatment in patients 

with drug allergie~.3~ Minimum serum 

bactericidal dilutions also have been used to 

ensure the adequacy of oral antibiotic ther- 

In a typical patient with osteomyelitis 

where optimal antibiotics are selected by 

mean inhibitory concentration testing, the 

likelihood of success is governed by the adequacy 

of debridement surgery rather than by 

the adequacy of serumcidal levels. 

ANTIBIOTIC CHARACTERISTICS 

In selecting specific antibiotics for the treatment 

of osteomyelitis, the type of infection, 

current hospital sensitivity and resistance 

patterns, and the risk of adverse reactions 

must be appraised strongly. No one antibiotic 

or antibiotic combination can be expected 

to be effective in all clinical settings.

50 Maderetal 

Antibiotic factors that may lead to the decreased 

activity of antibiotics include pH, 

the presence of purulent material, and decreased 

blood flow.56 It has been shown that 

the aminoglycosides such as gentamicin, tobramycin, 

amikacin, and netilmicin are less 

active under anaerobic, acidic, and hypercapnic 

conditions. Although agents may diffuse 

into infected tissue, the conditions present 

in the area may reduce significantly the 

ability of these antibiotics to eradicate sensitive 

organisms.71.96 

There are also organism factors that must 

be considered in the treatment of osteomyelitis. 

The most common organism involved 

in osteomyelitis is Staphylococcus 

aureus, which has three recognized types of 

staphylococcal resistance: P-lactamase production, 

intrinsic resistance, and tolerance.79 

ANTIBIOTICS 

The initial choice of antibiotics for Gram 

positive, Gram negative, and anaerobic organisms 

are shown in Tables 1, 2, and 3. The 

initial antibiotic regimen is modified, if necessary, 

by the culture and sensitivity results. 

Penicillins 

The penicillin class of antibiotics frequently 

is used for the treatment of osteomyelitis. 

The penicillins can be divided into general 

groups on the basis of their antibacterial activity. 

Overlap exists among the groups, but 

the differences within a group are usually of 

a pharmacologic nature, although one compound 

within a group may be more active 

than another. The major penicillin groups of 

interest to an orthopaedic surgeon are natural 

penicillins, aminopenicillins, penicillinase 

resistant penicillins, antipseudomonal penicillins, 

and extended spectrum penicillins. 

Penicillin G is the major natural penicillin. 

Penicillin G has a half life of 30 to 60 minutes, 

but it can be combined with procaine or 

benzathine to make a repository penicillin. 

This antimicrobial negatively interacts with 

erythromycin and tetracyclines to reduce an- 



timicrobial effectiveness. Penicillin is the 

drug of choice for the treatment of Streptococcus 

pyogenes and Streptococcus agalactiae. 

However, Streptococcus pneumoniae 

continues to become more resistant to penicillin. 

Currently, Streptococcus pneumoniae 

has an intermediate resistance of 28% and a 

high level resistance of 16% to penicillin. In 

addition, penicillin has a good anaerobic 

spectrum of activity except for the Bacteroides 

fragilis group. Penicillin G is a drug 

of choice for the treatment of Clostridia perfringens. 

The parenteral penicillinase resistant 

penicillins include methicillin, nafcillin, and 

the isoxazolyl penicillins (including cloxacillin, 

dicloxacillin, flucoxacillin, and oxacillin). 

These drugs are resistant to staphylococcal 

P-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, 

but they have no activity against Enterococcus 

species or Gram negative bacilli. 

The most active parenteral semisynthetic 

penicillins are nafcillin and oxacillin. Nafcillin 

and oxacillin may cause interstitial 

nephritis, leukopenia, and reversible hepatic 

dysfunction.29.66 Methicillin is associated 

with the greatest potential for producing interstitial 

nephritis.IO4 Cloxacillin and dicloxacillin 

are the oral semisynthetic penicillins 

of choice. 

The major aminopenicillins include ampicillin 

and amoxicillin. Ampicillin may be 

given parenterally or orally, whereas amoxicillin 

is only an oral agent. The antibacterial 

activity of the aminopenicillins is similar. 

They are not stable to P-lactamase, and are 

less active than penicillin G against Streptococcus 

pyogenes and Streptococcus agalactiae. 

They are the antibiotics of choice for the 

treatment of Enterococcus species (Enterococcus 

faecalis, Enterococcus faecium).55 The 

aminopenicillins are also active against many 

highly susceptible Gram negative rods, such 

as Escherichia coli and Proteus mirabilis.

Number 360 


TABLE 1. Gram Positive Organisms: Initial Choice of Antibiotics for Therapy 

(Adult Doses) 

Organism First Choice Antibiotics Alternative Antibiotics 

Methicillin sensitive 

Staphylococcus aureus or 

Coagulase negative 

Staphylococcus species 

Methicillin Resistant 

Staphylococcus aureus or 

Coagulase negative 

Staphylococcus species 

Group A streptococcus 

Streptococcus pyogenes 

Group B streptococcus 

Streptococcus agalactiae 

Penicillin Sensitive 

Streptococcus pneurnoniae 

Intermediate Penicillin Resistance 


Penicillin Resistant 


Enterococcus species 

Nafcillin 2 g every 6 hours or 

Clindarnycin 900 rng every 8 hours 

Nafcillin 2 g every 6 hours or 

Clindarnycin 900 rng every 8 hours 

Vancornycin 1 g every 12 hours 

Vancornycin 1 g every 12 hours or 

Clindarnycin 900 ever 8 hours** 

Penicillin G 2 rnU every 4 hours 



Cefotaxirne 1 g every 6 hours 


L-Ofloxacin 500 rng daily 

Ampicillin 1 g every 6 hourst 


Cefazolin 

Vancornycin 

Cefazolin 

Vancornycin 

SXT* or Minocycline k Rifarnpin 

SXT* or Minocycline k Rifarnpin 

Clindamycin, Cefazolin, Vancornycin 

Clindarnycin, Cefazolin, Vancornycin 

Erythromycin, Clindarnycin 

Erythromycin, Clindarnycin 

Sparfloxacin 

Ampicillin-Sul bactarn 

*Sulfamethoxazole-Trimethoprim 

**Dose every 8 hours if sensitive to Clindamycin 

+In a serious Enterococcus species infection ampicillin + Sulbactam plus an aminoglycoside is used 

Ticarcillin is an antipseudomonal penicillin. 

Ticarcillin has a p-lactam ring and is 

susceptible to P-lactamase of 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 

species.57 Side effects include sodium 

loading and bleeding problems because of 

platelet dysfunction.59 

The extended spectrum penicillins include 

mezlocillin and piperacillin. These 

penicillins have an antibacterial spectrum 

similar to ticarcillin. In vitro, these antibiotics 

are active against Enterococcus 

species, Streptococcus species and they inhibit 

the majority of Klebsiella species. They 

are also more active than ticarcillin against 

Haemophilus influenza and the Bacteroides 

fragilis group.19367 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. 

P-lactamase Inhibitors 

Clavulanic acid, sulbactam, and tazobactam 

are potent inhibitors of P-lactamase produced 

by Gram positive and Gram negative 

organisms.58 Beta-lactamase of Gram positive 

species are exoenzymes. Clavulanic 

acid, sulbactam, and tazobactam have been 

shown to inhibit P-lactamase for numerous 

clinically important Gram positive organisms 

including Staphylococcus aureus and 

Staphylococcus epidermidis.70 Beta-lacta-

52 Maderetal 



TABLE 2. Gram Negative Organisms: Initial Choice of Antibiotics for Therapy 

(Adult Doses) 

Organism Antibiotics of First Choice Alternative Antibiotics 

Acinetobacter species 

Enterobacter sDecies 

Escherichia coli 

Haemophilus influenza 

Klebsiella species 

Proteus mirabilis 

Proteus vulgaris 

Proteus rettgeri or 

Morganella morganii 

Neisseria gonorrhea 

Providencia species 

Pseudomonas aeruginosa 

Serratia marcescens 

Ceftazidime 1 g every 8 hours 

Cefotaxime 1 g every 8 hours; Mezlocillin; 

Ceftazidime 

Ampicillin 1 g every 6 hours; Gentamicin; SXT* 

Cefotaxirne 1 g every 8 hours; Ampicillinsulbactam; 

SXT* 

Cefazolin 2 g every 8 hours: Cefotaxime 

Ampicillin 1 g every 6 hours; Gentarnicin 

Cefotaxirne 2 g every 8 hours 

Ceftriaxone 125 mg 

Cefotaxime 2 g intravenously every 8 hours 

Gentamicin 1.67 mg/kg every 8 hours 

Ceftazidirne* 2 g every 8 hours or Ciprofloxacin* 

400 mg every 12 hours Piperacillin* 3 g 

every 6 hours 

Cefotaxime 2 g every 8 hours 

Gentamicin, lmipenem 

L-Ofloxacin, Gentamicin 

Cefazolin, L-Ofloxacin 

Ampicillin,** L-Ofloxacin 

L-Ofloxacin, Gentamicin 

L-Ofloxacin, Cefazolin 

Mezlocillin, L-Ofloxacin, or 

Gentamicin 

Doxycycl i ne, L-Of loxac i n, 

Ampicillin 

SXT* Tobramycin 

Ticarcillin Clavulanic Acid 

Ticarcillin Clavulanic Acid 

Tobramycin, lrnipenern 

Ofloxacin, Gentamicin 

'Sulfamethoxazole-Trimethoprim 

"Nonp-lactarnase producing strain of Haernophilus influenzae 

tNonpenicillinase producing strain of Neisseria gonorrhea 

*In a serious infection should be used with an aminoglycoside-Gentamicin or Tobramycin 5 mglkg per day every 8 hours 

mase of Gram negative and most anaerobic 

organisms is situated in the periplasmic 

space and is chromosome and plasmid induced.73 

Clavulanic acid, sulbactam, and 

tazobactam will inhibit P-lactamase of many 

Gram negative organisms including most Escherichia 

coli, Klebsiella species, and Bac- 

teroides species. Currently, clavulanic acid is 

commercially available with amoxicillin 

(AugmentinB Smithkline Beecham, Philadelphia, 

PA), and ticarcillin (Timentin@, 

Smithkline Beecham). Sulbactam is available 

with ampicillin (UnasynB, Pfizer Inc, 

New York, NY). Tazobactam is combined 

TABLE 3. Anaerobic Organisms: Initial Choice of Antibiotics for 

Therapy (Adult Doses) 

Organism Antibiotic of First Choice Alternative Antibiotics 

Bacteroides fragilis group Clindamycin 900 rng every 8 hours Ampicillin-sulbactam, 

Metronidazole 500 rng every 8 hours Ticarcillin-clavulanic acid 

Prevotella species Clindamycin 900 mg every 8 hours Ampicillin-sulbactam, 

Cefotetan 

Peptostreptococcus species 

Metronidazole 500 mg every 8 hours 

Penicillin G 2 mU every 4 hours 

Ticarcillin-clavulanic acid 

Clindarnycin, Metronidazole 

Cefotetan 

Clostridiurn species Clindarnycin 900 mg every 8 hours Metronidarole, Penicillin

Number 360 


with piperacillin (Zosyna), Wyeth-Ayerst 

Laboratories, Philadelphia, PA). The p-lactam 

inhibitors enhance the Gram positive 

coverage and to a lesser extent the Gram 

negative spectrum of these 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 Eschericia coli, Klebsiella species, 

and Proteus mirabilis. The first generation 

cephalosporins are safe antibiotics, but occasionally 

are associated with the production 

of allergic reactions, drug eruptions, 

phlebitis, and diarrhea. Cefazolin is the first 

generation cephalosporin most widely used 

by the orthopaedic community for the treatment 

of staphylococcal infections, including 

osteomyelitis. Large amounts of p-lactamase 

produced by Staphylococcus aureus ( lo9 organisms 

per gram tissue) will inactivate 

cefazolin.17 However, high numbers of 

Staphylococcus aureus are not the norm in 

staphylococcal osteomyelitis where lo5 or 

less organisms per gram of bone usually are 

found. Cefazolin has a longer half life and 

higher serum concentration than the other 

first generation cephalosporins.36 The remainder 

of the first generation cephalosporins 

is comparable. They are all more stable 

to P-lactamase than they are to cefazolin. 

There are many second generation 

cephalosporins, but the major ones include 

cefamandole, cefoxitin, cefotetan, cefuroxime, 

ceforanide, and cefonicid. The second 

generation cephalosporins have somewhat 

increased activity against Gram negative organisms 

as compared with the first generation, 

but are less active than the third generation 

agents. Cefoxitin and cefotetan are 

more active than the other first or second 

generation cephalosporins against the anaer- 

obes, especially the Bacteroides fragilis 

group.35 

The major third generation cephalosporins 

include: cefotaxime, ceftriaxone, ceftizoxime, 

cefoperazone, and ceftazidime. The 

third generation cephalosporins are generally 

less active than the first generation 

cephalosporins against Gram positive organisms, 

but are more active against the enterobacteriaceae.95 

Cefotaxime, ceftriaxone, and 

ceftizoxime and are third generation 

cephalosporins with similar antibacterial activity. 

They are highly resistant to p-lactamase, 

and 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 hours, respectively. 

Ceftazidime is similar in activity to cefotaxime, 

ceftizoxime, and ceftriaxone against 

the Enterobacteriaceae, but it has superior 

activity against Pseudomonas aeruginosa. It 

inhibits approximately 9 1 % of the Pseudomonas 

aeruginosa strains found in the University 

of Texas Medical Branch Hospitals. 

However, this percentage may differ in other 

hospitals. Ceftazidime is the cephalosporin 

of choice for the treatment of sensitive 

Pseudomonas aeruginosa.60 For serious 

Pseudomonas aeruginosa infections ceftazidime 

should be combined with an aminoglycoside 

or quinolone.84 Ceftazidime is half 

as active against Gram positive organisms as 

is 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 suggest increased activity 

of cefepime against multiresistant Enterobacter 

species. Similar to other cephalosporins, 

cefepime has no activity against Enterococcus 

species.

54 Maderetal 

Other b-lactam Antibiotics 

Aztreonam is a monocyclic p-lactam antibiotic, 

which is active against most Enterobacteriaceae 

and Pseudomonas aeruginosa.93 

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. It also offers low liability 

of cross sensitivity in patients allergic to 

penicillin or cephalosporin. 

Imipenem is an antimicrobial agent belonging 

to the p-lactam class of antibiotics. 

Biochemically they are carbapenems. Imipenem 

has excellent in vitro activity against 

aerobic Gram positive organisms including 

Staphylococcus aureus, Staphylococcus epidermidis, 

Streptococcal species, and Enterococcus 

species. Imipenem has excellent 

Gram negative activity including the Enterobacteriaceae 

and Pseudomonas aeruginosa. 

Imipenem also inhibits most anaerobic 

species, including the Bacteroides fragilis 

group.61 Side effects include seizure activity. 

Resistance to Pseudomonas aeruginosa may 

develop during therapy and fungal superinfection 

may occur. 

Vancomy cin 

Vancomycin has excellent activity against 

Staphylococcus aureus, Staphylococcus epidermidis, 

and the Enterococcus species. It is 

the antibiotic of choice in individuals who are 

unable to tolerate either the penicillins or the 

cephalosporins.23 Vancomycin is also the antibiotic 

of choice for the treatment of methicillin 

resistant Staphylococcus aureus89 and 

Staphylococcus epidermidis.' Recent reports 

of vancomycin resistant Enterococcus species 

dictate increased vigilance and caution.52.88 

Vancomycin may be associated with nephrotoxicity 

or ototoxicity, especially when given 

concurrently with an aminoglycoside.85 When 

used as monotherapy, the end organ toxicity 

of vancomycin is minimal. A red man syndrome 

often is observed when vancomycin is 

administered in less than 1 hour. 



Clindamycin 

Clindamycin is one of the most active antibiotics 

against clinically significant anaerobic 

bacteria, particularly the B acteroides fragilis 

group. However, clindamycin is ineffective 

against 10% to 20% of clostridial species 

other than perfringens.92 In addition to its 

anaerobic activity, clindamycin is also effective 

against Staphylococcus aureus, Staphylococcus 

epidermidis, and the Streptococcus 

species. The half life of clindamycin is 2.4 

hours, clindamycin is ideally given every 8 

hours. Clindamycin has good penetration 

into most tissues including bone,65.91 and it 

penetrates well into abscesses. Clindamycin 

is relatively nontoxic, but may cause diarrhea 

and pseudomembranous colitis in a 

small percentage of patients.38 

Rifampin 

Rifampin exhibits bactericidal activity 

against various Gram positive and negative 

organisms. Rifampin is the most active antistaphylococcal 

agent known.78 However, rifampin 

has less activity than the aminoglycosides 

against most Gram negative bacteria. 

When rifampin is used alone for the treatment 

of bacterial infections, a rifampin resistant 

subpopulation rapidly develops.16 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 methicillin sensitive Staphylococcus 

species osteomyelitis. Trimethoprim and sulfamethoxazole 

or minocycline plus rifampin 

have been used to treat methicillin resistant 

Staphylococcus species osteomyelitis. In a 

multicenter study, Norden et a164 has shown 

that the combination of rifampin and nafcillin 

was slightly superior to nafcillin alone. 

However, the results of the study only 

reached a 0.2 statistical significance. Side effects 

of rifampin include red discoloration of 

body fluids, gastrointestinal complaints, hepatitis, 

and possibly mild immunosuppression. 

Rifampin induces liver enzyme activity

Number 360 


resulting in the inactivation of numerous 

drugs, including verapamil, corticosteroids, 

quinidine, cyclosporin, oral anticoagulants, 

estrogens, and oral contraceptives. Drug regimens 

for patients must be monitored carefully 

with adjustments of drug doses when 

indicated. 

Aminoglycosides 

The aminoglycosides include gentamicin, tobramycin, 

amikacin, and netilmicin. The 

aminoglycosides are the standard to 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 to 

the aminoglycoside may develop 

rapidly.62.IOi They have no effect against the 

Streptococcus species or anaerobes. The 

aminoglycosides 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 for tobramycin, gentamicin, or netilmicin.80 

There is no evidence to support 

amikacin having greater or lesser activity 

than the other aminoglycosides. Toxicity of 

the aminoglycosides includes nephrotoxicity 

and ototoxicity. 

Fiuoroquinolones 

The fluoroquinolones currently are being 

used to treat adult patients with orthopaedic 

infections including osteomyelitis. The 

quinolones are divided into four generations. 

The first generation quinolone, nalidixic 

acid, is not used to treat orthopaedic infections. 

The second generation quinolones include 

ciprofloxacin and ofloxacin. Ciprofloxacin 

and ofloxacin provide adequate serum, tissue, 

and urine concentrations. Ciprofloxacin 

and ofloxacin have efficacy against most 

Gram negative organisms. Most streptococcal 

strains and anaerobic organisms are resistant 

to ciprofloxacin and ofloxacin. Reports 

of resistance in some Staphylococcus aureus 

and Staphylococcus epidermidis strains dictate 

ca~tion.3~39.81 Ciprofloxacin is particularly 

advantageous in the treatment of Gram 

negative bone infections, which traditionally 

require prolonged parenteral antibiotic therapy.45 

Ciprofloxacin is the more active 

quinolone against Pseudomonas aeruginosa. 

The third generation includes levofloxacin 

and sparfloxacin. L-ofloxacin and 

sparfloxacin provide higher serum levels 

than either ciprofloxacin or ofloxacin. These 

agents have excellent activity against Streptococcus 

species including penicillin intermediate 

and resistant Streptococcus pneumoniae. 

These agents are also active against atypical 

respiratory pathogens (Mycobacterium pneumoniae, 

Legionella species, and Chlamydia 

pneumoniae). These agents have efficacy 

against most Gram negative organisms. The 

fourth generation (trovafloxacin, grepafloxacin) 

quinolones have similar aerobic Gram 

positive and Gram negative coverage as the 

third generation quinolones. Unlike the third 

generation quinolones, the fourth generation 

quinolones have excellent anaerobic organism 

coverage.15.97 These agents have efficacy 

against most Gram negative organisms. 

Although second, third, and fourth generation 

quinolones are formulated for parenteral 

administration, the oral mode of 

these quinolones provides excellent serum 

concentrations. Oral administration of these 

quinolones results in decreased length of 

hospitalization and reduced treatment costs. 

In most cases, the patient is begun on the 

parenteral quinolone and switched to oral 

quinolone therapy unless the patient has a 

contraindication to oral antibiotic therapy. 

The switch to oral therapy usually occurs at 

1 to 2 days into therapy. Patients who have 

not completed puberty should not be given 

antimicrobial therapy with the quinolone 

class of antibiotics because of bone growth

56 Maderetal 

problems found in young beagle dogs. Toxicity 

to the quinolones is low. Gastrointestinal 

disturbances (nausea, vomiting, and dyspepsia) 

are the more commonly found side effects 

(2%-5%). Central nervous system reaction 

(1%-2%) may occur in the form of 

headache, dizziness, tiredness, or insomnia. 

Moderate to severe phototoxicity may be 

manifested by some of the quinolones (lomefloxacin, 

sparfloxacin). Sparfloxacin causes 

prolongation of the Q-T interval. Rarely, 

Achilles tendon rupture may occur as a result 

of quinolone therapy. 

None of the quinolones have reliable Enterococcus 

species coverage. The current 

quinolones have variable Staphylococcus 

aureus and Staphylococcus epidermidis coverage, 

and resistance to the second generation 

quinolones is increasing.3 

Trimethoprim-sulfamethoxazole 

Trimethoprim-sulfamethoxazole is an antimetabolite 

composed of a fixed combination 

of a trimethoprim and sulfonamide. In 

vitro these agents are more active together 

than either agent is alone.6 Aerobic Gram 

negative bacteria including Escherichia coli, 

Proteus mirabilis, Haemophilas influenzae, 

and Stenotrophomonas maltophilia are consistently 

susceptible. In addition, Klebsiella 

pneumoniae, Enterobacter species, Serratia 

marcescens, indolepositive proteus, and nonaeruginosa 

Pseudomonas are also frequently 

susceptible. The principle 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 susceptible.102 

In some hospitals, the combination of 

trimethoprim-sulfamethoxazole and rifampin 

may be effective for the oral treatment of 

methicillin resistant Staphylococcus aureus 

and Staphylococcus epidermidis.100 Trimethoprim-sulfamethoxazole 

may be given 

either parenterally or orally. The combination 

is useful as suppressive therapy for osteomyelitis. 

Side effects include gastroin- 



testinal disturbances, serum sicknesslike 

syndrome, hemolytic anemia, and hypersensitivity 

reactions. Trimethoprim-sulfamethoxazole 

should not be administered during 

the last month of pregnancy. 

Metronidazole 

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 

0, radicals. Toxic 0, radicals are lethal for 

strict anaerobic organisms because they 

lack the protective enzymes superoxide dismutase 

and catalase. Metronidazole is active 

against all anaerobic organisms except 

for actinomycetes and microaerophilic streptococci.75 

The drug is well absorbed and penetrates 

into tissues and abscesses. Side effects 

are rare, but include metallic taste, 

seizures, cerebellar dysfunction, disulfiram 

reaction with alcohol, and pseudomembranous 

colitis. 

Investigational Agents 

Several new antimicrobial agents are currently 

in clinical trials. They offer much 

needed alternatives to currently available antimicrobials, 

particularly in the treatment of 

infections caused by multiresistant Gram 

positive bacteria such as vancomycin resistant 

Enterococcus species and methicillin resistant 

Staphylococcus aureus. 

Teicoplanin is a glycopeptide antibiotic 

related to vancomycin but possessing several 

properties that make it clinically useful. Teicoplanin 

has a prolonged elimination half 

life of approximately 60 hours allowing one 

per day administration. The antimicrobial 

spectrum of teicoplanin includes Staphylococcal 

species and Streptococcus species including 

some methicillin resistant Staphylococcus 

aureus and vancomycin resistant 

Enterococcus species Type B organisms. Teicoplanin 

toxicity profile is similar to vancomycin 

including reports of ototoxicity. Teicoplanin 

may be given by intramuscular or 

intravenous route.2.69

Number 360 


Quinupristin and dalfopristin (Synercid 8 

RhGne-Poulenc Rorer Inc, Collegeville, PA), 

is a fixed combination of two streptogramins 

in a ration of 30:70 recently approved for use 

in the United States by the Food and Drug Administration. 

It possesses in vitro inhibitory 

and bactericidal activity against most Gram 

positive organisms including vancomycin resistant 

Enterococcus faecium.20 Quinupristiddalfopristin 

may have a role in the 

treatment of methicillin resistant Staphylococcus 

aureus, Group D enterococcus, and 

possible coagulase negative Staphylococcus 

species infections in patients who cannot receive 

vancomycin therapy. Adverse reactions 

seem to be mild and include self limited local 

reactions such as itching, pain and burning, 

vomiting, and diarrhea. Additional clinical 

experience is needed to define the role of this 

antibiotic in clinical practice.8.20 

New synthetic classes of antimicrobials, 

the oxazolidinones, currently are undergoing 

clinical trials. The analogs linezolid and 

eperezolid are representatives of this new 

class. These agents have bacteriostatic activity 

against numerous important organisms 

including methicillin resistant Staphylococcus 

aureus, penicillin resistant Streptococcus 

pneumoniae, and vancomycin resistant Enterococcus 

species.13 They seem to have efficacy 

when administered either orally or 

parenterally. Tongue discoloration and a folliculitis 

type rash are the commonly reported 

adverse effects. 

LENGTH OF THERAPY 

Osteomyelitis traditionally is treated with 4 

to 6 weeks of parenteral antibiotics after definitive 

debridement surgery. However, this 

time frame has no documented superiority 

over other time intervals. Because of failure 

rates of 20% in clinical studies, some authors 

advocate treatment with 6 to 8 weeks of intravenous 

therapy followed by a course of 3 

months or longer of oral therapy.40.98 In this 

era of resistance development, long duration 

antibiotic therapies must be scrutinized care- 

fully. There is no evidence that prolonged 

parenteral antibiotics will penetrate necrotic 

bone. Surgical debridement is necessary to 

ensure the physician that he or she is treating 

living vascularized bone. It takes approximately 

4 to 6 weeks for debrided bone to be 

protected by revascularized tissue.98 Because 

patient treatment failures are caused mostly 

by inadequate surgical debridement rather 

than the duration of antimicrobials, some 

clinicians advocate administering intravenous 

antimicrobials for as little as 2 weeks 

followed by 4 weeks of oral therapy. In cases 

of relapse, redebridement is advocated. This 

treatment method is based on the assumption 

that if 4 to 6 weeks of antibiotics fail to cure 

the disease, then longer treatment courses 

are unlikely to be curative unless the dead 

devitalized bone is removed.98 

TREATMENT MODALITIES 

Parenteral Versus Oral 

Osteomyelitis is a difficult problem for patients 

and the treating physicians. Flareups of 

infection require multiple admissions, surgeries 

leading to pain, and lengthy antibiotic 

therapy with the associated administration 

problems and toxicities. The ultimate goal in 

management of osteomyelitis is to eradicate 

and prevent recurrence of infection. 

Four to 6 weeks of parenteral antibiotic 

administration after the last major debridement 

has become the standard length of antibiotic 

therapy. In the past, patients were 

hospitalized for the entire duration of antimicrobial 

treatment. Now home health and outpatient 

services use heparin locks, peripheral 

inserted central catheter lines, and implantable 

catheters, which allow parenteral 

antibiotic treatment outside the hospital setting. 

Although outpatient antibiotic therapy 

has decreased costs, 4 to 6 weeks of outpatient 

intravenous therapy is still expensive 

for the patient and healthcare systems.11,25,32,48 

An antibiotic treatment regimen 

that begins with parenteral therapy and 

ends with the self administration of oral an-

58 Maderetal 

tibiotic therapy would reduce significantly 

the cost of antibiotic administration. 

There is little difference in effectiveness 

between the intravenous and oral administration 

of an antibiotic as long as both routes 

provide adequate serum and bone concentrations. 

Oral antibiotic therapy has been used 

for treatment of childhood osteomyelitis. It 

is recommended that the patient initially receives 

1 to 2 weeks of parenteral antibiotic 

therapy before changing to an oral regimen.5.33,37,94 

The patient must be compliant 

and have close outpatient followup. In the 

child, serumcidal levels usually are used to 

monitor absorption and activity of the orally 

administered antibiotic. 

Currently 4 to 6 weeks of intravenous antibiotics 

and close followup is recommended 

for adult patients with 0steomyelitis.~8.63 

Comparable therapeutic experience with intravenous 

antibiotics followed by oral antibiotics 

and oral antibiotic therapy alone is not 

well described in adults. In a small series of 

patients, oral ciprofloxacin and ofloxacin 

have been shown to be safe and effective as 

parenteral antibiotics in the treatment of 

chronic osteomyelitis caused by susceptible 

organisms.22,45 

Shirtliff et a187 retrospectively compared 

the clinical efficacy of 4 weeks of intravenous 

antibiotics versus 2 weeks of intravenous 

antibiotics followed by 4 weeks of 

appropriate oral antibiotics. The patients 

were followed up at least 12 months after 

treatment for outcome determination. Osteomyelitis 

was arrested in 16 of 19 patients 

in the group treated with 4 weeks of intravenous 

antibiotic therapy, resulting in an arrest 

rate of 84.3%. Osteomyelitis was arrested 

in 17 of 19 in the group treated with 2 

weeks of antibiotics followed by 4 weeks of 

oral antibiotics, resulting in an arrest rate of 

89.5%. The data were analyzed and the difference 

was not statistically significant (p > 

0.05, chi2 analysis). Treatment results for 4 

weeks of intravenous antibiotics versus 2 

weeks of intravenous antibiotics followed by 

4 weeks of oral antibiotics in the treatment of 



long bone osteomyelitis are not significantly 

different in this study. This study was limited 

because of the small sizes of the groups and 

the variables between the groups. 

The major treatment variable between 

orally prescribed and intravenous antibiotics 

is patient compliance. Every treating physician 

must judge whether the patient will be 

compliant and will be able to independently 

complete the prescribed oral regimen. If the 

patient is not compliant, oral antibiotic therapy 

can be monitored in a direct observation 

oral dosing program. Increased reliance on 

oral antibiotic therapy for osteomyelitis will 

lead to a reduction of intravenous catheter 

associated infections. 

Because osteomyelitis is a surgical disease, 

complete surgical debridement and not 

a particular antibiotic regimen is the most 

important factor for a successful outcome.48.98 

Osteomyelitis is characterized by its ability to 

recur after long periods of quiescence and long 

term followup is required for these patients. 

Various authors have proposed the use of parenteral 

antibiotics for periods ranging from 14 

days to 6 weeks followed by a variable course 

of oral antibiotics for the treatment of osteornyelitis.9.11.22-45,48f~337 

Antibiotics work best 

when used in conjunction with adequate debridement, 

foreign body and dead bone removal, 

abscess drainage, and dead space 

obliteration. 

Local Therapy Through 

Antibiotic Beads 

In patients with osteomyelitis implant materials 

impregnated with antibiotics have been 

used to manage dead space created by debridement 

surgery. Beads are placed in local 

defects and spacers are used after the infected 

total joint prothesis is removed. Antibiotic 

beads provide high local concentrations 

of an antimicrobial agent(s) to the 

infected dead space. Thus, a high local concentration 

of antibiotic can be attained without 

exposing the patient to systemic toxic antibiotic 

levels, which could result in toxic 

side effects.

Number 360 


Polymethylmethacrylate is an implant material 

that has been used successfully with numerous 

antibiotics, including vancomycin, 

clindamycin, tobramycin, and gentamicin. 

However, various problems have been associated 

with polymethylmethacrylate use. 

First, antibiotic impregnated polymethylmethacrylate 

requires a second surgery for its 

removal. Second, the implant produces local 

immune compromise by impairing natural 

luller, lymphocytic, and phagocytic cell activity. 

Polymethylmethacrylate implants also 

have been linked to decreasing the amount of 

superoxide, a mediator of bacterial killing 

within phagocytic cell phagosome and reducing 

the amount of lymphocyte blastogenesis.7 

Normal phagocytic processes are devoted to 

the removal of the implant foreign material 

and polymethylmethacrylate particles use energy 

and resources of the immune system that 

normally would be used to fight infection. 

Third, polymethylmethacrylate beads usually 

provide local bactericidal levels of antibiotics 

for only 2 to 4 weeks. Once the level of antibiotics 

eluting from the implant has waned, 

there is an increased propensity for the overgrowth 

of antibiotic resistant organisms that 

were not eliminated by the original high concentration 

of antimicrobials. Finally, the antibiotics 

in the polymethylmethacrylate material 

often leech from the outer cortex of 

implant, leaving behind a central core of unused 

antibiotics. Once the antibiotics have 

leeched from the implant cortex, the polymethylmethacrylate 

material provides a perfect 

substrate for additional bacterial colonization. 

Once colonized, many bacteria are 

able to synthesize a slime layer, termed the 

glycocalyx. This layer prevents the inward 

diffusion of numerous antimicrobials, allowing 

bacterial escape from the bactericidal and 

bacteriostatic effects of antimicrobial therapy. 

Also, the glycocalyx displays host antigenic 

properties, thereby allowing the bacteria 

to evade detection by the immune system 

of the host. 

New implant materials may be able to reduce 

or eliminate many of the problems as- 

sociated with the clinical standard of polymethylmethacrylate 

bead therapy for dead 

space management. Several studies have 

been performed that use alternative materials 

for implantation. Zhang et all05 showed that, 

in vitro, gentamicin containing high molecular 

weight biodegradable poly (D,L-lactide) 

cylinders provided a small initial burst followed 

by a gradual and sustained release of 

gentamicin. Although this group did not test 

the eluted antibiotic against known osteomyelitic 

organisms, the detected gentamicin 

concentrations were sufficiently above 

minimum bactericidal concentrations for 

these pathogens. In another related in vitro 

model, Shinto et a186 described the ability of 

gentamicin impregnated Ca hydroxyapatite 

biodegradable beads to deliver five times the 

minimum inhibitory concentrations for 

Staphylococcus species for at least 12 

weeks. Although in vivo models are lacking, 

there has been some research in this area. 

Garvin et a121 showed that polyglycolic 

beads loaded with gentamicin resulted in the 

effective treatment of tibia1 Staphylococcus 

aureus osteomyelitis in a canine model. In 

another study, Calhoun and Mader7 showed 

the efficacy of a biodegradable antibiotic implant 

composed of polylactic acid and 

poly(D1-lactide): co-glycolide combined 

with vancomycin. In the localized rabbit tibial 

Staphylococcus aureus osteomyelitis 

model, antibiotic impregnated, biodegradable 

implant treatment resulted in a significant 

reduction in infection when compared 

with treatment with systemic vancomycin. 

However, this study did not compare the efficacy 

of infection reduction with polymethylmethacrylate 

beads. 

Cripps et all0 showed vancomycin impregnated 

hydroxyapatite implant material 

had approximately equal efficacy in clearing 

Staphylococcus aureus osteomyelitis when 

compared with vancomycin polymethylmethacrylate 

beads in rabbits. Hydroxyapatite 

material impregnated with antibiotics 

may be better than polymethylmethacrylate 

beads and intravenous antibiotics in various

60 Maderetal 

ways. First, this material could provide bactericidal 

concentrations of antibiotics for the 

prolonged period necessary to treat completely 

the particular orthopaedic infection. 

Second, because the hydroxyapatite material 

is resorbed, there is no need for bead removal 

such as in the case of polymethylmethacrylate 

antibiotic impregnated beads. 

Third, variable resorbability from weeks to 

months may allow many types of infections 

to be treated. Fourth, the polymethylmethacrylate 

and polylactic acid material 

does not provide for a Ca source necessary 

for new bone formation in the repair process 

after infection. Finally, because the hydroxyapatite 

material is replaced slowly by new 

bone formation, the soft tissue or bone defect 

may fill slowly with tissue eliminating additional 

need for reconstruction. 

BONE CONCENTRATIONS 

Studies quantifying the bone concentrations 

of the semisynthetic penicillins, first 

generation cephalosporins, clindamycin, 

levofloxacin, and vancomycin have been performed.'O,4l342,65,9l 

There still are unresolved 

methodologic problems. The results of bone 

concentrations studies are provided in pg per 

gram and serum concentrations are in pg per 

mL. Most investigators use an elution technique 

to recover antibiotic from bone, and 

optimal extraction procedures that recover 

antibiotic completely from bone still have to 

be standardized for each antibiotic. Current 

methodology does not allow for the reliable 

distinction between cancellous or cortical 

bone antibiotic concentrations. Despite these 

problems an estimate of mean bone concentrations 

can be determined and evaluated. 

Vancomycin, clindamycin, nafcillin, cefazolin, 

and tobramycin bone concentrations 

have been determined using an identical elution 

technique. The reference curves were 

performed in bone powder suspensions. Simultaneous 

bone and serum concentrations 

were determined using antibiotic doses that 

provided optimal serum concentrations for 



each antibiotic. Clindamycin was found to 

have the greatest bone to serum ratio followed 

by vancomycin, nafcillin, tobramycin, 

and cefazolin (Table 4). The significance of 

antibiotic bone concentrations is unclear, but 

clindamycin had the best results of any single 

antibiotic therapy (nafcillin, oxacillin, 

cephalothin, cefamandole, moxalactam, vancomycin, 

rifampin, trimethoprim, gentamicin) 

in eradicating experimental Staphylococcus 

aureus osteomyelitis.4' 

HYPERBARIC OXYGEN THERAPY 

The results of several open clinical trials 

have shown that adjunctive hyperbaric 0, 

therapy may be useful in the treatment of 

chronic osteomyelitis.43 Morrey et a151 reported 

on 40 patients with chronic osteomyelitis 

who met all of the following criteria: 

the infection had persisted longer than 

1 month; at least one surgical debridement 

had been performed; at least 2 weeks of parenteral 

antibiotics had been administered; 

and all had been followed up for at least 1 

year after treatment. All patients had chronic 

refractory osteomyelitis with a recurrence of 

this infection despite previous aggressive antibiotics 

and surgical treatment. After hyperbaric 

0, therapy, appropriate surgery, and 

treatment with antibiotics, 34 patients (85%) 

remained clinically free of disease, and six 

experienced recurrences of their osteomyelitis. 

Using the same criteria, Davis et 

all2 evaluated 38 patients who were treated 

with adjunctive hyperbaric 0,. Of these 38 

patients, 34 remained free of clinical signs of 

osteomyelitis. Although the results of these 

clinical trials are encouraging, the adjunctive 

role of hyperbaric 0, in the treatment of osteomyelitis 

is difficult to assess because of 

patient, surgical, organism, bone, and antibiotic 

variables. 

Animal studies performed in an experimental 

Staphylococcus aureus osteomyelitis 

model have shown that hyperbaric 0, administered 

under standard treatment conditions 

was as effective as cephalothin in eradicating

~~ ~ ~~ 

Number 360 

March, 1999 Antimicrobial Treatment of Osteomvelitis 61 

TABLE 4. Infected Bone Concentrations After Antibiotic Administration in 

Experimental Staphylococcus aureus Osteomyelitis 

Antibiotic (dose) Infected Serum pg/mL Bone pg/g Percentage 

Clindamycin (70 rng/kg) 

Vancomycin (30 rng/kg) 

Nafcillin (40 mg/kg) 

Moxalactam (40 mg/kg) 

Tobrarnycin (5 rng/kg) 

Cefazolin (15 mg/kg) 

Cefazolin (5 mg/kg) 

Cephalothin (40 mg/kg) 

12.1 k0.6 

36.4 f 4.6 

21.8 f 4.6 

65.2 f 5.2 

14.3k 1.3 

67.2 f 2.6 

45.6 k 3.2 

34.8 f 2.8 

11.9k1.9 

05.3 f 0.8 

02.1 k 0.3 

06.2 f 0.7 

01.3 +_ 0.1 

04.1 f0.7 

02.6 k 0.2 

01.3 f 0.2 

98.3 

14.5 

9.6 

9.5 

9.1 

6.1 

5.7 

3.7 

Staphylococcus aureus from infected bone.46 

Osteomyelitic bone in this experimental 

model has decreased blood flow and greatly 

decreased partial pressure of 0,. Hyperbaric 

0, was found to restore intramedullary 

0, tensions to physiologic or 

supraphysiologic tensions, but did not 

acutely increase blood flow in osteomyelitic 

bone. Because in vitro hyperoxia 

does not directly affect this strain of 

Staphylococcus aureus, hyperbaric 0, was 

effective in Staphylococcus aureus osteomyelitis 

because it increased intramedullary 

0, to tensions at which phagocytic killing 

may proceed more efficiently.44 

Whereas superoxide dismutase and catalase 

are among the enzymatic mechanisms 

used by aerobic bacteria to degrade toxic 0, 

radicals,26 anaerobic and many microaero: 

philic organisms lack these enzymes.50 

Therefore, anaerobic organisms are rendered 

sensitive to 0, radicals developed intracellularly 

and extracellularly during hyperbaric 

0, therapy. As a result, increased 0, tension 

is directly lethal to fastidious anaerobic organisms 

and to some microaerophilic organisms, 

but not aerobes.4 In addition, several 

clinical reports support the adjunctive role 

of hyperbaric 0, therapy in the treatment of 

nonclostridial anaerobic infections.47>83.94 The 

role of hyperbaric 0, therapy in the treatment 

of infection secondary to Clostridial species 

is well validated.28 Also, in vivo studies have 

shown hyperbaric 0, to have an indirect 

killing mechanism on Clostridium perfringens 

mediated through the polymorphonuclear 

leukocytes. Thus, hyperbaric 0, provides 

the necessary substrate (0,) for the killing of 

aerobic and probably anaerobic organisms by 

the polymorphonuclear leukocyte. 

The effects of hyperbaric 0, on antibiotic 

efficacy were shown in a Pseudomonas 

aeruginosa osteomyelitis model, in which 

hyperbaric 0, potentiated the aminoglycoside 

tobramycin.42372.66 Other aminoglycosides 

and antibiotics including vancomycin, 

the quinolone class of antibiotics, nitrofurantoin, 

and certain sulfonamides are far less active 

in hypoxic environments. Such conditions 

are found readily in ischemic tissues and 

in normal bone. Therefore, hyperbaric 0, therapy 

also may be beneficial by augmenting the 

effects of these antibiotics. 

Wound healing is a dynamic process that 

requires an adequate 0, tension to proceed.30.31 

In the ischemic or infected wound, 

hyperbaric 0, provides 0, to promote collagen 

production, angiogenesis, and ultimately 

wound healing. 

Hyperbaric 0, therapy often is used as adjunctive 

therapy in the treatment of posttraumatic 

osteomyelitis and chronic refractory osteomyelitis. 

Posttraumatic osteomyelitis often 

requires significant bone healing because 

trauma and the infective process can result in 

significant bony destruction. Besides the beneficial 

effects of direct inhibition of anaerobes, 

upregulation of polymorphonuclear in-

~~ 

62 Maderetal 



tracellular killing, augmenting antibiotic activity, 

and maintaining muscle and skin 

flaps, hyperbaric 0, therapy can promote accelerated 

bone repair. The optimum hyperbaric 

0, treatment regimens are one to two 

treatments per day for 60 to 120 minutes at 

two to three atmospheres of pressure with 

100% 0,. Oxygenation below this level 

(such as occurs in infected bone) will result 

in slow bone healing because of inhibition of 

fibroblast, osteoclast, osteoblast, and macrophage 

activity.103 When 0, levels are raised 

beyond optimum levels for a sustained period, 

fibroblast activity is highly upregulated, 

resulting in a thick collagenous deposition.49 

Many in vitro studies have reported 

an upregulated osteoclast activity caused by 

long exposures to 0, radicals including hydrogen 

peroxide associated with hyperoxygen 

growth conditions.18J4.’7 The end result 

of sustained hyperoxygenation is the development 

of a repair process that is rich in collagen 

and structurally weak. Therefore, maximal 

bone healing may be achieved when 

hyperbaric 0, treatment is provided within 

the optimal range of treatments for 90 to 120 

minutes at two to three atmospheres of pressure 

with 100% 0, - once daily. 

Acknowledgments 

The authors thank Michael Cripps, BS, Donna 

Milner Mader, BA, and Maureen D. Shirtliff, RN, 

for manuscript research and preparation. 

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Number 360 


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