Antibacterials

What antiseptics inhibit urinary pathogens?

Nitrofurantoin and methenamine

Nitrofurantoin is used to treat what?

used in uncomplicated UTIs

Methenamine gets hydrolyzed at acidic pH to produced what?

produces ammonia and formaldehyde

What type of activity does formaldehyde have?

antibacterial activity

Why do mycobacterial infections require prolonged treatment?

They are extremely slow growing, inhibition can take weeks to months

What is the first line of drugs for 2 months for tuberculosis?

**RIPE** (__**R**__ifampicin, __**I**__soniazid, __**P**__yrazinamide, __**E**__thambutol)

Is Rifampicin bactericidal or bacteriostatic?

bactericidal

What is the MOA of Rifampicin?

binds to DNA-dependent RNA polymerase, blocking the synthesis of mRNA

Can Rifampicin cross the blood-brain-barrier?

Yes

What is the MOA of Isoniazid?

inhibits mycobacteria specifically by inhibiting mycelia acid synthesis

Is Isoniazid bactericidal or bacteriostatic?

bactericidal

Why is pyridoxine administered alongside isoniazid?

Isoniazid can have neurological complications if taken along

Pyrazinamide is a synthetic analog of what?

nicotinamide

What is the MOA of pyrazinamide?

targets mycolic acid synthesis

What must pyrazinamide be used in combination with other first line agents?

due to resistance during monotherapy

What is a common toxicity associated with pyrazinamide?

hepatoxicity

What is the MOA of Ethambutol?

synthetic molecule that inhibits mycobacteria

Is Ethambutol bactericidal or bacteriostatic?

bacteriostatic

When does resistance occur in Ethambutol use?

when drug is used along

What are known toxicities associated with Ethambutol?

Optic neuritis

What pathogen causes leprosy?

*Mycobacteria leprae*

What must leprosy be treated for prolonged periods of time?

due to persistence of organism in the tissues for years

Mono-treatment of what drug to treat leprosy resulted in resistance?

Dapsone

What combination of drugs are commonly used as therapy for leprosy?

Dapsone, Rifampicin, Clofazimine

What type of tests, performed in a laboratory, examine the interactions between antibiotics and bacteria and are a helpful guide to the likely outcomes of therapy?

susceptibility tests

What patient factors must be taken into consideration during antibiotic therapy?

Age, Underlying disease, Sit and Type of Infection, Renal and Liver Function

Disk Diffusion

a type of susceptibility test that involves seeing the organisms on an agar plate and the application of filter paper disks containing antibiotics where overnight incubation is observed for zones of inhibition around each antibiotic disk

Dilution Test

susceptibility test that is a quantitative estimate of antibiotic susceptibility that can be assessed through minimum inhibitory concentration test (MIC test) and finds the lowest concentration that inhibit visible bacterial growth

For dilution susceptibility tests, where are serial dilutions of the test antibiotics prepared?

in broth or agar

Minimum Bacterial Concentration

the lowest concentration of an antibiotic required to kill the organism

What is the killing curve?

it provides a dynamic estimate of bacterial susceptibility

The killing curve is typically used in a research setting to determine what?

used to determine synergistic effects

Combination therapy can be described as what?

Synergistic or antagonistic

Synergistic

activity is greater than the sum of individual activities

Antagonistic

activity of one drug is compromised by the other

Do antiviral drugs kill viruses?

No, they only stop viral replication

Viruses are dependent on what part of the host?

dependent on host cell protein synthesis machinery

What medication is used in the treatment of herpes simplex virus (HSV) and Varicella-Zoster virus (VZV)?

Acyclovir

What type of drug is acyclovir?

a prodrug (it is unactivated until phosphorylated)

What phosphorylates Acyclovir to activate it?

herpesvirus thymidine kinase

Acyclovir is incorporated into what, resulting in chain termination?

incorporated into the viral DNA

Acyclovir is used in the treatment of what?

HSV encephalitis

HSV and VZV infections

Primary and recurrent genital herpes

The use of Acyclovir in patients with HSV and VZV infections have experience an accelerated recovery if they have what underlying issue?

shingles

What toxicities are associated with Acyclovir?

Neutropenia and thrombocytopenia (rare)

Possible crystallization in the renal tract in kidney patients

What virus is Ganciclovir active against?

Cytomegalovirus (CMV)

Cytomegalovirus (CMV) does not encode what enzyme?

thymidine kinase

Ganciclovir is monophosphorylated by what virus?

UL97 gene-specified kinase

Although selective toxicity is NOT seen for Ganciclovir, what type of toxicity is seen?

bone marrow toxicity

What are the clinical uses of Ganciclovir?

CMV retinitis

CMV encephalitis

CMV GI disease seen in immunocompromised patients

What medication is used as pre-emotive therapy in bone marrow transplant and solid organ transplant recipients?

Ganciclovir

What is the MOA of Cidofovir?

Chain terminating agent that targets viral DNA polymerase and is added to the 3’ end of the viral DNA chain

What are the clinical uses for Cidofovir?

effective against CMV and adenovirus infections

In what cases can Cidofovir be applied topically/intralesionally?

In cases of acyclovir-resistant genital warts caused by HSV

What is the MOA of Foscarnet?

Attaches to the pyrophosphate-binding site of the herpesvirus DNA polymerase, preventing nucleotide binding and inhibiting viral replication

What is the clinical use of Foscarnet?

used to treat CMV infections

Active against HSV and VZV

Acyclovir-resistant HSV

Is Foscarnet a first-line drug or a second-line drug?

a second-line drug

What are the 6 classes of antiretroviral drugs?

Nucleoside and nucleotide reverse transcriptase inhibitors

Non-nucleoside reverse transcriptase inhibitors

Protease inhibitors

Fusion inhibitors

Integrase inhibitors

Chemokine receptor antagonists

Zidovudine is an analog of what?

nucleoside thymidine (NRTI)

What is present on the ribose of Zidovudine instead of hydroxyl group?

an azido group

What is the MOA of Zidovudine?

acts as an inhibitor of/substrate for viral reverse transcriptase and acts as a competitive substrate of reverse transcriptase incorporated into proviral DNA

What are the adverse effects of Zidovudine?

Bone marrow suppression (Macrocytic anemia, neutropenia, leukopenia)

Vomiting, nausea, headache, myalgia, and malaise

Lactic acidosis, hyperlipidemia, lipoatrophy, and insulin resistance

What is the MOA of Non-nucleoside reverse transcriptase inhibitors (NRTIs)?

noncompetitive inhibitors of HIV-1 reverse transcriptase and bind to a hydrophobic pocket proximal to the enzyme catalytic site; induce cytochrome P450

What side effects are associated with NRTIs?

Pancreatitis

Peripheral neuropathy

Lipodystrophy

Hypersensitivity

The following drugs are apart of what class of antiretroviral drugs?

* Nevirapine, efavirenz, delavirdine, etravirine, rilpivirine

\
A. Chemokine receptor antagonists

B. Fusion inhibitors

C. Integrase inhibitors

D. Non-nucleoside reverse transcriptase inhibitors

E. Nucleoside and nucleotide reverse transcriptase inhibitors

F. Protease inhibitors

D. Non-nucleoside reverse transcriptase inhibitors

Are Non-nucleoside reverse transcriptase inhibitors active against HIV-2?

No, only active against HIV-1

The following drugs are apart of what class of antiretroviral drugs?

* Nelfinavir, saquinavir, indinavir, ritonavir, kaletra, atazanavir, amprenavir, darunavir, fosamprenavir, tipranavir

\
A. Chemokine receptor antagonists

B. Fusion inhibitors

C. Integrase inhibitors

D. Non-nucleoside reverse transcriptase inhibitors

E. Nucleoside and nucleotide reverse transcriptase inhibitors

F. Protease inhibitors

F. Protease inhibitors

What is the MOA of protease inhibitors?

Acts in post-translational cleavage of the gag and gag-pol polyproteins, inhibits the structural proteins and enzymes critical for viral replication which results in immature and defective viral particles

What side effects are associated with protease inhibitors?

GI distress, lipodystrophy, increased triglycerides, insulin resistance

The following drugs are apart of what class of antiretroviral drugs?

* •Enfuvirtide

\
A. Chemokine receptor antagonists

B. Fusion inhibitors

C. Integrase inhibitors

D. Non-nucleoside reverse transcriptase inhibitors

E. Nucleoside and nucleotide reverse transcriptase inhibitors

F. Protease inhibitors

B. Fusion inhibitors

What is the MOA of fusion inhibitors?

blocks HIV before it enters the host cell and competitively binds to gp41; Blocks post-fusion structure from forming

What side effects are associated with fusion inhibitors?

pain at injection site and rare hypersensitive reactions

The following drugs are apart of what class of antiretroviral drugs?

* Dolutegravir, raltegravir, elvitegravir

\
A. Chemokine receptor antagonists

B. Fusion inhibitors

C. Integrase inhibitors

D. Non-nucleoside reverse transcriptase inhibitors

E. Nucleoside and nucleotide reverse transcriptase inhibitors

F. Protease inhibitors

C. Integrase inhibitors

What is the MOA of integrate inhibitors?

transferring virally encoded DNA into the host chromosome and inhibiting the strand transfer step

The following drugs are apart of what class of antiretroviral drugs?

* Marviroc

\
A. Chemokine receptor antagonists

B. Fusion inhibitors

C. Integrase inhibitors

D. Non-nucleoside reverse transcriptase inhibitors

E. Nucleoside and nucleotide reverse transcriptase inhibitors

F. Protease inhibitors

A. Chemokine receptor antagonists

HIV-1 enters the cells via what type of receptors?

CD4 and either CCR5 or CXCR4

In what type of patients are chemokine receptor antagonists used?

Used in patients who have been given HAART and have an R5 HIV-1 infection

What is the typical treatment combination of antiretroviral drugs?

2 Non-nucleoside reverse transcriptase inhibitors (NRTIs)

1 Integrase inhibitor

What is the MOA of Ribavirin?

guanosine analog that inhibits production of guanosine triphosphate pool needed viral nucleic acid synthesis

What type of viruses can Ribuvirin target?

Both RNA and DNA viruses

(After triphosphorylation, can interfere with RNA polymerases too)

What are the clinical uses for Ribavirin?

Used as an aerosol to treat RSV in infants, Lassa fever, active against measles, Hep C, and Hep E

Of the following drugs, which are used for influenza A?

A. Amantadine

B. Oseltamivir

C. Peramivir

D. Rimantadine

E. Zanamivir

A. Amantadine

D. Rimantadine

Of the following drugs, which are used for both influenza A and B?

A. Amantadine

B. Oseltamivir

C. Peramivir

D. Rimantadine

E. Zanamivir

B. Oseltamivir

C. Peramivir

E. Zanamivir

What is the MOA of Amantadine and Rimantadine?

Inhibit the penetration of the virus into the cell, fusion of the viral envelop is prevented

On what channel does Amantadine act?

acts on the viral matric protein ion channel

Neuraminidase

a glycoprotein on the influenza virus surface that cleaves sialic acid residues on the host cell to release the influenza virus and further spread

What are examples of neuraminidase inhibitors?

Oseltamivir, zanamivir, peramivir

What is the MOA of neuraminidase inhibitors?

Acts as a competitive reversible inhibitors of the neuraminidase enzyme active site

Interferons

natural glycoproteins produced by the innate immune system in response to infections; encode proteins thought to inhibit intracellular virus multiplication

Interferons are used to treat what?

Used to treat chronic HBV and HCV infections; has effect on HPV infections

What is the role of IFNα?

binds to immune cells and results in class I MHC antigen expression, activation of effector cells, cytokine cascade, and production of Th1 cells

What tests are critical in the diagnosis, treatment, assessment, and prognosis of viral infections?

Qualitative and quantitative nucleic acid test

What can detect the presence of viral RNA?

Reverse-transcriptase PCR

What can determine the number and percent of T cell counts?

Flow cytometry

What can detect gene expression of specific viruses?

Quantitative real-time PCR

What is the MOA of azoles?

Inhibits cell membrane synthesis and inhibits the lanosterol C14-demethylase (which is important for sterol synthesis)

What type of Azole is used to treat Candida infections?

Fluconazole

What newer azole is used to treat aspergillosis?

Posaconazole

What azole is used to treat invasive mucormycosis?

Isavuconazole

What is the MOA of Echinocandins?

Interfere with cell wall synthesis by inhibiting β-(1,3)-D-glucan synthase – required for fungal cell wall synthesis

Echinocandins are used to treat what?

invasive *Aspergillus* infections, candidemia, invasive candiadiasis, and *Pneumocystis*