Usually

when the nature of the microorganism is unknown and a lifethreatening condition exists, an empiric antimicrobial regimen is begun before the offending organism is identified and sometimes prior to the documentation of the presence of infection A definitive regimen is instituted when the causative organism is known.

CONFIRMING THE PRESENCE OF INFECTION FEVER

Elevation of body temperature above the normal range of 36.7 to 37.0C (98.1 to 98.6F) Pyrogens are substances that cause fever Induction of fever following infection is initiated by interleukins by acting on thermoregulatory neurons to elevate the internal thermostat Many drugs have been identified as causes of fever. Hypersensitivity reaction Drug-induced fever is defined as persistent fever in the absence of infection or other underlying condition. The fever must coincide temporally with the administration of the offending agent and disappear promptly upon its withdrawal, after which the temperature remains normal.

CONFIRMING THE PRESENCE OF INFECTION

Fever
False positives False negatives
Absence

of fever in a patient with signs and symptoms Antipyretic Obtain careful history Partial effective therapy
Bacteriostatic

CONFIRMING THE PRESENCE OF INFECTION

White

Blood Cell Count

Most infections result in elevated white blood cell

(WBC) counts (leukocytosis) because of the mobilization of granulocytes and/or lymphocytes to destroy invading microbes. Bacterial infections are associated with elevated granulocyte counts (neutrophils,basophils) Lymphocytosis increases with viral infections Many types of infections, however, may be accompanied by a completely normal WBC count and differential.

CONFIRMING THE PRESENCE OF INFECTION

Pain

and Inflammation

Swelling, erythema, tenderness, and purulent drainage Elevation of ESR Negative result does not rule out infection C-reactive protein Cytokines

Confirming the presence of an infection

Colonization versus infection

Colonization

Presence of an organism without production of a disease in a host Many body tissues are colonized with normal flora These bacteria are considered normal flora in their site, however, when introduced to other areas , they may become infectious when introduced to other body sites; e.g strep epidermis is a skin flora, however, it is a pathogen in the CSF

Infection

Presence of an organism within the tissue with invasiveness that often results in a response

VERIFICATION OF INFECTION

Direct examination Gram stain

Infected body materials must be sampled, if at all possible or practical, before the institution of antimicrobial therapy, for two reasons. First, a Gram stain of the material may reveal bacteria, or an acid-fast stain may detect mycobacteria or actinomycetes. Second, a delay in obtaining infected fluids or tissues until after therapy is started may result in false negative culture results or alterations in the cellular and chemical composition of infected fluids. Abscesses and cellulitic areas should also be aspirated.

VERIFICATION OF INFECTION

Cultures

Media Bactec, 14 C labeled carbohydrates and amino acids Early growth determined by radiolabelled CO2

Inoculate Aseptically collected sample

Antigen antibody detection

Rapid Sensitive Specific

VERIFICATION OF INFECTION

Molecular techniques
Probes specific for a pathogen's nucleotides

Oligonucleotide sequence Hybridizes with a complementary nucleotide from the m.o Probe is labelled with a signal emitting molecule PCR http://www.maxanim.com/genetics/PCR/PCR.htm

Nucleic acid amplification

HOST FACTORS
External

CHOICE OF THE PROPER ANTIMICROBIAL

Local susceptibility data

data may be misleading Allergy or history of adverse drug reactions Age of patient Identifying the etiology of pathogen Meningitis Detoxification Neonates Metabolism Drug selection Drug dosing

CHOICE OF THE PROPER ANTIMICROBIAL

Age

Kernicterus in neonates when given sulphonamides Grey baby when given chloramphenicol Teratogenicity Kinetics of drug absorption G6PDH deficiency

Replacement of bilirubin from plasma binding proteins

Pregnancy

Metabolic abnormalities

Concomitant drug therapy Concomitant disease states.

Slow acetylaors and INH (peripheral neuropathy, vit b supplement) Hepatic and renal problems
INH and phenytoin results in phenytoin toxicity Diabetes and soft tissue infection Immunosupressed patients

Sulphonamides, nitrofurantoin, nalidixic acid, dapsone---etc

CHOICE OF THE PROPER ANTIMICROBIAL

DRUG FACTORS
Importance of tissue penetration varies with the site of infection. The CNS is one body site where the importance of antimicrobial penetration is relatively well defined and correlations with clinical outcomes are established Drugs that do not reach significant concentrations in cerebrospinal fluid should either be avoided or instilled directly when treating meningitis. Pharmacokinetic parameters such as area under the concentration-time curve (AUC) and maximal plasma concentration can be predictive of treatment outcome when specific ratios of AUC or maximal plasma concentration to the minimum inhibitory concentration (MIC) are achieved

CHOICE OF THE PROPER ANTIMICROBIAL

Drug Toxicity Cost

Dramatic increase

Biotechnology Total economic impact of antimicrobial therapy

Cost benefit ratios

Drug acquisition cost Storage/inventory cost Preparation Distribution Administration Monitoring Adverse effects Impact on length of stay Cost of control systems

COMBINATION ANTIMICROBIAL THERAPY

Combinations of antimicrobials are generally used to broaden the spectrum of coverage for empiric therapy achieve synergistic activity against the infecting organism, prevent the emergence of resistance Increasing the coverage of antimicrobial therapy is generally necessary in mixed infections where multiple organisms are likely to be present, such as intraabdominal and female pelvic infections in which a variety of aerobic (aminglycosides)and anaerobic bacteria (metronidazole) may produce disease. Another clinical situation in which increased spectrum of activity is desirable is with nosocomial infection. Prevent emergence of resistance

Gram-negative bacilli in immunosuppressed patients. Traditionally, combinations of aminoglycosides and -lactams have been used since these drugs together generally act synergistically against a wide variety of bacteria. Weak supportive data Synergistic combinations may produce better results in infections caused . by Pseudomonas aeruginosa, in certain infections caused by Enterococcus spp. The use of combinations to prevent the emergence of resistance is widely applied but not often realized. The only circumstance where this has been clearly effective is in the treatment of tuberculosis.

SYNERGISM

DISADVANTAGES OF COMBINATION THERAPY

Increased cost Greater risk of drug toxicity Superinfection with even more resistant bacteria. Some combinations of antimicrobials are potentially antagonistic. For example, agents that are capable of inducing -lactamase production in bacteria (such as cefoxitin) may antagonize the effects of enzyme-labile drugs such as penicillins or imipenem.

MONITORING THERAPEUTIC RESPONSE White blood cell count

Temperature Signs and symptoms of infection Physical complaints from the should diminish (i.e., decreased pain, shortness of breath,cough, or sputum production). Appetite Radiologic studies as appropriate, Antimicrobial concentrations in body fluids Volume of distribution Low volume of distribution Dehydration High volume of distribution edema,, acitis As the patient improves the route of antibiotic administration should be re-evaluated. Switch to oral therapy is an accepted practice for many infections.

CRITERIA FAVORING SWITCH TO ORAL THERAPY INCLUDE:

Overall clinical improvement Lack of fever for 8 to 24 hours Decreased WBC A functioning GI tract

Failures Caused by Drug Selection

FAILURE OF ANTIMICROBIAL THERAPY

Inappropriate selection of drug, dosage, or route of administration. Malabsorption of a drug product because of GI disease (e.g., shortbowel syndrome) or a drug interaction (e.g., complexation of fluoroquinolones with multivalent cations resulting in reduced absorption) may lead to potentially sub-therapeutic serum concentrations Accelerated drug elimination is also a possible reason for failure and may occur in patients with cystic fibrosis or during pregnancy, when more rapid clearance or larger volumes of distribution may result in low serum concentrations, particularly for aminoglycosides. A common cause of failure of therapy is poor penetration into the site of infection. This is especially true for the so-called privileged sites such as the CNS, the eye, and the prostate gland.

immunosuppressed (e.g., granulocytopenia from chemotherapy, acquired immune deficiency syndrome) may respond poorly to therapy because their own defenses are inadequate to eradicate the infection despite seemingly adequate drug regimens. Other host factors are related to the necessity for surgical drainage of abscesses or removal of foreign bodies and/or necrotic tissue. If these situations are not corrected, they result in persistent infection and, occasionally, bacteremia, despite adequate antimicrobial therapy.

FAILURES CAUSED BY HOST FACTORS

FAILURES CAUSED BY MICROORGANISMS

Factors related to the pathogen include the development of drug resistance during therapy. Primary resistance refers to the intrinsic resistance of the pathogens producing the infection. However, acquisition of resistance during treatment has become a major problem as well. The increase in resistance among pathogenic organisms is believed to be due, in large part, to continued overuse of antimicrobials in the community, as well as in hospitals, and the increasing prevalence of immunosuppressed patients receiving long-term suppressive antimicrobials for the prevention of infections.