7.2 Antibiotic, Antiviral/Anti–COVID-19, and Antifungal Drugs

Penicillins

Penicillin, which was discovered in 1928 by Alexander Fleming, was the first antibiotic (American Chemical Society, n.d.). Since then, different drugs within the penicillin family have been developed, including nafcillin, piperacillin, and the aminopenicillins amoxicillin and ampicillin. These agents are used for a variety of infections, including streptococcal pharyngitis (strep throat), acute otitis media, and endocarditis.

Penicillins are part of the family of beta-lactam antibiotics because they include a beta-lactam ring in their chemical structure. The beta-lactam ring is critical for the antibiotic actions of penicillins. Penicillin-binding protein is a bacterial enzyme that is necessary to form the cross-links in the bacterial cell wall that provide structural integrity. When a penicillin is administered, the beta-lactam ring of penicillin will bind to the penicillin-binding protein and inhibit it. This inhibition causes fewer cross-links to form, thereby producing holes in the bacterial cell wall, leakage of internal contents, and cellular death of the bacteria.

Beta-Lactamase Inhibitors

One way that bacteria become resistant to antibiotics, such as penicillins, is by producing enzymes that can neutralize the drug. Beta-lactamase is one such enzyme; it is produced in resistant bacteria to cleave the beta-lactam ring found in drugs like penicillin to render it ineffective. Beta-lactamase inhibitors such as sulbactam, clavulanic acid, and tazobactam were produced to be administered with certain penicillins to help them retain and expand their activity to treat even more types of bacteria, such as anerobic organisms (e.g., Peptostreptococcus sp.). The most common combinations include amoxicillin plus clavulanic acid (Augmentin), ampicillin plus sulbactam (Unasyn), and piperacillin plus tazobactam (Zosyn).

Cephalosporins

Cephalosporins are another group of beta-lactam antibiotics and share the same mechanism of action as penicillin. The major differences between cephalosporins and penicillins are the various bacteria they have activity against and, thus, the types of infections they are best suited to treat.

Cephalosporins are divided into several different generations based on their spectrum of activity. First-generation cephalosporins include cephalexin and cefazolin; these are used for a variety of conditions such as uncomplicated urinary tract infections, upper respiratory tract infections, and prevention of infection during surgery. Second-generation cephalosporins, such as cefoxitin and cefprozil, are used for similar conditions, including otitis media, pneumonia, and urinary tract infections. Third-generation cephalosporins include ceftriaxone and cefotaxime. These agents have increased gram-negative bacterial coverage and are useful in the hospital setting for a variety of more serious infections, such as meningitis, pneumonia, and neonatal sepsis. The only fourth-generation cephalosporin currently available is cefepime. Cefepime has broad antimicrobial coverage, including the difficult-to-treat gram-negative organism Pseudomonas aeruginosa. Finally, the fifth-generation cephalosporin ceftaroline is relatively new and has the unique aspect of being the only cephalosporin to have activity against methicillin-resistant Staphylococcus aureus (MRSA), which is associated with significant morbidity and mortality.

Macrolides

Macrolide antibiotics include the agents azithromycin, clarithromycin, and erythromycin. These agents work by inhibiting protein production by the bacterial ribosomes. Macrolides and other protein synthesis inhibitors do not directly kill bacterial cells, but they sufficiently suppress their reproduction enough to allow the client’s immune system to eliminate the bacteria. Macrolides treat infections caused by atypical bacteria that do not fall into the gram-positive or gram-negative categorization, including Mycoplasma pneumoniae, Legionella pneumophila, and Chlamydia pneumoniae. Therefore, macrolides are useful for treating a variety of respiratory conditions, such as pneumonia and Legionnaires’ disease, as well as chlamydia, a sexually transmitted infection (STI).

Macrolides inhibit the liver enzyme cytochrome P450 3A4 (CYP3A4), which is responsible for metabolizing many medications. Medications that use the CYP enzyme system for metabolism will not undergo metabolism at the rate expected, leading to increased serum drug levels. This can result in adverse reactions and toxicity. Some examples of drugs that would be affected include amlodipine, nifedipine, diltiazem, verapamil, lovastatin, simvastatin, carbamazepine, buspirone, midazolam, fluoxetine, sertraline, fluvoxamine, and dextromethorphan. (This is not an exhaustive list.)

Glycopeptides

The glycopeptide class of drugs includes vancomycin, a common antibiotic used in the hospital setting for treating infections caused by gram-positive bacteria, including MRSA. Vancomycin works by disrupting the integrity of the bacterial cell wall, leading to cellular death. Interestingly, oral vancomycin has good activity against Clostridioides difficile, which is an opportunistic pathogen that can cause colitis and severe diarrhea after clients receive antibiotics that disrupt the gut’s normal bacterial flora. However, it is completely ineffective against bloodstream pathogens. Vancomycin is entirely renally eliminated and must be monitored by checking renal function and serum blood levels of the drug to ensure proper dosing.

Oxazolidinones

Oxazolidinones include the medication linezolid, which is commonly used to treat gram-positive infections that are highly resistant to agents such as vancomycin. One such infection is vancomycin-resistant Staphylococcus aureus (VRSA), which is difficult to treat. Oxazolidinones work by inhibiting bacterial protein synthesis to suppress further growth and multiplication of the bacteria.

Lincosamides

The lincosamide category is primarily represented by the drug clindamycin, a protein synthesis inhibitor. Clindamycin possesses strong gram-positive coverage (including against MRSA) and is also able to treat anaerobic bacterial infections. This allows clindamycin to be used in a variety of conditions, such as skin infections, animal bites, and topically as a treatment for acne.

Tetracyclines

The tetracyclines include the medications tetracycline, doxycycline, and minocycline. These work by inhibiting bacterial protein synthesis, which suppresses their growth. They possess good coverage against a wide variety of bacteria, making them ideal agents for treating conditions such as acne, Lyme disease, and anthrax.

Aminoglycosides

The aminoglycosides, including gentamicin, tobramycin, and amikacin, are used commonly in the hospital setting for their broad-spectrum gram-negative activity, including against infections caused by Pseudomonas aeruginosa. The aminoglycosides work by inhibiting bacterial protein synthesis. They are entirely renally eliminated, and renal function must be monitored along with serial serum drug levels to ensure that aminoglycosides do not accumulate in the body.

Fluoroquinolones

The fluoroquinolones include drugs such as ofloxacin, levofloxacin, ciprofloxacin, and moxifloxacin. These are commonly used to treat a variety of respiratory and urinary tract infections due to their excellent coverage of gram-negative, gram-positive, and atypical bacteria. Fluoroquinolones work by inhibiting the bacterial enzyme DNA gyrase. This enzyme is responsible for the winding and unwinding of bacterial DNA. Inhibition of this enzyme leads to increased DNA strand breakage, leading to eventual programmed cell death (apoptosis).

Sulfonamides

The sulfonamide category of antibiotics includes the combination product of sulfamethoxazole and trimethoprim (Bactrim). This combination has a broad spectrum of coverage, making it effective for treating urinary tract infections, infectious diarrhea, and skin infections. Sulfamethoxazole and trimethoprim work at different steps along the folic acid pathway necessary for the bacterial cell to produce nucleotides and, subsequently, DNA, RNA, and proteins; the drug combination’s interference thus leads to cell death.

Nitroimidazoles

The nitroimidazoles include the drugs metronidazole and tinidazole. These agents are unique in the antibacterial category because they have good activity against anaerobic bacteria and protozoa, making this class useful for treating a number of STIs and vaginal infections. Nitroimidazoles work by entering the bacterial cell and disrupting the cell’s DNA structure, leading to eventual cell death.

Table 7.1 lists common antibiotic drugs and typical routes and dosing for adult and pediatric clients.

Adverse Effects and Contraindications

Most oral antibiotics can cause gastrointestinal discomfort, including nausea, vomiting, and diarrhea. A contraindication to any antibacterial is known hypersensitivity.

Allergic reactions, including anaphylaxis, are possible with penicillins. If a client has a severe allergy to any penicillin, then they should not receive any other drug in the penicillin class because they may experience a cross-sensitivity.

Most cephalosporins, except for ceftriaxone, must be renally dose adjusted to avoid adverse effects in clients with renal insufficiency. For many years there was concern that clients with a penicillin allergy could not receive cephalosporins due to risk for cross-reactivity and anaphylaxis. More recent data have shown that this concern is unfounded and that the largest risk is for clients with true anaphylactic reactions to penicillins receiving a first-generation cephalosporin. Later generations of cephalosporins carry a much lower risk and are safe to administer to clients with a history of penicillin allergy.

Macrolides are known to cause gastrointestinal discomfort because they activate motilin receptors in the intestines, which increases peristalsis, cramping, and diarrhea. Macrolides are also capable of inhibiting potassium efflux out of myocardial cells, leading to prolongation of the heart rate–corrected QT interval (QTc) on an electrocardiogram (ECG/EKG) and increasing the client’s risk for developing torsades de pointes, a potentially fatal ventricular dysrhythmia.

Vancomycin is known to cause a severe flushing reaction when given too quickly intravenously, known as vancomycin flushing syndrome. Vancomycin flushing syndrome can be mistaken for an allergic reaction, but all that is necessary to manage it is to slow the infusion of vancomycin and infuse it over at least 60 minutes. Elevated vancomycin levels are associated with risk for renal injury and hearing damage (ototoxicity). Older adults and those who are critically ill are especially at risk, so close monitoring of renal function and vancomycin blood levels is critical for successful use of the drug.

Unique adverse effects seen with tetracyclines include photosensitivity, skin discoloration, and risk for skeletal growth stunting and tooth discoloration. These last two effects occur because of the tetracyclines’ ability to bind to calcium in developing bones and teeth. Recommendations to help prevent these effects include avoiding prolonged therapy (more than 21 days) in children who still have their baby teeth and avoiding use in pregnant clients during the second and third trimesters. Oral tetracyclines should not be taken with multivitamins or calcium-containing products. When taken together, tetracyclines will bind to metal ions such as iron and calcium, and the drug will not be absorbed; instead, it will be eliminated in the feces, leading to therapeutic failure.

Fluoroquinolones have a variety of safety issues, making screening for contraindications particularly important. In older adults and in clients with poor kidney function, fluoroquinolones are known to induce neuropsychiatric issues, including hallucinations and psychosis. Fluoroquinolones also increase the risk for tendonitis and tendon rupture. Fluoroquinolones can increase the QTc interval on ECG, which should be monitored for clients taking multiple QTc-prolonging medications and for those with congenital prolonged QTc to reduce risk for torsades de pointes. Fluoroquinolones should not be taken orally with multivitamins or calcium-containing products because this will cause the drug to bind to the metal and not be absorbed.

Table 7.2 is a drug prototype table for antibiotics featuring amoxicillin. It lists drug class, mechanism of action, adult and pediatric dosage, indications, therapeutic effects, drug and food interactions, adverse effects, and contraindications.

Nursing Implications

The nurse should do the following for clients who are taking antibiotics:

• Monitor for signs and symptoms of anaphylaxis (e.g., shortness of breath, difficulty breathing, difficulty swallowing).
• Advise the client to take the entire prescribed course of the medication to ensure adequate treatment and to reduce the development of antibiotic drug resistance.
• Instruct the client to maintain adequate hydration; monitor kidney function for renally eliminated medications, such as penicillins, most cephalosporins, vancomycin, aminoglycosides, and particularly fluoroquinolones.
• For clients taking macrolides, always review their medication list for medications metabolized by CYP3A4.
• Monitor for thrombocytopenia, leukopenia, and anemia in clients receiving linezolid. Monitor complete blood count (CBC) periodically. Notify prescriber if blood counts drop.
• If client is taking any medication that can increase serotonin levels (SSRIs, SNRIs, or MAOIs), the nurse should observe for signs of serotonin syndrome, including hyperthermia, headache, confusion, agitation, increased blood pressure, tachycardia, tremor, ataxia, muscle rigidity, and seizures.
• Ensure that any ordered samples for serum levels of agents such as vancomycin and aminoglycosides are obtained at the intended time so that accurate dosage adjustments can be made. Timing may include peak levels drawn after a dose of the antibiotic has been given or trough levels drawn immediately before a dose.
• Monitor for severe or bloody diarrhea and, if ordered, obtain a sample to check for C. difficile.
• Provide client teaching regarding the drug and when to call the health care provider. See below for client teaching guidelines.

Hepatitis Antivirals

Hepatitis viruses are clinically important because they can cause inflammation and damage to the liver. The three main types are hepatitis A virus (HAV), hepatitis B virus (HBV), and hepatitis C virus (HCV). HAV infection is usually self-limited, with many individuals being able to rid themselves of it without any intervention. HBV and HCV infections are of more clinical concern because without intervention, many clients will develop chronic infection, which can lead to cirrhosis, liver failure, and risk for liver cancer. HAV is spread via the fecal–oral route, and HBV and HCV are usually spread through parenteral transmission (such as by sharing contaminated needles) and during sexual intercourse. Vaccines can prevent HAV and HBV infections.

Medications to treat chronic HBV infection are not always curative and are used with the goal of preventing complications such as cirrhosis and liver cancer. HBV infection is typically managed with nucleoside/nucleotide antivirals, which include entecavir, tenofovir, lamivudine, adefovir, and telbivudine. These drugs work against viral DNA polymerase, an enzyme critical for DNA production and viral replication. They are incorporated into the viral DNA and function as “chain terminators,” meaning that no other nucleotides may be added onto them in the chain of DNA, and DNA production is thereby halted. Another treatment option is interferon (interferon alfa); however, due to toxicity, this medication is considered a last resort when all else fails.

HCV infection previously was a chronic disease with no definitive cure and consisted of treatment with parenteral medications with poor tolerability (e.g., interferons). This condition has radically changed, and now many clients with HCV can achieve virologic cure (no presence of the virus in the body) with 12–24 weeks of oral drug therapy using a direct-acting antiviral (DAA) agent such as sofosbuvir. The DAAs can work on a variety of steps in the HCV life cycle to prevent replication or transmission of active virus. Nurses should stress to clients that they must take the entire course of their DAA regimen because resistance can develop if the virus is not completely suppressed. More resistant cases may require treatment with the injectable drug ribavirin, the action of which is not currently understood.

Herpes Antivirals

Two main types of herpes viruses are responsible for causing clinically significant disease. Herpes simplex virus (HSV)-1 is usually responsible for causing lesions (e.g., cold sores) on the mouth, face, and skin. HSV-2 is usually responsible for infections in the genitals and rectum. No curative therapy for HSV-1 or HSV-2 currently exists, but medication is useful to reduce the duration and severity of symptoms a client experiences and to help prevent spread of the virus to other individuals. Agents used to treat herpes viruses include acyclovir and its oral prodrug, valacyclovir, as well as famciclovir. Ganciclovir, valganciclovir, and cidofovir also have activity against herpes viruses, but due to multiple adverse effects, they are reserved for cases of resistance to the first-line agents. These agents work by inhibiting the formation of new viral DNA by acting as chain terminators.

Clients with herpes virus infections may take these medications either when symptoms occur (episodic therapy) or every day for chronic suppression. Chronic suppression is linked to lower incidence of transmission of the virus to uninfected individuals and is useful for clients who have multiple outbreaks each year. Clients using the episodic method must be instructed to begin taking their therapy within 24 hours of symptom onset for the medication to be effective. They should also be informed that viral shedding can occur even without an active lesion, which may increase transmission risk.

Influenza Antivirals

Influenza refers to a diverse set of viruses known to cause upper respiratory tract illnesses, most commonly in the winter months. Annual vaccination will not prevent all infections but may help reduce the symptoms that individuals experience, and it is critical for protecting people most at risk for complications, such as older adults and immunocompromised individuals. However, vaccines are able to protect against only four strains each year with the current quadrivalent vaccines, which protect against two strains of influenza A and two of influenza B. This means that many people still go on to develop influenza infections that require treatment with medications.

The primary class of drugs used to treat influenza infection includes the neuraminidase inhibitors oseltamivir, zanamivir, and peramivir. Neuraminidase inhibitors work by inhibiting the enzyme neuraminidase, which is used to cleave mature copies of the virus from an infected cell to allow it to go infect other cells. Inhibiting this enzyme prohibits the virus from infecting host cells. If the client has had flulike symptoms for more than 48 hours, neuraminidase inhibitors should not be used due to lack of efficacy.

Oseltamivir is considered the first-line option for treatment of influenza and is given orally over 5 days. Zanamivir is an inhaled neuraminidase inhibitor that can be used as an alternative to oral oseltamivir. Peramivir is the only intravenous neuraminidase inhibitor and should be reserved for clients who cannot take oral or inhaled medications.

Table 7.3 lists common antivirals and typical routes and dosing for adult and pediatric clients.

Adverse Effects and Contraindications

Antiviral agents are known to cause gastrointestinal discomfort, including nausea, vomiting, and diarrhea. A contraindication to any antiviral drug is known hypersensitivity.

The nucleoside/nucleotide analogs used to treat HBV infection are considered safer than interferon products, but individual agents may be linked to serious complications such as entecavir-induced lactic acidosis and adefovir-induced nephrotoxicity.

Side effects of herpes antivirals are mild but can include blood cell production suppression, malaise, and risk for renal injury.

Zanamivir is given via inhalation and should not be used in clients with a history of asthma or chronic obstructive pulmonary disease due to risk for bronchospasm (tightening of the airways).

Table 7.4 is a drug prototype table for antivirals featuring acyclovir. It lists drug class, mechanism of action, adult and pediatric dosage, indications, therapeutic effects, drug and food interactions, adverse effects, and contraindications.

Nursing Implications

The nurse should do the following for clients who are taking antivirals:

• Monitor for signs and symptoms of anaphylaxis (e.g., shortness of breath, difficulty breathing, difficulty swallowing).
• Advise the client to take the entire prescribed course of the medication to ensure adequate treatment and to reduce the development of drug resistance.
• Instruct the client to maintain adequate hydration; monitor kidney function for renally eliminated antivirals such as acyclovir and valacyclovir.
• Monitor the client’s complete blood count to check for bone marrow suppression.
• Monitor for mental status changes in clients receiving intravenous antivirals who have poor renal function.
• For clients using antiviral medication episodically, teach them to begin taking it as soon as possible after symptom onset.
• Use appropriate personal protective equipment (e.g., mask and gloves) when clients are diagnosed with influenza to prevent infection spread.
• Check a pregnancy test in clients capable of pregnancy prior to initiating antiviral therapy.
• Provide client teaching regarding the drug and when to call the health care provider. See below for client teaching guidelines.

Nirmatrelvir

Nirmatrelvir is an oral antiviral medication that works by inhibiting the protease enzyme that is necessary to develop mature proteins. Because these proteins are prevented from being made, new mature virus copies cannot be made. Nirmatrelvir is combined with ritonavir, which is used as a strong CYP3A4 inhibitor to boost levels of nirmatrelvir and reduce dosing frequency. Because ritonavir is combined with nirmatrelvir, the nurse must review a client’s medication profile to avoid any significant CYP3A4 interactions. Nirmatrelvir should be taken as soon as possible once symptoms occur because it loses efficacy and is not recommended after 5 days of symptom onset.

Remdesivir

Remdesivir works by inhibiting viral RNA polymerase, causing inhibition of viral protein synthesis and reproduction. Remdesivir is an intravenous product, so it is usually reserved for hospitalized clients or those who cannot receive nirmatrelvir within 7 days of symptom onset.

Molnupiravir

Molnupiravir is an oral product that works by being incorporated into the SARS-CoV-2 RNA; it then induces errors that lead to inhibited viral reproduction. There are some questions about the efficacy of molnupiravir in the treatment of COVID-19, so it is recommended as an alternative if clients cannot receive nirmatrelvir due to drug interactions or impaired renal function. Initiation of molnupiravir should occur within 5 days of symptom onset.

Table 7.5 lists anti–COVID-19 drugs and typical routes and dosing for adult clients.

Adverse Effects and Contraindications

Anti–COVID-19 drugs are known to cause gastrointestinal discomfort, including nausea, vomiting, and diarrhea. A contraindication to any antiviral drug is known hypersensitivity.

Nirmatrelvir is well tolerated, with diarrhea and dysgeusia (impaired sense of taste) being the most frequently reported adverse effects. Adverse effects seen with the use of remdesivir include elevated serum glucose levels and reduced kidney function. Remdesivir should be administered only when emergency airway tools (e.g., laryngoscope) are available in case of a severe allergic reaction.

Table 7.6 is a drug prototype table for anti–COVID-19 drugs featuring nirmatrelvir/ritonavir. It lists drug class, mechanism of action, adult dosage, indications, therapeutic effects, drug and food interactions, adverse effects, and contraindications.

Nursing Implications

The nurse should do the following for clients who are taking anti–COVID-19 drugs:

• Monitor for signs and symptoms of anaphylaxis (e.g., shortness of breath, difficulty breathing, difficulty swallowing).
• Advise the client to take the entire prescribed course of the medication to ensure adequate treatment and to reduce the development of drug resistance.
• Monitor clients taking remdesivir for elevated serum glucose levels and renal function abnormalities.
• Monitor clients receiving nirmatrelvir/ritonavir for hepatic dysfunction.
• Advise the client to begin taking medications as soon as possible after symptom onset to ensure efficacy.
• Review the client’s medication list prior to initiating ritonavir to evaluate for CYP3A4 interactions.
• Provide client teaching regarding the drug and when to call the health care provider. See below for client teaching guidelines.

Polyenes

Polyene antifungal drugs include amphotericin B and nystatin. These are broad-spectrum antifungals that bind to ergosterol in the fungal cell membrane, leading to membrane breakdown and fungal cell death. Amphotericin B is used intravenously to treat severe systemic fungal infections. Nystatin is used orally for infections such as oropharyngeal candidiasis (thrush). Nystatin is not absorbed systemically when taken orally or topically; therefore, it is ineffective for systemic infections.

Azoles

The azole antifungals include two broad classes: imidazoles and triazoles. Examples of imidazoles include clotrimazole, miconazole, and ketoconazole. Examples of triazoles include fluconazole, voriconazole, and posaconazole. These drugs work by inhibiting the enzyme 14-alpha-sterol demethylase. This enzyme is necessary for the fungal cell to produce ergosterol, which is then transferred to the cell membrane. Inhibition of this enzyme leads to arrest of fungal cell growth.

Antimetabolites

Flucytosine is the only antifungal antimetabolite. It works by being converted to 5-fluorouracil (5-FU) in the fungal cell; 5-FU inhibits the enzyme thymidylate synthase as well as DNA, RNA, and protein production in fungal cells, leading to arrested growth.

Echinocandins

The echinocandins include the drugs caspofungin, anidulafungin, and micafungin. These work by inhibiting the enzyme 1,3-beta-glucan synthase, which is responsible for providing structural integrity to the fungal cell wall. Inhibiting this enzyme decreases glucan synthesis and disrupts the cell wall, leading to fungal cell death.

Table 7.7 lists antifungal drugs and typical routes and dosing for adult and pediatric clients.

Adverse Effects and Contraindications

Antifungals are known to cause gastrointestinal discomfort, including nausea, vomiting, and diarrhea. A contraindication to any antifungal drug is known hypersensitivity.

Amphotericin B is very toxic and can cause flulike symptoms during infusion, hypotension, renal toxicity, and electrolyte disturbances. To reduce these adverse effects, several formulations have been developed that incorporate the drug into a lipid membrane. This significantly increases medication costs but is much better in reducing client harm.

Table 7.8 is a drug prototype table for antifungal drugs featuring fluconazole. It lists drug class, mechanism of action, adult dosage, indications, therapeutic effects, drug and food interactions, adverse effects, and contraindications.

Nursing Implications

The nurse should do the following for clients who are taking antifungal drugs:

• Monitor for signs and symptoms of anaphylaxis (e.g., shortness of breath, difficulty breathing, difficulty swallowing).
• Advise the client to take the entire prescribed course of the drug to ensure adequate treatment and to reduce the development of drug resistance.
• Instruct the client to maintain adequate hydration; monitor kidney function with renally eliminated medications.
• Ensure that blood samples for any drug levels ordered are obtained at the intended time in order to allow accurate assessments regarding dosage adjustments.
• Monitor the ECG for prolongation of the QTc interval when clients are taking systemically acting agents.
• Monitor liver function tests to assess for liver injury.
• Check a client’s medication list prior to administering a systemic azole antifungal because oral and intravenous azole antifungals inhibit CYP3A4 and can cause many drug interactions.
• Provide client teaching regarding the drug and when to call the health care provider. See below for client teaching guidelines.