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The most widely used drug family is that of the anti-microbial agents, especially the antibiotics. Fully 1/3 of all hospital patients will be taking antibiotics during their stay.

Antibiotics are substances created by microbes that kill bacteria. Many molds & fungi exist by halting the growth of competing organisms, so the first antibiotic came from these organisms.

Bactericidal antibiotics kill the bacteria while Bacteriostatic antibiotics hamper their growth so that the body’s defenses have a chance to kill the bacteria.

Mode of action of antibiotics

·         Cell wall disruption: Antibiotics derived from mold tend to attack the cell wall. Bacteria are classified as plants because they have cell walls. Humans are animals with cell membranes so antibiotics will not kill the host cells as it kills the bacteria. The presence of a cell wall makes the bacteria subject to osmotic disasters once the cell wall is breeched. 

Broad-spectrum antibiotics are classified as gram negative or gram positive antibiotics. A gram negative antibiotic harms bacteria with certain types of cell walls while gram positive antibiotics do their damage with the other type of common bacterial wall. There are a few broad-spectrum antibiotics that work on some from both gram - and gram + families.

·         Inhibition of enzymes needed by the bacteria: There are some enzymes used by bacteria that their hosts [us] don’t need. Sulfa drugs kill by inhibiting these enzymes.

·         Disruption of protein synthesis: Bacteria and human cells use ribosome for protein synthesis. Fortunately for us, their ribosomes are different from ours so we can disrupt theirs without hurting ours. Antibiotics are further classified as lethal disruptors or non-lethal protein disruptors. Drugs that are non-lethal are limited in their use to slow-growing bacteria.

Treating patients with antibiotics

Empiric Treatment: while it would be nice to wait for the cultures & sensitivities [C & S] to come back with a definite pathogen, some infections are too far advanced or are too dangerous to wait for confirmation, so the doctor treats the patient with the broad-spectrum antibiotic most likely to be the causative agent based on the time of year [flu season] or the symptoms or the patient's age or status.  

Sputum Cultures are obtained before the empiric treatment so that specific antibiotics can be started as soon as possible. It is critical that the RCP get sputum samples for C & S before antibiotics are started. 

Gram-staining or Acid-Fast [AFB]: identification of the type of cell wall can be done by the lab within minutes. This will limit the list of broad-spectrum antibiotics the doctor can use. 

C&S: culture and sensitivity determination [Kirby- Bauer disc] is done by growing bacteria on an agar plate that contains disc of antibiotics. The area with the least growth shows the lab tech which antibiotic is most effective against the bacteria. This C & S can show results within 24 hours.  

Prophylactic treatment: There are a few occasions when a patient needs to be started on antibiotics before infection is diagnosed. Pre-treatment prior to surgery or dental work is one example. Pre-Treatment of patients with artificial heart valves or valve damage is necessary prior to dental work.  Preventative antibiotics for some exposures such as for TB, syphilis, gonorrhea or bacterial meningitis is well-known.   

Adverse hazards of all antibiotics

·         Drug-resistant bacteria: Because antibiotics—even broad-spectrum antibiotics work on only some microbes, they will kill off those, leaving the body susceptible to supra-infection with resistant bacteria or fungal infections. Examples of this problem include the repeated vaginal yeast infections that plague so many women while they are on antibiotic therapy. Misuse [over-using or starting & stopping too soon] can render a bacterial strain resistant to a particular antibiotic. Staph A and TB bacilli are two bacteria famous for having drug resistant strains. Antibiotics aren’t mutagenic; rather they make it easier for resistant bacteria to exist as antibiotics kill off the competition. Bacteria can become resistant when they lose their drug receptor sites for antibiotics or once they start to create enzymes that break down antibiotics. Multiple drug resistance can happen when there is conjugation between different bacteria in which DNA is transferred [this transfer can happen between different species]. Gram negative bacteria are famous for this interaction.  

·         Allergies: Because molds are organic material, composed of proteins, they can be irritating to atopic individuals. As much as 10% of the USA population may be allergic to penicillin. Antibiotic allergies can be fatal. Sulfa drugs are also notorious for allergic reactions 

·         Liver damage: Because these chemicals are broken down in the liver, they tend to be toxic to the liver. 

·         Ototoxic:  Many antibiotics are toxic to the auditor nerve so are ototoxic and can cause hearing loss. 

·         Gastro-Intestinal:  Because antibiotics kill normal flora in the gut, they tend to cause diarrhea, cramping and abdominal pain. This can be minimized by the ingestion of live cultures in yogurt 

·         Neurotoxin: some antibiotics can cause muscle weakness. Some of the anti-TB antibiotics are known for muscle weakness that persists for months while the patient is on therapy.

 

Treating patients empirically with antibiotics for respiratory tract infections 

Because it takes time to get cultures, frequently the MD starts a patient on a broad spectrum antibiotic based on [1] patient age/ condition or [2] time of year—flu season? [3] risk factors such as IV drug users, underlying disease states.   

Certain antibiotics are used for different patient populations who will be at higher risk for a specific bacterial infection.

·         Community-acquired infections in the healthy person

·         Hospital-acquired infections in the immuno-suppressed patient

o    suspected aspiration of stomach contents: persons who cannot protect their airways

o    VAP [ventilator associated pneumonias]

o    drugs for patients with decreased WBC differ from those given to patients with normal WBC levels

o    burn patients have a list of infections that they can catch

o    newborn babies are at risk for a specific list of bacterial infections

·         Anti-TB drugs: kill mycobacterium. All have serious side effects and if the patient gets no response from one drug, the next one is added-- never DC’d.

o    INH [Isoniazid] will be given for exposure without active disease.

o    Rifampin: will be added if INH doesn’t work  

o    Pyrazinamide: will be added if INH doesn’t work   

o    streptomycin: was the first anti-TB drug discovered in the 1940s will be added if INH doesn’t work  

In cases of drug resistant TB, all drugs will be given.

 

 

Regardless of the drug[s] ordered, patients getting TB antibiotics must take them for 6-9 months. They must be followed by routine liver functions- particularly if the patient is middle-aged or older.  

Inhaled & systemic antibiotics

General statements about families of antibiotics

Look up specific drug for exact indications & hazards

Inhaled antibiotics

Aerosolized Tobramycin (Tobi ®) is a member of the aminoglycoside family of antibiotics. Tobramycin insert 

Indications: to treat or prevent the cystic fibrosis patient from getting a chronic pulmonary infection with Pseudomonas Aeruginosa. Patients with CF have copious secretions that are very thick and hard to expectorate. Needless to say this makes them fall prey to bacterial infections. Because patients with CF have malabsorption problems, most of their meds need to be given by routes other than oral.  

Studies showed that after 6 months of inhaled (Tobi ®), the microbe levels in the secretions were down and the pulmonary functions in these patients closer to normal & they had not developed significant bacterial resistance. Best of all, there were fewer hospitalizations for these patients.

Mode of action: Inhibits protein synthesis of the Pseudomonas A. bacteria.

Dose and frequency:  300mg/unit dose BID [no more than 12 hours apart] for 28 days followed by 28 days off

Side effects/hazards/ cautions:

·         Do not mix Tobi ® with any other drug. In fact, use a separate SVN for tobramycin. 

·         The company recommends the use of a specific pneumatic SVN, the PARI® nebulizer. The greatest advantage of the PARI® nebulizer is that it can be sterilized by boiling, and it can be put into the dishwasher for cleaning-perfect attributes for a home-based SVN. Because this is the only SVN studied with Tobi at this point, it is recommended that this device be used.  

·         Tobi ® could cause reflex bronchospasm due to the osmotic pressures of the drug so you may need to pre-treat with a short-acting Beta II agonist. Get a PRN order. 

·         Even by inhalation, use of this drug could lead to an insignificant increase in bacterial resistance 

·         The RCP should avoid inhaling this drug. Wear a mask while the drug is being nebulized—even if the patient is not in isolation. Aerosolized antibiotics were tried in the 1960s  and were  discarded after only a few years because the families, nursing & respiratory staff got sensitive to the drugs. 

·         Pregnant women should not be allowed in the room while this drug is being aerosolized because of the high chances of fetal defects.

·         If the patient is receiving bronchodilators or Mucolytics, give that SVN first-then follow by CPT or other secretion mobilization, finally followed by inhaled Tobi ®. (Tobramycin insert )

If the CPT precedes the antibiotic, the patient is less likely to cough and expectorate the medication—it is more likely to land on the tissue rather than the huge amounts of thick secretions in the CF’s airways.

 

First SVN with bronchodilator/Mucolytics,

Followed by CPT,

Followed by inhaled antibiotic by SVN

 

·         Because antibiotics are so thick & sticky, you might have to increase the flow rate a bit.

·         Because antibiotics are so thick & sticky, rinse the nebulizer cup with sterile water or sterile saline after a treatment.

·         Use of this drug during periods of dehydration [common problem with CF] or during use of furosemide, a common diuretic, can increase the chances of ototoxic problems.

·         Among the s/s of ototoxicity are tinnitus, nausea & vomiting, and involuntary eye movement [remember, the ear is involved with balance]

·         inhaled Tobramycin can alter the voice

 

Inhaled Antiviral agents

It is difficult to kill a virus because the organism lacks a lot of the traits required for life. Killing bacteria is fairly easy, because bacteria are plants with plant-like structures we can disrupt. A virus, on the other hand, is an obligate cellular parasite because it lacks enough actions to live without a host cell’s chemicals and function. Because it is so simple, killing a virus is difficult. 

Animals and plants have both DNA and RNA, but viruses are so simple, they have only one of these. Drugs that have antiviral action tend to be anti-DNA or anti-RNA virostatic agents.

Inhalable siRNA: Potential as a Therapeutic Agent in the Lungs

Ribavirin (Virazole®) is active against both DNA and RNA viruses. The drug probably inhibits cellular enzymes 

Indications:

This inhaled antiviral agent is indicated for the treatment of Respiratory Syncytial Virus [RSV] pneumonia or bronchiolitis in the child under the age of 2 years of age.

80% of all children younger than 2 years of age will get RSV every winter; if the child is in daycare, the chances rise to 100%. They will get a mild fever, runny nose, cough and wheeze enough to miss 1 or 2 days. Ribavirin is not for them. Ribavirin is indicated for the small child who is sick enough to be hospitalized for 02 & IVs or who gets intubated and ventilated for RSV pneumonia. Babies with underlying cardiopulmonary disorders, immunosuppression or newborns under 6 weeks of age are particularity susceptible to RSV.

Information on RSV infections:

RSV 

Ribavirin is used systemically as a treatment for hepatitis and Lassa fever and is being explored for a lot of other viral illnesses.

Dose:

6 grams/300 ml sterile water Q day X 18 hours for 3 days; may repeat for three more days.

Ribavirin may be given inline with mechanical ventilation but the College of Pediatricians recommends that this be done only in institutions that routinely ventilate babies & toddlers and routinely use Ribavirin. This drug can obstruct ventilator circuits if not handled properly.

Side effects/cautions/hazards

·         Because Ribavirin is virostatic, rather than virocidal, it must be started within 24 hours of symptoms or it will not work. If RSV is suspected, get a nasal wash, place on ice send to lab, start Ribavirin. If the ELISA for RSV is positive, continue the drug, if not, stop treatment.

·         The FDA Ok’d Ribavirin for use only with the SPAG pneumatic aerosol generator--- because the SPAG can get the particles down to close to 1 micron in diameter to reach the respiratory zone where the virus is located.

·         Inhaled Ribavirin, like any other aerosol can cause bronchospasm in patients & caretakers.

·         RSV pneumonia presents with wheezing as an s/s. Relieve distress with Beta II agonist by SVN.

·         Don’t mix other drugs into the SPAG medicine cup.

·         Ribavirin can cause anemia and reticulocytosis [increased RBC]. This is more common with the IV or oral Ribavirin used to treat hepatitis C than with inhaled form, but is still possible. 

·         Inhaled Ribavirin can cause conjunctivitis and rash. It can damage contact lens with prolonged exposure to mist.

·         Ribavirin has been associated with cardiovascular instability & hypotension and arrest.

Because Ribavirin is teratogenic, it is classified as a Category X for use during pregnancy.

·         Per OSHA requirements, pregnant care takers and visitors should not be present in the room while the drug is being aerosolized.

·         A sign should be posted on the patient’s room.

·         Pregnant pharmacists should not draw up this drug.  

Babies and toddlers with RSV are highly contagious & should be in droplet isolation, but because the drug is nebulized for 12-18 hours at a time, exposure to the drug is also a potential problem. OSHA considers 8 hours of exposure prolonged. It may take as long as 8 hours of constant exposure before serum levels of Ribavirin in the blood stream approach therapeutic levels.  

Once it lands on a surface such as 02 aerosol hoses, Ribavirin will stick and can clog hoses & valves. Be ready to change out circuits as needed. Try to avoid keeping 02 analyzers inline. Spot checks to keep the sensors clean. 

Zanamivir [Relenza®]: is given by DPI to minimize the effects of Influenza A & B. It interferes with an enzyme. Zanamivir can decrease the s/s of the flu by 1 day. 

·         Give 2 doses BID for 5 days. This must be administered in the first days of infection.

·         There is a high risk of bronchospasm with asthmatics and persons with COPD

·         Zanamivir is not for prophylaxis and will not lessen the chances of a person being contagious.

·         The best treatment for the flu is still vaccination.

Inhaled antifungal/parasitic/protozoan agents

Systemic antifungal agents

Because internal parasites and fungi are more complex organisms than bacteria, the drugs that kill these organisms are nastier with more adverse side effects than antibiotics. In the USA, fungal & parasitic pulmonary infections are extremely rare. 

Fungal pulmonary infections are most likely to happen to patients who are immunosuppressed by chemotherapy, radiation therapy, or by diseases such as AIDS or leukemia.

Amphotericin: a common systemic anti-fungal agent for pulmonary infections.

Side effects include: Fever and chills; headache; increased or decreased urination; irregular heartbeat; muscle cramps or pain; nausea; pain at the place of injection;  unusual tiredness or weakness;  vomiting  

 

Inhaled anti-parasitic agent

Pentamidine [NebuPent®]: inhaled agent that kills the causative organism of pneumocystis carinii pneumonia (PCP). There is some controversy regarding the exact status of the causative agent. It was once felt to be a protozoan, but now is felt to be a parasite. Pneumocystis jiroveci  

No matter what the name, PCP pneumonia is the most common initial opportunist infection in the adult male and pre-puberty children of both sexes with AIDS. The causative agent of Pneumocystis carinii pneumonia is easily devoured by the macrophages, but in AIDS patients, the macrophages don’t do their job so PCP pneumonia is the result.  

The diagnosis of PCP pneumonia suggests a patient get HIV testing. 

Dosage for treatment: For treatment, the patient gets a daily dose for 14-21 days and for prevention, the patient gets a dose every 2 to 4 weeks.

When the patient is sick with PCP, he gets 600 mg in 6 mL of sterile water Q day

Dosage for prophylaxis: The doses for prevention are based on the patient’s ability to tolerate higher doses.

If he can take 300 mg/ 6ml he can take it Q 4 weeks. If he can’t tolerate it, he gets 30-150 mg./6 ml sterile water Q 2 weeks. The drug is expensive and must not be mixed until just prior to treatment

Side effects

Pentamidine is irritating and can cause bronchospasm and coughing. Because the patient must inhale and exhale completely [VC each breath] the 20-minute treatment is exhausting.

Inhaled via a Respigard II nebulizer that will get the particle size down to less than 2 microns. This is done by the use of baffles between the patient and the nebulizer.

 

 

·         Baffle between the nebulizer and the reservoir will keep medication from entering the room

·         Baffle between the nebulizer and the mouthpiece will reduce the particle size to less than 2 microns

·         Bacterial filter in the expiratory limb will keep drugs and bacteria from entering the room

 

For this nebulizer to work optimally it must be powered off of 50 psig [not portable air compressor created for SVN].  The flow meter needs to stay at 5 -7 LPM.  

Other measures used if the patient cannot tolerate the drug: [1] to decrease the dose from 150 mg down to 30 mg. [2] pre-treat with Beta II agonist [3] decrease the flow rate to 4-5 LPM.

Inhaled pentamidine is used less often because there are other oral drugs that work, but if someone fails to respond to the other drugs or gets sensitive or has too many adverse side effects, this is a fall back.

Links

Pentamidine Administration

Tobi Administration

Nebulized Amphotericin B

Nebulized Colistin

Aerosolized amikacin for treatment of pulmonary Mycobacterium aviuminfections

Inhalable siRNA: Potential as a Therapeutic Agent in the Lungs

Aerosolized Antibiotics

Resistant Organisms in the ICU