Oral Antibiotic Therapy

H. Breithaupt

Introduction

There exist several antibiotics for the treatment of bone infections; most are administered intravenously. The antibiotic treatment of osteomyelitis raises several questions:

Acute Diffuse Osteomyelitis

Acute diffuse osteomyelitis arises through hematogenous spread and affects patients of all ages. Staphylococcus aureus is the most common pathogen; other germs are less often involved.

Therapy for acute, diffuse osteomyelitis should be both specific and applied in high daily doses—with bactericidal antibiotics for 6-8 weeks:

Empirical antibiotic therapy for unidentified pathogens can begin after a sample of infected material has been taken:

Oral sequential therapy can be initiated after 2-4 weeks of parenteral therapy if there has been clinical improvement and the C-reactive protein (CRP) has normalized:

Chronic Osteomyelitis

Chronic osteomyelitis usually arises when pathogens are spread after a trauma, or following soft-tissue infection, or through intraoperative contamination, but also when acute infections have not been sufficiently cured. The spectrum of pathogens depends on the origin of the infection:

Surgical debridement is of decisive importance in the therapy of chronic osteomyelitis:

Antibiotic therapy is only a supportive or inflammation-suppressing measure without curative intent in chronic osteomyelitis. Usually long-term therapy (clinical symptoms, CRP) is required with the accompanying risk of developing antibiotic resistance. Antibiotics with confirmed effect which enter the bone constitute the specific treatment of chronic osteomyelitis:

Antibiotic Profiles

Benzylpenicillin

Penicillin G

Evaluation:

+++ strepto-, pneumo-, and meningococci

++ Treponema, Borrelia, Leptospira, gonococci (except β-lactamase producers), S. aureus (except β-lactamase producers), Corynebacterium diphtheriae, P. multocida, Clostridia (except Clostridium difficile), Bacteroides (except Bacteroides fragilis), fusobacteria, peptostreptococci, actinomycetes

— enterobacteria, Pseudomonas, β-lactamase producers (Haemophilus, Moraxella catarrhalis, etc.) Nocardia, Mycoplasma, Chlamydia

Side effects: Allergies (exanthema, fever) 2%, anaphylaxis 1:40 000, neurotoxicity (myoclonia, coma, and fits with high doses)

Dosage: Up to 3 × 10 million IU/day

Penicillins Suitable for Staphylococci

Flucloxacillin: Staphylex, etc. (IV, per os)

Oxacillin: InfectoStaph (IV)

Dicloxacillin: InfectoStaph (per os)

Evaluation: Antibiotic of choice for S. aureus (except when methicillin-resistant), narrow-spectrum antibiotic

Side effects: Like penicillin G, hepatitis ± cholestasis 3%)

Dosage: 3 × 2-4 g/d (IV), 3 × 1-2 g/d (per os)

Obsolete combinations: Amoxicillin + flucloxacillin, mezlocillin + oxacillin

Aminopenicillins

Ampicillin: Binotal, etc. (IV)

Amoxicillin: Clamoxyl, etc. (per os)

Evaluation:

+++ enterococci, Haemophilus, Listeria

++ strepto-, pneumo-, meningococci, Salmonella, Shigella, Proteus mirabilis, E. coli (30%-50% are resistant) — other enterobacteria, Pseudomonas, β-lactamase producers (e.g., S aureus, M. catarrhalis)

Side effects: Like penicillin G, ampicillin exanthema (approximately 15%, in mononucleosis 70%-100%)

Dosage: Ampicillin 3 × 2-5 g/d (IV), amoxicillin 3 × 1 g/d (per os)

Aminopenicillin + Betalactamase Inhibitors

Ampicillin/sulbactam: Unacid (IV)

Sultamicillin: Unacid PD (per os)

Amoxicillin/clavulanate: Augmentan, etc. (per os, IV)

Evaluation: Extended broad-band effectiveness against Gram-positive, Gram-negative, and anaerobic pathogens

+++ enterococci, Haemophilus, Listeria

++ S. aureus, streptococci, pneumococci, meningococci, M. catarrhalis, E. coli, Klebsiella, P. mirabilis / vulgaris, Salmonella, Shigella, and anaerobic bacteria (including B. fragilis)

— Pseudomonas, problematic Gram-negative pathogens, Enterococcus faecium, Mycoplasma, Chlamydia

Side effects: Like those of aminopenicillins (exanthemas are rarer, diarrhea is more frequent.). Clavulanate: hepatitis ± cholestasis 1:10000

Dosage: Ampicillin/sulbactam 3 × 3 g/d (IV), amoxicillin/ clavulanate 3 × 2.2 g/d (IV) or 3 × 500 mg (per os), sultamicillin 2 × 750 mg (per os)

Acylureido Penicillins

Mezlocillin: Baypen, etc.

Piperacillin: Pipril, etc.

Evaluation:

+++ Gram-negative pathogens (antibiogram!), enterococci

++ Pseudomonas (piperacillin)

+ Gram-positive pathogens

— β-lactamase producers (e.g., S. aureus, Haemophilus), E. faecium

Side effects: Like those of penicillin G, reversible neutropenia (after a cumulative dosage of >100 g)

Indications: Piperacillin/sulbactam for severe (nosocomial) infections with Gram-negative pathogens (+ aminoglycoside)

Dosage: Piperacillin 3 × 4 g/d + sulbactam 3 × 1 g/d or piperacillin + tazobactam 3 × 4/0.5g IV

Betalactamase Inhibitors

Sulbactam: Combactam

Evaluation: β-lactamase inhibitor is licensed for combination with mezlocillin, piperacillin, cefotaxim, or penicillin G

Broadened spectrum and increased effectiveness against:

The resistances of Pseudomonas, enterobacteria, and Serratia are not influenced.

Side effects: Diarrhea

Indications: Used in combination with piperacillin for severe Gram-negative infections and severe aerobic-anaerobic mixed infections. Combined with penicillin G for diabetic gangrene or infection with actinomycosis.

Dosage: 3 × 1 g/d (IV)

Fixed combination (with a reserve penicillin): Piperacillin + tazobactam

Standard Cephalosporin

Cefazolin: Elzogram, etc.

Evaluation:

++ effective against pneumococci, streptococci, staphylococci, E. coli, Klebsiella, and P. mirabilis

— enterococci, Pseudomonas, problematic Gram-negative pathogens

Side effects: Allergies (3%, 10% cross allergies with penicillins)

Indications: Initial treatment for mild and moderately severe infections, intraoperative prophylaxis

Dosage: 3 × 2 g/d, 1 × 2 g (for a 3-hour operation)

Cephalosporins (Second Generation)

Cefuroxim: Zinacef, etc.

Cefotiam: Spizef

Evaluation:

++ effective against pneumococci, streptococci, staphylococci, Haemophilus, Klebsiella, P. mirabilis, E. coli — enterococci, Pseudomonas, problematic Gram-negative pathogens

Side effects: Like those of standard cephalosporins.

Indications: Initial treatment of moderately severe infections that are probably caused by Gram-negative pathogens

Dosage: Cefuroxim 3 × 1.5 g/d, cefotiam 3 × 2 g/d

Reserve Cephalosporins

Cefotaxim: Claforan, etc.

Ceftriaxon: Rocephin, etc.

Ceftazidim: Fortum (Pseudomonas)
Cefepim: Maxipime (Pseudomonas)

Evaluation:

+++ Gram-negative pathogens (e.g., E. coli, Klebsiella, all Proteus species, H. influenzae), P. aeruginosa (ceftazidim, cefepim)

+ less effective against Gram-positive pathogens.

— enterococci, anaerobic pathogens, Listeria

Side effects: Like those of other cephalosporins

Dosage: Cefotaxim 2-3 × 2 g/d, ceftriaxon 1 × 2 g/d (1st day: 1 × 4 g), ceftazidim 3 ×2 g/d

Carbapenems

Imipenem + cilastatin: Zienam

Meropenem: Meronem
Ertapenem: Invanz

Doripenem: Doribax

Evaluation:

++ very broad spectrum against Gram-positive and Gram-negative pathogens, including P. aeruginosa and anaerobic bacteria

— Stenotrophomonas maltophilia, Burkholderia cepacia, C. difficile, and fungi

Cilastatin inhibits the breakdown of imipenem in the kidneys.

Side effects: Diarrhea (3%), allergies (3%), cross-allergies with other β-lactams (20%), elevation of transaminases (5%), phlebitis, fits (imipenem)

Indications: Severe, therapy-resistant nosocomial infections and therapy-resistant meningitis (meropenem). Not to be used as primary therapy or on a normal ward!

Dosage: Imipenem/cilastatin 3 × 1 g/d, meropenem 3 × 1 g/d (in meningitis 3 × 2 g/d)

Aminoglycosides

Gentamicin: Refobacin, etc.

Netilmicin: Certomycin

Tobramycin: Gernebcin, etc. (Pseudomonas)

Amikacin: Biklin, etc. (reserve aminoglycoside)

Evaluation:

+++ Gram-negative enterobacteria

++ S. aureus

— streptococci, pneumococci, enterococci, anaerobic bacteria

Side effects: Oto- and nephrotoxicity, curarelike effect (respiratory paralysis) if infused too rapidly

Dosage: 1 × 3-5 mg/kg (30-60-minute infusion), for example 1 × 240-360 mg/d; amikacin 1 × 7.5-15 mg/kg

Precaution: Because of the risk of irreversible deafness:

Lincosamides

Clindamycin: Sobelin, etc.

Evaluation:

+++ anaerobic bacteria (including B. fragilis), S. aureus, streptococci, pneumococci

— enterobacteria, enterococci, Haemophilus, Pseudomonas

Kinetics: Bioavailability approximately 90%. No dose reduction in renal insufficiency

Side effects: Soft stools, diarrhea, colitis, hepatotoxicity, phlebitis, allergies (rare)

Dosage: 3 × 600-900 mg/d (IV), 3 × 300-600 mg/d (per os)

Glycopeptides

Vancomycin: half-life 5 hours

Teicoplanin: half-life 50 hours

Evaluation:

+++ S. aureus (even if methicillin resistant), coagulasenegative staphylococci, streptococci, pneumococci, enterococci, C. difficile

— enterobacteria, B. fragilis

Side effects: Allergies up to 12% (e.g., skin, fever, anaphylaxis), histamine flush (vancomycin), phlebitis, oto-and nephrotoxicity?

Dosage: Vancomycin: 2 × 1 g/d (30-60-minute infusion. Avoid infusing rapidly!)

Teicoplanin: 1 × 400 mg/d (1st day 800-1200 mg)

Monitoring: Do not go below a valley level of 15 ug/mL. Avoid peak values higher than 40 ug/mL.

Fosfomycin

Fosfomycin: Infectofos

Evaluation:

++ S. aureus, streptococci, pneumococci, Haemophilus, E. coli, P. mirabilis, Serratia, Salmonella, Shigella, Citrobacter

— enterococci, Pseudomonas, Listeria, anaerobic bacteria

Side effects: Nausea, vomiting, diarrhea (10%), headache, phlebitis, hypernatremia, hepatotoxicity, allergies (rare)

Indications: Severe infections with sensitive pathogens (antibiogram!), for example, osteomyelitis, endocarditis, and brain abscess. Combine with betalactam antibiotics.

Dosage: 3 × 3-5 g/d

Gyrase Inhibitors

Norfloxacin: Barazan, etc. (urinary-tract infections)

Enoxacin: Enoxor (per os)

Ofloxacin: Tarivid (IV, per os)

Ciprofloxacin: Ciprobay (IV, per os)

Levofloxacin: Tavanic (IV, per os)

Moxifloxacin: Avalox (IV, per os)

Evaluation:

+++ enterobacteria, P. aeruginosa (ciprofloxacin), Yersinia, Legionella, Brucella, Haemophilus, M. catarrhalis

++ S. aureus, atypical mycobacteria, Chlamydia, Mycoplasma, Rickettsia

— streptococci, pneumococci, enterococci, anaerobic bacteria. Moxifloxacin is effective against Gram-positive and anaerobic pathogens!

Side effects: Ca. 1 % central nervous system (CNS) manifestations (like sleep disturbances and restlessness), psychoses 1: 14 000, tendopathies (0.1 %), GI complaints (1 %), allergies (1 %, e.g., exanthemas, fever, liver damage)

Dosage:

Ofloxacin: 2 × 200 mg/d per os, up to 2 × 400 mg/d IV

Levofloxacin: 1 × 250 mg/d per os

Ciprofloxacin: 2 × 500 mg/d per os, up to 3 × 400 mg/d IV

Moxifloxacin: 1 × 400 mg/d IV, per os

Oxazolidinon

Linezolid: Zyvoxid (IV, per os)

Evaluation:

+++ Gram-positive pathogens, also penicillin-resistant pneumococci, MRSA, coagulase-negative staphylococci, glycopeptide-resistant enterococci

— H. influenzae, M. catarrhalis, Neisseria, enterobacteria, Pseudomonas

Side effects: IG complaints (vomiting in 1%-2%), mild CNS symptoms, reversible thrombo- and leukopenia, anemia, increase in blood pressure with serotoninergic or adrenergic drugs

Kinetics: Complete resorption, half-life 5-7 hours, renal elimination (30% unchanged)

Dosage: 2 × 600 mg (IV, per os). No dose restriction with hepato- or renal insufficiency.

Fusidinic Acid

Fusidinic acid: Fucidine

Evaluation:

+++ staphylococci, even penicillinase producers and some methicillin-resistant species, some B. fragilis

+ streptococci, pneumococci, enterococci

— enterobacteria

Side effects: GI complaints (stomach ache, vomiting, diarrhea), rarely disturbances of liver function and allergies

Kinetics: Almost complete resorption, good tissue penetration, half-life 4-6 hours (in terminal renal failure 6-8 hours), metabolic clearance 80%-90%

Dosage: 3 × 500 mg per os with meals

Comment: reserve antibiotic for severe staphylococcal infections

Ansamycin

Rifampicin: Rifa, etc.

Evaluation:

+++ Mycobacterium tuberculosis, Mycobacterium leprae, staphylococci (also MRSA), streptococci (also when penicillin G resistant), enterococci, meningococci, gonococci, H. influenzae, Legionella, Chlamydia

++ Mycobacterium kansasii, Mycobacterium marinum

+ Mycobacterium avium-intracellulare, Mycobacterium fortuitum, enterobacteria

— Mycoplasma

Side effects: Rise in transaminases (5%-20%; if above 100 IU/L ± cholestasis, discontinue treatment). Allergic reactions (exanthema, fever, eosinophilia), reversible neutropenia and thrombocytopenia (blood counts), colors saliva, tears, sweat, urine, and stools orange. Induces enzymes dependent on cytochrome P450.

Kinetics: Good bioavailability and penetration (also intracellular). Half-life: 2-5 hours. Mostly metabolic clearance.

Dosage: Up to 1 × 600 mg IV to 1 × 750 mg per os. No dose reduction with renal insufficiency.

Comment: First-choice tuberculostaticum. For combination therapy of infections that are difficult to reach (like foreign-body infections).

Further Reading

Kucers A, Crowe SM, Grayson ML, Hoy JF, eds. The Use of Antibiotics. A Clinical Review of Antibacterial, Antifungal and Antiviral Drugs. 5th ed. Oxford: Butterworth Heinemann; 1997

Kuntz P, Pieringer-Müller E, Hof H. Infektionsgefährdung durch Bißverletzungen. Dtsch Arztebl 1996;93:B765-B768

Lew DP, Waldvogel FA. Osteomyelitis. N Engl J Med 1997;336(14):999-1007

Mader JT, Calhoun J. Osteomyelitis. In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas and Bennett’s Principles and Practice of Infectious Diseases. 5th ed. Philadelphia: Churchill Livingstone: 2000:1182-1200

Nadal D, Zbinden R. Illnesses caused by Bartonella. Catscratch disease, bacillary angiomatosis, bacillary peliosis hepatis, endocarditis. [Article in German] Internist (Berl) 1996:37(9):890-894

Norden C, Gillespie WJ, Nade S, eds. Infections in Bones and Joints, Boston: Blackwell Scientific Publications; 1994

Schultheis K-H, Rehm KE, Ecke H, eds. Chirurgische Infektionen von Knochen, Gelenken und Weichteilen. Berlin: De Gruyter; 1991

Simon C, Stille W. Antibiotika-Therapie in Klinik und Praxis, 10th ed. Stuttgart: Shattauer; 1999

Simth JW, Hasan MS. Infectious arthritits. In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas and Bennetts’s Principles and Practice of Infectious Diseases. 5th ed. Philadelphia: Churchill Livingstone: 200:1175-1182

Local Antibiotic Therapy

L. Frommelt

Why Use Local Antibiotics to Treat Infections of the Musculoskeletal System?

Local antibiotics for the treatment of surgical wound infections have rightly been in disfavor, because their application is difficult to control and there is always a risk that adjacent flora will develop resistance. Considering the increasing number of resistant pathogens worldwide, this is of great importance. In 2002 the first vancomycin-resistant S. aureus (VRSA) species in patients after very long-term treatment with vancomycin was reported in the USA. The published correlation between the use of vancomycin in the USA and the increase in clinically relevant vancomycin-resistant enterococci (VRE) by Kirst et al. in 1998 is especially impressive. Between 1984 and 1996 the use of vancomycin increased from 2000 kg to almost 12 000 kg per year. Up to 1989 there were no known enterococcal resistances to vancomycin, however thereafter the portion of resistant pathogens identified in clinical settings continually increased to almost 25%. The current skepticism concerning the uncontrolled use of local antibiotics in wound treatment is thus understandable.

Infections of the skeletal system are, however, exceptional because of their special pathogenesis, which appears to justify the local application of anti-infectious substances. The application of local antibiotics must, however, play only an adjuvant role alongside surgical debridement. These infections have a strong tendency to recur, and therapeutic success depends decisively on the thoroughness of surgical debridement. Antibiotics alone cannot control these infections. If local and systemic antibiotics are integrated into the surgical concept, they can ensure the success of the surgical intervention and its sustainability. The key to understanding lies in the formal pathogenesis of bone infections, especially chronic forms.

Periprosthetic infections in joint prostheses represent a special situation. This foreign-body infection can serve as a model for chronic osteomyelitis and is, therefore, an ideal example of pathogenesis.

In these infections it is the foreign body which maintains the infection. In osteomyelitis there are naturally occurring foreign bodies, that is, bone sequestra, with which pathogens interact as with foreign bodies. Recurrences originate from these sequestra, and they are also the place where the pathogens withdraw and wait.

In the presence of a foreign body, there is a competing interaction, that is, between the foreign body and the immune system. The incorporation of bone substitute triggers a foreign-body reaction, whose goal is to remove the bone substitute. If this is not successful, a granuloma is formed. The foreign body is isolated from the internal milieu and can no longer be attacked by the immune defenses. This phenomenon can be observed with foreign bodies as well as with certain bacteria, like tuberculosis bacteria.

However, not only the host interacts with the foreign body, but also the pathogen. Bacteria that are able to produce amoeboid forms colonize foreign bodies by building a biofilm and are then irreversibly bound to the surface of the foreign body. The bacteria then transform from the planktonic form, which is characterized by rapid multiplication, rapid metabolism, and high sensitivity to antibiotics, to the amoeboid form, characterized by extremely slow multiplication, reduced metabolism, and a generally high resistance to several antibiotics. Costerson et al. (1995) observed among amoeboid forms of P. aeruginosa an 800-fold higher minimal inhibitory concentration (MIC) than among planktonic forms. Among staphylococci, an approximate 250-fold increase in the MIC has been reported. This means conventional systemic therapy only reaches these bacteria in concentrations which cannot influence them, or only inadequately.

A mixture of planktonic and amoeboid forms of pathogens is present in clinically manifest chronic osteomyelitis or a periprosthetic infection, whereby the clinical symptoms are mainly caused by the planktonic forms. Systemic antibiotic therapy affects almost exclusively the planktonic bacteria, influencing symptoms of the infection without eliminating the pathogen reservoir of the amoeboid forms. To clear up the infection, both the planktonic and the amoeboid forms must be eradicated. For this reason the application of local antibiotic therapy in these infections is justified.