Principles of Antimicrobial Selection and Administration
I. Match “drug with bug” principle
A. Identify pathogen: culture, gram stain (positive vs. negative), common cause
B. Determine microbial susceptibility to drug: culture and sensitivity, genotype and phenotype, literature
C. Role of infectious disease consultant
1. Suggest appropriate therapy
2. Prevent overuse or inappropriate use of antimicrobials
Principles of Antimicrobial Selection and Administration
II. Consider Drug Spectrum:
Narrow vs. Broad Spectrum drug
IV. Consider Site of Infection:
Principles of Antimicrobial Selection and Administration
V. Maintain Adequate Blood Levels
Many antibiotics should be administered around-the-clock, i.e. every six hours for 4 times per day, every eight hours for 3 times per day, etc.
Oral antibiotics should be administered on an empty stomach and should not be co-administered with other oral medications.
Principles of Antimicrobial Selection and Administration:
VI. Antibiotic Combinations:
Combinations of antibiotics that work by different mechanisms may be synergistic or they may work against each other.
In the case of mixed infections with more than one bacterial species, a combination may be required.
In some instances, antibiotic resistance is discouraged by combinations.
Combinations should be used only when indicated.
Which of the following promote antimicrobial resistance?
Administering antimicrobials when needed
Maintaining adequate drug levels
Non-adherence to regimen
Using antimicrobial to which the organism is sensitive
Patient Variables in Administering Antimicrobials
Health status: comorbidities, immunosuppressive therapy, etc.
B. Life span and gender: appropriateness of dose & agent
C. Ethnicity/culture: belief about medications may hinder compliance
D. Environment: access to refrigeration, running water, etc.
Adverse Effects of Antibiotic Therapy
Normal gut flora are killed which produces diarrhea and can pave the way for colonization with pathogenic bacteria.
Suprainfection – infection with a second (antibiotic resistant) organism that occurs during antibiotic therapy. In pseudomembranous colitis, the bowel is colonized with Clostridium difficile , producing a severe diarrhea that is sometimes fatal.
Allergy – most common with the penicillins.
Nursing Implications for Antimicrobial Therapy
I. Assess history carefully for hypersensitivity (allergic) reactions, possible pregnancy and lactation
II. Assess kidney and/or liver function, especially in hypertensives, diabetics and elderly.
III. Review culture and sensitivity reports.
IV. Monitor for response to therapy.
Nursing Implications for Antimicrobial Therapy
V . Patient Education:
Patient should complete full course of antibiotics
Take missed doses as soon as remembered
Teach signs and symptoms of hypersensitivity reaction. Can develop hypersensitivity AT ANY TIME. (See following photos)
May need a backup method of birth control
Stevens Johnsons Syndrome
Note extensive sloughing of epidermis from Stevens-Johnson syndrome. Courtesy of David F. Butler, MD. http://emedicine.medscape.com/article/756523-overview
Nursing Implications: VI. Intravenous Administration of Antibiotics
Many antibiotics are easy to give IV – they can be given in small volumes of fluid over short infusion times.
A few antibiotics have stringent requirements for IV administration – they require large volumes of fluid and lines in large veins, and/or they must be administered slowly.
Erythromycin and other macrolides – large volumes and large veins.
Vancomycin and clindamycin – administer slowly.
If you don’t know – LOOK IT UP!
Antimicrobials: PART II
I. Antibiotics Affecting the Bacterial Cell Wall: Beta-Lactam Antibiotics
Beta-lactam antibiotics penetrate the cell wall and bind to targets on cytoplasmic membrane
Disrupt synthesis/maintenance of the cell wall: bacterium is killed by osmotic pressure.
Can be inactivated by beta-lactamases: enzymes that degrade the drug.
Gram-negative organisms have an additional component to their cell wall that most beta-lactam antibiotics cannot penetrate. Therefore, most of these agents are not effective against gram-negative bacteria.
Types of Beta-Lactam Antibiotics:
Lehne, 2007, Pharmacology for Nursing Care, 6 th ed., Elsevier, p. 963
Therapeutic: used for gram-positive bacteria such as Strep and Staph & a few gram-negatives such as Neisseria, and syphilis ( Treponema ). Some will cover anaerobes such as Enterobacter & also Pseudomonas , and Klebsiella .
Prophylactic: used to prevent bacteremia in selected populations at risk for endocarditis, such as people with artificial or damaged heart valves.
Individual penicillins have varying resistance to beta-lactamases (bacterial enzymes that break apart the beta-lactam ring).
Pharmacokinetics of Penicillins
Different penicillins are orally active or not.
Most have a short half-life.
Depot forms: benzathine penicillin G and procaine penicillin G are administered by deep IM injection and released over a long time.
Distribution: bound to plasma proteins and do not cross blood-brain barrier well except when it is compromised as in infection.
Blood Levels of Different Formulations of Penicillin G Lehne, 2007, Pharmacology for Nursing Care, 6 th ed., Elsevier, p. 966
As with any drug allergy, penicillin allergy involves the immune system and antibodies that bind to the drug or its degradation products.
Can be as mild as rash or severe as anaphylaxis.
Can occur with first or repeated exposure.
Cross-allergy to other beta-lactam antibiotics.
Skin testing may not be dependable and may cause an anaphylactic reaction in sensitive individuals.
Adverse Effects & Drug Interactions of Penicillins
Adverse effects include gastrointestinal symptoms and suprainfections related to loss of normal flora.
Overdose can cause neurologic problems, including seizures.
Synergistic with aminoglycoside antibiotics, but can’t be administered in the same IV line.
Enzymes that cut the beta-lactam ring, inactivating beta lactam antibiotics
Bacteria that manufacture beta-lactamases may be resistant to all or most beta lactam antibiotics.
Lehne, 2007, Pharmacology for Nursing Care, 6 th ed., Elsevier, p. 964
Drugs that bind to the active site of beta-lactamases, preventing these enzymes from cutting the beta-lactam ring. This prevents resistance of the bacteria to these antibiotics.
Many beta-lactamase inhibitors are irreversible.
Beta-lactam antibiotics can be administered along with beta-lactamase inhibitors.
Penicillin-Beta-Lactamase Inhibitor Combinations
Drugs that combine a penicillin drug and the inhibitor:
Amoxicillin + clavulanic acid = Augmentin
Ampicillin + sulbactam = Unasyn
Ticarcillin + clavulanic acid = Timentin
Piperacillin + tazobactam = Zosyn
Penicillin works by:
Affecting the bacterial cell wall
Inhibiting protein synthesis
Altering protein synthesis
Inhibiting an enzyme in bacterial DNA replication
Similar to penicillins in structure and activity.
Four generations, each with its own spectrum of
activity, susceptibility to beta-lactamases, and uses.
Widely distributed to body fluids including bone
1 st and 2 nd generations do not cross blood-brain barrier.
Most eliminated by the kidney: may need decreased dose with decreased renal function
Major Differences between Cephalosporin Generations Lehne, 2007, Pharmacology for Nursing Care, 6 th ed., Elsevier, p. 973 Generation Activity against Gram Negative Resistance to Beta-Lactamases Distribution to CSF 1 st (e.g., cephalothin) Low Low Poor 2 nd (e.g., cefamandole) Higher Higher Poor 3 rd (e.g. cefotaxime) Higher Higher Good 4 th (e.g. cefepime) Highest Highest Good
Possible Problems with Cephalosporins
Chance of increased bleeding with warfarin because of interference with Vitamin K metabolism – cefmetazole, cefoperazone, & cefotetan.
The same three can trigger a disulfiram-like reaction if used with alcohol (Lehne, p. 411).
To avoid the development of resistant populations of bacteria, third and fourth generations should be reserved for serious infections!
3. Carbapenems: (imipenem, meropenem & ertapenem)
Beta-lactam antibiotics with extremely broad spectrum
Gram positive cocci
Gram negative cocci and bacilli
Not absorbed from the GI tract (IV administration)
Cross allergy with penicillins
Suprainfection is a problem
Especially valuable in mixed infections
II. Non-Beta-Lactam Antibiotic Affecting the Bacterial Cell Wall: Vancomycin
A potentially toxic antibiotic used to treat serious infections.
Not a beta-lactam, but interferes with cell wall synthesis.
Can be used in treating gram + infections in penicillin-allergic patients
Synergism with aminoglycosides
Poor penetration into CSF
Oral preparation can be used for bowel infections, particularly Clostridium difficile (a suprainfection). In this use, the drug isn’t absorbed into the bloodstream.
Adverse Effects of Vancomycin
Ototoxicity and nephrotoxicity.
Multiple drug interactions with hyperlipidemic drugs, muscle relaxants, and ototoxic drugs
Rapid infusion causes a severe reaction of flushing, tachycardia, and hypotension which can be fatal (infuse over 60 minutes).
Irritating to the vein, causing thrombophlebitis (use large vein and change IV site often).
III. Bacteriostatic Inhibitors of Protein Synthesis:
Porth, Pathophysi-ology, Concepts of Altered Health States, 7 th ed., 2005, Lippincott, p. 123. Protein Synthesis
Tetracycline, doxycycline, minoclycline and others
Bind to the 30S ribosomal subunit and prevent elongation of the peptide chain.
Broad spectrum but resistance has developed in many bacterial species, limiting their use.
Agents of choice for rickettsial diseases (Rocky Mountain spotted fever) and for Chlamydia .
Used in acne, periodontal disease.
Mainly oral use, rare IV.
Poor CSF penetration
Problems with Tetracyclines
Poor absorption of some: all form insoluble compounds with calcium, iron, magnesium, aluminum and zinc. So don’t give with antacids/laxatives, milk/dairy, iron.
Bind to calcium in developing teeth and form a discolored area. So don’t give to pregnant women (will only affect baby teeth) or children below 8 years.
Suprainfection with bowel organisms or Candida
Tetracycline-Stained Teeth http://www.wisconsinreconstructiveimplantdentist.com/images/tetracycline4.jpg The patient was treated with tetracycline while the permanent teeth were developing. Dark staining is present in the parts of the teeth that were forming during treatment.
Erythromycin, clarithromycin, azithromycin.
Inhibit 50 S ribosomal subunit.
Erythromycin is commonly used for gram-positive and some gram-negative bacteria.
Drug of choice for Legionella and Chlamydia
An alternative to penicillin in allergic patients.
Poor CSF penetration
Some forms of erythromycin are corrosive to the GI tract and can cause erosive esophagitis. Other formulations have fewer problems and can be taken with food.
IV erythromycin is corrosive to veins and must be diluted in large quantities of fluid and infused slowly into a large vein.
Hepatotoxicity is a concern.
Erythromycin and clarithromycin are strong inhibitors of cytochrome P450 – administer with caution in patients taking drugs metabolized by these enzymes.
3 . Clindamycin
Inhibits 50S ribosomal subunit: shouldn’t be used with a macrolide.
Good for anaerobes and gram-positive aerobes.
Poor penetration of the brain.
Suprainfection with Clostridium difficile .
IV infusion must be SLOW .
Reserve for serious infections
IV. Bacteriocidal Antibiotics that Alter Protein Synthesis: Aminoglycosides
Tobramycin, gentamycin, amakacin and others
Bind to the 30S ribosomal subunit. They are bacteriocidal because they promote the formation of abnormal proteins whose abnormal functioning kills the cell.
No activity against anaerobes.
Good coverage of gram-negative bacteria including Pseudomonas, Klebsiella, and Serratia .
Charged drugs that are not absorbed— used IV.
Can be used topically to sterilize the gut or on the skin (neomycin) or eye.
Ototoxic and nephrotoxic— adjust for renal impairment
For many patients, once daily infusion is as good as divided doses because it produces very high levels that kill bacteria even after the blood level declines.
Low levels in between the daily dose allows washout from body cells in between doses and lowers the risk of toxicity.
Aminoglycoside: Gentamicin Levels Lehne, RA, Pharmacology for Nursing Care, 5 th ed., 2004, Saunders, p. 922
V. Sulfamethoxazole-trimethroprim (Bactrim)
Bactrim blocks bacterial enzymes that are important for the synthesis of the building blocks of DNA, RNA and proteins.
This is a combination of a sulfa drug (sulfamethoxazole) and an inhibitor of a bacterial enzyme called dihydrofolate reductase (trimethoprim).
The two drugs block different steps in the pathway and therefore are synergistic in their activity. Broad spectrum, including many gram negative and gram positive
Used extensively for UTI and for Pneumocystis carinii pneumonia of AIDS
Lehne, RA, Pharmacology for Nursing Care, 5 th ed., 2004, Saunders, p. 927
Hypersensitivity reactions are most concerning
Rash, including rare Stevens-Johnson syndrome.
The trimethoprim component can cause blood dyscrasias.
Crystalluria (kidney/bladder stones) – patient should remain well-hydrated.
CNS effects – headache, psychosis
Ciprofloxacin, levofloxacin, oxofloxacin and others
Inhibit an enzyme (DNA gyrase) important in bacterial DNA replication
Active against aerobic organisms, most gram negative and some gram positive.
Shouldn’t be taken with aluminum, iron, calcium, iron or zinc supplements.
Can increase plasma levels of theophylline and warfarin.
Adverse Effects of Fluoroquinones
Can cause irreversible joint disease in children <18.
Rarely, tendon rupture in adults.
Candida suprainfections, especially of the oropharynx.
Infrequent but serious CNS effects.
Vyas H and Krishnaswamy G. N Engl J Med 2007;357:2067 An 81-year-old woman with rheumatoid arthritis, Sjogren's syndrome, and hypertension presented with swelling and pain in the area of the left heel, which had developed suddenly a week after a short course of levofloxacin for acute bronchitis
VII. Metronidazole (Flagyl)
Targets anaerobic organisms, including parasites and bacteria
C. difficile, Bacteroides, Entameba histolytica
A prodrug that is activated only in anaerobic cells.
Darkening of the urine
CNS adverse effects
Caution during pregnancy, avoid during lactation
Cytochrome P450 interactions
VIII. Antibiotics for Tuberculosis Target Mycobacteria
TB is always treated with 2 or more drugs to avoid the emergence of resistant strains.
Treatment is prolonged (6-10 months) because the bacteria grow very slowly. Compliance is a huge issue.
The sensitivity of the bacterium to the proposed regimen must be determined ahead of time.
Treatment is evaluated for efficacy.
Patients with HIV infection are very susceptible to TB and other mycobacteria and are treated differently than other patients.
A reactive skin test in a previously negative patient indicates a new exposure. The patient should be treated.
TB infection can be followed by a latent phase where the disease is inactive. Persons in the latent phase should be treated to avoid the re-emergence of active disease.
Patients with newly reactive skin tests & patients in the latent phase can be treated with monotherapy, frequently isoniazid but sometimes rifampin.
VIII. Tuberculosis Drug: Isoniazid
Inhibits the formation of the mycobacterial cell wall – highly specific for TB.
Pharmacokinetics- distributed to all body tissues and fluids, crosses blood-brain barrier to achieve therapeutic levels.
Used alone to treat latent TB and with at least one other drug for active TB.
Risk of peripheral neuropathy is decreased by giving with pyridoxine (vitamin B 6 ).
Hepatotoxic, especially in older people. Contraindicated for people with pre-existing liver disease. Monitor liver enzymes.
Alcohol consumption increases the risk of hepatotoxicity.
Increases levels of phenytoin – draw phenytoin levels and decrease the dose if necessary.
VIII. Tuberculosis Drug: Rifampin
Used with at least one other drug for active TB
Distributed to the CSF.
Hepatotoxic and increases the hepatotoxicity of isoniazid and pyrazinamide.
Induces cytochrome P450 enzymes – decreases levels of birth control pills, seizures meds, and others.
Turns body fluids red! (Warn the patient)
VIII. Tuberculosis Drug: Pyrazinamide
Often combined with isoniazid, rifampin, and ethambutol.
Hepatotoxic – follow liver enzymes.
VIII. Tuberculosis Drug: Ethambutol
Distributed widely but doesn’t penetrate the brain
Can cause optic neuritis. Need eye exam by ophthalmologist
Antifungals: Amphotericin B
Nickname – Amphoterrible!
Binds to sterols in the fungal membrane and increases permeability – the fungal cell swells and bursts
Toxic to mammalian cells (human) because of the cholesterol in cell membranes.
Used for systemic fungal infections.
Infusion reactions – phlebitis and systemic symptoms (fever, chills, rigors, nausea and headache).
Nephrotoxic – use with caution with other nephrotoxic drugs (aminoglycosides)
Dose reduction when used with flucytosine – a highly synergistic combination.
Inhibits the synthesis of a sterol component of the fungal cell membrane.
Oral alternative to amphotericin B for systemic fungal infections.
Can be used topically for fungal skin infections.
Strong inhibitor of cytochrome P450 enzymes – use with extreme caution in hepatically metabolized drugs – Table 91-3 Lehne.
Rare hepatic necrosis.
Active against all herpes viruses: herpes simplex, herpes zoster, and cytomegalovirus (CMV)— although most strains of CMV are resistant.
Suppresses synthesis of viral DNA – but must be activated by a viral enzyme, thymidine kinase.
Resistance is commonly due to thymidine kinase deficiency.
Topical, oral, and IV.
Nephrotoxic – maintain high hydration to dilute drug in renal tubules.
Valacyclovir (Valtrex) is a prodrug of acyclovir – but it is more bioavailable.
NOTE – immunization for chicken pox and shingles (both are manifestations of herpes zoster) is available
Active against all herpes viruses, including CMV – but has serious toxicities.
Reserved for treatment of CMV in immunocompromised patients, including HIV-infected and transplant patients.
Poor oral bioavailability is slightly increased by food.
Excreted unchanged in the urine – decrease dose for patients with renal impairment.
Granulocytopenia and thrombocytopenia are prominent adverse effects – monitor blood counts.
Teratogenic and embryotoxic – birth control should be in place.
Antivirals: Drugs for Influenza
First line of defense is immunization ! (practically everyone should be immunized).
Traditional injected vaccine is approved for everyone
Live inhaled vaccine (Flu-Mist) is approved for people 2-49 years old
The seasonal flu vaccine for this season (2010-2011) will include H1N1.
Drugs for Influenza
Amantadine and rimantadine – work as prophylaxis during epidemics and as treatment.
Only effective against influenza A
Oseltamivir (Tamiflu) is an oral drug that can be used as prophylaxis or to shorten the duration of flu
Zanamivir (Relenza) is inhaled but works similarly to oseltamivir – not approved for prophylaxis.
Both must be taken very soon after the first flu symptoms appear to be effective in shortening the duration of the flu.
Amphotericin B is an:
Human Immunodeficiency Virus Photo: Hardin MD/University of Iowa and CDC http://www.lib.uiowa.edu/HARDIN/MD/cdc/948.html
HIV drugs have many overlapping toxicities and many interactions with each other and other drugs.
When administering these drugs – LOOK THEM UP!
Don’t depend on physicians or other nurses to prevent your mistakes!
Of particular note!
HIV is always treated with combinations of drugs. The current combinations are collectively referred to as ART ( A nti- R etroviral T herapy), ARV ( A nti- R etro v irals) or HAART (highly active antiretroviral therapy). To avoid development of viral resistance, it is very important that patients receiving HAART take their medications reliably and on time.
Skipping doses can have devastating results, both for the individual patient and for society if the patient infects someone else with a resistant strain of virus.
Because the medications have a variety of side effects that can be very bothersome, it may be tempting to patients to discontinue treatment when they feel better.
A combination of three or four drugs that target different aspects of the viral life-cycle.
Can reduce viral load so that it is undetectable in blood, but does not cure HIV infection.
Controversy: when to begin ART, ARV or HAART? Currently wait until CD4+ cells drop below 500 cells/mm 3 but some recommend earlier treatment.
HIV Drugs Lehne, 2007, Pharmacology for Nursing Care, 6 th ed., Elsevier, p. 1067
Pregnant HIV-Infected Patients
Pregnant patients who would otherwise receive treatment should receive it while pregnant, although particular drugs might have to be avoided.
Treatment of the patient’s infection will reduce viremia and thereby reduce the risk of transmission to the fetus.
In women who have not received therapy during pregnancy, RT inhibitors can be given during labor, and to both mother and child after delivery. This strategy reduces maternal to fetal transmission dramatically.
PMTCT programs = Prevention of Mother to Child Transmission.
Work at same stage in the replication cycle but in different ways
I. Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
Inhibit viral enzyme, reverse transcriptase, that converts viral RNA into DNA, by terminating the growing DNA strand. This activity can also inhibit human DNA polymerases so these drugs are toxic to dividing cells.
Zidovudine (AZT), ddi, ddc, 3tc, d4t and others.
Can cause mitochondrial toxicity in liver (hepatomegaly and fatty liver) and elsewhere leading to lactic acidosis.
Bone marrow depression, anemia, neutropenia.
All have GI toxicity – stomatitis, nausea, diarrhea, etc.
All are metabolized by cytochrome P450 enzymes. Concurrent administration with inducers or inhibitors of cytochrome P450 can affect half-lives and drug levels (recall that the non-nucleoside RT inhibitors have varying effects on the cytochrome P450 enzymes). See table 93-6 in Lehne.
St. John’s wort and garlic preparations should be avoided.
Most have GI side effects similar to the nucleoside and non-nucleoside RT inhibitors.
IV. Entry Inhibitors
Inhibits entry of HIV into CD4 positive cells.
Lehne, RA, Pharmacology for Nursing Care, 5 th ed., 2004, Saunders, p. 986 Fusion Inhibitor Attachment Inhibitor
Fusion Inhibitor (Enfuvirtide (Fuzeon)
The drug binds to gp41, a viral envelope protein.
Resistance occurs when the viral gene encoding gp41 mutates to alter its shape so the drug can’t bind.
Fusion Inhibitor: Enfuvirtide
The only fusion inhibitor currently on the market.
Must be given by subcutaneous injection twice a day.
Reserved for patients who have failed more standard HAART with RT inhibitors and protease inhibitors.
Injection-site reactions (pain & tenderness) are common and may persistent for days.
Risk of bacterial pneumonia is increased.
Hard to manufacture – supply is limited.
Blocks the CCR5 receptor so HIV does not attach to the CD4 cell
A.k.a. CCR5 antagonist
Maraviroc (Selzentry™) only approved CCR5 antagonist
Need to have tropism testing (only works for CCR5 receptor not other receptor types)
IV. Attachment Inhibitors: Maraviroc
Dosage is adjusted depending on whether it is combined with a CYP 450 inducer or inhibitor
Use with caution in people with cardiovascular disease
V. Integrase Inhibitors
A critical step in the HIV life cycle is the integration of viral genetic information into the host cell DNA which then turns into a viral factory.
The enzyme integrase aids in this task.
Integrase inhibitors block this enzyme.
There is one opportunity for this to be effective. If it fails, there is no other opportunity since the genetic information from the virus is already incorporated
Lehne, RA, Pharmacology for Nursing Care, 5 th ed., 2004, Saunders, p. 986 Integrase Inhibitor
V. Integrase Inhibitors: Raltegravir
Currently one approved drug –raltegravir (Isentress)
Given twice daily (a compliance issue)
Diarrhea, nausea, and headache are possible adverse effects.
Eliminated by metabolism – plasma concentrations may be reduced by enzyme inducers, particularly rifampin.
Pregnancy category C
All of the following are classes of HIV medications EXCEPT:
Reverse Transcriptase Inhibitor
Resistance and Adherence
Replication rate of HIV is between 1 and 10 billion virions/day
There is a high probability of introducing base-pair errors by HIV reverse transcriptase
HIV can mutate into a drug-resistant form very quickly
Combining antiretroviral drugs that work at different points in the replication cycle minimizes resistance.
Recommend > 95% adherence to antiretroviral medications to prevent resistance.
Therapy for HIV infection is complicated and drugs have significant toxicity and interactions with other drugs.
Management of HIV-infected patients is best done by health care providers who are very experienced with these drugs and their side effects.
When HIV-infected patients are hospitalized on general medical or surgical floors, nurses must become knowledgeable about the patient’s regimen and how it might interact with other drugs the patient might be given as part of his/her hospital treatment.