Antimicrobial prophylaxis "...cover it with antibiotics...

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Introduction

It is clear that correct application of antibacterial prophylaxis CAN reduce the incidence of infection resulting from the bacterial inoculation in a variety of clinical situations. It is equally clear that antibiotic administration CANNOT prevent all infections any more than it can eliminate all established infections. Optimum antibacterial prophylaxis depends on:

rational selection of the drug(s) adequate concentrations of the drug in the tissues that are at risk attention to timing of administration.

Finally, the risk of infection in some situations (either because the infection rate for an exposed population is low or the consequences minor) does not outweigh the risks which attend the administration of even the safest antibacterial drug.
General Principles

Definition - the administration of antimicrobial drugs to a patient to prevent establishment of infection in previously un-infected tissue. Examples
Case Osteotomy to correct a valgus deformity Biopsy of the radius for culture of an osteomyelitis lesion Clinical State All involved tissues were "clean" prior to the surgery. The patient is likely to experience a transient septicemia during the procedure. The wound has been seeded with a heavy inoculum of bacteria. Rationale Antibiotics administered just prior to and during the procedure are correctly considered prophylactic. Antibiotics administration during this procedure "prophylactic" for bacterial endocarditis. However, continued therapy is necessary for the osteomyelitis for an extended (3 - 6 week) period. Antibiotic administered before reduction should not be thought of as prophylactic for osteomyelitis. The number of bacteria is excessive and trauma to the tissues reduces the efficiency of antimicrobial delivery. Treatment should be initiated for the infection which is already established.

Contaminated compound fracture

Timing of Administration

Single injections of penicillin G, erythromycin, chloramphenicol, and tetracycline reduced the severity of experimental wound infections if given

before or within the first 3 hours of wound creation. The greatest reduction in lesion size occurred when the antibiotic was given immediately before or at the time of bacterial inoculation. If the antibiotics were given later than 3 hours post-infection, the resulting lesions were not different than controls.
Tissue Concentrations
Cephaloridine Concentrations > 4 mg/l < 4 mg/l Infection Rate (6% of 143) (16% of 19)

Effectiveness (of cephaloridine administered peri-operatively) was directly correlated with the tissue concentration produced. Prophylactic success is associated with some minimum antimicrobial concentration and that high concentrations probably improve success rates. Inoculum Size It takes a higher concentration of antibiotic to affect inhibition of larger numbers of organisms. Also, the greatest reductions in post-surgical infection rates have come from a reduction in bacterial inoculum. Antimicrobial administration cannot replace aseptic technique even though it may reduce infection rates further. Host Immunity It is an accepted principle that local immune mechanisms play an important role in post-operative infection rate. Such things as interruption of blood supply, and failure of complement activation have a demonstrated relationship with the infection rate. Improper tissue handling and failures of homeostasis give increased opportunity to infecting bacteria. From the perspective of antimicrobial therapy, continued ischemia interferes with the delivery of antimicrobials to the site of infection. Further, experimental evidence suggests that satisfactory concentrations of gentamicin, ampicillin, and clindamycin cannot be achieved in implanted fibrin clots and fail to prevent abscess formation. Clearly, good surgical technique contributes to both a direct reduction in infection rate and an optimum environment for successful antimicrobial prophylaxis.

Secondary Sepsis Following Surgery Specific Therapeutic Objective: To provide bactericidal antibiotic concentrations in all tissues and fluids at the time of bacterial innoculation. Selection of Cases
Table 1. Classification of Surgeries for the Purposes of Antimicrobial Prophylaxis
Surgery Class Clean Clean-contaminated Description No trauma, inflammation, or break in technique No entry of respiratory, genitourinary, or gastrointestinal tracts Gastrointestinal (incl. mouth) or respiratory tract entered, no obvious spillage Genitourinary or biliary tract entered Long-duration clean orthopedics Minor break in technique Gross spill of gastrointestinal tract Genitourinary or biliary tract entered (infected urine, discharges, or bile) Fresh, traumatic wound (minimal gross contamination) Compound fracture (no gross contamination) Major break in technique Obvious purulence, inflammation Perforated viscus Compound fracture, gross contamination

Contaminated

Dirty and infected

Antimicrobial Prophylaxis is probably effective for clean-contaminated surgical wounds

Risk of infection in these cases is great enough Results of surgical infection are sufficiently adverse

Antimicrobial Prophylaxis is probably inappropriate for clean surgical wounds

Risks to the patient for an adverse reaction to an antimicrobial outweigh potential benefits

Antimicrobial Prophylaxis is not appropriate for contaminated and dirty wounds. These are not considered in this context because the infections are either established or lodged in extremely high numbers, these cases are treated as infections with full courses of therapeutic antibiotics.
Selection of Antimicrobials for Surgical Prophylaxis

First, selection of antimicrobials should be based on the susceptibility of anticipated bacteria. The authors of all clinical trials reviewed selected the

antibiotic for study on the basis of spectrum against the historical operative isolates in similar circumstances. Infections contracted while receiving prophylactic antibiotics will usually be resistant to the antibiotic chosen. Drug choices can be based on published retrospective analyses of surgical infections if they are designed to identify expected flora without the influence of antimicrobials. It is also wise to maintain susceptibility profiles of isolates for a given surgical facility. While general recommendations for gram positive and anaerobic organisms can be readily made, the susceptibility profiles for gram negative infections are not easily predicted. Awareness of this profile for a recurrent nosocomial isolate in a given hospital is an invaluable piece of therapeutic information.
Cephalosporins are probably used more than any other single class for surgical prophylaxis

Good spectrum (in a general sense) Considerable safety Tissue penetration is likely to be sufficient as confirmed experimentally.

Cefazolin and Cefamandole

Good activity against Staphylococcus spp., anaerobes excepting certain Bacteroides spp., and gram negative organisms including the Enterobacteriaceae Effective against this range of organisms but is less active against gram negative infections Effective against this range of organisms AND against anaerobes that may be resistant to other beta lactams. Reserve for Bacteroides fragilis. Activity for Klebsiella spp. and Pseudomonas spp. Use for Anticipated "E. coli from hell"

Cephalothin Cefoxitin Ceftriaxone, Ceftiofur, or Ceftazidime

Penicillins are used less frequently than cephalosporins for surgical prophylaxis

Tend to be limited in spectrum Large subset of resistant organisms (producing penicillinase) exist within susceptible species. Extremely safe Produce acceptable tissue and wound fluid concentrations

Ampicillin, Amoxicillin, Ticarcillin, and Piperacillin

Susceptible to penicillinase produced by gram (+) organisms Not for Staphylococcus aureus or intermedius Enterobacter sp., E. coli resistant to ampicillin and amoxicillin Klebsiella sp. often resistant to ticarcillin Piperacillin is active against most gram (-)bacteria and Pseudomonas spp. Occasionally chosen for surgical prophylaxis on this basis Some improvement in activity and protection from gram positive penicillinase Delivery of sufficient inhibitor to the site of infection is not always possible Relatively inactive against gram negative organisms (should not be used)

Penicillinase inhibitors (clavulanic acid) Methicillin, Cloxacillin,

Dicloxacillin and Oxacillin Aminoglycosides are used when other antimicrobials will not work (or are impractical because of cost)

Appropriate spectrum of activity Penetrate tissue and wound fluids well Used locally

o o

reduced numbers of GI microflora part of surgical implants

Toxicity

o o

Usually renal damage and dysfunction, loss of hearing and vestibular nerve damage Interactions between aminoglycosides and anesthetic agents which include cardiac depression and neuromuscular blockade which can result in apnea during anesthesia

Clindamycin is occasionally chosen for orthopedic surgical prophylaxis

Excellent activity against Staphylococcus spp. and Bacteroides fragilis Good reputation for tissue penetration No activity against enteric (not appropriate for general application in surgical prophylaxis)

Dose regimens (Surgical Prophylaxis)

Attention to appropriate route, dose form, dosage, timing, and repetition are important because adequate antibiotic concentrations in "at risk" tissues can be correlated with prophylactic success. Systemic Administration: intravenous or intramuscular Rules:

Administered to produce the highest tissue concentrations which can reasonably be attained Injections of therapeutic doses of water soluble formulations
o o o o o

Sodium and potassium salts of the penicillins Sodium salts and neutral cephalosporins All injectable forms of aminoglycosides Clindamycin for injection (phosphate salt) Sustained release forms of the penicillins, specifically procaine and benzathine penicillins cannot be recommended

Tissue concentrations should be highest at the time the tissue is incised Concentrations above the target MIC should be maintained throughout the operative No additional doses required AFTER wound closure is complete. A single postop dose is often given.

Drug characteristics

cephalothin, cephaprin, cephradine, cefazolin, cefamandole and cefsulodin

o o

Peak tissue concentrations within the first hour after administration Effective concentrations are maintained for at least 5 hours Peak concentration somewhat later Effective tissue concentrations are achieved within the first hour Effective concentrations are maintained for at least 5 hours Peak within the first hour after administration Effective concentrations of penicillins maintained for 4 to 6 hours Peak concentration 1.0 - 1.5 hours after intravenous administration MICs were maintained for 4.0 to 6.0 hour Effective concentrations of clindamycin may not be achieved during the first dose interval Accumulate in excess of the MIC within the first 2 - 3 dose intervals Stable concentrations are then maintained for greater than 6 hours (after last dose)

cefoxitin and ceftazidime

o o o

ampicillin, oxacillin, ticarcillin, and piperacillin

o o

aminoglycoside
o o

clindamycin
o o o

Dose regimens

cephalosporin, penicillin, and aminoglycoside

o

o o

First dose: Intravenous administration 1.0 - 2.0 hours before the incision is made Intramuscular injections should be made 0.5 - 1.5 hours sooner Maintenance: Doses repeated at six hour intervals ( extended in cases with poor renal function) Conclusion: A single dose administered post-operatively. Begin 16 - 24 hours prior to surgery Repeated every 8 hours Continue through a single dose post-operatively

Clindamycin
o o

Single dose prophylaxis

Advantages
o o o o

Reduced total cost of the prophylactic regimen Decreased adverse effects on normal flora, and (relatively minor) reductions of toxicity No references to this approach in veterinary surgical patients were found The main limitation to this extrapolation may be a difference in pharmacokinetics for drugs chosen because of prolonged elimination (in man). Such drugs may not work as well if they are eliminated more rapidly by the animal considered cefonicid and ceforanide (long duration of action - people)

New antimicrobial agents with extended durations of action

o

o o

cefotaxime (extended spectrum and duration) First generation cephalosporins, penicillins, doxycycline and metronidazole gastrointestinal and biliary surgery

Local administration

Non-absorbable antibiotics for gastrointestinal tract preparation Infiltration of antibiotics into incision lines
o o o

Wound infections can be reduced The rate of abscess formation and sepsis higher (unless combined with systemic doses) No additional reduction of wound infections if both routes were used simultaneously

Bonding of beta-lactam antibiotics to dacron vascular grafts before grafting (soak the grafts in high concentrations of antibiotics)
o

Superior to parenteral administration of the same antibiotics (in vivo study)

90% infection rate in controls 80% of parenteral antibiotic recipients 30% of antibiotic-bonded grafts

Incorporation of aminoglycosides into acrylic bone cement

o

Increases concentrations in tissues directly adjacent to the implant in total joint replacement

Urinary Catheter-Associated Infections

Specific Therapeutic Objective:To provide bacteriostatic or bacteriocidal concentrations of antimicrobials to the epithelial surface of the lower urinary tract in order to reduce the incidence of urinary tract infection (or delay its onset). A bacterial infection incidence of 5 - 10% each day can be expected during chronic catheterization; by the end of 30 days, nearly 100% of patients will be infected. Intermittent catheterization (2 - 3 x's daily) reduces the incidence of infection as compared to chronic catheterization by 50% or more. The incidence of infection can be reduced further still by judicious application of antimicrobial prophylaxis. Urinary tract infections cannot be completely prevented, they can only be delayed. As long as a catheter is introduced into the bladder on some routine basis. Prophylactic antibacterial techniques and agents employed to delay urinary tract infections include systemic and intra-vesicular antibiotics, systemic administration of methenamine supplemented with systemic or intravesicular acidifiers, and urinary acidification alone.

Antimicrobial prophylaxis for urinary catheters is, by no means, universally practiced. It is not uncommon, nor is it inappropriate, to accept the fact that urinary tract infections WILL OCCUR as long as the catheter is used and decide that the infection will be treated after the catheterization is no longer necessary.
Antimicrobials

Range of pathogens

Patients normal gastrointestinal and dermal flora.

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E. coli is the most common isolate, followed by Proteus mirabilis, Pseudomonas aeruginosa, Klebsiella pneumoniae, Staphylococcus epidermidis, and enterococci

Systemic antimicrobials New since 2011 notes were printed: The manner of administration for this purpose is likely different than surgical prophylaxis. Intermittent catheterization are "as needed" so timing is unpredictable. Generally, antimicrobials will be given continuously while the catheterizations continue. end new material.

Nitrofurantoin, sulfamethoxazole, trimethoprim - sulfamethoxazole (TMP\SMX) and nalidixic acid.

o o o o

Appropriate spectrum versus the expected pathogens Relative low cost Ease of oral administration Lack of application in other situations

When infection rates were high (50% infected by 5 - 15 days, 100% by 30 - 80 days), performance of nalidixic acid (fluoroquinolone) and TMP\SMX was poor When infection rates were lower, antimicrobial prophylaxis appeared to be more effective Infection was also defined differently in these studies. The high infection rate included any sample containing >1,000 microorganisms/ml while the latter two only included those infections of >10,000/ml. This opens these results for speculation that antimicrobial prophylaxis may be less effective for colonization than for so called clinically significant infections.

Methenamine (Systemic)

Mechanism of action:
o o

Eliminated in the urine and collects in the bladder In acid urine (pH 5.0 - 6.0), hydrolyzed to formaldehyde

Broad (or perhaps complete) spectrum of action No mechanisms for bacterial resistance to formaldehyde exist Efficacy:
o o o o o

Conversion of methenamine to formaldehyde is variable at best low pH (low enough anyway) is difficult to maintain. Usually given in combination with either sodium hippurate or mandelate Additional acidification with ammonium chloride is also recommended Less effective than systemic TMP/SMX or nitrofurantoin (human studies)

Intra-vesicular antimicrobials

Proprietary combination of neomycin and polymyxin B is available for this purpose (GU irrigant) Advantages
o o o

Excellent activity against the predominant spectrum of pathogens Lack of systemic adverse effects Certainty about the delivery of the drug to the site of action

Urine Acidification (alone)

ascorbic acid, sodium hippurate and sodium mandelate, d,l-methionine, and ammonium chloride
o o o

Conclusive studies of acidification as a sole means of prophylaxis were not found Ascorbic acid failed to reduce the infection rate in one study Failure may have been related to a general inability of ascorbic acid to produce aciduria

Urine acidification alone, as a means to reduce catheter associated urinary tract infection, deserves further investigation using ammonium chloride or some other effective acidifier. At this time acidification alone cannot be recommended as appropriate prophylactic therapy.

Dental Procedures Specific Therapeutic Objective:To provide bactericidal antimicrobial concentrations in plasma during and immediately after the dental procedure in order to reduce the incidence of bacterial endocarditis, bacterial arthritis, and other soft tissue infections. Assumptions (from human medicine)

Dental procedures are associated with a high incidence of bacteremia

o o

oral mucosa is expected to have a lively flora and simple teeth cleaning can be a very extensive procedure

Some fraction of patients have an increased susceptibility to endocarditis associated with specific heart conditions.

Antimicrobial administration can decrease the severity of bacteremia and colonization of the myocardium. Sufficient experimental evidence exists (human medicine)

Cardiac patients with increased risk for bacterial endocarditis during bacteremia:

Prosthetic heart valves Most congenital malformations Traumatic and other acquired valvular dysfunction Hypertrophic subaortic stenosis Previous history of bacterial endocarditis

Should also be concerned for ANY tissues that are "set up" for infection. Wounds, bruises, damaged joints, orthopedic implants, etc.
Antibiotic Selection

Flora

Dogs mostly anaerobic gram negative rods

o

Healthy gingiva Enterococcus, Lactobacillus, Eubacterium, and Bacteroides spp., while Fusobacterium, Enterobacteriaceae, yeast and molds were less prevalent. Gingivitis Bacteroides asaccharolyticus and Fusobacterium nucleatumprobably others...

Drugs organisms most likely involved should be susceptible to penicillin G, ampicillin, or amoxicillin If the dog has recently been treated with antimicrobials for oral infections, these assumptions may not be valid and alternate antimicrobials should be considered. Dose regimens

same as for surgical prophylaxis Administration of non-irritating disinfectants may also reduce the bacterial density on the mucous membrane and during the subsequent (Swab gums and teeth with non-irritating disinfectanct 1/2 hour before procedure).

Bacterial Prophylaxis in Immuno-compromised Patients

The risk of hospital acquired infection is extremely high in human patients who are critically ill. Hospital acquired infections not only increase mortality rates in these patients, but additional hospital days and increased costs have been documented. Depressed resistance of the oropharynx, digestive and respiratory tracts, and acquired non-specific immunodeficiency are the main causes of infection. Infection rates of 50 to 90% per week have been reported in these patients. Rates of infection in critically ill veterinary patients have not been reported but are, in this authors experience, probably similar. The recurring theme of antibacterial prophylaxis in these patients, has been a general failure of standard single agent systemic therapy to reduce the acquisition of infections. Often single agent therapy merely resulted in infections caused by resistant gram negative bacteria and yeasts. Recently, efforts have been redirected toward a reduction of colonization by hospital acquired microorganisms. Oral and topical antibacterial and antifungal drugs have been added to preventative schemes in an effort to selectively decontaminate and protect the oropharynx, respiratory tree, and gastrointestinal tract. Although the effectiveness of decontamination schemes has been documented for human patients, their application to veterinary patients would seem questionable. Strict hygiene is almost impossible in domestic animal patients and the costs involved in these procedures may well outweigh any conceivable benefit that may be derived. Careful prospective evaluation of infection rates with and without these techniques should be performed before any specific recommendations are made.
Topic Summary (Antimicrobial Prophylaxis) 1. Antibacterial prophylaxis can reduce the incidence of infection which might be anticipated following certain clinical procedures. 2. All antimicrobial prophylaxis should follow these "rules":
a. Bactericidal concentrations of the drug should be present in the tissue of interest before bacterial inoculation occurs. b. Inoculum size determines the frequency of infection. Antimicrobial prophylaxis should not be substituted for measures designed to reduce the number of bacteria that enter the tissue of interest. c. If it is likely that bacterial infection already exists, full courses of therapy, appropriate for the specific infection, should be initiated. d. Local instillation of antibiotics ("incision line doses", mixtures with bone cement, etc.) is most appropriate when prosthetic devices are installed. Local instillation may actually contribute to infection, suture failure, etc. if the antimicrobial is irritating. Be careful of drug and vehicle selection.

e. Urinary catheter-associated infections can be delayed using antimicrobials but cannot be prevented entirely.