Antimicrobial drugs

Antimicrobial drugs
Dr. Entisar Al-Mukhtar

Drugs used for treatment of infections because they have selective toxicity; as they inhibit the growth or kill the invading microorganisms (MOs) without harming the cells of the host.
The concentration of the drug should be carefully controlled to attack the MOs, while still being tolerated by the host.
Antibiotics (ABs): substances produced by MO & act against another MO.
ABs do not include synthetic (sulfonamides & quinolones), or semisynthetic (methicillin and amoxicillin) AMs, or those which come from plants (quercetin and alkaloids) or animals (lysozyme).
Classification of Antimicrobial (AM) Drugs
AM agents may be classified according to the type of organism against which they are active as follows:
• Antibacterial drugs.
• Antiviral drugs.
• Antifungal drugs.
• Antiprotozoal drugs.
• Anthelminthic drugs.

Antimicrobial are classified according to:
(1) Spectrum of activity
(2) Effect on bacteria
(3) Mode of action
1. Spectrum of activity:
A. Narrow-spectrum ABs: effective against a single or a limited group of MOs, e.g, isoniazid against M. tuberculosis only.
B. Extended-spectrum ABs: e.g, ampicillin against G + & some G - bacteria.
C. Broad-spectrum ABs: e.g, tetracycline, fluoroquinolones & carbapenems act against a wide variety of MOs, they can precipitate superinfection due to organisms such as C. difficile.

2. Effect on bacteria:
A. Bacteriostatic, i.e. sulfonamides, tetracyclines and chloramphenicol, act by arresting bacterial multiplication.
B. Bactericidal, i.e. penicillins, aminoglycosides (AGs) and rifampicin act by killing bacteria.
However, most bacteriostatic drugs are bactericidal at high concentrations, under certain incubation conditions in vitro, and against some bacteria.

Bacteriostatic versus bactericidal drugs:
Bacteriostatic drugs arrest the growth & replication of bacteria at serum (or urine) levels achievable in the patient, thus limiting the spread of infection until the immune system attacks, immobilizes, and eliminates the pathogen.
If the drug is removed before the immune system has scavenged the MOs, enough viable organisms may remain to begin a second cycle of infection.

Bactericidal drugs kill bacteria at drug serum levels achievable in the patient &
they are the drugs of choice in seriously ill & immunocompromised patients.

Although, it is possible for an AB to be bacteriostatic for one MO & bactericidal for another. E.g, linezolid is bacteriostatic against Staph. aureus & enterococci but is bactericidal against most strains of S. pneumoniae.
3. Mode of action:
A. inhibit cell wall synthesis
B. inhibit protein synthesis
C. inhibit nucleic acid synthesis
D. inhibit folate metabolism (anti-metabolites)
E. inhibit cell membrane function


Mechanism of Actions of Antimicrobials
Selection of Antimicrobial Agents
AM selection requires knowing the
1) Organism’s identity
2) Organism’s susceptibility to a particular agent
3) Site of the infection e.g., lipid solubility, molecular weight & protein binding of the drug affect its penetration & concentration in the CSF.
4) Patient’s factors
5) Safety of the AM agent
6) Cost of therapy.
However, some patients require empiric therapy (immediate administration of drug(s) prior to bacterial identification and susceptibility testing).

Empiric therapy prior to identifcation of the organism
An immediate empiric therapy is indicated in critically ill patient.
1. Timing: Acutely ill patients with infections of unknown origin e.g, a neutropenic patient (predisposed to infections) or a patient with meningitis require immediate treatment. If possible, therapy should be initiated after specimens for laboratory analysis have been obtained but before the results of the culture and sensitivity are available.
2. Selecting a drug: Drug choice in the absence of susceptibility data is in?uenced by the site of infection and the patient’s history (e.g, previous infections, age, recent travel history, recent AM therapy, immune status, and whether the infection was hospital- or community-acquired). Broad-spectrum therapy may be indicated initially when the organism is unknown or polymicrobial infections are likely. The choice of agent(s) may also be guided by known association of particular organisms in a given clinical setting. For example, G + cocci in the spinal ?uid of a newborn infant is unlikely to be Streptococcus pneumonia and most likely to be Streptococcus agalactiae, which is sensitive to penicillin G. By contrast, G + cocci in the spinal ?uid of a 40-year-old patient are most likely to be S. pneumonia, which is frequently resistant to penicillin G and often requires treatment with a high-dose third generation cephalosporin (such as ceftriaxone) or vancomycin.
Minimum inhibitory concentration (MIC): a lowest AM concentration that prevents visible growth of a MO after 24 hours of incubation. It serves as a quantitative measure of in vitro susceptibility and is commonly used in practice to streamline therapy.
Minimum bactericidal concentration (MBC): a lowest AM concentration that results in a 99.9% decline in colony count after overnight broth dilution incubations.
Concentration-dependent killing: Certain AMs , e.g, AGs & daptomycin, show a significant increase in the rate of bacterial killing as the concentration of AB increases from 4- to 64-fold the MIC. Thus, once-a-day bolus infusion achieves high peak levels, favoring rapid killing of the infecting pathogen.
Time-dependent (concentration-independent) killing: In contrast, ?-lactams, glycopeptides, macrolides, clindamycin & linezolid do not exhibit concentration-dependent killing. The clinical efficacy of these AMs is best predicted by the percentage of time that blood concentrations of a drug remain above the MIC. For example, dosing schedules for the penicillins and cephalosporins that ensure blood levels greater than the MIC for 50% and 60% of the time, respectively, provide the most clinical efficacy. Therefore, extended (generally 3 to 4 hours) or continuous (24 hours) infusions can be utilized instead of intermittent dosing (generally 30 minutes) to achieve prolonged time above MIC & kill more bacteria.
Postantibiotic effect (PAE): A persistent suppression of microbial growth that occurs after levels of AB have fallen below the MIC. E.g, AGs & fluoroquinolones exhibit a long PAE, thus often require only one dose per day, particularly against G - bacteria.

Combinations of antimicrobial drugs Single therapy decrease superinfections, resistance and toxicity. However, some situations e.g, TB benefits from drug combinations.
? Combinations advantages:
• Synergism (e.g, ?-lactams & AGs combination is more effective than either of the drugs used separately; such combination is indicated for unknown origin infection or to treat enterococcal endocarditis).

? Combinations disadvantages:
1. Bactericidal drugs act most effectively on rapidly dividing MOs, thus a bacteriostatic drug (e.g, tetracycline) by reducing multiplication may interfere with the effect of bactericidal drug (e.g, penicillins and cephalosporins).
2. Risk of the development of AB resistance.
Drug resistance
Bacterial resistant: either inherent e.g., most G- MOs are resistant to vancomycin, or may developed due to spontaneous mutation or acquired resistance.
A. Genetic alterations resistance:
developed due to DNA mutation or its acquired (move from one organism to another).
B. Altered expression of proteins in drug-resistant organisms:
Mechanisms of drug resistance
1. Modification of target sites: a mutation in bacterial PBPs, e.g, resistance of
S. pneumoniae to ?-lactam ABs.
3. Decreased accumulation: either due to? permeability of an AB [e.g, G- MOs limits penetration of ?-lactam ABs as a result to an alteration in the number and structure of porins (channels) in the outer membrane] or ?efflux of an AB [e.g, efflux pump can limit tetracyclines levels in an organism].
3. Enzymatic inactivation: Examples include
1) ?-lactamases (penicillinases) inactivate ?-lactam ring of penicillins & related drugs
2) Acetyltransferases inactivate chloramphenicol or AGs.
3) Esterases hydrolyze the lactone ring of macrolides.

Prophylactic use of antibiotics
Due to bacterial resistance and superinfection the prophylactic use of ABs is restricted to certain situations:
1) Pretreatment may prevent streptococcal infections in patients with a history of rheumatic heart disease (patients may require years of treatment).
2) Pretreating of patients undergoing dental extractions who have implanted prosthetic devices, such as artificial heart valves.
3) Prevent TB or meningitis among individuals who are in close contact with infected patients.
4) Treatment prior to surgical procedures can decrease the incidence of infection.
Complications of antibiotic therapy
A. Hypersensitivity e.g., penicillins can cause serious hypersensitivity ranging from urticaria (hives) to anaphylactic shock. Patients with a history of Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis reaction to an ABs should never be rechallenged, not even for ABs desensitization.
B. Direct toxicity e.g., aminoglycosides high levels can cause ototoxicity.
C. Superinfections due to use of broad-spectrum or combinations of AMs leading to an alterations in normal flora of the upper respiratory, oral, intestinal & genitourinary tracts, permitting the overgrowth of opportunistic organisms, especially fungi or resistant bacteria. These infections usually require secondary treatments with specific agents.