14 Antimicrobial Agents (68) Flashcards
Case
A 35-year-old woman presents with a 5-day history of an axillary cutaneous abscess. The abscess is drained and the pus is sent for microscopy and culture. Gram stain of the pus shows pus cells and Gram-positive cocci in clusters. The culture grows Gram-positive cocci which produce β-hemolysis on blood agar and a golden yellow pigment on nutrient agar. The isolate is catalase-positive, coagulase-positive, and ferments mannitol with acid production. It grows on Mueller-Hinton agar containing 4% sodium chloride and 6 mcg/mL of oxacillin.
Ability to grow on this medium correlates with the presence of what genetic elements in the isolate?
1 β-lactamase plasmid
2 MecA gene
3 VanA gene
4 Spa gene
5 PVL genes
MecA gene
he bacterial isolate has the characteristic features of methicillin-resistant Staphylococcus aureus (MRSA). The ability to grow on an oxacillin-containing medium indicates oxacillin resistance that correlates with the presence of the mecA gene in the isolate. This gene codes for a penicillin-binding protein PBP2a; it is not affected by oxacillin or methicillin. Normal PBPs are inactivated by β-lactamase, while PBP2a continues to function because of the lack of avidity for the drugs. MRSA shows resistance to β-lactam agents (e.g., cephalosporins and carbapenems). MRSA is associated with nosocomial and community-associated infections; outbreaks of infections are also common. Community-associated MRSA (CA-MRSA) often causes skin and soft tissue infections and necrotic pneumonia. Isolates of CA-MRSA strains are found resistant to β-lactams and erythromycin. Health care-associated/hospital-acquired (HA-MRSA) strains are usually resistant to most of the commonly used antibiotics (e.g., erythromycin, clindamycin, and tetracyclines). HA-MRSA is mostly associated with wound infections, catheter-associated infections, and bacteremia. Vancomycin and newer antibiotics (i.e., linezolid and daptomycin) are used for treating severe infections caused by MRSA. For less severe cutaneous and soft tissue infections by CA-MRSA, treatment with TMP/SMX, tetracycline, or clindamycin is found to be effective. The MRSA strains are found sensitive to rifampin, but this drug is not used as a single agent to treat the infections because of the possibility of rapid development of resistance. MRSA strains with decreased susceptibility to vancomycin (VISA) and strains with full resistance to vancomycin (VRSA) have been reported.
Screening for MRSA can be done by the cefoxitin or oxacillin disc diffusion test, latex agglutination for PBP2a, or by testing for oxacillin resistance using growth on oxacillin-containing salt agar. Polymerase chain reaction (PCR) is done to detect the mecA gene, which mediates oxacillin/methicillin/nafcillin resistance.
The mecA gene is located on a mobile genetic element known as staphylococcal cassette chromosome mec (SCCmec); it has a unique chromosomal integration locus. PCR assays have been used for the characterization and subtyping of MRSA into SCCmec types I to V. Typing is based on the nature of the mec and the putative recombinase genes ccrA and ccrB. The recombinase genes ccrA and ccrB code for a pair of recombinase proteins by which SSCmec are excised from the chromosome and integrated into a specific site on the recipient chromosome.
There are worldwide reports of community-onset skin abscesses, outbreaks of furunculosis, and severe pneumonia caused by CA-MRSA in persons without any traditional risk factors. Physical contact with the infected lesion is thought to be a mode of transmission of CA-MRSA leading to the outbreaks. Such outbreaks have been reported among competitive sports participants, prison inmates, and military personnel. Most of the CA-MRSA strains are found to belong to SCCmec type IV and carry the PVL gene for the cytotoxin. In the United States, the most prominent CA-MRSA belongs to the pulsed-field gel electrophoresis (PFGE) type of USA300 that carries SCCmec type IV and PVL genes.
Methicillin resistance is independent of β-lactamase plasmid. The plasmid controls β-lactamase production and confers resistance to antibiotics (e.g., penicillin G, ampicillin, ticarcillin, and piperacillin). About 90% of clinical isolates of Staphylococcus aureus in the United States produce β-lactamase (penicillinase). These strains are generally found sensitive to penicillinase-resistant penicillins, cephalosporins, and vancomycin. Methicillin, oxacillin, nafcillin, and cloxacillin are penicillinase-resistant penicillins.
β-lactamase produced by Staphylococcus opens the β-lactam ring of penicillins and destroys their antimicrobial activity. The β-lactamase plasmid is transmitted among the Staphylococcus strains, mainly by bacteriophage-mediated transduction.
Vancomycin-resistant determinant (vanA) is a system of genes packaged in a self-transmissible plasmid. Vancomycin is a glycopeptide that interferes with the early stages in cell wall peptidoglycan synthesis. It was the main drug recommended for treating MRSA infections, but resistance to this drug has been observed in recent years; this is a matter of worldwide concern. MRSA with high-level resistance to vancomycin was shown to harbor a multi-resistance conjugative plasmid within which vanA was integrated. Vancomycin resistance is much more common in Enterococcus, especially Enterococcus fecium. There are multiple vancomycin-resistant phenotypes. Vancomycin resistance in MRSA is likely to be acquired from vancomycin-resistant Enterococcus (VRE).
The spa gene codes for protein A, a cell wall component found in many Staphylococcus aureus strains. It helps the organism to evade host microbicidal mechanisms by adsorbing the normal host component to the surface. Protein A binds to the Fc portion of immunoglobulin G (IgG). The Fab fragment of IgG bound to protein A is free to combine with a specific antigen. This property is used in the coagglutination technique used for the identification of bacteria. Protein A with attached IgG molecules against a particular bacterial antigen will be able to agglutinate the bacteria that possess that antigen. Based on the spa gene, a typing system for Staphylococcus (spa typing) has been developed; this method is useful for the epidemiological studies of staphylococcal infections, and has the advantage of having a shorter turnaround time than PFGE.
PVL genes code for Panton-Valentine leukocidin (PVL), one of the virulence factors of Staphylococcus aureus. PVL is a cytotoxin causing leukocyte destruction and necrosis. About 3% of Staphylococcus aureus strains produce PV-leukocidin, and they often produce necrotic lesions (e.g., furunculosis and necrotizing pneumonia). The PVL encoding genes lukF and lukS are prevalent among a high percentage of CA-MRSA strains. The presence and expression of these genes are not uniform among the strains. PVL genes can be detected by PCR-based methods. PVL is one of the important virulence determinants in CA-MRSA strains; PVL-positive MRSA strains can produce life-threatening infections.
Case
A sample of cerebrospinal fluid (CSF) from a 12-month-old infant, clinically diagnosed as having pyogenic meningitis, is received in a microbiology laboratory.
Gram stain of the CSF shows numerous polymorphs and small Gram-negative pleomorphic bacilli with coccoid and filamentous forms. The CSF is cultured on sheep blood agar and chocolate agar with a strain of Staphylococcus streaked across the medium. The plates are incubated at 37° C in the presence of 5% carbon dioxide. After 24 hours of incubation, small, opaque colonies appear on the medium. The colonies are larger and more developed near the staphylococcal growth than those away from it. The bacterium is oxidase and catalase-positive and produces beta-lactamase. It is non-motile and fails to grow on MacConkey’s medium. The isolate is identified and the serotype is determined using specific antisera. It is 1 of the important agents of bacterial meningitis in children.
A vaccine is now widely used in developed countries for the prevention of this bacterial infection and has helped to reduce the disease incidence considerably. What does this childhood immunizing agent contain?
1 Killed whole bacterial cells
2 Live, attenuated bacteria
3 Capsular polysaccharide
4 Outer membrane protein antigens
5 Bacterial lipooligosaccharide
Capsular polysaccharide
The bacterium seen in this patient in the Gram-stained smear of CSF has the characteristic morphology of Haemophilus influenzae. The phenomenon of satellitism in culture, biochemical reactions, and serotyping help in the identification, and the isolate is likely to be Haemophilus influenzae type b (Hib). Among the 6 capsular types of H. influenzae, Hib is associated with about 95% of acute invasive infections; the most common is meningitis in children below 5 years of age. The vaccine against Hib infection contains the capsular polysaccharide of the organism. The capsular polysaccharide of type b contains the pentose sugars ribose and ribitol instead of the hexoses and hexosamines found in the other types (i.e., a, c, d, e, and f). The capsular polyribose-ribitol phosphate (PRP) antigen is a primary virulence factor for the bacterium. It also induces antibodies which are protective and, therefore, is used for immunization. Though the vaccine prepared using purified PRP of Hib is immunogenic in older children and adults, as are other polysaccharide antigens, it is poorly immunogenic in children under 2 years of age. To overcome this problem, PRP is conjugated with protein carriers (e.g., diphtheria, tetanus toxoids, or meningococcus outer membrane proteins). Chemically binding a polysaccharide to a protein carrier changes the polysaccharide to a T cell-dependent antigen, increasing immunogenicity in young children. Hib conjugate vaccine not only confers immunity to the recipients, it also decreases the rate of carriage of Hib among the vaccinated; this decreases the chance of exposure for unvaccinated children. The vaccine is usually given to children below 5 years of age; in older children and adults it is indicated only if they are at risk (e.g., having sickle cell disease, HIV/AIDS, immunodeficiencies, or immunosuppression). The vaccine should not be given to children less than 6 weeks old.
3 types of Hib conjugate vaccines are licensed in the United States: HbOC, PRP-T, and PRP-OMP having mutant diphtheria protein, using tetanus toxoid and meningococcal group B outer membrane protein as respective carriers. 2 types of combination vaccines, Hib conjugate with DTaP and Hib conjugate with hepatitis B, are also available. The high cost of the Hib conjugate vaccine has prevented developing countries from incorporating it in their routine immunization programs. To deal with this problem, a conjugate vaccine containing synthetic PRP (sPRP) and tetanus toxoid has been developed and tried in adult human volunteers. The safety and immunogenicity of this vaccine is comparable to the Hib conjugate vaccine (containing native capsular polysaccharide). A hexavalent combination vaccine containing Hib conjugate vaccine, diphtheria toxoid, tetanus toxoid, acellular pertussis vaccine, hepatitis B, and inactivated polio vaccine has been found to produce sustained immunity when given as a booster in 2-year-old children, irrespective of the type of primary vaccine used.
Killed whole cell vaccine is not used for immunizing against Hib infections. Though capsulated strains are responsible for most of the invasive infections, noncapsulated, nontypeable H. influenzae (NTHi) can also be pathogenic. They are commonly associated with acute exacerbations of chronic bronchitis, mainly in adults, and otitis media in young children. Since Hib vaccine is directed against the type-specific polysaccharide capsule of Hib, it does not prevent infections caused by noncapsulated NTHi. To prevent acute exacerbation of chronic bronchitis by NTHi, an oral whole cell killed, nontypeable H. influenzae vaccine has been developed.
Live attenuated bacteria are not used for the Hib vaccine.
Outer membrane proteins (OMPs) are not used in the Hib vaccine. OMPs are major surface antigens of NTHi. Being principal targets of bactericidal and protective antibodies in NTHi infections, they have received attention in the field of vaccine development. Some of the outer membrane proteins (e.g., P2, P6, and P5 fimbrin adhesion proteins) are under investigation as possible vaccine candidates. Intranasal vaccines composed of different surface protein antigens have been found to render local mucosal immunity in experimental animals.
The Hib vaccine in use in bacterial lipooligosaccharide (LOS) does not contain LOS of H. influenzae. LOS is a major surface-exposed antigen of NTHi. It is a major virulence factor of the bacterium and is toxic for humans. A detoxified LOS (dLOS) tetanus-toxoid conjugate vaccine and dLOS, conjugated with NTHi outer membrane protein P6 as a carrier, have been tried in animal models with encouraging results.
Development of an effective vaccine against NTHi is a subject of ongoing research.
Case
A sample of pus collected from a 4-year-old boy diagnosed with pleural empyema complicating lobar pneumonia was received in the microbiology laboratory. Gram-stained smears of the pus showed intracellular and extracellular small Gram-positive diplococci. Cultures were done on sheep blood agar and incubated at 37°C in the presence of 5-10% carbon dioxide. After overnight incubation, alpha hemolytic small (0.5-1mm) dome-shaped glistening colonies appeared on the blood agar medium. Further study of the colonies showed that the isolate was oxidase and catalase negative, fermented various carbohydrates with acid production, and was bile soluble and sensitive to optochin. The organism was resistant to penicillin with minimum inhibitory concentration (MIC) of >8mcg/mL. It was sensitive to vancomycin and resistant to erythromycin and cephalosporins.
The high resistance to penicillin shown by the isolate is most likely due to what mechanism?
1 Alteration in the penicillin binding proteins
2 Production of chromosomal beta-lactamase
3 Efflux pump activity
4 Change in porin channels
5 Production of plasmid-mediated beta-lactamase
Alteration in the penicillin binding proteins
The isolate from pus is Streptococcus pneumoniae, one of the common agents of community-acquired pneumonia in children, and the penicillin resistance is due to alteration in the penicillin-binding proteins (PBPs). Pleural empyema can occur as a complication, especially in small children and the elderly.
PBPs are membrane-associated serine peptidases required for biosynthesis of peptidoglycan, an important constituent of the bacterial cell wall. Penicillin has the ability to bind and inactivate the PBPs so that peptidoglycan synthesis is blocked. Of the 6 PBPs found in S.pneumoniae, PBPs 1a, 2b, and 2x are the major targets associated with activities of penicillin and some cephalosporins. Pneumococcal resistance is attributed to alteration in these PBPs. The PBPs are under chromosomal control of the bacterium and low-affinity variants may result in mutations in the strain. Altered PBPs can also occur as a result of recombination with foreign DNA sequences that code for low-affinity PBPs in other pneumococcal strains or closely related species. Low-level resistance mainly depends on alterations in PBP 2x. High-level resistance requires a combination of altered PBPs 1a, 2b, and 2x.
According to National Committee for Clinical Laboratory Standards (NCCLS), S. pneumoniae strains with MIC of 0.06 mcg/mL are considered as susceptible, MIC of 0.1-1.0 mcg/mL as non-susceptible (intermediate resistance), and MIC of >2 mcg/mL as resistant to penicillin. Penicillin-susceptible strains of S. pneumoniae are usually found to be susceptible to other antibiotic agents as well. Strains with high-level resistance (MIC >8 mcg/mL) are likely to show resistance to cephalosporins, erythromycin, and trimethoprim-sulfamethoxazole. Vancomycin and linezolid are useful for treating infections caused by multidrug-resistant strains.
Penicillin resistance in pneumococci is a worldwide problem. In the U.S. in the 1990s, the incidence of infections due to penicillin-resistant and multi-drug resistant S. pneumoniae was high. The emergence of S. pneumoniae with very high-level resistance (MIC of >8mcg/mL) has also been documented. A 7-valent conjugate vaccine containing the 7 most common serotypes causing invasive infections in children (14, 6B, 19F, 18C, 23F, 4, and 9V) was licensed in the year 2000. It has helped in reducing the incidence of penicillin-resistant pneumococcal infections. Serotypes 23F, 14, and 6B, to which most of the high-level penicillin-resistant strains belong, have been included in this vaccine. The CDC recommends this vaccine for children under 5 years, as it reduces colonization (nasopharyngeal carriage which acts as a source of transmission) and prevents pneumococcal disease. This heptavalent conjugate vaccine has the advantage of being immunogenic and protective even in children less than 2 years, unlike the 23-valent polysaccharide vaccine introduced earlier.
Recently, polymerase chain reaction (PCR)-based genotyping of PBP genes has been found to be a rapid and useful method to detect the genetic susceptibility of S. pneumoniae to beta-lactams.
Production of chromosomally mediated beta-lactamase causes the development of penicillin resistance in anaerobic bacteria like Bacteroides fragilis and in various other Gram-negative bacilli. Several types of chromosomal beta-lactamases are described, which confer resistance to different beta-lactam antibiotics.
Bacterial genomes contain genes coding for multidrug efflux pumps. Active efflux is known to play a major role in the intrinsic as well as acquired drug resistance in various bacterial species. The active efflux pump of the bacterium forces the antibiotic, which crosses the cell membrane out of its cytoplasm so that the concentration of the drug is too low to be effective.
Overproduction of efflux pumps or acquisition of pump genes from extraneous sources often results in an increased level of resistance. Efflux pumps have been identified in S. pneumoniae that contribute to the development of fluoroquinolone resistance. The major mechanism of tetracycline resistance in Gram-negative bacteria has been recognized as being due to drug-specific efflux.
This mechanism often contributes to resistance of a bacterium to more than one antibiotic. Different quinoline derivatives have been successfully used as efflux pump inhibitors. These drugs have been shown to block the efflux pump mechanism and restore drug susceptibility to multidrug-resistant clinical isolates of Gram-negative bacteria.
Change in porin channels leading to alteration in permeability is a mechanism of antibiotic resistance seen in Gram-negative bacteria. The outer membrane present in the cell wall of Gram-negative bacteria has channels containing protein molecules called porins, which allow passive diffusion of small hydrophilic molecules across the membrane. Large molecules like antibiotics penetrate the outer membrane slowly. The membrane permeability is an important determinant of the intrinsic resistance of bacteria to antibiotics. In acquired resistance, loss or deficiency of specific porins reduce the outer membrane permeability and prevent the antibiotic from crossing the cell membrane. Deficiency in porin-outer membrane protein F (OmpF) has been shown to mediate beta-lactam resistance in Escherichia coli. Deficiency in OmpK35 and Omp36 porins mediate beta-lactam resistance in Klebsiella pneumoniae. Loss or deficiency of porins can augment resistance caused by beta-lactamase production. Antibiotic resistance can develop as a result of low membrane permeability working synergistically with other mechanisms like active drug reflux or enzymatic degradation of the antibiotic.
Penicillin resistance by the production of plasmid-mediated beta-lactamase is the mechanism commonly found in Staphylococcus aureus and Gram-negative bacteria like N. gonorrheae and H. influenzae. Beta-lactamases hydrolyze the beta-lactam ring and abolish its activity. This type of resistance can be spread by bacteriophage-mediated transduction, as in S. aureus, or by conjugation, as in some of the Gram-negative bacteria.
Case
A 33-year-old pregnant woman nearing term presented with a 4-day history of migratory joint pains, swelling and pain in her right wrist joint, and chills and fever. Her previous medical history was not significant and she did not have allergy to drugs. Her right wrist showed an increase in temperature with tenderness and effusion. Clinical diagnosis was acute septic arthritis and arthrocentesis was done. The fluid was purulent, and the patient was placed on empirical antibiotic therapy.
Direct smear from the fluid showed predominance of neutrophils. A few intracellular Gram-negative diplococci were also present. Culture on chocolate agar incubated in the presence of 10% carbon dioxide at 37°C for 48 hours and grew small, round, translucent colonies of Gram-negative diplococci. The isolate was oxidase positive, fermented glucose, and failed to grow on ordinary media and at room temperature (28 - 30°C). Cervical swab from the patient cultured on Thayer-Martin medium also grew bacterium with the same characteristics.
What antibiotic would most likely be used for this patient?
1 Penicillin G
2 Linezolid
3 Ofloxacin
4 Tetracycline
5 Ceftriaxone
6 Spectinomycin
Ceftriaxone
The patient has gonococcal arthritis, one of the manifestations of disseminated gonococcal infection (DGI). Ceftriaxone, a third-generation cephalosporin, is the drug of choice for disseminated gonococcal infection and is safe to be administered during pregnancy. Centers for Disease Control and Prevention (CDC) recommends initial therapy for treatment of DGI as Ceftriaxone 1g IM or IV every 24 hours continued for 24 to 48 hours after clinical improvement, which is to be followed by oral therapy with Cefixime or Cefpodoxime (400mg twice daily) for at least a week.
Cephalosporins are produced by cephalosporium fungi. These are beta lactam compounds with a nucleus of 7-aminocephalosporinic acid. The mechanism of action on bacteria is by binding to specific penicillin-binding proteins (PBPs), inhibiting cell wall synthesis and activation of autolytic enzymes in the cell wall, leading to bacteria cell death. Persons with severe allergy to penicillin may show cross-allergy to cephalosporins. Those with a mild allergy to penicillin can often tolerate cephalosporins.
Pregnancy has been recognized as a risk factor for dissemination in women having gonococcal infection. Primary mucosal infection may be asymptomatic and infection may remain undetected and untreated. Dissemination can also occur during postpartum period, following pelvic surgery, or after insertion of intrauterine devices. Persons with a deficiency in the terminal components of serum complement are at high risk of developing DGI. Gonococcal arthritis is a rare complication of gonococcal infection. DGI presents more commonly with migratory arthralgia, moderate fever, dermatitis, and tenosynovitis. Classic skin lesions manifest as small erythematous papules progressing to vesicular and pustular lesions and are mostly seen on the extremities.
Penicillin G can be taken safely during pregnancy, and it is considered the drug of choice in infection due to penicillin-sensitive N. gonorrheae. It cannot be used as empirical therapy, as the incidence of penicillin-resistant N. gonorrheae is very high. In the US, nearly 30% of Neisseria gonorrheae are resistant to penicillin, tetracycline, or both. 2 types of resistance have been observed in N. gonorrheae, plasmid-mediated and chromosomally mediated. Prevalence of penicillinase (beta-lactamase) producing N. gonorrheae (PPNG) has increased, and high incidence of PPNG has been observed in certain areas, including focal areas in the U.S. Outbreaks of PPNG infections have been reported from many areas of U.S.
Linezolid is a synthetic antibiotic and belongs to a new class of antibacterial agents, oxazolidinones. It is found useful for treating infections by resistant Gram-positive pathogens like methicillin-resistant staphylococcus aureus, coagulase-negative staphylococcus, vancomycin-resistant enterococcus, and nocardia species. This antibiotic is bacteriostatic. The drug interferes with the first step of bacterial ribosome assembly, thus blocking formation of an initiation complex.
Ofloxacin, one of the fluoroquinolones, is used for treating gonococcal infection. It is not advisable to give this drug as empirical treatment in the above patient. It should not be used in pregnant women and young children. The mode of action is by inhibiting bacterial DNA synthesis by blocking of the DNA gyrase. Prevalence of N. gonorrheae with quinolone resistance has increased due to the widespread use of fluoroquinolones.
Tetracycline is mainly a bacteriostatic agent. The antibiotic gets deposited in the bones and teeth, especially in the fetus and in the first 6 years of life, so it is not indicated in pregnant patients. The mechanism of action is by inhibiting protein synthesis by blocking the binding of aminoacetyl t-RNA to the 30S subunit of bacterial ribosome.
Spectinomycin is an amiocyclitol antibiotic. This antibiotic is useful for treating penicillin-resistant gonorrhea and patients allergic to beta-lactam antibiotics. Spectinomycin can be administered to patients who cannot tolerate cephalosporins. It is more often used for treatment of uncomplicated gonorrhea. Resistance of N. gonorrheae to spectinomycin is reported to be infrequent.
A 40-year-old man who recently immigrated to the U.S. from Latin America was clinically diagnosed with pulmonary tuberculosis. Mycobacterium tuberculosis was grown from his sputum samples. The strain was tested for susceptibility to the first line antituberculous drugs. It was found to be resistant to isoniazid (INH) and rifampin. Which of the genes listed below is associated with INH resistance?
1 katG gene
2 rpoB gene
3 embB gene
4 rpsL gene
5 gyrA gene
katG gene
Resistance of Mycobacterium tuberculosis to INH is associated with katG gene. Deletion or mutation in 1 of several regions of the gene can cause development of resistance. Other genes listed are not involved in the development of resistance to INH. Mutation in a relatively small fragment of the rpoB gene that encodes for the b subunit of the RNA polymerase results in rifampin resistance. Mutations in rpsL gene (gene encoding ribosomal S12 protein), gyrA gene (DNA gyrase gene) and embB gene mediate resistance to streptomycin, fluoroquinolones, and ethambutol respectively.
INH is a first line antituberculous drug that is bactericidal. It has a simple chemical structure consisting of a pyridine ring and a hydrazide group. katG gene encodes KatG enzyme, the bifunctional catalase-peroxide enzyme. The enzyme converts INH to a range of toxic radicals that attack multiple targets in the mycobacterial cell wall, the best characterized target being the cell wall mycolic acid. Deletion of katG gene or mutations in the gene results in loss of catalase and peroxidase activity. Mutations in other genes like inhA (that encodes for an enzyme that functions in mycolic acid synthesis), ahpC-oxyR, ndh, and kas genes can also mediate INH resistance.
Drug resistance in M. tuberculosis is due to spontaneous mutation. Mutation occurs with an approximate rate of once in 108 divisions. Problems caused by such resistance could be checked effectively by combination therapy. Various factors like incomplete therapy and patient non-compliance favor selection and multiplication of drug resistant mutants, resulting in drug resistant strains. In non-compliant patients with chronic infection, co-existence of several subpopulations with different drug susceptibility profiles has been observed. Implementation of directly observed therapy under supervision (DOTS) ensures patient compliance to therapy and helps to reduce the development of drug resistant strains.
The strain isolated from the patient is a multi-drug resistant strain (MDR). MDR M. tuberculosis refers specifically to strains resistant to INH and rifampin, with or without resistance to 1 or more other drugs.
First line drugs used for antituberculosis therapy include the bactericidal drugs rifampin, INH, pyrazinamide and streptomycin, and a bacteriostatic drug ethambutol. Second line drugs include quinolones, aminoglycosides, macrolides, cycloserine, ethionamide, and capreomycin. A 4 drug regimen with INH, rifampin, pyrazinamide, and ethambutol is recommended in U.S. as first line treatment for persons proven or strongly suspected to have tuberculosis.
Resistant strains can be detected by various methods. Conventional proportion method on Lowenstein-Jensen medium has a long turn over time. BACTEC radiometric method also requires about 10 days. Recently Resazurin test, a rapid colorimetric test with good sensitivity and specificity has been developed. The test is reported to be inexpensive and suitable for use in developing countries. Polymerase chain reaction-based assays are used for rapid detection of katG and rpoB mutations. Using such assays, MDR strains can be directly detected in clinical samples without prior culture.
Outbreaks of infection by MDR strains of M. tuberculosis have been observed in settings like hospitals, prisons, and homeless shelters. MDR-TB Beijing/W genotype is one of such outbreak strains reported from different countries. Genotyping of the isolates is important in epidemiological studies. The traditional IS6110 finger printing for genotyping requires cultural isolation of the strain. Spoligotyping (spacer oligotyping) is the most widely used genotyping method.
In recent years, emergence of extensively drug resistant (XDR) tuberculosis has become a world wide problem. In XDR-TB, resistance is present to INH and rifampin, to any fluoroquinolone, and to at least 1 of the 3 injectable second line drugs (amikacin, kanamycin, or capreomycin). In patients with concomitant HIV infection, XDR strains of M. tuberculosis cause fatal disease.
Recent studies on M. tuberculosis genome analysis have revealed presence of several genes encoding putative drug efflux pumps. Possible involvement of efflux pumps in transporting INH has been considered. It is suggested that compounds capable of inactivating the pumps may help to improve efficacy of anti-tuberculous treatment.
Case
A pregnant woman of 36 weeks gestation presented at the obstetric clinic for her monthly follow-up appointment. Her anorectal and vaginal cultures were screened for Group B hemolytic streptococcus (GBS). The cultures grew GBS. Routine susceptibility test results of the isolate showed sensitivity to penicillin, ampicillin, cefazolin, clindamycin, vancomycin, and levofloxacin. It was resistant to erythromycin. The patient had a history of anaphylactic reaction to penicillin.
To prevent GBS infection of her newborn, what antibiotic should be administered to this patient as the intrapartum prophylactic agent?
1 Ampicillin
2 Cefazolin
3 Clindamycin
4 Levofloxacin
5 Vancomycin
Vancomycin
The correct response is vancomycin.
Generally, penicillin G is considered the antibiotic of choice because of its effective action on GBS and its narrow spectrum of activity. Ampicillin is the alternative; however, both these antibiotics are contraindicated in the patient because of her penicillin allergy. In persons with penicillin allergy other than anaphylaxis or urticaria, cefazolin is the antibiotic preferred and recommended, as this antibiotic achieves effective intra-amniotic concentrations. But GBS-positive women who are at high risk of anaphylaxis should not receive cephalosporins (e.g., cefazolin) because of the risk of cross-reactivity. Such individuals can be treated with erythromycin or clindamycin if the colonizing strain is susceptible. Erythromycin is less preferred because of its high resistance rates and poor placental transfer. The strain isolated from the above patient is resistant to erythromycin; therefore, it cannot be used. Resistance to erythromycin is often, though not always, associated with resistance to clindamycin. Strains that are resistant to erythromycin and appear sensitive to clindamycin by routine susceptibility testing may have inducible resistance to clindamycin; therefore, it is preferable not to use clindamycin for this patient, and the drug of choice is vancomycin.
All the antibiotics listed except levofloxacin are used as intrapartum prophylactic agents in GBS-colonized mothers. Levofloxacin is a fluoroquinolone that acts by impairing DNA topoisomerase enzymes. It is active against many Gram-positive and Gram-negative organisms as well as mycoplasma. It is not recommended in pregnancy because it may impair cartilage development.
GBS is the most common cause of early-onset neonatal sepsis in developed countries. Use of intrapartum prophylaxis significantly reduces the rate of neonatal colonization with GBS and the incidence of early-onset GBS disease (EOGBS). Need for prophylaxis during a pregnancy is determined by detection of GBS colonization during that pregnancy. Maternal screening for vaginal and rectal colonization is done at 35-37 weeks of gestation.
Intrapartum prophylaxis against GBS without screening is indicated in women having GBS bacteriuria during current pregnancy; in pregnant women with history of previous delivery of an infant with invasive GBS disease; and if the mother’s GBS status is unknown within 6 weeks of delivery and risk factors develop, such as premature rupture of membranes occurring 18 hours or more before delivery.
Herd immunity is the process by which:
1 Entire communities are protected from disease by mass vaccination efforts
2 Herds of animals are considered resistant to disease
3 Disease spread is controlled by selective immunization of highly susceptible individuals
4 Immune people are brought into contact with nonimmune people for the purposes of passive immunization
5 Spread of communicable diseases within a population is prevented by high rates of immunity, despite individual susceptibility
Spread of communicable diseases within a population is prevented by high rates of immunity, despite individual susceptibility
Herd immunity describes the concept that spread of a communicable disease within a population can be prevented if enough of the individuals are immune, despite the presence of susceptible individuals. Smallpox is an example of a disease that was eradicated by herd immunity despite not having a 100% level of active immunization.
Penicillins act by
1 Inhibiting cell wall synthesis
2 Inhibiting protein synthesis
3 Alteration of cell membrane function
4 Inhibition of nucleic acid synthesis
Inhibiting cell wall synthesis
Penicillins act by inhibiting transpeptidases, the enzymes that catalyze the final cross-linking step in the synthesis of peptidoglycan.
Sulfonamides act by
1 Blocking the synthesis of tetrahydrofolic acid
2 Blocking cell wall synthesis
3 Blocking protein synthesis
4 Blocking DNA synthesis
Blocking the synthesis of tetrahydrofolic acid
Sulfonamides act by blocking synthesis of tetrahydrofolic acid, which is required as a methyl donor in the synthesis of the nucleic acid precursors adenine, guanine, and thymine. Sulfonamides are structural analogues of p-aminobenzoic acid (PABA) and compete with PABA for the active site of the enzyme dihydropteroate synthetase.
A 34-year-old man is diagnosed as having pulmonary tuberculosis. As a result, he is advised to start combination chemotherapy with the standard antitubercular drugs, including rifampin. Rifampin acts by:
1 Inhibiting the production of tetrahydrofolic acid
2 Blocking DNA synthesis
3 Blocking cell wall synthesis
4 Binding to 50S subunit
5 Blocking mRNA synthesis
Blocking mRNA synthesis
The selective mode of action of rifampin is based on blocking mRNA synthesis by bacterial RNA polymerase without affecting the RNA polymerase of human cells.
R factors mediate
1 Drug resistance
2 Cell mediated immunity
3 Toxic properties of pathogenic bacteria
4 Allergic reactions
Drug resistance
Resistance plasmids (R factors) are extrachromosomal, circular, double-stranded DNA molecules that carry the genes for a variety of enzymes that can degrade antibiotics and modify membrane transport systems. They can replicate independently of the bacterial chromosome and can be transferred from one species to another.
Erythromycin exerts its antimicrobial effect by:
1 Inhibition of DNA synthesis.
2 Inhibition of RNA synthesis.
3 Inhibition of protein synthesis by inhibiting synthesis of 50S ribosomal unit.
4 Inhibition of cell wall synthesis by inhibition of cross linking (transpeptidation)
of proteoglycan.
5 An unknown mechanism.
Inhibition of protein synthesis by inhibiting synthesis of 50S ribosomal unit.
Erythromycin inhibits protein synthesis by inhibiting synthesis of 50S ribosomal unit.
Quinolones cause inhibition of DNA synthesis. Rifampin causes inhibition of mRNA synthesis, and penicillins, cephalosporins, imipenem, and aztreonam cause inhibition of cell wall synthesis by inhibition of cross linking (transpeptidation) of proteoglycan.
Pasteurization of milk is best described as
1 Application of steam at 15 lb./in2 until a temperature of 121° C is reached and held for 15-20 min
2 Application of dry heat, about 180° C for 2 hrs
3 Heating to 62° C for 30 min followed by
rapid cooling
4 Application of UV light at 250-260 nm
5 Application of X-rays
Heating to 62° C for 30 min followed by rapid cooling
Pasteurization of milk is best described as heating to 62° C for 30 min followed by rapid cooling. This process kills vegetative cells of milk-borne pathogens, e.g. M. tuberculosis, Salmonella, Streptococcus, and Bacillus. Application of steam at 15 lb/in2 until a temperature of 121° C is reached and held for 15-20 min is autoclaving. This kills spores that are resistant to boiling even Clostridium botulinum. Application of dry heat, about 180° C for 2 hours, is used for sterilizing glassware. Application of UV light at 250-260 nm results in formation of thymine dimers and adds hydroxyl groups to bases. X-rays prevent formation of free radicals, e.g. production of hydroxyl radicals by hydrolysis of water.
Chlorine exerts its disinfecting action by
1 Acting as an oxidizing agent that kills by crosslinking essential sulfhydryl groups in enzymes to form the inactive disulfide thus modifying proteins
2 Disorganizing lipid in membranes and denaturing protein
3 Acting as a surface agent composed of a long-chain soluble hydrophobic portion and a polar hydrophobic group
4 Alkylating proteins and nucleic acids
5 Forming thymine dimers and adding hydroxyl groups to bases
Acting as an oxidizing agent that kills by crosslinking essential sulfhydryl groups in enzymes to form the inactive disulfide thus modifying proteins
Chlorine acts as an oxidizing agent that kills by crosslinking essential sulfhydryl groups in enzymes to form the inactive disulfide, thus modifying proteins. Ethanol disorganizes lipids in membranes and denatures protein. Detergents, including quaternary ammonium compounds, act as surface agents composed of a long-chain soluble hydrophobic portion and a polar hydrophobic group. Ethylene oxide, formaldehyde, and glutaraldehyde alkylate protein and nucleic acids. UV light forms thymine dimers and adds hydroxyl groups to bases.
An intestinal nematode that causes mostly asymptomatic or chronic low-grade infections is recognized as a medically important parasite because it can trigger life-threatening hyperinfection syndrome in immunocompromised hosts. This nematode species infects humans by skin penetration by its filariform larvae. It also produces auto-reinfection, which helps to sustain an infection in the host for many years.
What antihelminthic is the drug of choice for this nematode infection?
1 Diethylcarbamazine
2 Ivermectin
3 Praziquantel
4 Pyrantel pamoate
5 Thiobendazole
Ivermectin
The intestinal nematode species that fulfills the description in the question is Strongyloides stercoralis. S. stercoralis infects by penetration of human skin by its filariform larvae, which are infective because of contact with fecally-contaminated soil. Producing autoreinfection and causing hyperinfection syndrome in immunosuppressed persons by overwhelming autoinfective cycle and massive larval invasion are unique features of S. stercoralis.
Of the listed drugs, the antihelminthics used for treating strongyloides infection (strongyloidiasis) are ivermectin and thiabendazole. Better rates of larval clearance, better tolerance, being least toxic, and successful use with high cure rates have made ivermectin the preferred drug for strongyloidiasis. So the correct answer is ivermectin.
Ivermectin was first discovered and used in veterinary medicine >20 years ago. It is a semisynthetic derivative of avermectin isolated from fermentation products of Streptomyces avermitilis. It is reported as a safe and potent antihelminthic with broad-spectrum activity. The drug is approved for oral administration.
In patients with strongyloides hyperinfection involving the gastrointestinal tract who failed to respond to oral administration of the drug, successful parenteral administration of ivermectin has been reported.
Ivermectin is found effective against cutaneous larva migrans and against other nematodes like Mansonella ozzardi, Onchocerca volvulus, and Wuchereria bancrofti. It has been successfully used in control programs for O. volvulus and W. bancrofti, for treatment of ectoparasitic infections like scabies and pediculosis, and also in myiasis.
In the U.S., strongyloidiasis is rare but most commonly found among international travelers, immigrants, and refugees from areas of endemicity. It is endemic in certain portions of the U.S., particularly in the Appalachian region, in eastern Kentucky, and in rural Tennessee.
Other listed antihelminthics are not used for treatment of strongyloidiasis. Praziquantel is used for treating schistosomiasis and cestode infections. Diethylcarbamazine is used for filariasis. Pyrantel pamoate is used against nematode infections like ascariasis, ancylostomiasis, and enterobiasis.
Case
A 44-year-old woman is in your office presenting with a strong urge to urinate often and a burning sensation when she urinates. You prescribe ciprofloxacin which you explain inhibits a specific bacterial enzyme involved in DNA replication.
This bacterial enzyme performs the same function during DNA replication as which of the following eukaryotic enzymes?
1 DNA polymerase
2 Topoisomerase
3 Helicase
4 Primase
5 DNA ligase
Topoisomerase
The bacterial enzyme DNA gyrase is equivalent to the eukaryotic topoisomerase. Ciprofloxacin and other drugs of this class including nalidixic acid, levofloxacin, and gemifloxacin inhibit bacterial DNA gyrase. Gyrase is an enzyme necessary for DNA replication and functions to remove the positive supercoiling of the DNA which occurs as the DNA strands unwind to allow DNA polymerase to access the single stranded DNA template. There are 2 classes of mammalian topoisomerases, Type I and Type II. The major difference between the two is that the Type I topoisomerase introduces a single stranded nick in the DNA in the process of relieving the supercoiling, while the Type II enzyme introduces a double stranded nick in the DNA.
DNA polymerase is the enzyme responsible for polymerizing the DNA during the replication process in both prokaryotes and eukaryotes. The helicase unwinds the DNA helix during replication while primase synthesizes the RNA primer required for DNA polymerase to initiate replication of the DNA. DNA ligase is responsible for joining fragments of DNA such as those formed on the lagging strand during replication.
Case
A 42-year-old sexually active G1P1 female presents with a greenish vaginal discharge. Motile, flagellated organisms are seen on wet prep. She is allergic to penicillin and has a history of anaphylactic reactions. Her current medications include warfarin, lisinopril, hydrochlorothiazide, and atenolol. She is treated with Metronidazole
What is the most likely outcome of the drug interaction with a therapy of choice for her condition?
1 Decreased blood pressure
2 Increased potassium levels
3 Increased INR
4 Increased calcium levels
5 Profound diarrhea
Increased INR
The patient presented with Trichomonas infection, which is treated with metronidazole. Metronidazole is a potent inhibitor of CYP 2C9 systems and it may affect warfarin metabolism. Although the duration of therapy is very short, the pharmacist should be aware of this interaction and watch INR closely.
Which of the following class of antibiotics effects cell wall synthesis?
1 Rifampin
2 β-lactam
3 Sulfonamides
4 Quinolones
5 Tetracyclines
β-lactam
Antimicrobial agents are classified according to their modes of action. Basic action of antibiotics includes interference in cell wall synthesis or cell membrane synthesis and interference in basic metabolite function, such as inhibition in synthesis of nucleic acid, folic acid, protein, and other metabolites.
β-lactam class of antimicrobial agents consists of group of natural and semisynthetic antibacterial agent, which shares β-lactam ring, a basic chemical structure that interferes with the final stage of peptidoglycan synthesis (an important constituent of the bacterial cell wall). β-lactam antibiotics bind to transpeptidase, which is required for the peptide bond formation in peptidoglycan synthesis.
Rifampin interferes with the mRNA synthesis and is used for treatment of mycobacterial disease.
Quinolones interfere with DNA synthesis by inhibiting the activity of DNA gyrase.
Sulfonamides inhibit folic acid synthesis.
Tetracyclines inhibit protein synthesis by binding to 30S ribosomes.
Which of the following antibiotics contains β-lactam ring and is produced by the fungus Acremonium?
1 Penicillin
2 Bacitracin
3 Cephalosporins
4 Vancomycin
5 Tetracyclines
Cephalosporins
Cephalosporins contain β-lactam ring and have penicillin-like structure but are less susceptible to the action of β-lactamase. Patients allergic to the penicillin can be treated with cephalosporins, which are produced by Acremonium. Cephalosporins bind to transpeptidase enzyme and interfere with the cell wall synthesis. Cephalosporins are active against a broad spectrum of gram negative and gram positive antibiotics.
Penicillin is produced by the species of fungus Penicillium or can also be synthesized by modification of penicillin acid. This β-lactam containing antibiotics interferes in the cell wall synthesis and is mostly active against gram positive bacteria and some gram negative bacteria.
Bacillus subtilis produces bacitracin just before sporulation by an enzymatic process. It inhibits the synthesis of peptidoglycan and is used as a topical agent for treating infected wounds.
Vancomycin is produced by species of Streptomyces and is active against gram positive bacteria. It interferes in the synthesis of peptidoglycan by inhibiting formation of peptide bond.
Tetracycline is a broad spectrum antibiotic that inhibits protein synthesis by binding to 30S ribosome. This bacteriostatic antibiotic is produced by species of Streptomyces.
Which of the following antibiotics is the structural analog of para-aminobenzoic acid that interferes with folic acid synthesis by inhibition of dihydropteroate synthetase?
1 Amphotericin B
2 Trimethoprim
3 Tetracycline
4 Penicillin
5 Rifampin
6 Bacitracin
7 Griseofulvin
8 Sulfonamides
Sulfonamides
The sulfonamides are a large group of antimicrobial agents that have bacteriostatic activity against a broad spectrum of gram-positive and gram-negative bacteria. Sulfonamides are also effective against Nocardia, chlamydiae, and some protozoa. Sulfonamides are structural analogs of para-aminobenzoic acid, which is a folic acid precursor. Sulfonamides prevent para-aminobenzoic acid conversion into dihydropteroic acid by competitive inhibition of the enzyme dihydropteroate synthetase. This results in inhibition of folic acid synthesis, which is an important intermediate in nucleotide synthesis.
Trimethoprim inhibits purine and DNA synthesis by preventing folic acid formation. Trimethoprim interferes with the conversion of dihydrofolate into tetrahydrofolate by inhibiting the enzyme dihydrofolate reductase. Trimethoprim is used in combination with sulfamethoxazole (co-trimoxazole) in the treatment of urinary tract infection and enteric fever.
Norfloxacin is a bactericidal quinolone that blocks DNA replication. Norfloxacin prevents DNA supercoiling by inhibiting the A subunit of DNA gyrase. Norfloxacin is effective in treating the infection caused by staphylococci, enterococci, and Pseudomonas.
Rifampin is a broad spectrum antimicrobial agent that inhibits protein synthesis by interfering in the mRNA production. Rifampin binds to the b-subunit of RNA polymerase and blocks the RNA chain initiation. Rifampin is effective against gram positive bacteria and mycobacterial infections. It is also used for meningococcal meningitis prophylaxis.
Amphotericin B is an antifungal agent that belongs to the polyene class of antibiotics. It is effective against microbial agents that contain sterols in the cytoplasmic membrane. It binds to the ergosterol in the cell membrane and causes disruption in barrier property of the membrane. It is used in the treatment of systemic mycoses.
Griseofulvin is also a fungistatic agent that inhibits protein assembly. It interferes with the assembly process of tubulin into microtubules. However, it is effective only in fungi whose cell wall contains chitin and is used for the treatment of dermatophyte infections.
Erythromycin is the macrolide that inhibits the 50S ribosomal subunit. This bacteriostatic agent is used primarily to treat pulmonary infection caused by Mycoplasma, Legionella, Campylobacter, and Chlamydia. It is also effective in treating infection caused by gram-positive organisms in penicillin allergic patients.
Bacitracin is a peptide antibiotic that prevents peptidoglycan synthesis. Bacitracin is poorly absorbed and is used as a topical agent for the treatment of infected wounds.
Penicillins are β-lactam antibiotics that are bactericidal agent. β-lactam antibiotics are cell wall inhibitors that prevent peptidoglycan synthesis. Penicillins inhibit transpeptidase (responsible for the cross-linking) and D-alanine carboxypeptidase (responsible for removing D-alanine from a pentapeptide side chain). Penicillins are effective against gram-positive and a limited number of gram negative bacteria.
Tetracycline is a broad spectrum antibiotic that inhibits protein synthesis in prokaryotes, as well as eukaryotes. It binds to phosphate residue of 30S ribosomal subunit and blocks the attachment of tRNA to the ribosome-mRNA complex and interferes in the incorporation of new amino acid into polypeptide chain.
Which of the following antibiotics is the inhibitor of DNA replication that binds to A-subunit of DNA-gyrase?
1 Amphotericin B
2 Trimethoprim
3 Tetracycline
4 Penicillin
5 Rifampin
6 Bacitracin
7 Griseofulvin
8 Sulfonamides
9 Erythromycin
10 Norfloxacin
Norfloxacin
The sulfonamides are a large group of antimicrobial agents that have bacteriostatic activity against a broad spectrum of gram-positive and gram-negative bacteria. Sulfonamides are also effective against Nocardia, chlamydiae, and some protozoa. Sulfonamides are structural analogs of para-aminobenzoic acid, which is a folic acid precursor. Sulfonamides prevent para-aminobenzoic acid conversion into dihydropteroic acid by competitive inhibition of the enzyme dihydropteroate synthetase. This results in inhibition of folic acid synthesis, which is an important intermediate in nucleotide synthesis.
Trimethoprim inhibits purine and DNA synthesis by preventing folic acid formation. Trimethoprim interferes with the conversion of dihydrofolate into tetrahydrofolate by inhibiting the enzyme dihydrofolate reductase. Trimethoprim is used in combination with sulfamethoxazole (co-trimoxazole) in the treatment of urinary tract infection and enteric fever.
Norfloxacin is a bactericidal quinolone that blocks DNA replication. Norfloxacin prevents DNA supercoiling by inhibiting the A subunit of DNA gyrase. Norfloxacin is effective in treating the infection caused by staphylococci, enterococci, and Pseudomonas.
Rifampin is a broad spectrum antimicrobial agent that inhibits protein synthesis by interfering in the mRNA production. Rifampin binds to the b-subunit of RNA polymerase and blocks the RNA chain initiation. Rifampin is effective against gram positive bacteria and mycobacterial infections. It is also used for meningococcal meningitis prophylaxis.
Amphotericin B is an antifungal agent that belongs to the polyene class of antibiotics. It is effective against microbial agents that contain sterols in the cytoplasmic membrane. It binds to the ergosterol in the cell membrane and causes disruption in barrier property of the membrane. It is used in the treatment of systemic mycoses.
Griseofulvin is also a fungistatic agent that inhibits protein assembly. It interferes with the assembly process of tubulin into microtubules. However, it is effective only in fungi whose cell wall contains chitin and is used for the treatment of dermatophyte infections.
Erythromycin is the macrolide that inhibits the 50S ribosomal subunit. This bacteriostatic agent is used primarily to treat pulmonary infection caused by Mycoplasma, Legionella, Campylobacter, and Chlamydia. It is also effective in treating infection caused by gram-positive organisms in penicillin allergic patients.
Bacitracin is a peptide antibiotic that prevents peptidoglycan synthesis. Bacitracin is poorly absorbed and is used as a topical agent for the treatment of infected wounds.
Penicillins are β-lactam antibiotics that are bactericidal agent. β-lactam antibiotics are cell wall inhibitors that prevent peptidoglycan synthesis. Penicillins inhibit transpeptidase (responsible for the cross-linking) and D-alanine carboxypeptidase (responsible for removing D-alanine from a pentapeptide side chain). Penicillins are effective against gram-positive and a limited number of gram negative bacteria.
Tetracycline is a broad spectrum antibiotic that inhibits protein synthesis in prokaryotes, as well as eukaryotes. It binds to phosphate residue of 30S ribosomal subunit and blocks the attachment of tRNA to the ribosome-mRNA complex and interferes in the incorporation of new amino acid into polypeptide chain.
Which of the following antibiotics inhibits protein synthesis by selectively inactivating the DNA-dependent RNA polymerase?
1 Amphotericin B
2 Trimethoprim
3 Tetracycline
4 Penicillin
5 Rifampin
6 Bacitracin
7 Griseofulvin
8 Sulfonamides
9 Erythromycin
10 Norfloxacin
Rifampin
The sulfonamides are a large group of antimicrobial agents that have bacteriostatic activity against a broad spectrum of gram-positive and gram-negative bacteria. Sulfonamides are also effective against Nocardia, chlamydiae, and some protozoa. Sulfonamides are structural analogs of para-aminobenzoic acid, which is a folic acid precursor. Sulfonamides prevent para-aminobenzoic acid conversion into dihydropteroic acid by competitive inhibition of the enzyme dihydropteroate synthetase. This results in inhibition of folic acid synthesis, which is an important intermediate in nucleotide synthesis.
Trimethoprim inhibits purine and DNA synthesis by preventing folic acid formation. Trimethoprim interferes with the conversion of dihydrofolate into tetrahydrofolate by inhibiting the enzyme dihydrofolate reductase. Trimethoprim is used in combination with sulfamethoxazole (co-trimoxazole) in the treatment of urinary tract infection and enteric fever.
Norfloxacin is a bactericidal quinolone that blocks DNA replication. Norfloxacin prevents DNA supercoiling by inhibiting the A subunit of DNA gyrase. Norfloxacin is effective in treating the infection caused by staphylococci, enterococci, and Pseudomonas.
Rifampin is a broad spectrum antimicrobial agent that inhibits protein synthesis by interfering in the mRNA production. Rifampin binds to the b-subunit of RNA polymerase and blocks the RNA chain initiation. Rifampin is effective against gram positive bacteria and mycobacterial infections. It is also used for meningococcal meningitis prophylaxis.
Amphotericin B is an antifungal agent that belongs to the polyene class of antibiotics. It is effective against microbial agents that contain sterols in the cytoplasmic membrane. It binds to the ergosterol in the cell membrane and causes disruption in barrier property of the membrane. It is used in the treatment of systemic mycoses.
Griseofulvin is also a fungistatic agent that inhibits protein assembly. It interferes with the assembly process of tubulin into microtubules. However, it is effective only in fungi whose cell wall contains chitin and is used for the treatment of dermatophyte infections.
Erythromycin is the macrolide that inhibits the 50S ribosomal subunit. This bacteriostatic agent is used primarily to treat pulmonary infection caused by Mycoplasma, Legionella, Campylobacter, and Chlamydia. It is also effective in treating infection caused by gram-positive organisms in penicillin allergic patients.
Bacitracin is a peptide antibiotic that prevents peptidoglycan synthesis. Bacitracin is poorly absorbed and is used as a topical agent for the treatment of infected wounds.
Penicillins are β-lactam antibiotics that are bactericidal agent. β-lactam antibiotics are cell wall inhibitors that prevent peptidoglycan synthesis. Penicillins inhibit transpeptidase (responsible for the cross-linking) and D-alanine carboxypeptidase (responsible for removing D-alanine from a pentapeptide side chain). Penicillins are effective against gram-positive and a limited number of gram negative bacteria.
Tetracycline is a broad spectrum antibiotic that inhibits protein synthesis in prokaryotes, as well as eukaryotes. It binds to phosphate residue of 30S ribosomal subunit and blocks the attachment of tRNA to the ribosome-mRNA complex and interferes in the incorporation of new amino acid into polypeptide chain.
Which of the following antibiotics is the inhibitor of cytoplasmic membrane that binds to ergosterol molecule in the fungal cell membrane?
1 Amphotericin B
2 Trimethoprim
3 Tetracycline
4 Penicillin
5 Rifampin
6 Bacitracin
7 Griseofulvin
8 Sulfonamides
9 Erythromycin
10 Norfloxacin
Amphotericin B
The sulfonamides are a large group of antimicrobial agents that have bacteriostatic activity against a broad spectrum of gram-positive and gram-negative bacteria. Sulfonamides are also effective against Nocardia, chlamydiae, and some protozoa. Sulfonamides are structural analogs of para-aminobenzoic acid, which is a folic acid precursor. Sulfonamides prevent para-aminobenzoic acid conversion into dihydropteroic acid by competitive inhibition of the enzyme dihydropteroate synthetase. This results in inhibition of folic acid synthesis, which is an important intermediate in nucleotide synthesis.
Trimethoprim inhibits purine and DNA synthesis by preventing folic acid formation. Trimethoprim interferes with the conversion of dihydrofolate into tetrahydrofolate by inhibiting the enzyme dihydrofolate reductase. Trimethoprim is used in combination with sulfamethoxazole (co-trimoxazole) in the treatment of urinary tract infection and enteric fever.
Norfloxacin is a bactericidal quinolone that blocks DNA replication. Norfloxacin prevents DNA supercoiling by inhibiting the A subunit of DNA gyrase. Norfloxacin is effective in treating the infection caused by staphylococci, enterococci, and Pseudomonas.
Rifampin is a broad spectrum antimicrobial agent that inhibits protein synthesis by interfering in the mRNA production. Rifampin binds to the b-subunit of RNA polymerase and blocks the RNA chain initiation. Rifampin is effective against gram positive bacteria and mycobacterial infections. It is also used for meningococcal meningitis prophylaxis.
Amphotericin B is an antifungal agent that belongs to the polyene class of antibiotics. It is effective against microbial agents that contain sterols in the cytoplasmic membrane. It binds to the ergosterol in the cell membrane and causes disruption in barrier property of the membrane. It is used in the treatment of systemic mycoses.
Griseofulvin is also a fungistatic agent that inhibits protein assembly. It interferes with the assembly process of tubulin into microtubules. However, it is effective only in fungi whose cell wall contains chitin and is used for the treatment of dermatophyte infections.
Erythromycin is the macrolide that inhibits the 50S ribosomal subunit. This bacteriostatic agent is used primarily to treat pulmonary infection caused by Mycoplasma, Legionella, Campylobacter, and Chlamydia. It is also effective in treating infection caused by gram-positive organisms in penicillin allergic patients.
Bacitracin is a peptide antibiotic that prevents peptidoglycan synthesis. Bacitracin is poorly absorbed and is used as a topical agent for the treatment of infected wounds.
Penicillins are β-lactam antibiotics that are bactericidal agent. β-lactam antibiotics are cell wall inhibitors that prevent peptidoglycan synthesis. Penicillins inhibit transpeptidase (responsible for the cross-linking) and D-alanine carboxypeptidase (responsible for removing D-alanine from a pentapeptide side chain). Penicillins are effective against gram-positive and a limited number of gram negative bacteria.
Tetracycline is a broad spectrum antibiotic that inhibits protein synthesis in prokaryotes, as well as eukaryotes. It binds to phosphate residue of 30S ribosomal subunit and blocks the attachment of tRNA to the ribosome-mRNA complex and interferes in the incorporation of new amino acid into polypeptide chain.
Which of the following antibiotics is the macrolide that binds to 23S RNA in 50S ribosomal subunit and blocks translation?
1 Amphotericin B
2 Trimethoprim
3 Tetracycline
4 Penicillin
5 Rifampin
6 Bacitracin
7 Griseofulvin
8 Sulfonamides
9 Erythromycin
10 Norfloxacin
Erythromycin
The sulfonamides are a large group of antimicrobial agents that have bacteriostatic activity against a broad spectrum of gram-positive and gram-negative bacteria. Sulfonamides are also effective against Nocardia, chlamydiae, and some protozoa. Sulfonamides are structural analogs of para-aminobenzoic acid, which is a folic acid precursor. Sulfonamides prevent para-aminobenzoic acid conversion into dihydropteroic acid by competitive inhibition of the enzyme dihydropteroate synthetase. This results in inhibition of folic acid synthesis, which is an important intermediate in nucleotide synthesis.
Trimethoprim inhibits purine and DNA synthesis by preventing folic acid formation. Trimethoprim interferes with the conversion of dihydrofolate into tetrahydrofolate by inhibiting the enzyme dihydrofolate reductase. Trimethoprim is used in combination with sulfamethoxazole (co-trimoxazole) in the treatment of urinary tract infection and enteric fever.
Norfloxacin is a bactericidal quinolone that blocks DNA replication. Norfloxacin prevents DNA supercoiling by inhibiting the A subunit of DNA gyrase. Norfloxacin is effective in treating the infection caused by staphylococci, enterococci, and Pseudomonas.
Rifampin is a broad spectrum antimicrobial agent that inhibits protein synthesis by interfering in the mRNA production. Rifampin binds to the b-subunit of RNA polymerase and blocks the RNA chain initiation. Rifampin is effective against gram positive bacteria and mycobacterial infections. It is also used for meningococcal meningitis prophylaxis.
Amphotericin B is an antifungal agent that belongs to the polyene class of antibiotics. It is effective against microbial agents that contain sterols in the cytoplasmic membrane. It binds to the ergosterol in the cell membrane and causes disruption in barrier property of the membrane. It is used in the treatment of systemic mycoses.
Griseofulvin is also a fungistatic agent that inhibits protein assembly. It interferes with the assembly process of tubulin into microtubules. However, it is effective only in fungi whose cell wall contains chitin and is used for the treatment of dermatophyte infections.
Erythromycin is the macrolide that inhibits the 50S ribosomal subunit. This bacteriostatic agent is used primarily to treat pulmonary infection caused by Mycoplasma, Legionella, Campylobacter, and Chlamydia. It is also effective in treating infection caused by gram-positive organisms in penicillin allergic patients.
Bacitracin is a peptide antibiotic that prevents peptidoglycan synthesis. Bacitracin is poorly absorbed and is used as a topical agent for the treatment of infected wounds.
Penicillins are β-lactam antibiotics that are bactericidal agent. β-lactam antibiotics are cell wall inhibitors that prevent peptidoglycan synthesis. Penicillins inhibit transpeptidase (responsible for the cross-linking) and D-alanine carboxypeptidase (responsible for removing D-alanine from a pentapeptide side chain). Penicillins are effective against gram-positive and a limited number of gram negative bacteria.
Tetracycline is a broad spectrum antibiotic that inhibits protein synthesis in prokaryotes, as well as eukaryotes. It binds to phosphate residue of 30S ribosomal subunit and blocks the attachment of tRNA to the ribosome-mRNA complex and interferes in the incorporation of new amino acid into polypeptide chain.
Which of the following antibiotics is the polypeptide antibiotic that interferes with the third stage of peptidoglycan synthesis?
1 Amphotericin B
2 Trimethoprim
3 Tetracycline
4 Penicillin
5 Rifampin
6 Bacitracin
7 Griseofulvin
8 Sulfonamides
9 Erythromycin
10 Norfloxacin
Bacitracin
The sulfonamides are a large group of antimicrobial agents that have bacteriostatic activity against a broad spectrum of gram-positive and gram-negative bacteria. Sulfonamides are also effective against Nocardia, chlamydiae, and some protozoa. Sulfonamides are structural analogs of para-aminobenzoic acid, which is a folic acid precursor. Sulfonamides prevent para-aminobenzoic acid conversion into dihydropteroic acid by competitive inhibition of the enzyme dihydropteroate synthetase. This results in inhibition of folic acid synthesis, which is an important intermediate in nucleotide synthesis.
Trimethoprim inhibits purine and DNA synthesis by preventing folic acid formation. Trimethoprim interferes with the conversion of dihydrofolate into tetrahydrofolate by inhibiting the enzyme dihydrofolate reductase. Trimethoprim is used in combination with sulfamethoxazole (co-trimoxazole) in the treatment of urinary tract infection and enteric fever.
Norfloxacin is a bactericidal quinolone that blocks DNA replication. Norfloxacin prevents DNA supercoiling by inhibiting the A subunit of DNA gyrase. Norfloxacin is effective in treating the infection caused by staphylococci, enterococci, and Pseudomonas.
Rifampin is a broad spectrum antimicrobial agent that inhibits protein synthesis by interfering in the mRNA production. Rifampin binds to the b-subunit of RNA polymerase and blocks the RNA chain initiation. Rifampin is effective against gram positive bacteria and mycobacterial infections. It is also used for meningococcal meningitis prophylaxis.
Amphotericin B is an antifungal agent that belongs to the polyene class of antibiotics. It is effective against microbial agents that contain sterols in the cytoplasmic membrane. It binds to the ergosterol in the cell membrane and causes disruption in barrier property of the membrane. It is used in the treatment of systemic mycoses.
Griseofulvin is also a fungistatic agent that inhibits protein assembly. It interferes with the assembly process of tubulin into microtubules. However, it is effective only in fungi whose cell wall contains chitin and is used for the treatment of dermatophyte infections.
Erythromycin is the macrolide that inhibits the 50S ribosomal subunit. This bacteriostatic agent is used primarily to treat pulmonary infection caused by Mycoplasma, Legionella, Campylobacter, and Chlamydia. It is also effective in treating infection caused by gram-positive organisms in penicillin allergic patients.
Bacitracin is a peptide antibiotic that prevents peptidoglycan synthesis. Bacitracin is poorly absorbed and is used as a topical agent for the treatment of infected wounds.
Penicillins are β-lactam antibiotics that are bactericidal agent. β-lactam antibiotics are cell wall inhibitors that prevent peptidoglycan synthesis. Penicillins inhibit transpeptidase (responsible for the cross-linking) and D-alanine carboxypeptidase (responsible for removing D-alanine from a pentapeptide side chain). Penicillins are effective against gram-positive and a limited number of gram negative bacteria.
Tetracycline is a broad spectrum antibiotic that inhibits protein synthesis in prokaryotes, as well as eukaryotes. It binds to phosphate residue of 30S ribosomal subunit and blocks the attachment of tRNA to the ribosome-mRNA complex and interferes in the incorporation of new amino acid into polypeptide chain.
Which of the following antibiotics is the diaminopyrimidine that inhibits folic acid synthesis by inhibiting dihydrofolate reductase?
1 Amphotericin B
2 Trimethoprim
3 Tetracycline
4 Penicillin
5 Rifampin
6 Bacitracin
7 Griseofulvin
8 Sulfonamides
9 Erythromycin
10 Norfloxaci
Trimethoprim
The sulfonamides are a large group of antimicrobial agents that have bacteriostatic activity against a broad spectrum of gram-positive and gram-negative bacteria. Sulfonamides are also effective against Nocardia, chlamydiae, and some protozoa. Sulfonamides are structural analogs of para-aminobenzoic acid, which is a folic acid precursor. Sulfonamides prevent para-aminobenzoic acid conversion into dihydropteroic acid by competitive inhibition of the enzyme dihydropteroate synthetase. This results in inhibition of folic acid synthesis, which is an important intermediate in nucleotide synthesis.
Trimethoprim inhibits purine and DNA synthesis by preventing folic acid formation. Trimethoprim interferes with the conversion of dihydrofolate into tetrahydrofolate by inhibiting the enzyme dihydrofolate reductase. Trimethoprim is used in combination with sulfamethoxazole (co-trimoxazole) in the treatment of urinary tract infection and enteric fever.
Norfloxacin is a bactericidal quinolone that blocks DNA replication. Norfloxacin prevents DNA supercoiling by inhibiting the A subunit of DNA gyrase. Norfloxacin is effective in treating the infection caused by staphylococci, enterococci, and Pseudomonas.
Rifampin is a broad spectrum antimicrobial agent that inhibits protein synthesis by interfering in the mRNA production. Rifampin binds to the b-subunit of RNA polymerase and blocks the RNA chain initiation. Rifampin is effective against gram positive bacteria and mycobacterial infections. It is also used for meningococcal meningitis prophylaxis.
Amphotericin B is an antifungal agent that belongs to the polyene class of antibiotics. It is effective against microbial agents that contain sterols in the cytoplasmic membrane. It binds to the ergosterol in the cell membrane and causes disruption in barrier property of the membrane. It is used in the treatment of systemic mycoses.
Griseofulvin is also a fungistatic agent that inhibits protein assembly. It interferes with the assembly process of tubulin into microtubules. However, it is effective only in fungi whose cell wall contains chitin and is used for the treatment of dermatophyte infections.
Erythromycin is the macrolide that inhibits the 50S ribosomal subunit. This bacteriostatic agent is used primarily to treat pulmonary infection caused by Mycoplasma, Legionella, Campylobacter, and Chlamydia. It is also effective in treating infection caused by gram-positive organisms in penicillin allergic patients.
Bacitracin is a peptide antibiotic that prevents peptidoglycan synthesis. Bacitracin is poorly absorbed and is used as a topical agent for the treatment of infected wounds.
Penicillins are β-lactam antibiotics that are bactericidal agent. β-lactam antibiotics are cell wall inhibitors that prevent peptidoglycan synthesis. Penicillins inhibit transpeptidase (responsible for the cross-linking) and D-alanine carboxypeptidase (responsible for removing D-alanine from a pentapeptide side chain). Penicillins are effective against gram-positive and a limited number of gram negative bacteria.
Tetracycline is a broad spectrum antibiotic that inhibits protein synthesis in prokaryotes, as well as eukaryotes. It binds to phosphate residue of 30S ribosomal subunit and blocks the attachment of tRNA to the ribosome-mRNA complex and interferes in the incorporation of new amino acid into polypeptide chain.
Which of the following antibiotics is the inhibitor of cell wall synthesis that reacts with transpeptidase to form an inactive complex?
1 Amphotericin B
2 Trimethoprim
3 Tetracycline
4 Penicillin
5 Rifampin
6 Bacitracin
7 Griseofulvin
8 Sulfonamides
9 Erythromycin
10 Norfloxacin
Penicillin
The sulfonamides are a large group of antimicrobial agents that have bacteriostatic activity against a broad spectrum of gram-positive and gram-negative bacteria. Sulfonamides are also effective against Nocardia, chlamydiae, and some protozoa. Sulfonamides are structural analogs of para-aminobenzoic acid, which is a folic acid precursor. Sulfonamides prevent para-aminobenzoic acid conversion into dihydropteroic acid by competitive inhibition of the enzyme dihydropteroate synthetase. This results in inhibition of folic acid synthesis, which is an important intermediate in nucleotide synthesis.
Trimethoprim inhibits purine and DNA synthesis by preventing folic acid formation. Trimethoprim interferes with the conversion of dihydrofolate into tetrahydrofolate by inhibiting the enzyme dihydrofolate reductase. Trimethoprim is used in combination with sulfamethoxazole (co-trimoxazole) in the treatment of urinary tract infection and enteric fever.
Norfloxacin is a bactericidal quinolone that blocks DNA replication. Norfloxacin prevents DNA supercoiling by inhibiting the A subunit of DNA gyrase. Norfloxacin is effective in treating the infection caused by staphylococci, enterococci, and Pseudomonas.
Rifampin is a broad spectrum antimicrobial agent that inhibits protein synthesis by interfering in the mRNA production. Rifampin binds to the b-subunit of RNA polymerase and blocks the RNA chain initiation. Rifampin is effective against gram positive bacteria and mycobacterial infections. It is also used for meningococcal meningitis prophylaxis.
Amphotericin B is an antifungal agent that belongs to the polyene class of antibiotics. It is effective against microbial agents that contain sterols in the cytoplasmic membrane. It binds to the ergosterol in the cell membrane and causes disruption in barrier property of the membrane. It is used in the treatment of systemic mycoses.
Griseofulvin is also a fungistatic agent that inhibits protein assembly. It interferes with the assembly process of tubulin into microtubules. However, it is effective only in fungi whose cell wall contains chitin and is used for the treatment of dermatophyte infections.
Erythromycin is the macrolide that inhibits the 50S ribosomal subunit. This bacteriostatic agent is used primarily to treat pulmonary infection caused by Mycoplasma, Legionella, Campylobacter, and Chlamydia. It is also effective in treating infection caused by gram-positive organisms in penicillin allergic patients.
Bacitracin is a peptide antibiotic that prevents peptidoglycan synthesis. Bacitracin is poorly absorbed and is used as a topical agent for the treatment of infected wounds.
Penicillins are β-lactam antibiotics that are bactericidal agent. β-lactam antibiotics are cell wall inhibitors that prevent peptidoglycan synthesis. Penicillins inhibit transpeptidase (responsible for the cross-linking) and D-alanine carboxypeptidase (responsible for removing D-alanine from a pentapeptide side chain). Penicillins are effective against gram-positive and a limited number of gram negative bacteria.
Tetracycline is a broad spectrum antibiotic that inhibits protein synthesis in prokaryotes, as well as eukaryotes. It binds to phosphate residue of 30S ribosomal subunit and blocks the attachment of tRNA to the ribosome-mRNA complex and interferes in the incorporation of new amino acid into polypeptide chain.
A mother brings her 2-year-old daughter into your office and reports that the child does not want to eat and appears to have a fever. Upon examination, you confirm that the child has an inflamed throat and decide to treat her with 7 days of penicillin. After 4 days, the mother calls your office to report that the child has not significantly improved. You know that this problem is somehow related to bacterial plasmids. The transfer of a plasmid from one bacteria to another is an example of what?
1 A mechanism of spreading bacterial resistance to antibiotics
2 A situation which can never be harmful to the patient
3 A mechanism of conveying sensitivity to all antibiotics to the bacteria
4 A means of restoring sensitivity to the antibiotic
5 A mechanism of preventing antibiotic resistance
A mechanism of spreading bacterial resistance to antibiotics
Bacteria carrying a plasmid with the gene for β-lactamase would confer resistance to antibiotics containing the β-lactam ring, such as penicillin and amoxicillin. The plasmid contains a gene involved in the metabolism of a specific compound, penicillin in this case, and does not work on other compounds. Therefore, unless the antibiotic was acted on by the gene expressed in the plasmid, sensitivity to other antibiotics is not affected. Antibiotic resistance can be harmful to the individual in cases where no other antibiotic is available or effective in treating the specific infection. Limiting use of antibiotics to conditions where they are really needed can help prevent increased antibiotic resistant bacteria.The antibiotic penicillin consists of a thiazolidine ring fused to a β-lactam ring (see image). A variable “R” group is attached to the β-lactam ring by a peptide bond. Penicillin inhibits bacterial cell growth by inhibiting the enzyme catalyzing the last step in cell wall synthesis. This step involves the cross-linking of the peptidoglycan strands. Under normal conditions, a peptide bond forms between the terminal glycine on one proteoglycan strand, with the terminal D-Ala-D-Ala unit on the other strand forming the Gly-D-Ala cross-link. The enzyme catalyzing this reaction is glycopeptide transpeptidase. Penicillin inhibits this reaction by mimicking the D-Ala-D-Ala unit, forming a covalent bond between the R-group of penicillin and the active site serine of glycopeptide transpeptidase. The penicilloyl-enzyme complex is enzymatically inactive. Therefore, penicillin acts as a transition-state analog. Bacterial plasmids often carry genes that confer resistance to a specific antibiotic. β-Lactamase is an enzyme that cleaves and inactivates antibiotics like penicillin. Other examples of enzymes carried on plasmids that convey antibiotic resistances are chloramphenicol acetyltransferase, which inactivates chloramphenicol, and phosphotransferases, which modify aminoglycosides such as neomycin and gentamicin. These plasmids can be passed from a resistant to a sensitive bacterial cell, conveying resistance to a particular antibiotic. Therefore, many strains of resistant bacteria have arisen, which cause problems in treatment of the patient.
The major classes of antibiotics used today include penicillins, cephalosporins, aminoglycosides, macrolides, and tetracyclines. A patient who is allergic to one type of penicillin (ampicillin, amoxicillin) is allergic to all types. Often, these patients are allergic to the cephalosporins (cephalexin, cefaclor). Aminoglycosides (gentamicin, tobramycin) work by interfering with protein synthesis in the bacteria. Macrolide antibiotics (erythromycin) interfere with the protein synthesis in the bacteria. Tetracyclics (tetracycline and doxycycline) reversibly bind to the ribosome and inhibit protein synthesis.
The antiviral agent acyclovir can be used to promote the healing and relieve the pain of skin lesions caused by chicken pox in adults. Acyclovir is an effective antiviral drug because it
1 Inhibits host cell DNA polymerase
2 Inhibits viral thymidine kinase
3 Is an analog of pyrimidine nucleotides
4 Terminates DNA synthesis when incorporated
5 Inhibits coat protein assembly
Terminates DNA synthesis when incorporated
Acyclovir (acycloguanosine) is an antiviral agent that is used in the treatment of herpes simplex, herpes genitalis, and herpes zoster infections. It is an analog of the purine nucleoside guanosine and must be activated in order to be active. It is converted to the monophosphate form by the viral enzyme thymidine kinase. Subsequent to this, it is converted to the di- and then tri-phosphate form by host enzymes. Acyclovir triphosphate competes with deoxyguanosine triphosphate and is incorporated into the viral DNA. The incorporation of acyclovir into DNA terminates DNA synthesis because it lacks the free hydroxyl group necessary for the continued addition of nucleotides. Mutations in viral thymidine kinase or polymerase genes lead to acyclovir resistance. Acyclovir is effective only against actively replicating viruses.
Compounds such as ritonavir or indinavir inhibit the protease required to process the coat protein precursors so they can assemble into the virus particle. The coat proteins are structural and not enzymes, and therefore cannot be affected by acyclovir. Nucleotide and non-nucleotide compounds such as zidovudine (AZT) or etravirine inhibit reverse transcriptases. Guanylate kinase uses ATP to form GDP from GMP and is not affected by acyclovir.
The antiviral agent acyclovir can be used to promote the healing and relieve the pain of skin lesions caused by chicken pox in adults. Acyclovir is an analog of which of the following compounds?
1 Guanosine
2 Thymidine
3 Adenosine
4 Cytosine
5 Hypoxanthine
Guanosine
Acyclovir (acycloguanosine) is an antiviral agent that is used in the treatment of herpes simplex, herpes genitalis, and herpes zoster infections. It is an analog of the purine nucleoside guanosine and must be activated in order to be active. It is converted to the monophosphate form by the viral enzyme thymidine kinase. Subsequent to this, it is converted to the di- and then tri-phosphate form by host enzymes. Acyclovir triphosphate competes with deoxyguanosine triphosphate and is incorporated into the viral DNA. The incorporation of acyclovir into DNA terminates DNA synthesis because it lacks the free hydroxyl group necessary for the continued addition of nucleotides. Mutations in viral thymidine kinase or polymerase genes lead to acyclovir resistance. Acyclovir is effective only against actively replicating viruses.
Compounds such as ritonavir or indinavir inhibit the protease required to process the coat protein precursors so they can assemble into the virus particle. The coat proteins are structural and not enzymes, and therefore cannot be affected by acyclovir. Nucleotide and non-nucleotide compounds such as zidovudine (AZT) or etravirine inhibit reverse transcriptases. Guanylate kinase uses ATP to form GDP from GMP and is not affected by acyclovir.
