Respiratory DrugsPart 3

XV. Respiratory anti-infective agents

A. Introduction

• 1. Cell wall synthesis inhibitors

• One of the categories of antimicrobials used in the treatment of respiratory infections are the cell wall synthesis inhibitors.

• There are numerous medications in this class including the:

• penicillins

• cephalosporins

• monobactams

• vancomycin

a. penicillins

• The feature which all penicillins have in common is a beta lactam ring, and it is this ring that is necessary for the antibacterial activity of the penicillins.

• These drugs bind to specific proteins in bacteria called penicillin binding proteins (PBP’s) and then prevent cross links from forming between constituents in the bacterial cell wall.

PBP1 and 2B in diagram b

• In addition, they activate enzymes which cause lesions in the cell wall.

• There are 3 major categories of penicillins:

• “regular penicillins” (Penicillin G, Penicillin V)

• Broad spectrum penicillins: amoxicillin, ampicillin, azlocillin, carbenicillin, mezlocillin, piperacillin and ticarcillin

• anti S. aureus penicillins: cloxacillin, dicloxacillin, methicillin, naficillin and oxacillin.

• None of these are effective against MRSA (methicillin resistant S. aureus).

• Over 25% of S. aureus infections are currently classified as MRSA.

• Most staphylocci and many gram negative bacteria form beta lactamases (also known as penicillinases), and this is the major mechanism for the bacterial resistance on penicillins.

• A possible strategy is to combine an inhibitor of beta lactamase (sulbactam, tazobactam, or clavulanate)) with a penicillin.

• Examples of these combination drugs include:

• Augmentin (amoxicillin and clavulanate)

• Unasyn (ampicillin and sulbactam)

• Timentin (ticarcillin and clavulanate)

• Zosyn (piperacillin and tazobactam)

• Adverse effects of the penicillins include allergic reactions, anaphylaxis, nausea and diarrhea.

b. cephalosporins

• Cephalosporins are derivatives of 7-aminocephalosporanic acid.

• There are now 5 generations of cephalosporins, based on their introduction into clinical use.

• In general, the lower generation cephalosporins are more effective against staphylococcal and streptococcal organisms.

• The higher generation cephalosporins are more effective against gram negative organisms (i.e. E. coli species, Klebsiella species, Proteus species).

Examples of cephalosporins include:

• For “general use”: cefazolin (Kefzol, Ancef, IV) and cephalixin (Keflex, oral)

• For use against anerobes, as in prophylaxis of appendicitis: cefotetan (Cefotan, IV)

• For use agains H. influenza: ceftriaxone (Rocephin, IV) and cefuroxime (Ceftin, oral)

• For use against meningitis, where penetration of the blood brain barrier into the central nervous system and cerebrospinal fluid is necessary: cefotaxime (Claforan, IV) and ceftriaxone (Rocephin, IV)

• For use against Pseudomonas species: ceftazidime (Fortaz)

• Their mechanism of action is similar to that of the penicillins, they bind to PBP’s and inhibit cell wall synthesis.

• They are less susceptible to penicillinases due to structural differences that are different from the penicillins.

• Similar to, but less frequent than the penicillins, the cephalosporins have a range of allergic effects from skin rashes to anaphylactic shock.

c. monobactams

• Monobactams are monocyclic beta lactam antibiotics, and aztreonam is the only commercially available agent here.

• It’s mechanism of action is similar to the other beta lactam cell wall synthesis inhibitors.

• Aztreonam is most effective against gram negative aerobes such as Pseudomonas aeruginosa and various enterobacter species.

• It is administered parenterally, and its adverse effects include GI disturbances, headache, and skin rashes.

d. vancomycin

• Vancomycin is active against gram positive, but not gram negative bacteria.

• It is indicated for infections caused by MRSA (pneumonia, as well as skin infections, peritonitis, endocarditis).

• There are numerous resistant bacilli emerging, including vancomycin intermediate Staphylococcus aureus (VISA) and vancomycin resistant Staphylococcus aureus (VRSA).

• Adverse effects include chills, fever ototoxicity and diffuse flushing from rapid intravenous infusion (called red man syndrome).

2. Bacterial protein synthesis inhibitors

• There are numberous medications that are inhibitors of bacterial protein, that have applications in the treatment of respiratory infections including:

• the tetracyclines

• the macrolides and ketolides

• the streptogramins

• linezolid

• the aminoglycosides

• Antimicrobial agents that inhibit bacterial protein synthesis have actions that are centered on the ribosome.

• In humans, as well as other eukaryotes, there are 80S ribosomes consisting of a small (40S) and large (60S) subunit.

• In prokaryotes (bacteria), there are 70S ribosomes consisting of a small (30S) and a large (50S) subunit.

• The S stands for Svedberg unit, which measures the rate of sedimentation (S) in a centrifuge, and NOT the size, therefore the fragments are not additive.

• These drugs are targeted for the 70S bacterial ribosomes, and do not cause major effects on protein synthesis in humans.

a. the tetracyclines

• The tetracyclines are also broad spectrum antibiotics that are the drug of choice in the treatment of infections with Rickettsia, Chlamydia, and Mycoplasma species.

• They are also used in the treatment of cholera, acne, Lyme disease, exacerbations of bronchitis and community acquired pneumonia.

• Members of this family include tetracycline, doxycycline, and minocycline.

• GI effects are fairly common (nausea, diarrhea), as is enhanced skin sensitivity to UV light.

• Tetracyclines are usually contraindicated in pregnancy, they lead to fetal tooth enamel dysplasia and bone growth irregularities.

b. Macrolides

• Macrolide antibiotics contain a large lactone ring attached to various sugars.

• They have good oral bioavailability, although the absorption of some are impeded by food.

• They are active against a few gram positive bacteria ( MSSA), gram negative species (i.e.Hemophillus influenzae), and atypical bacteria (i.e. Legionella, Mycoplasma).

• The prototype of the macrolides is erythromycin. Newer macrolides include azithromycin (Zithromax) and clarithromycin (Biaxin).

•  

c. Streptogramins

• The combination of 2 streptogramins quinupristin and dalfopristin (Synercid) are active against gram positive cocci, including Streptococcus pneumoniae, MSSA, and MRSA.

• It is indicated in the treatment of pneumonias and is administered parenterally.

• This combination of drugs inhibits a cytochrome P450, and therefore increases the plasma concentration of cyclosporine, diazepam, warfarin and terfenadine

d. oxazolidinones

• Linezolid is the first in a new class of antibiotics called oxazolidinones.

• Headache and GI disturbances are the most commonly reported adverse effects associated with linezolid administration.

e. aminoglycosides

• Aminoglycosides inhibit protein synthesis by binding to the smaller subunit of ribosomes.

• This blocks the formation of the initiation complex necessary to begin translation of the mRNA.

• The prototype for aminoglycosides is gentamicin. Other aminoglycosides include tobramycin and amikacin.

• Aminoglycosides are administered either parenterally (IM or IV), or by inhalation as they are very poorly absorbed through the GI tract.

• When administered alone, aminoglycosides are effective against gram negative species (especially Enterobacter species).

• For the treatment of infection from gram + species, aminoglycosides are generally combined with a cell wall synthesis inhibitor (i.e. a penicillin).

3. Sulfonamides

• Today, sulfonamides have limited uses due to bacterial resistance. Sulfamethazole is used in the treatment of UTI’s (urinary tract infections).

• Sulfamethoxazole combined with trimethoprim ( Bactrim, Septra) is used in the treatment of respiratory and urinary tract infections.

• Sulfonamides are inhibitors of tetrahydrofolic acid (often referred to as simply, folic acid).

• Bacteria require folic acid to synthesize proteins and the nucleic acids DNA and RNA.

• Sulfonamide side effects include hypersensitivity reactions and GI disturbances.

• Trimethoprim may cause granulocytopenia, leukopenia or megaloblastic anemia.

4. Fluoroquinolones

• The fluoroquinolones inhibit 2 enzymes involved in bacterial DNA synthesis:

• DNA gyrase, which is necessary to “relax” supercoiled DNA so that replication can occur;

• and topoisomerase IV, which is involved in the separation of already replicated DNA during cell division.

• Fluoroquinolones include ciprofloxacin (Cipro), levofloxacin (Levaquin), lomefloxacin (Maxaquin), norfloxacin (Noroxin) and ofloxacin (Floxin). Newer fluoroquinolones include gemifloxacin (Factive) and moxifloxacin (Avelox).

B. Mycobacterium tuberculosis

• One-third of the world's population is infected with Mycobacterium tuberculosis, according to the World Health Organization (WHO), with an estimated 8 million new cases of tuberculosis and nearly 2 million deaths each year.

• There are approximately 10 million people who are co-infected with Mycobacterium tuberculosis and HIV, with over 90% of these individuals residing in developing nations.

• Worldwide, tuberculosis is the most common opportunistic infection affecting HIV positive individuals, and it is the most common cause of death in patients with AIDS.

• In these HIV patients, TB may be located in the brain, bones, kidneys, larynx, or lymph nodes.

• New guidelines for the treatment of TB were released in 2003, jointly, by the Centers for Diseases Control and Prevention (CDC), the American Thoracic Society (ATS), and the Infectious Diseases Society of America.

• The first-line drugs include:

• isoniazid, INH (INH)

• rifampin, RIF (Rimactane)

• rifabutin, RFB (Mycobutin)

• ethambutol, EMB (Myambutol)

• pyrazinamide, PZA (Tebrazid)

• The recommendation for treatment for drug susceptible tuberculosis is INH, RIF, PZA, and EMB daily for 8 weeks, followed by INH and RIF daily for 18 weeks or INH and RIF twice-weekly for 18 weeks.

• Drug-resistant TB is TB that is resistant to at least one first-line drug.

• The second-line drugs that are used, along with the first-line drugs when drug-resistant TB is present or suspected, include:

• streptomycin, SM (Streptomycin)

• cycloserine, (Seromycin)

• ethionamide, (Trecator-SC)

• Multidrug-resistant TB (MDR TB) is TB that is resistant to at least two of the first-line drugs, isoniazid and rifampicin.

• The treatment of multidrug-resistant TB involves using the most active of the second-line drugs:

• the fluoroquinolones (i.e ciprofloxacin, levofloxacin)

• various injectable aminoglycosides (capreomycin, CM; kanamycin, KM).

• Patients on TB medications should receive a vitamin and mineral supplement in order to prevent depletions.

• The results of a study published in May 2008 in the Journal of Infectious Diseases demonstrated that vitamin and mineral supplements can reduce the risk of recurrence of TB.

• This study was conducted by Eduardo Villamor, MD, of the Harvard School of Public Health in Tanzania, using doses of vitamins A, B-complex, C, E, and selenium or placebo in 887 patients receiving tuberculosis therapy, and followed for a median of 43 months.

• Approximately half of these patients (471) were also HIV-coinfected.

• The study demonstrated that supplementation was associated with reduced rates of TB recurrence.

• In this study, there was a decreased risk of TB recurrence, 45% overall and 63% in HIV-infected patients.

• Vitamin and mineral supplementation is an inexpensive addition to TB therapy to reduce relapses and increase survival.

C. Pneumocystis pneumonia (PCP)

• Pneumocystis carinii has previously been classified as a protozoan, however, other researchers claim it is a fungus, and should be re-named as Pneumocystis jiroveci.

• The pneumocystis microorganism is commonly found in the lungs of healthy individuals and is communicable via air borne transmission.

• It causes disease when immunity is compromised (i.e. individuals with CD4 lymphocyte count less than 200/mm3).

• In the U.S. prior to the 1980s, there were less than one hundred cases of PCP each year.

• In the first decade of the HIV epidemic in the U.S., more than 100,000 cases of PCP were reported.

• It is the most common opportunistic infection in patients with HIV infection in the U.S.

Treatments for PCP:

• 1. inhaled aerosol pentamidine isoethionate (NebuPent)

• This is normally administered for prophylaxis of PCP, but has been used also during acute illness.

• It can also be administered IV or IM, but not orally.

• There are less severe adverse effects associated with inhaled aerosol treatment (bronchospasm, sore throat, cough, shortness of breath, wheezing)

• as compared with IV or IM treatment (hypoglycemia in over 60% of patients, hypotension, pancreatitis, nephrotoxicity, anemia, leukopenia).

• Mechanism of action: It prevents RNA and DNA synthesis.

2. trimethoprim,TMP/sulfamethoxaz

ole, SMX (Bactrim, Septra)• This is normally administered for the

treatment of PCP.

• It is available in 80 mg TMP/400 mg SMX tablets or 80 mg TMP/400 mg SMX per 5 ml for injection.

• The most common adverse effects associated with TMP/SMX include: nausea, vomiting, rash.

• Mechanism of action:

• The combination of these 2 agents prevents the synthesis of RNA and DNA by inhibiting 2 different enzymes in the biosynthetic pathway in various bacteria, as well as the protozoa which causes PCP.

• Sulfamethoxazole is a sulfonamide which prevents the synthesis of folate from PABA by inhibiting the enzyme dihydropteroate synthetase.

• Trimethoprim inhibits the enzyme dihydrofolate reductase, which prevents the synthesis of tetrahydrofolate from folate.

• PABA → folate → tetrahydrofolate → purines, pyrimidines in RNA, DNA

D. Other Pneumonias1. Community-acquired pneumonia

• Community–acquired pneumonias develop in people that are in contact with a group of individuals.

• These pneumonias do not include those contracted in hospitals and nursing homes, which are classified as nosocomial pneumonias.

• Community–acquired pneumonias are normally caused by:

• Streptococcus pneumoniae

• Haemophilus influenzae

• Chlamydia pneumoniae

• Mycobacterium pneumoniae

• Legionella pneumophila.

a. Streptococcus pneumoniae

• Streptococcus pneumoniae aka pneumococcal pneumonia, is the most common of the bacterial pneumonias.

• It may be carried and spread, by healthy individuals, who do not experience illness.

• Streptococcus pneumoniae is transmitted by airborne droplets (coughing, sneezing).

• Children under age 2 and adults over 65 are now routinely vaccinated in an attempt to prevent this disease.

• The 2007 Infectious Diseases Society of America/American Thoracic Society guidelines recommend either a β-lactam, a macrolide, or a fluoroquinolone, for the treatment of Streptococcus pneumoniae.

• Penicillin had been the β-lactam of choice in treating this type of pneumonia.

• It may still be effective, however, significant resistance (between 20 – 40%) to this drug has developed.

• Augmentin, which is a combination of the β-lactam amoxicillin with the β-lactamase inhibitor clavulanate is often prescribed.

• In addition, ticarcillin clavulanate (Timentin) is effective, but is only administered IV or IM.

• There are 2 components to this medication, similar to Augmentin. It contains the β-lactam ticarcillin and the β-lactamase inhibitor clavulanate.

• Resistance associated with the macrolides, mostly clarithromycin (Biaxin) and azithromycin (Zithromax) are increasing.

• Telithromycin remains active against Streptococcus pneumoniae.

• The second generation fluoroquinolones (ciprofloxacin and ofloxacin) as well as the third generation levofloxacin, are poorly active against Streptococcus pneumoniae.

• Antibiotic resistance has been less common when using the fourth generation moxifloxacin and gemifloxacin.

b. Hemophilus influenzae

• Hemophilus influenzae is an opportunistic bacteria which often causes pneumonia in people suffering from COPD.

• Antibiotic resistance is now seen with many of the β-lactams.

• Combination drugs which include a β-lactam and a β-lactamase inhibitor such as piperacillin with tazobactam (Taxocin, Zosyn) or ticarcillin clavulanate (Timentin) are effective.

• Third generation cephalosporins such as cefdinir (Omnicef) and cefditoren (Spectracef) are recommended.

• Fluoroquinolones that are recommended include gatifloxacin (Tequin), gemifloxacin (Factive), and moxifloxacin (Avelox).

• c. Chlamydia pneumoniae

• Chlamydia pneumoniae accounts for a small percentage of community-acquired pneumonia and is most commonly seen in two distinct age groups: teenagers and adults over age 60.

• This type of pneumonia is not usually severe and generally doesn’t require the patient to be hospitalized.

• Chlamydia pneumoniae is generally treated with either a macrolide: azithromycin (Zithromax), clarithromycin (Biaxin); or a tetracycline: doxycycline.

• Chlamydia pneumoniae has been implicated the development of atherosclerosis, as is has been found within plaques in the walls of coronary arteries.

d. Mycoplasma pneumoniae

• Mycoplasma pneumoniae cause a pneumonia that is often referred to as "atypical” or “walking” pneumonia.

• Symptoms of this pneumonia include fever, headache, and nonproductive cough.

• It accounts for up to 20% of all bacterial pneumonias.

• It tends to be found in places where young people congregate (dorms, army barracks) and occurs at unusual times of the year (summer and fall).

• It is usually a slow developing pneumonia, with an incubation period of up to 3 weeks.

• The macrolides erythromycin (E-mycin), clarithromycin (Biaxin) and azithromycin (Zithromax) are commonly prescribed.

• e. Legionella pneumophila

• Legionnaire’s disease is a serious, often fatal pneumonia caused by the bacterium Legionella pneumophilia.

• The first outbreak of this disease occurred in 1976 at an American Legion convention in Philadelphia, PA, where more that 200 people became ill and 34 died.

• The bacterium grew in the standing water in the air conditioning system and was distributed throughout the building.

• It is not transmitted by human to human contact, only by aerosol.

• There was an outbreak of in the summer of 2008 in Syracuse, N.Y. The bacterium was located in a cooling tower at Community General Hospital.

• According to Onondaga County Health Commissioner Dr. Cynthia Morrow, there were 10 reported cases of Legionnaires Disease in the area surrounding the hospital.

• About 70% of those individuals who contact Legionnaire’s disease are heavy smokers, and/or elderly, and/or have some predisposing illness.

• Each year in the U.S. between eight and eighteen thousand people are hospitalized with Legionnaire’s disease.

• The majority of cases seem to be in the summer (maybe due to re-starting of air conditioning units after sitting all winter).

• The drugs of choice in treating Legionnaire’s disease, according to the CDC, are the macrolides erythromycin (E-mycin), clarithromycin (Biaxin) and azithromycin (Zithromax).

2. nosocomial pneumonia

• Nosocomial refers to hospital acquired, and these pneumonias are found in patients who are: extremely ill, and/or intubated, and/or immunocompromised, and/or have cardiopulmonary disease.

• Nosocomial pneumonias are usually caused by: Pseudomonas aeruginosa and Staphylococcus aureus (especially methicillin resistant).

a. Pseudomonas aeruginosa

• According to the CDC, Pseudomonas aeruginosa is one of the most common gram-negative bacterium causing pneumonia in hospitalized patients.

• To minimize the emergence of resistance, multidrug therapy is recommended in the treatment of Pseudomonas aeruginosa pneumonia.

• The recommended treatment includes at least two drugs: an aminoglycoside and either an extended spectrum penicillin with pseudomonal activity or a cephalosporin.

• Aminoglycosides commonly prescribed include gentamicin (G-Mycin, Garamycin).

• Aerosolized antibiotics to treat Pseudomonas aeruginosa pneumonia have, in the past, generally only been used in cystic fibrosis patients.

• Until recently, there has not been sufficient data to support their use in either hospital-acquired pneumonia (HAP) or ventilator acquired pneumona (VAP) caused by Pseudomonas aeruginosa.

• In a recent Phase II study (Journal of Antimicrobial Chemotherapy 2009 64(2):229-238), intubated and mechanically ventilated patients with HAP or VAP

• were randomized to receive either the aerosolized aminoglycoside Amikacin (400 or 800 mg) or placebo every 12 hours for between 7 and 14 days.

• High levels of the drug were found in the fluid lining the epithelial surface of the lower respiratory tract, without compromising safe serum levels.

• Based on the results of this trial, a Phase III trial is currently underway.

• spectrum penicillins include ticarcillin clavulanate (Timentin) and piperacillin with tazobactam (Taxocin, Zosyn).

• Carbapenems, which are structurally related to the β-lactam antibiotics, have good activity against Pseudomonas aeruginosa.

• Imipenem is a carbapenem which is often combined with the fluoroquinolone levofloxacin (Levaquin) for prevention of emergence of resistance during treatment.

• Doripenem is a new carbapenem which is 2-4 times more potent than imipenem against Pseudomonas aeruginosa.

• Tomopenem is another new carbapenem whose use is associated with a very low tendency for the emergence of resistance.

• One of the recommended cephalosporins is ceftazidime (Fortraz, Tazidime).

• In addition, ceftobiprole is a fifth generation cephalosporin which completed Phase III trials in June 2009.

• Seventy patients with Pseudomonas aeruginosa pneumonia were randomized to receive either ceftobiprole or a combination therapy of ceftazidime/linezolid.

• The results were quite similar: they was a 77% cure rate for ceftobiprole as compared to 76% for those receiving the combination therapy.

• Polymyxins are peptide antibiotics that act like detergents.

• They attach to and breach membranes, causing the leakage of intracellular contents.

• Polymyxin E (colistin) has been used both alone and in combination therapy.

• Administered systemically, it has serious neurotoxic and nephrotoxic adverse effects, so it is generally reserved for the most serious infections caused by MDR Pseudomonas aeruginosa.

• A Phase III trial for an aerosolized versions of aztreonam for the treatment of hospital-acquired pneumonia (HAP) or ventilator acquired pneumona (VAP) caused by Pseudomonas aeruginosa has recently been completed, and is currently under review by the FDA.

• A Phase III trial for an aerosolized liposomal formulation of ciprofloxacin for the same treatment is underway (as of November 2009).

b. Staphylococcus aureus (methicillin resistant)

• Vancomycin had been the cornerstone for the treatment of methicillin resistant Staphylococcus aureus (MRSA).

• However, there are vancomycin intermediate Staphylococcus aureus (VISA) and vancomycin resistant Staphylococcus aureus (VRSA) that have emerged.

• vancomycin sensitive and vancomycin intermediate S. aureus (VSSA and VISA, respectively), showing thickening of the cell wall

in the resistant isolate

• The combination of the 2 streptogramins quinupristin-dalfopristin (Synercid) is active against gram positive cocci, including MRSA.

MRSA

MRSA sensitive to Synercid

• Linezolid is the first in a new class of antibiotics called oxazolidinones.

• Linezolid blocks the formation of the initiation complex in protein synthesis

• It is indicated for use against many of the same drug resistant gram positive cocci that quinupristin-dalfopristin is used for (i.e. MRSA).

• It is available in both oral and parenteral formulations, and it is suggested that its use be limited to treatment of infections caused by multidrug resistant gram positive bacteria.

linezolid (Zyvox)