Overview of Antimicrobial Drugs: Classification, Activity, and Spectrum

1. Oula Mohammed M.B.Ch.B/ MSc. Clinical pharmacology

2. Antimicrobial drugs have the ability to injure or kill an invading microorganism without harming the cells of the host (biochemical differences that exist between microorganisms and human). In most instances, this selective toxicity is relative rather than absolute, requiring that the concentration of the drug be carefully controlled to attack the microorganism, while still being tolerated by the host. Theantimicrobial drugs can be subclassified as antibacterial, antifungal, antiviral agents, and antiparasitic drugs. These agents include natural compounds, called antibiotics, as well as synthetic compounds. An antibiotic is a substance produced by one microbe that can inhibit the growth or viability of another microbe.

3. Classification of Antimicrobial Drugs Antimicrobial drugs are usually classified on the basis of their site and mechanism of action and are subclassified on the basis of their chemical structure. 1. cell wall synthesis inhibitors 2. cell membrane inhibitors 3. protein synthesis inhibitors 4. nucleic acid inhibitors 5. metabolic inhibitors

5. Antimicrobial Activity The antimicrobial activity of a drug can be characterized in terms of its : 1. bactericidal or bacteriostatic effect 2. spectrum of activity 3. concentration- and time-dependent effects Bactericidal or Bacteriostatic Effect A bactericidal drug kills sensitive organisms at serum levels achievable in the patient so that the number of viable organisms falls rapidly after exposure to the drug. In contrast, a bacteriostatic drug arrest the growth and replication of bacteria at serum levels achievable in the patient but does not kill them. For this reason, the number of bacteria remains relatively constant in the presence of a bacteriostatic drug, and immunologic mechanisms are required to eliminate organisms. (The same principle applies to a drug that kills or inhibits the growth of fungi and is referred to as a fungicidal drug or a fungistatic drug, respectively.) A bactericidal drug is usually preferable to a bacteriostatic drug .This is because bactericidal drugs typically produce a more rapid microbiologic response and more clinical improvement and are less likely to elicit microbial resistance.

10. • Bactericidal drugs have actions that induce lethal changes in microbial metabolism or block activities that are essential for microbial viability. For example, drugs that inhibit the synthesis of the bacterial cell wall (e.g., penicillins) prevent the formation of a structure that is required for the survival of bacteria. • Bacteriostatic drugs usually inhibit a metabolic reaction that is needed for bacterial growth but is not necessary for survival. For example, sulfonamides block the synthesis of folic acid, which is a cofactor for enzymes that synthesize DNA components and amino acids. Some drugs can be either bactericidal or bacteriostatic, depending on their concentration and the bacterial species against which they are used. For example, linezolid is bacteriostatic against Staphylococcus aureus and enterococci but is bactericidal against most strains of S. pneumoniae. Recent data have demonstrated that bactericidal and bacteriostatic agents have similar efficacy for treating common clinical infections. Other factors may have a greater impact, including the host immune system, drug concentration at the site of infection, and underlying severity of the illness.

11. Antimicrobial Spectrum The spectrum of antimicrobial activity of a drug is the primary determinant of its clinical use. 1. Antimicrobial agents that are active against a single species or a limited group of pathogens are called narrow- spectrum drugs e.g., isoniazid is active only against Mycobacterium tuberculosis 2. Whereas agents that are active against a wide range of pathogens are called broad-spectrum drugs e.g., tetracycline, carbapenems. 3. Agents that have an intermediate range of activity are sometimes called extended-spectrum drugs e.g., ampicillin. fluoroquinolones and

12.  Narrow-spectrum drugs are sometimes preferred because they target a specific pathogen without disturbing the normal flora of the gut or respiratory tract.  Broad-spectrum drugs are sometimes preferred for the initial treatment of an infection when the causative pathogen is not yet identified.  Administration of broad-spectrum antimicrobials can severely alter the nature of the normal bacterial microbiota and precipitate a superinfection due to organisms such as Clostridium difficile, the growth of which is normally kept in check by the presence of other colonizing microorganisms.

14. Concentration- and Time-Dependent Effects Antimicrobial drugs exhibit various concentration- and time-dependent effects that influence their clinical efficacy, dosage, and frequency of administration. Examples of these effects are the minimal inhibitory concentration (MIC) , the concentration-dependent killing (concentration-independent) killing and the postantibiotic effect (PAE). The MIC is the lowest concentration of a drug that inhibits bacterial growth after 24 hours of incubation. Based on the MIC, a particular strain of bacteria can be classified as susceptible or resistant or with intermediate sensitivity to a particular drug and is commonly used in practice to streamline therapy. rate (CDKR), Time-dependent The minimum bactericidal concentration MBC is the lowest concentration of antimicrobial agent that results in a 99.9% decline in colony count after overnight broth dilution incubations. It is rarely used in clinical practice due to the time and labor requirements.

15. MIC

16. MBC

19. Concentration-dependent killing rate CDKR: some aminoglycosides (e.g., tobramycin) and some fluoroquinolones (e.g., ciprofloxacin) show a significant increase in the rate of bacterial killing as the concentration of antibiotic increases from 4- to 64-fold the MIC of the drug for the infecting organism. Giving these drugs by a one dose per day achieves high peak levels, favoring rapid killing of the infecting pathogen. After an antibacterial drug is removed from a bacterial culture, evidence of a persistent effect on bacterial growth may exist. This effect is the PAE. Antimicrobial drugs that exhibit a long PAE are aminoglycosides and fluoroquinolones which often require only one dose per day, particularly against gram-negative bacteria. Time-dependent (or concentration-independent) killing. In contrast, β-lactams, macrolides, clindamycin, and linezolid effects are best predicted by the percentage of time that blood concentrations of a drug remain above the MIC. This effect is sometimes called 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, frequent dosing ,extended or continuous infusions is important to achieve prolonged time above the MIC and kill more bacteria.

21. Selection of Antimicrobial Agents requires knowing: 1) The organism’s identity 2) The organism’s susceptibility to a particular agent 3) Pharmacokinetic Properties 4) Host factors 5) Adverse effects 6) The cost However, some patients require empiric therapy (immediate administration of drug(s) prior to bacterial identification and susceptibility testing).

22. Identification of the infecting organism A rapid assessment of the nature of the pathogen can sometimes be made on the basis of the Gram stain, which is particularly useful in identifying the presence and morphologic features of microorganisms in body fluids that are normally sterile (blood, serum, cerebrospinal fluid [CSF], pleural fluid, synovial fluid, peritoneal fluid, and urine). It is essential to obtain a sample culture of the organism prior to initiating treatment to differentiate whether a negative culture is due to the absence of organisms or is a result of antimicrobial effects of administered antibiotic. Definitive identification of the infecting organism may require other laboratory techniques, such as detection of microbial antigens, DNA, or RNA utilizing rapid polymerase chain reaction (PCR), or an inflammatory or host immune response to the microorganism.

23. Empiric therapy prior to identification of the organism 1. Timing: Acutely ill patients with infections of unknown origin for example, a neutropenic patient or a patient with meningitis require immediate treatment. 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 influenced by the site of infection and the patient’s history (for example, previous infections, age, recent travel history, recent antimicrobial 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 poly-microbial 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, gram-positive cocci in the spinal fluid of a newborn infant is unlikely to be Streptococcus pneumoniae and most likely to be Streptococcus agalactiae (a group B streptococci), which is sensitive to penicillin G. By contrast, gram- positive cocci in the spinal fluid of a 40-year-old patient are most likely to be S. pneumoniae. This organism is frequently resistant to penicillin G and often requires treatment with a high-dose third- generation cephalosporin (such as ceftriaxone) or vancomycin.

26. Determining antimicrobial susceptibility of infective organisms After a pathogen is cultured, its susceptibility to specific antibiotics serves as a guide in choosing antimicrobial therapy. Some pathogens, such as Streptococcus pyogenes and Neisseria meningitidis, usually have predictable susceptibility patterns to certain antibiotics. In contrast, most gram-negative bacilli, enterococci, and staphylococcal species often show unpredictable susceptibility patterns and require susceptibility testing to determine appropriate antimicrobial therapy.

27. Pharmacokinetic Properties Include oral bioavailability, peak serum concentration, distribution to sites of infection, routes of elimination, and half-life. An ideal antimicrobial drug for patients would have good oral bioavailability and a long plasma half-life so that it would need to be taken only once a day. Azithromycin is an example of an antibiotic that meets these criteria. The oral route of administration is appropriate for mild infections that can be treated on an outpatient basis. Parenteral administration is used for drugs that are poorly absorbed from the GI tract (such as vancomycin, and the aminoglycosides) and for treatment of patients with serious infections such as bacterial meningitis or endocarditis, for whom it is necessary to maintain higher serum concentrations of antimicrobial agents, for critically ill patients and for patients with, gastrectomy, ileus, or diseases that may impair oral absorption. nausea, vomiting. The peak serum concentration of an antimicrobial drug should be several times greater than the MIC of the pathogenic organism for the drug to eliminate the organism. This is partly because the tissue concentrations of a drug are sometimes lower than the plasma concentration. The urine concentration of an antimicrobial drug can be 10 to 50 times the peak serum concentration. For this reason, infections of the urinary tract can be easier to treat than are infections at other sites.

28. Some sites of infection that are not readily penetrated by many antimicrobial drugs include the central nervous system, bone, prostate gland, and ocular tissues. The treatment of meningitis requires that drugs achieve adequate concentrations in the cerebrospinal fluid. The penetration and concentration of an antibacterial agent in the CSF are particularly influenced by lipid solubility of the drug (lipid soluble drugs as chloramphenicol and metronidazole penetrate significantly whereas β-lactam antibiotics, such as penicillin, are ionized and penetrate the blood-cerebrospinal fluid barrier only when the meninges are inflamed), molecular weight ( low molecular weight drugs tend to cross BBB) and protein binding of the drug ( high binding restricts entry into the CSF). Because antimicrobial drug concentrations are low in bone, patients with osteomyelitis must usually be treated with antibiotics for several weeks to produce a cure. The prostate gland restricts the entry of some antimicrobial drugs because the drugs have difficulty crossing the prostatic epithelium and because prostatic fluid has a low pH. These characteristics favor the entry and accumulation of weak bases (e.g., trimethoprim) and tend to exclude the entry of weak acids (e.g., penicillin). The route of elimination affects both the selection and the use of antimicrobial drugs. Drugs that are eliminated by renal excretion (e.g., fluoroquinolones) are more effective for urinary tract infections than are drugs that are largely metabolized or undergo biliary excretion (e.g., erythromycin). Antibiotics that are eliminated by the kidneys (e.g., the aminoglycosides) can accumulate in patients whose renal function is compromised, so their dosage must be reduced in these patients.

29. Host Factors Host factors that influence the choice of a drug include pregnancy, drug allergies, age and immune status, and the presence of renal impairment, hepatic insufficiency, circulation status, abscesses, or indwelling catheters and similar devices. Most antimicrobial drugs cross the placenta and can thereby affect the fetus. For example, administering tetracyclines to a woman during pregnancy can cause permanent staining of her offspring’s teeth. Penicillins and cephalosporins, however, cause very little fetal toxicity and can be safely administered to pregnant women who are not allergic to these drugs.

30. Many individuals are allergic to one or more antimicrobial drugs. Penicillins are the most common cause of drug allergy. Renal or hepatic elimination processes are often poorly developed in newborns, making neonates particularly vulnerable to the toxic effects of chloramphenicol and sulfonamides. Young children should not be treated with tetracyclines or quinolones, which affect bone growth and joints, respectively. Decreased circulation to an anatomic area, such as the lower limbs of a diabetic patient, reduces the amount of antibiotic that reaches that site of infection, making it more difficult to treat.

31. The patient’s immune status is an important factor determining the success of antimicrobial therapy. Advanced age, diabetes, cancer chemotherapy, and human immunodeficiency virus (HIV) infection are among the more common causes of impaired immunity. Immunocompromised individuals should be treated with larger doses of bactericidal drugs and may require a longer duration of therapy than do immunocompetent individuals. Many antibiotics are excreted unchanged by the kidneys, and lower doses must be used if the patient has significant renal impairment. Less commonly, hepatic insufficiency may require dosage adjustment for antimicrobial drugs that are extensively metabolized in the liver. Antibiotic access to an abscess is poor, and the concentration of an antibiotic in an abscess is usually lower than in the surrounding tissue. Moreover, immune function is often impaired in an abscess. For these reasons, it is often necessary to surgically drain an abscess before the infection can be cured. Foreign bodies, such as indwelling catheters, provide sites where microbes can become covered with a glycocalyx coating (biofilm) that protects them from antibiotics and immunologic destruction.

32. Safety of the agent β-Lactam antibiotics are among the least toxic of all antimicrobial drugs because they interfere with a site or function unique to the growth of microorganisms. Other antimicrobial agents (for example, chloramphenicol have less specificity and are reserved for life threatening infections because of the potential for serious toxicity to the patient. Only 5% of patients that receive vancomycin experience nephrotoxicity. If other medications with a risk for nephrotoxicity are administered concomitantly, then the patient may be at a higher risk of experiencing the reaction. For example, the combination of an aminoglycoside antibiotic and vancomycin therapy .

33. Microbial Sensitivity and Resistance Microbial sensitivity to drugs can be determined by various means, including the broth dilution test, the disk diffusion method (Kirby-Bauer test), and the E-test method.

34. Either the broth dilution test or the E-test method can be used to determine the MIC or MBC of a drug. On the basis of the MIC, the organism is classified as having susceptibility, intermediate sensitivity, or resistance to the drug tested. These categories are based on the relationship between the MIC and the peak serum concentration of the drug after administration of typical doses. In general, the peak serum concentration of a drug should be 4 to 10 times greater than the MIC in order for a pathogen to be susceptible to a drug. Pathogens with intermediate sensitivity may respond to treatment with maximal doses of an antimicrobial agent.

35. Microbial Resistance to Drugs Antimicrobial resistance (AMR) is one of the world’s most serious public health problems resulting in prolonged illness and hospitalization. antimicrobial resistance is due to : 1. Overuse, misuse, and irrational use by doctors : e.g. prolonged antibiotic treatment, inadequate doses, prior use of a less-effective drug of the same antibiotic class. 2. Noncompliance to prescribed regimen: When antibiotics are not taken for the entire prescribed course, pathogenic bacteria can adapt to the presence of low-dose antibiotics and eventually form a population that is completely resistant to the antibiotic regardless of the dosage. 3. Poor infection control in healthcare settings: It leads to spread of outbreaks and transmission of resistant organisms among patients. 4. failures to maintain hospital hygiene and sanitation and Poor hand hygiene. 5. Absence of new antibiotics being discovered

36. Origin of Resistance Resistance can be innate or acquired. Acquired drug resistance arises from mutation and selection or from the transfer of plasmids. Mutation and Selection Microbes can resistant to a particular antimicrobial drug. These mutations occur at a relatively constant rate, such as in 1 in 1012organisms per unit of time. If the organisms are exposed to an antimicrobial drug during this time period, the sensitive organisms may be eradicated, enabling the resistant mutant to multiply and become the dominant strain. spontaneously mutate to a form that is The probability that mutation and selection is increased during the exposure of an organism to suboptimal concentrations of an antibiotic, and it is also increased during prolonged exposure to an antibiotic. Laboratory tests should be used to guide the selection of an antimicrobial drug, and the dosage and duration of therapy should be adequate for the type of infection being treated. Whenever possible, the bacteriologic response to drug therapy should be verified by culturing samples of appropriate body fluids.

37. Transferable Resistance: Transferable resistance usually results from bacterial conjugation and the transfer of plasmids (extrachromosomal DNA) that confer drug resistance. Transferable resistance, however, can also be mediated by transformation (uptake of naked DNA) or transduction (transfer of bacterial DNA by a bacteriophage). Bacterial conjugation enables a bacterium to donate a plasmid containing genes that encode proteins responsible for resistance to an antibiotic. These genes are called resistance factors. The resistance factors can be transferred both within a particular species and between different species, so they often confer multidrug resistance. Studies have shown that resident microflora of the human body can serve as reservoirs for resistance genes, allowing the transfer of these genes to organisms that later invade and colonize the host.

38. Mechanisms of Resistance (1) inactivation of the drug by microbial enzymes (2) decreased accumulation of the drug by the microbe (3) reduced affinity of the target macromolecule for the drug. Inactivation of the drug by enzymes is an important mechanism of resistance to β-lactam antibiotics, including the penicillins , results from bacterial elaboration of β-lactamase enzymes that destroy the β- lactam ring. Resistance to aminoglycosides (e.g., gentamicin) is partly caused by the elaboration of drug-inactivating enzymes that acetylate, adenylate, or phosphorylate these antibiotics.

39. Decreased accumulation of an antibiotic can result from increased efflux or decreased uptake of the drug. Both of these mechanisms contribute to the resistance of microbes to tetracyclines and fluoroquinolones. • Increased drug efflux is often mediated by membrane proteins that transport antimicrobial drugs out of bacterial cells. • Decreased uptake of antimicrobial drugs can result from altered bacterial porins. Porins are membrane proteins containing channels through which drugs and other compounds enter bacteria. Resistance to penicillins by gram-negative bacilli is partly caused by altered porin channels that do not permit penicillin entry.

40. Reduced affinity of target molecules for antimicrobial drugs is a common mechanism of microbial resistance to most classes of antibiotics. This type of drug resistance often results from bacterial mutation. For example, S. pneumoniae resistance to β-lactam antibiotics involves alterations in one or more of the major bacterial penicillin-binding proteins, resulting in decreased binding of the antibiotic to its target.

41. Combination Drug Therapy It is therapeutically advisable to treat patients with a single agent that is most specific to the infecting organism. This strategy reduces the possibility superinfections, decreases the emergence of resistant organisms, and minimizes toxicity. However, some situations require combinations of antimicrobial drugs. For example, the treatment of mixed infections e.g. intra-abdominal abscess , life-threatening infections (to provide broad spectrum empiric therapy) and to decrease the emergence of resistant strains as in tuberculosis. When antimicrobial drugs are given in combination, they can exhibit antagonistic, additive, synergistic, or indifferent effects against a particular microbe. The relationship between two drugs and their combined effect is as follows: antagonistic if the combined effect is less than the effect of either drug alone; additive if the combined effect is equal to the sum of the independent effects; synergistic if the combined effect is greater than the sum of the independent effects; and indifferent if the combined effect is similar to the greatest effect produced by either drug alone. Some bacteriostatic drugs (e.g., chloramphenicol or tetracycline) are antagonistic to bactericidal drugs. Bactericidal drugs are usually more effective against rapidly dividing bacteria, and their effect may be reduced if bacterial growth is slowed by a bacteriostatic drug.

42. If two bactericidal drugs that target different microbial functions are given in combination, they often exhibit additive or synergistic effects . For example, penicillins, which are cell wall synthesis inhibitors, often show additive or synergistic effects with aminoglycosides, which inhibit protein synthesis, against gram- negative bacilli such as P. aeruginosa and against gram-positive enterococci and staphylococci. Likewise, sulfamethoxazole and trimethoprim inhibit sequential steps in bacterial folate synthesis and have synergistic activity against organisms that may be resistant to either drug alone. Combination therapy may also serve to reduce the emergence of resistant organisms, such as in the treatment of tuberculosis. This is because about 1 in 106Mycobacterium tuberculosis organisms will mutate to a resistant form during treatment with any single drug. The rate of mutation to a form resistant to two drugs is the product of the individual drug resistance rates, or about 1 in 1012organisms. Because fewer than 1012organisms are usually present in a patient with tuberculosis, it is unlikely that a resistant mutant will emerge during combination therapy.

43. Prophylactic Use of Antimicrobials Certain clinical situations, such as dental procedures and surgeries, require the use of antimicrobials for prevention rather than for the treatment of infections. Manipulation of gingival tissue during dental procedures can introduce oral microbiota such as Streptococcus spp. into the bloodstream, leading to an infection. In addition, healthcare workers can also introduce skin microbiota such as S. aureus into the bloodstream. This can be a concern because if unmanaged, it can lead to the development of endocarditis in the patient. Oral amoxicillin is commonly used for prophylaxis before dental procedures, and intravenous cefazolin and vancomycin are examples of antimicrobial agents utilized for surgical prophylaxis. Because of bacterial resistance and superinfection, prophylactic use is restricted to clinical situations in which the benefits outweigh the potential risks. The duration of prophylaxis should be closely controlled to prevent antibiotic resistance.