Antibiotics Resistant infections

Nosocomial Infection ( Community acquired)

A substance that is :1. produced by or synthesized from other microorganisms,

such as molds.2. capable of destroying or weakening certain

microorganisms, especially bacteria or fungi , that cause infections or infectious diseases.

3. inhibit pathogens by interfering with essential intracellular processes as protein synthesis .

NB : Antibiotics are derived from three sources: moulds or fungi; bacteria; or synthetic or semi-synthetic compounds. And they don’t kill viruses.

What is an AntiBiotic ??

Classification according to Mechanism:

Cell wall inhibitors, such as Penicillin and

Vancomycin.

Protein synthesis inhibitors, such as Aminoglycoside.

Inhibitors of nucleic acid synthesis, such as Fluoroquinolones(DNA)and Rifampin(RNA)

Anti-metabolites, such as the sulfa drugs.

Cell Membrane Damaging such as PolymyxinB,Gramicidin and Daptomycin.

Antibiotic Resistance:

Def. : Ability of a microorganism to withstand the effects of an antibiotic through mutation or plasmid exchange between bacteria of the same species.

•Bacterium carries several resistance genes, it is called multiresistant or, informally, a superbug.

•What are Causes of Resistance ?? :

1. Antibiotic overuse, abuse, and in some cases, misuse, due to incorrect diagnosis.

2. Antibiotic use in animal husbandry .3. Increased Globalisation (Movement and contact of people).4. hospital settings often give rise to antibiotic resistant bacteria.

We are prepared , are

you ??

What are kind of Resistance ?

Ex : Streptomyces

Natural bacteria are ‘intrinsically’

resistant. resistance can be due to :1. some genes responsible

for resistance to its own antibiotic.

2. lack a transport system or a target for the antibiotics

3. increased efflux activity.

Acquired sensitive to antibiotics, but

are liable to develop resistance.

caused by mutations in chromosomal genes.

acquisition of mobile genetic elements, such as plasmids or transposons, which carry the antibiotic resistance genes.

1. Reduced drug accumulation: by decreasing drug permeability ,increasing active efflux (pumping out) of the drugs across the cell surface.

2. Enzymatic inactivation ((β-lactamase inactivate penicillin G )).

3. Alteration or over-expression of the drug target.4. Loss of enzymes involved in drug activation. This

mechanism is relatively new.5. Alteration of metabolic pathway((sulfonamide-

resistant bacteria ))

Main Mechanisms of resistance :

Definition:Is usually one that first appears three days after a patient is admitted to a hospital or other health care facility.

Causes :1. Contact with contaminated hands of hospital staff 2. Contact with contaminated surfaces such as door handles, overbed

tables and call bells .3. Contact with contaminated equipment, such as stethoscopes and

blood pressure cuffs. 4. Urinary bladder catheterization and respiratory procedures.5. Surgery and wounds and intravenous (IV) procedures.

Examples on Hospital-Acquired Infetions :a) Staphylococcus aureus .b) Enterococcus (urinary tract infections).c) Pseudomonas aeruginosa .d) Acinetobacter baumannii .e) proteus species .

Hospital-Acquired (nosocomial) Infections: 

•According to the CDC(Center for Disease Control) , the most common pathogens that cause nosocomial infections are Staphylococcus aureus, Pseudomonas aeruginosa, and E. coli.

•The common nosocomial infections are urinary tract infections, respiratory pneumonia, surgical site wound infections, bacteremia, gastrointestinal and skin infections.

Enterococci are part of the normal intestinal flora of humans and animals .

important pathogens responsible for serious infections.

includes more than 17 species but only a few cause clinical infections in humans.

capable of cellular respiration in both oxygen-rich and oxygen-poor environments.

Causes  urinary tract infections, bacterial endocarditis, and meningitis.

1- Enterococcus:

MOA: binds to the two D-alanine residues on the end of the peptide chains No interaction with the cell wall cross-linking enzyme inhibiting proper cell wall synthesis.

Major side effects: "Red man syndrome": RMS is characterized by :

flushing, erythema, and pruritus, usually affecting the upper body, neck, and face more than the lower body.

Treatments : 1st Vancomycin

MOR:

D-alanine residue replaced by a D-lactate, so vancomycin cannot bind vancomycin cannot bind stable cross links are formed successfully (normal cell wall synthesis)

Six different types of vancomycin resistance are shown by enterococcus(V.R.E) : Van-A, Van-B, Van-C, Van-D, Van-E and Van-F. Of these, only Van-A, Van-B and Van-C have been seen in general clinical practice, so far.

Van-A VRE is resistant to both vancomycin and teicoplanin.Van-B VRE is resistant to vancomycin but sensitive to teicoplanin.Van-C VRE is only partly resistant to vancomycin, and sensitive to teicoplanin.

NB : In the US, Linezolid is commonly used to treat VRE, as teicoplanin is not available.Vancomycin is contraindicated in patients with known hypersensitivity to this antibiotic

MOA : via inhibition of protein synthesis by binding 23S ribosomal RNA of the 50S subunit.

Major side effects:Diarrhea headache nausea. MOR: point mutation , in which a guanine base is replaced

with thymine in base pair 2576 of the genes coding for 23S ribosomal RNA.

Contraindications : hypersensitivity to linezolid or any of the other product

components. Or patients with carcinoid syndrome . or in patients taking directly and indirectly acting

sympathomimetic agents, vasopressive agents

2nd Linezolid

with the presence of bacterial motility and fimbriae Urease production by Proteus may favor the production of upper urinary tract infections (UTIs) by organisms such as Proteus.

Treatment: 1st Usually used for UTIs Methenamine (anti-bacterial

agent). MOA:

Methenamine, an inactive weak base, slowly hydrolyzes in acidic urine to ammonia and the nonspecific antibacterial (formaldehyde). Urinary formaldehyde concentrations may be bactericidal or bacteriostatic.

2-Catheter-Associated Urinary Tract Infections caused by proteus species bacteria :

1. An allergic reaction (shortness of breath).2. Lower back or side pain.3. Blood in urine.4. Painful or difficult urination. MOR:a. rod shaped bacterium has the ability to produce high

levels of urease,Urease hydrolyzes urea to ammonia (NH3).

b. makes the urine more alkaline stop Methenamine hydrolysis and HCHO release

Major side effects:

MOA :inhibit the topoisomerase II leaving the two nuclease domains intact leads to DNA fragmentation.

Quinolones can enter cells easily via porins , therefore, are often used to treat intracellular pathogens such as Legionella pneumophila and Mycoplasma pneumoniae.

For many Gram-negative bacteria, DNA gyrase is the target.

2nd Ciprofloxacin (2nd generation fluoroquinoline) :

By three Mechanisms :1. efflux pumps act to decrease

intracellular quinolone concentration.2. Gram-negative bacteria, plasmid-mediated

resistance genes, produces proteins that bind to DNA gyrase, protecting it from quinolones.

3. mutations at key sites in DNA gyrase or topoisomerase IV can decrease binding affinity to quinolones.

MOR :

with patient takes drugs metabolized by CYP1A2 as theyleads to increased plasma concentrations of Quinolones drugs Thus, leads to clinically significant adverse events of the coadministered drug.

For your Knowledge :

Proteus is a genus of Gram-negative Proteobacteria. Widely distributed in nature . Found in decomposing animal

matter, in sewage, in manure soil, and in human and animal feces.

They are opportunistic pathogens responsible for urinary and septic infections, often nosocomial.

Contraindications:

Most common pathogen isolated from patients who have been hospitalized longer than 1 week.

frequent cause of nosocomial infections such as pneumonia, urinary tract infections (UTIs), and bacteremia.

complicated and can be life threatening.

3-pseudomonas aeruginosa infections:

administered intravenously and intramuscularly. Some are used in topical preparations for wounds.

Oral administration can be used for gut decontamination (e.g., in hepatic encephalopathy).

MOA: act by binding to the aminoacyl site of 16S ribosomal RNA within the 30S ribosomal subunit, leading to misreading of the genetic code and inhibition of translocation.

Treatment : 1st   Aminoglycosides (gentamicin, amikacin, tobramycin) :

Contraindications Aminoglycosides should not be used in patients with:a) previous vestibular or auditory toxicity due to an

aminoglycosideb) serious hypersensitivity reaction to an

aminoglycoside AMGs cross placenta ,not used in case of pregnancy

Major side effects: a) Irreversible ototoxicity: loss of hearing, dizzinessb) Reversible nephrotoxicity.c) Neuromuscular blockade may lead to respiratory

paralysis

MOR

increased impermeability across the cell wall mechanism of this type of resistance is not known. 

up-regulation of the efflux system (efflux pump)

isolatedPseudomonas aeruginosa have been shown to contain AMGs modifying enzymes.

2nd Treatment :combination of an antipseudomonal beta-lactam (eg, penicillin or cephalosporin) and an aminoglycoside.

3rd Carbapenems (eg, imipenem, meropenem) with antipseudomonal quinolones may be used in conjunction with an aminoglycoside.

MOA: Carbapenems act as penicillins on cell wall destruction of bacteria.Major side effects:

1-GI distress and skin rashes. 2-CNS toxicity at very hight plasma lvl.

one of the leading causes of infections acquired in the community and after surgery or hospital.

30% of individuals carry S. aureus in their nose, pharynx or back of throat and on their skin.

presence of S. aureus does not always indicate infection. S. aureus can survive from hours to months, on dry

environmental surfaces, depending on strain. Although it is not always pathogenic, it is a common cause

of skin infections (e.g. boils), respiratory disease (e.g. sinusitis), and food poisoning.

The emergence of antibiotic-resistant forms of pathogenic S. aureus (e.g. MRSA(Methicillin-resistant S.A) is a worldwide problem in clinical medicine.

4-Staphylococcus aureus (MRSA)

1st treatment of choice for S.aureus infection is penicillins :

MOA: By binding to specific penicillin-binding proteins

(PBPs) located inside the bacterial cell wall, inhibits the third and last stage of bacterial cell wall synthesis.

Cell lysis is then mediated by bacterial cell wall autolytic enzymes such as autolysins; it is possible that penicillin G interferes with an autolysin inhibitor. (( increased effect))

Treatment:

MOR: the bacterium produces the enzyme β-lactamase or the enzyme penicillinase which will hydrolyse the β-lactam ring of the antibiotic, rendering the antibiotic ineffective.

Major side effects:A. Hypersensitivity: difficulty breathing,

skin rash, hives, itching. B. Stomach upset, diarrhea, nausea, and

vomiting.

MOR & Side Effects

like Methicilin or flucloxacillin or β-lactam antibiotics may be co-administered with a β-lactamase inhibitor.

For example, Augmentin is made of amoxicillin, a β-lactam antibiotic, and clavulanic acid, a β-lactamase inhibitor.

MOR: modification in the mecA gene of the bacteria which codes

for an altered penicillin-binding protein leads to a lower affinity for binding β-lactams (penicillins, cephalosporins and carbapenems). This allows for resistance to all β-lactam antibiotics.

3rd vancomycin is used.

2nd Treatment penicillinase-resistant penicillins

MOA : stop the growth and reproduction of bacteria by disrupting

translation of messenger RNA (mRNA) into proteins in the ribosome.

MOR: The intrinsic resistance of most Gram-negative bacteria to linezolid is due to the activity of efflux pumps, which actively "pump" linezolid out of the cell faster than it can accumulate.

Gram-positive bacteria usually develop resistance in which a guanine base is replaced with thymine in base pair 2576 of the genes coding for 23S ribosomal RNA .

4th finally if remain resistant Linezolid is used

Acinetobacter baumannii is a species of pathogenic bacteria involved in most nosocomial infections.

Aerobic gram-negative bacterium resistant to most antibiotics. Ventilator-associated pneumonia (VAP) is a sub-type of

hospital-acquired pneumonia (HAP) which occurs in people who are receiving mechanical ventilation.

Many of the typical symptoms of pneumonia will either be absent or unable to be obtained in VAP why ??

Ans. : because People who are on mechanical ventilation are often sedated and are rarely able to communicate.

The most important signs are fever, low body temperature, new purulent sputum, and hypoxemia (decreasing amounts of oxygen in the blood).

Acinetobacter baumannii ventilator-associated pneumonia (VAP)

MOA :inhibits bacterial wall synthesis like other B-lactam antibiotics. In contrast to other B-lactams, it is highly resistant to degradation by B-lactamases

MOR:1. Resistance generally arises due to mutations in penicillin binding

proteins. or resistance to diffusion across the bacterial outer membrane.

2. The most widespread B-lactamases with carbapenemase activity in A. baumannii are carbapenem-hydrolysing class D beta-lactamases (CHDLs) that are mostly specific for this species.

Unlike imipenem, it is stable to dehydropeptidase-1 and can therefore be given without cilastatin.

Treatment:1st carbapenem as (meropenem) was commonly used

MOA :by binding to a negatively charged site in the lipopolysaccharide layer,Polymyxin B Alters bacterial outer membrane permeability and the result is the destabilized outer membrane causing :

1. Fatty acid portion dissolves in hydrophobic region of cytoplasmic membrane and disrupts membrane integrity.

2. Leakage of cellular molecules. Major side effects:1. Nephrotoxic reactions: Albuminuria.2. Neurotoxic reactions.3. Thrombophlebitis at intravenous

injection sites.

Treatment :2nd used for multi drug resistant A.baumannii  Polymyxin B

Ways to prevent antibiotic resistance :

Limiting the Spread of Drug Resistant Bacteria:

A. Ensure that antibiotics are used only when necessary.

B. Ensure that they are used for the appropriate amount of time.(( Complete to be fully effective and not breed resistance))

C. Third strategy for limiting drug resistance is to use antibiotics combinations.

Development of New Antibiotics.

Phage Therapy.

Mobilisation of Host Defence Mechanisms,This can be achieved through :

1. the mobilisation of innate immunity such as defensins((They are small Cysteine-rich cationic proteins, and function as host defense peptides Cells of the immune system contain these peptides to assist in killing phagocytosed bacteria)).

2. through the development of vaccines, which make antibiotics less necessary.

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