antimicrobials and antimicrobial resistance mechanisms:
penicillin-Family Antibiotics:
The penicillin family inhibits cell wall synthesis. It was first used during World War II to provide treatment for bacterial infections, however, over time many bacterial species have grown resistant to and have developed resistance mechanisms to the antibiotic. Scientists have worked hard to develop other antibiotics to "trick" these antimicrobial defenses, and they continue to do so.
Bacteria that possess something known as the beta-lactamase enzyme destroy the beta-lactam ring in the biochemical makeup of penicillin, so that cell wall synthesis can continue. Penicillins are known as the "beta-lactam antibiotics" because of this. Penicillins are bacteriacidal because they kill, not just slow the growth, of certain bacteria.
Gram-positive and Gram-negative bacteria both possess peptidoglycan in their cell walls. Peptidoglycan is a combination of disaccharide sugar units cross-linked like chain-linked fences with amino-acids known as peptides. An enzyme called transpeptidase is like the key that catalyzes or kicks off this linkage. Penicillin is the medical "Army" that must invade this fence. It does so by "tricking" the bacterial defense mechanisms and penetrates the outer cell wall layers to get to the inner cytoplasmic membrane. This is where the transpeptidases live. Penicillin sneaks through tunnels in the cell membranes of Gram-negative bacteria. These tunnels are called porins. Here, the penicillin beta-lactam ring binds to and inhibits (blocks) the transpeptidase enzyme (also known as penicillin-binding protein) so it can no longer work. Cells can no longer build their membranes and walls, contents leak out, nutrients can no longer enter, and the bacteria die.
How do bacteria try to resist beta-lactam antibiotics? They defend themselves in 4 distinct ways:
Side Effects of Penicillin:
Some people have adverse reactions to penicillin. This may be a minor as development of a rash to severe, including anaphylactic allergic reactions where the throat closes up, making it difficult to breathe. This is an acute allergic reaction that can occur within minutes to hours after ingestion of the medication, resulting from an IgE-mediated immune response. Hives (urticaria) with itching, bronchospasm, and/or anaphylactic shock can occur. A delayed rash can occur a few days to weeks later. Approximately 10% of individuals with penicillin reactions will also have adverse reactions to the cephalosporins.
Penicillin can also cause diarrhea in some individuals by destroying the normal flora in the gut along with the offending bacteria, allowing resistant pathogenic bacteria to grow in their place.
The Family of Penicillins:
There are a variety of penicillins, including the following types:
Imipenem:
The carbapenems are a newer class of antibiotics and are broad spectrum in nature. They are resistant to beta-lactamases and ESBL's. Imipenem kills Gram-negatives, Gram-positives, and anaerobes. Because it is a strong antibiotic, it is not given to those with a history of seizures, strokes, brain cancer, meningitis, smokers, or prior allergic reactions to the drug.
Meropenem:
Meropenem is also a powerful antibiotic like imipenem. It's risk of causing seizures is lower, however.
Ertapenem:
This drug is nice in that it only requires 1 dose a day, given intravenously. Severe diabetic foot infections caused by anaerobes are effectively treated with this drug.
Bacteria that possess something known as the beta-lactamase enzyme destroy the beta-lactam ring in the biochemical makeup of penicillin, so that cell wall synthesis can continue. Penicillins are known as the "beta-lactam antibiotics" because of this. Penicillins are bacteriacidal because they kill, not just slow the growth, of certain bacteria.
Gram-positive and Gram-negative bacteria both possess peptidoglycan in their cell walls. Peptidoglycan is a combination of disaccharide sugar units cross-linked like chain-linked fences with amino-acids known as peptides. An enzyme called transpeptidase is like the key that catalyzes or kicks off this linkage. Penicillin is the medical "Army" that must invade this fence. It does so by "tricking" the bacterial defense mechanisms and penetrates the outer cell wall layers to get to the inner cytoplasmic membrane. This is where the transpeptidases live. Penicillin sneaks through tunnels in the cell membranes of Gram-negative bacteria. These tunnels are called porins. Here, the penicillin beta-lactam ring binds to and inhibits (blocks) the transpeptidase enzyme (also known as penicillin-binding protein) so it can no longer work. Cells can no longer build their membranes and walls, contents leak out, nutrients can no longer enter, and the bacteria die.
How do bacteria try to resist beta-lactam antibiotics? They defend themselves in 4 distinct ways:
- Efflux Pump: Both Gram-positive and Gram-negative bacteria may develop the ability to "vomit" or pump out the beta-lactam quickly before it binds to transpeptidase enzyme.
- Molecular Structure Breakdown: Some bacteria, including MRSA (Methicillin-Resistant Staphylococcus Aureus), develop the ability to alter or change the molecular structure of the transpeptidase enzyme so that the beta-lactam ring can't bind. This is why MRSA is resistant to ALL penicillin family drugs.
- Cleavage of the Ring: Both Gram-positive and Gram-negative bacteria sometimes have beta-lactamase (penicillinase) enzymes that, like scissors, "snip" or cleave the C-N bond in the beta-lactam ring, rendering it ineffective. Staphylococcus aureus is one such organism.
- Porin Alteration: Some Gram-negative bacteria alter their porin channels so that penicillin cannot get through.
- Enzyme Production: Some bacteria produce other types of enzymes that resist antimicrobial drugs. Cephalosporinases are one such example.
Side Effects of Penicillin:
Some people have adverse reactions to penicillin. This may be a minor as development of a rash to severe, including anaphylactic allergic reactions where the throat closes up, making it difficult to breathe. This is an acute allergic reaction that can occur within minutes to hours after ingestion of the medication, resulting from an IgE-mediated immune response. Hives (urticaria) with itching, bronchospasm, and/or anaphylactic shock can occur. A delayed rash can occur a few days to weeks later. Approximately 10% of individuals with penicillin reactions will also have adverse reactions to the cephalosporins.
Penicillin can also cause diarrhea in some individuals by destroying the normal flora in the gut along with the offending bacteria, allowing resistant pathogenic bacteria to grow in their place.
The Family of Penicillins:
There are a variety of penicillins, including the following types:
- Penicillin G: This is the original penicillin discovered by chemist and microbiologist Alexander Fleming, who noticed that the mold Penicillium notatum produced something that blocked the growth of Staphylococcus aureus on a petri dish filled with agar. This type of penicillin was first given to humans in 1941.
- Usually given intramuscularly (IM) or intravenously (IV)
- Given to fight pneumonia caused by S. pneumoniae
- Penicillin V: oral form of penicillin, which is acid-stable in the stomach and commonly given to treat streptococcal pharyngitis caused by Group A streptococci
- Aminopenicillins: This type has a wider, broader spectrum of effectiveness against Gram-negative bacteria such as E. coli, Proteus, Salmonella, Shigella, etc...and effective against the Gram-positive enterococci.
- Ampicillin (oral, IV)-IV ampicillin can be used in combination with the aminoglycosides, such as gentamicin, to treat Gram-negative infections. Serious UTI's can be treated with this broad-spectrum drug empirically until cultures show more specifically what is causing the infection.
- Amoxicillin (oral)-used to treat ear infections, bronchitis and sinusitis, as well as infections caused by Listeria.
- Penicillinase-Resistant Penicillins: This group of antibiotics is effective against beta-lactamase enzyme-producing Staphylococcus aureus. These are usually given by IV.
- Methicillin (This is not given as much anymore in the USA because it can cause interstitial nephritis due to kidney damage)
- Nafcillin (Effective against staph infections such as cellulitis, impetigo, endocarditis, sepsis)
- Oxacillin
- Cloxacillin
- Dicloxacillin
- Anti-Pseudomonal Penicillins: These are a broad-spectrum type that produce even more effective coverage against Gram-negative bacteria, including Pseudomonas aeruginosa and some anaerobes like Bacteroides fragilis . This group includes carboxypenicillins, ureidopenicillins, and monobactams.
- Carboxypenicillins
- Ticarcillin
- Carbenicillin (have to use high doses; risk of high sodium, platelet dysfunction, hypokalemia)
- Ureidopenicillins
- Piperacillin
- Mezlocillin
- Monobactams-can be given in combination with penicillins to inhibit beta-lactamase; Used to treat Gram-positives (S. aureus), Gram-negatives (H. influenzae), anaerobes (B. fragilis)
- Clavulanic Acid
- Sulbactam
- Tazobactam
- Aztreonam
- Kills Gram-negative anaerobic bacteria
- Used to treat hospital-acquired (nosocomial) multidrug-resistant bacterial infections, including those caused by P. aeruginosa
- Often given in combination with other drugs: + vancomycin, + clindamycin
- Kills Gram-negative anaerobic bacteria
- Augmentin-combination of amoxicillin and clavulanic acid
- Timentin-combination of ticaricillin and clavulanic acid
- Unasyn-combination of ampicillin and sulbactam
- Zosyn-combination of piperacillin and tazobactam
- Carboxypenicillins
- Cephalosporins: This family just keeps growing as researchers develop more effective antimicrobials to fight bacterial resistance. These have a beta-lactam ring that is resistant to beta-lactamase. This group is broad spectrum and provides coverage against Gram-positive and Gram-negative bacteria. Benefits include:
- Broad spectrum coverage
- Beta-lactam ring is much more resistant to beta-lactamases
- R-group side chain leads to drugs with different spectrums of activity
- First Generation: (For use when penicillin cannot be tolerated; for use before surgery to prevent infection from skin flora)
- Cephalothin
- Cephapirin
- Cephradine
- Cephalexin
- Cefazolin
- Second Generation: (For coverage of community-acquired pneumonia, ear infection, sinusitis, anaerobic infections)
- Cefamandole
- Cefaclor
- Cefuroxime
- Cefoxitin
- Cefotetan
- Cefmetazole
- Cefonicid
- Cefprozil
- Loracarbef
- Cefdinir
- Third Generation: (For inpatient treatment of community-acquired pneumonia, meningitis, kidney infection)
- Ceftriaxone-penetraes the blood-brain barrier to treat bacterial meningitis and to treat gonorrheal infections that are resistant to other antibiotics
- Ceftazidime
- Cefotaxime
- Ceftizoxime
- Ceftibuten
- Cefixime
- Cefoperazone
- Cefpodoxime
- Fourth Generation: (For tough Gram-positive infections and P. aeruginosa)
- Cefepime
- Cefpirome
- Fifth Generation: (For MRSA, resistant streptococci and resistant enterococci)
- Ceftaroline
- Ceftobiprole
- Ceftaroline
Imipenem:
The carbapenems are a newer class of antibiotics and are broad spectrum in nature. They are resistant to beta-lactamases and ESBL's. Imipenem kills Gram-negatives, Gram-positives, and anaerobes. Because it is a strong antibiotic, it is not given to those with a history of seizures, strokes, brain cancer, meningitis, smokers, or prior allergic reactions to the drug.
Meropenem:
Meropenem is also a powerful antibiotic like imipenem. It's risk of causing seizures is lower, however.
Ertapenem:
This drug is nice in that it only requires 1 dose a day, given intravenously. Severe diabetic foot infections caused by anaerobes are effectively treated with this drug.
anti-ribosomal antibiotics:
Anti-ribosomal antibiotics target the bacterial ribosomal subunits. While humans have an 80S ribosomal particle, bacteria have a 70S ribosomal particle with 2 subunits: a 50S particle (large) and a 30S particle (small). In order to live and grow, bacteria depend on production of the proteins that are translated by mRNA into the chains of polypeptides required to make up proteins. They depend on ribosomes to do just that. Antibiotics that block the action of ribosomes stop cellular survival and growth. These antibiotics target bacterial ribosomes without harming ours. Crucial types of anti-ribosomal antibiotics include:
- Chloramphenicol
- Broad-spectrum and kills most clinically significant bacteria, including Gram-positive, Gram-negative, and anaerobic organisms
- The downside to this antimicrobial is that it has rare but severe side effects, however, its benefits often outweight its risks
- Linked to bone marrow depression resulting in anemia (reversible) or aplastic anemia (irreversible) in rare cases, which can be fatal
- Linked to liver toxicity in rare cases, which can be particularly hard on the kidneys, liver, and gray baby syndrome
- Linked to pseudomembranous colitis if it destroys the normal flora along with the pathognic bacteria, allowing C. difficile to flourish
- Used to treat bacterial meningitis or aspiration pneumonia
- Can be combined with aminoglycosides to treat traumatic wound infections
- Given to treat acne
- Useful for treating female infections of the genital tract
- Can be combined with a beta lactam antibiotic to treat Group A streptococcal toxic shock syndrome or toxic shock syndrome treated by S. aureus
- Clindamycin
- Given to treat Gram-positive microbial infections
- Useful for treating anaerobic infections
- Can be combined with aminoglycosides to treat traumatic wound infections
- Given to treat acne
- Useful for treating female infections of the genital tract
- Can be combined with a beta lactam antibiotic to treat Group A streptococcal toxic shock syndrome or toxic shock syndrome treated by S. aureus
- Downside is that it can kill the normal flora along with the pathogenic bacteria, enabling an overgrowth of C. difficile, resulting in pseudomembranous colitis
- Linezolid
- Used to great Gram-positive microbial infections
- Blocks the 50S ribosomal subunit
- Used to treat nosocomial pneumonia
- Given to fight VRE and MRSA
- The downside to this medication is that it is expensive and in rare cases it can suppress the bone marrow, resulting in anemia, neutropenia, or thrombocytopenia, or in some cases, it can irritate the GI tract
- Macrolides (blocks the ribosomes at the 50S subunit by providing a broad spectrum against Gram-positives, some Gram-negatives and some atypical pathogens, and given for community-acquired pneumonia, skin and soft tissue infections not due to MRSA, some respiratory infections, ear infections, sinusitis, bronchitis)
- Erythromycin
- Azithromycin ("Z pack")
- Clarithromycin
- Telithromycin (ketolide)
- These are considered to be among the "safest" antibiotics in that they have the least amount of side effects
- GI irritation and abdominal pain
- Rare cholestatic hepatitis
- Prolonged QT syndrome
- Tetracycline
- Doxycycline
- Used to treat chlamydial infections
- Useful for treating mycoplasma walking pneumonia
- Used to treat acne
- Downside is that it can cause GI tract irritation with nausea and diarrhea, phototoxic dermatitis, hepatic toxicity, depressed bone marrow, discolored teeth
- Tigecycline
- Derived from tetracycline
- Only in IV form
- Used to treat complicated skin and soft tissue infections, peritonitis, and given to treat MRSA and VRE
- Binds to the 30S ribosomal subunit
- Aminoglycosides
- Diffuse across the cell wall by binding the 30S ribosomal subunit
- Combined with penicillin (breaks the cell wall to facilitate diffusion)
- Given to treat aerobic Gram-negative enteric bacteria
- Downside is that it is strong and it can cause renal, cochlear or vestibular toxicity
- Streptomycin
- Gentamicin
- Tobramycin
- Amikacin (broadest spectrum)
- Neomycin
- Netilmycin
- Quinupristin/Dalfopristin (Synercid)
- Used to treat life-threatening infections with VRE and MRSA and Group A strep
- Binds to the 50S ribosomal subunit
- Spectinomycin
- Attacks the 30S ribosomal subunit
- Given via IM injection
- Used to treat gonorrhea
the fluoroquinolones:
The fluoroquinolones are considered to be safe. They achieve a high blood level and successful oral absorption. The mechanism works by inhibiting the DNA gyrase, breaking the bacterial DNA structure. They are given to treat Gram-negative infections. They are not very effective against Gram-positives or anaerobes. The fluoroquinolones include:
Side effects may include GI irritation, cartilage damage, tendonitis, tendon rupture, difficulty sleeping, headaches, pseudomembranous colitis, and disruptions of blood sugar.
- Nalidixic acid (1st Generation)
- Norfloxacin (2nd Generation)
- Ciprofloxacin (2nd Generation)
- Enoxacin (2nd Generation)
- Lomefloxacin (2nd Generation)
- Ofloxacin (2nd Generation)
- Levofloxacin (2nd Generation)
- Gatifloxacin (3rd Generation)
- Trovafloxacin (no longer used due to liver toxicity) (4th Generation)
- Moxifloxacin (4th Generation)
- Gemifloxacin (4th Generation)
Side effects may include GI irritation, cartilage damage, tendonitis, tendon rupture, difficulty sleeping, headaches, pseudomembranous colitis, and disruptions of blood sugar.
Vancomycin and daptomycin:
Vancomycin is an IV antibiotic that is reserved for the severest and most resistant of infections. It covers ALL Gram-positive infections, including MRSA. It blocks the synthesis of Gram-positive peptidoglycan.
Daptomycin works by interrupting the microbial cell-membrane electrical charge, which in turn disrupts the electron transport chain. It only works on Gram-positives, including MRSA and VRE.
Daptomycin works by interrupting the microbial cell-membrane electrical charge, which in turn disrupts the electron transport chain. It only works on Gram-positives, including MRSA and VRE.
Antimetabolites:
Trimethoprim-sulfamethoxazole (Bactrim) is a drug combination that "tricks" microbes by resembling PABA, thus inhibiting DNA synthesis. It kills many Gram-positive and some Gram-negative bacteria.
VItek 2 ast (antimicrobial susceptibility testing) cards:
Vitek 2 AST cards are about the size of your palm or a playing card, and contain 64 wells, a transfer tube, weight about 15 grams, are bar-coded so that they can be tracked to easily find results, and each one contains a positive well. The Vitek 2 instrument continuously monitors growth in the wells based on turbidity and continues every 15 minutes until susceptibility testing is done.
vitek 2 ast-st03 for streptococcus pneumoniae, viridans strep, and group a and b streptococci
- Ampicillin
- Benzylpenicillin
- Cefotaxime
- Cetriaxone
- Chloramphenicol *
- Clindamycin
- Erythromycin
- Gentamicin *
- Inducible Clindamycin Resistance
- Levofloxacin
- Linezolid
- Moxifloxacin *
- Rifampicin *
- Teicoplanin *
- Tetracycline
- Tigecycline *
- Trimethoprim/Sulfamethoxazole
- Vancomycin
Vitek 2 ast-70 card
This susceptibility card is used to determine susceptibility of aerobic, enteric Gram-negative rods.
vitek 2 ast-91 card
This susceptibility card is used to determine susceptibility of Gram-negative rods.
vitek 2 ast-75 card
This susceptibility card is used to determine susceptibility of Gram-positive bacteria, including Staphylococcus, Streptococcus agalactiae, Enterococcus species.