Gram Negatives Flashcards
Gram Negative Pathogens
Gram Negative Organization:
-Two cell membranes (“balloon within a balloon”)
-Thin cell wall (between membranes); not much to attack.
-Surface protein: Lipopolysaccharide (LPS).
-The outer membrane does not let antibiotics penetrate or traps them in the inner membrane space.
Gram Positive Organization:
-One cell membrane
-Thick cell wall
-Surface protein: Lipoteichoic acid.
Antibiotic Resistance Threats
18 organisms listed as threat levels of urgent, serious or concerning
-9 (50%) are Gram Negatives
-2 new antibacterial agents between 2008-2012; none target gram negatives.
2013-2015: five new FDA-approved agents; two of which have activity against Gram Negatives; especially multi drug resistant GN
-Ceftolozane-Tazobactam (ZERBAXA); tazobactam is like a sacrificial molecule, it goes around the mechanism of resistance and allows the primary agent to work
-Ceftazidime-Avibactam (somewhat novel, still a beta lactamase inhibitor- preventing the mechanism of resistance) (AVYCAZ)
Not novel; more potent against mechanism we already target we already target; need to pressure organisms because they already have defense mechanisms against these agents.
Eight candidate agents are currently in Phase 3 trials, of which FIVE are predicted to have activity against Gram Negatives
Carbavance (vaborbactam and meropenem)
Imipenem/cilastin and relebactam
Delafloxacin
Eravacycline
Plazomicin
Solithromycin
Omadacycline
Same mixture of agents, just more potent.
Thinking about how to use old AB more effectively; colistin; traditionally thought of as toxic, but now thinking about how to use it against multi drug resistant GN.
Polymixins; eye drops, ointments; not thought of as systemic, but bringing them back.
Pathogenic features of GN
Infections: intraabdominal, UTI (number one cause is E coli, UT or kidney), pneumonia, cellulitis, osteomyelitis, meningitis, post surgical infections in abdomen.
GI tract microbes are overwhelmingly gram negative rods.
They do really good things in the GI, but when they get out they cause infection.
Endotoxin- LPS; rapid inflammation and E coli sepsis.
Enterotoxins- E coli, Shigella infectious diarrhea
Community and nosocomial acquisitions.
Intrinsic resistance mechanisms exist in some species:
-Beta lactamase production; can cleave simple and complex beta lactams.
-Efflux pumps; pump drugs out of the cell; tetracyclines and fluroquinolone resistance.
-Outer membrane; prevents penetration (drugs that are active in GP but not in GN); many beta lactamases sit in the inner membrane space.
Medically relevant GN bacteria
- Gram negative bacilli:
- Enterobacteriaceae (organisms that reside in the GI)
- Non-enterobacteriaceae; not normal GI related colonizers; environmental; non fermenting GN; do not ferment sugar; way to differentiate them. - Gram negative cocci/coccobacilli
- “Other” gram negative bacteria
- Gram negative anaerobes
Enterobacteriaceae
Diverse bacterial group-thousands of species.
Enteric gram negative bacilli (rods):
-E coli; classic gut related organism
-Klebsiella pneumoniae (UTI) and oxytoca.
-Enterobacter spp. (space)
-Proteus mirabilis and vulgaris (space).
-Serratia marcescens (space)
-Citrobacter spp (space)
-Morganella morganii
-Salmonella, Shigella, Campylobacter
Primary cause of clinically significant GN infections!
Less non-enterobacteriaceae.
Space organisms; types of GN, most are enterobacteriaceae; cause a lot of GI infections and highly drug resistant.
Pseudomonas (non-enterobacteriaceae).
Acitenobacter; non-enterobacteriaceae (space).
Enterobacteriaceae is currently considered a threat by the CDC.
Significant drug resistance; carbapenam resistance; this is a last line agent and now we are getting resistance to this.
Drug resistant non typhoidal Salmonella
Drug resistant Salmonella Serotype Type HI
Drug resistant Shigella
Extended spectrum beta lactamase producing enterobacteriaceae (ability to cleave more advanced beta lactams); can cleave cephalosporins and making them ineffective; created a real problem-do not have effective treatment option except maybe a carbipenam; new drugs are effective, the beta lactase inhibitor is inhibiting the cleavage.
Drug resistant campylobacter
Enterobacteriaceae-Food/water borne pathogens
-E coli
-Shigella; dysenteriae, flexneri, boydii, sonnei.
-Salmonella (typhoid and nontyphoid)
-Campylobacter jejuni
-Vibrio cholerae.
Commonly transmitted organism seen in community.
Some reside in the GI tract, especially in animals and get transmitted onto food.
E coli O157: H7
Most common shiva-toxin producing E coli.
Source: contaminated beef, lettuce, spinach, cabbage, sprouts, tomatoes.
Low inoculum (<100 cells) needed for infection unlike invasive pathogens like pneumonia; GI infections you really only need a low number to get infection event to occur in GI.
Effects similar to Shigellosis.
>110,00 cases, 80 deaths/year.
Non-Enterobacteriaceae
Non-fermentative, GN bacilli (rods)
Organisms:
-Psuedomonas aeruginosa; many hospital settings; a big burden, bleeds over in community setting also.
-Acinetobacter baumanii; this also leads to a big burden of infection
-Strenotrophomonas maltophilia
-Berkholderia cepacia; least common
-Not normal flora; no GI; reside in environments like water, soil; acquire through ingestion or skin.
-Environmental type of organism.
-Nosocomial infections; try to cover for pseudomonas; water, colonize bed rails, countertops
-Multi drug resistant organisms; extreme potential for drug resistant; high likelihood for resistance than other GN.
Pseudomonas aeruginosa
Non-enterobacteriaceae (non-fermentive) GN rod (bacilli).
Normally colonizes soil, water, plants.
Pathogenesis: cause of both chronic and acute disease; not benign, causes significant disease.
-Chronic: decreased cytotoxicity, resistance, boil and adhesion.
Cystic fibrosis pneumonia; caused by pseudosmonas but also Staph.
Can get in diabetic wounds; diverse organisms.
CDC rates as a serious threat
Infections:
-SSTI/folliculitis
-Endocarditis (IV drug users)
-Vertebral osteomyelitis (IV drug users)
-Sepsis
-HAP/VAP
-Post op wounds
-IV catheters
-Pneumoni,a bloodstream infections, UTI, surgical sites infetions.
-Multi drug resistant; aminoglycosides, cephalosporins, fluoroquinolones, carbapenems.
13% of healthcare-associated infections caused by this organism are multi drug resistant.
Acinetobacter baumanii
Non-enterobacteriaceae (non-fermentive) GN rod (bacilli).
Mostly found in hospitals in/on equipment; days to weeks duration; infection control is KEY!
Colonizes tracheal tubes and climb in to cause infection in the lung.
Takes a long time develop because not a highly pathogenic strain.
Infects immunocompromised hosts; not exclusive to these patients.
High crude mortality; high likelihood of death; other issues important to infection like immunocompromised states and few treatment options.
Infections: pneumonia (vents), open wounds, lines, bloodstream infections.
Less virulent than pseudomonas.
Tends to be hospital acquired whereas pseudomonas can be this and community.
Multi drug resistant acinetobacter; CDC rates this as a serious threat.
Some strains are resistant to all or nearly all AB including carbapenems (last resort medication)
63% is considered multi drug resistant (at least 3 different classes no longer cure this organism)
Clinical pearls- Non-Enterobacteraceae
Cover for Pseudomonas in suspected nosocomial infection until the pathogen is ID; double coverage often used initially; use a very potent AB, combination therapy to target organisms that are highly drug resistant.
Few treatment options for MDR Pseudomonas and Acinetobacter; few options in pipeline, older AB useful?
Narrow spectrum once C/S known- “de-escalate.”
Strenotrophomonas treatment of choice=TMP/SMX (bacterium)
Treatment of Burkholderia includes multiple AB-guided by susceptibility.
WASH UR HANDS!!!
C diff is commonly caused by trying to treat GN infections; broad spectrum AB treatment results in C diff infection.
Narrow AB treatment prevents collateral resistance by minimizing overexposing organisms to unnecessary AB.
Not really a hard set treatment for pseudomonas or aceinetobacter.
Gram negative Cocci/Coccobacilli
Community side
-Haemophilus spp: H. influenzae
-Moraxella catarrhalis: OM, sinusitis, bronchitis, pneumonia.
-Neisseris spp: N. meningitis (meningitis), N. gonorrhea (STI).
Look round and rod shaped; live in both realms.
Haemophilus Influenzae
Gram negative cocci/coccobacilli
-Encapsulated, facultative anaerobe
7 serotypes; Type b is the most clinically important (most pathogenic, common, and virulent); Hib vaccine since 1985 has decreased incidence.
Non-encapsulated can also cause disease.
-Colonizes the upper respiratory tract; recovered exclusively from humans; only transmitted and able to survive in humans.
-Infections (mostly children); CAP, Meningitis, Sinusitis, OM, Conjunctivitis.
Type B strains, typically cover in vaccine; causes CAI that cause hospitalization; vaccine has brought down the burden quite a bit.
Some that are no typeable and can cause OM and more URT infections.
-Antibiotic resistance variable.
Counteracting encapsulated organisms of those 7 serotypes; there are other types not covered that are not as clinically significant, but can still care infections.
Neisseria meningitidis
Gram negative diplococcus.
Carried in nasopharyngeal secretions; requires culture from sterile body fluid such as blood, CSF, or synovial, pleural, or pericardial fluid for dx; not just a nasal swab.
Transmitted through this route.
Don’t know what makes a patient become colonized and transferred to CSF.
-Produces a polysaccharide capsule.
-Cause of meningitis and associated sequelae; bacterial meningitis is a significant emergency.
-Outbreaks account for <5% of reported cases in the US but continue to occur in semi-closed populations, such as child care centers, military recruit camps, colleges, and schools.
-Ideal pharmacologic agents for therapy: beta lactams!!!
Most get into CNS really well; also effective in killing organism.
Meningococcal vaccine
Young people are most at risk; slow rise toward end of life; burden of disease in early period of life.
8 most common serotypes causing human disease: A, B, C, X, Y, Z, W-135, and L.
X, Z, L are not covered by the vaccine.
Some organisms that are not covered by some of the vaccines that are available.
