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Flashcards in Gram Negatives Deck (20):
1

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.

2

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.

3

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.

4

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.

5

Medically relevant GN bacteria

1. 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.
2. Gram negative cocci/coccobacilli
3. "Other" gram negative bacteria
4. Gram negative anaerobes

6

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

7

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.

8

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.

9

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.

10

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.

11

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)

12

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.

13

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.

14

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.

15

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.

16

Neisseria gonorrhoeae

Gram negative cocci/coccobacilli
Second most common reportable disease in the US.
Transmission: sexual intercourse with an infected partner; birth (children).
Risk of acquiring infection after a single exposure is 22-35%.
Reinfection occurs in >40% of high risk patients (treated and the no back to same behavior that caused infection) within one year of treatment.
Complications: PID, Epididymitis, disseminated gonococcal disease.
Most heavy burden of disease in southern parts; ride is going up in the Western US.
Young adults are at highest risk of infection.
Not benign.
Drug-resistant gonorrhea: CDC rates this as an urgent threat.
Discharge and inflammation at the urethra, cervix, pharynx, or rectum.
Showing resistance to AB usually used to treat it; cephalosporins; cefixime (an oral cephalosporin), ceftriaxone (an injectable cephalosporin- last line agent that we would use), azithromycin, tetracycline (resistance to tetracyclines is a major problem, about 23% of gonorrhea).
Recommend avoiding using one of the cephalosporins as being active and moving on to advanced and stable cephalosporin.
Resistant ot primary therapy that we would use in every patient; reports in US and around the world.

17

Chlamydia trachomatis

Gram negative cocci/coccobacilli
Number one bacterial STD in the USA: 1,244,120 new cases reported in 2009 (now 1.5 million); CDC reports the US incidence to be >406 cases per 100,000 persons.
About 50% of men have symptoms
75% of women have no symptoms so they can transmit the organism to others.
Typically confection with gonorrhea but it can exist as an infection by itself; can transmit both organisms.
Not a lot of resistance right now; do have effective treatment options; but many cases, so it could develop over time.

18

Other Gram Negative Pathogens

Helicobacter pylori
Brucella spp
Francisella tularensis (Tularemia)
Pasteurella spp (P. multocida; bite wounds)
Yersinia pestis (plague)
Bordetella pertussis (whopping cough)
Legionella (L. oneumophila; Legionaires diseae); atypical organism as far as its presentation, but it is actually a gram negative rod.

19

Gram Negative anaerobes

Once listed above are either aerobic or facultative anaerobes.
-Distinguished as
true "anaerobes" and metronidazole susceptible; GN rods
-Bacteroides fragilis; most common and pathogenic, lower GI, abdominal abscesses.
-Fusobacterium spp; mouth, upper respiratory; Lemierre's disease-acute jugular vein septic thrombophlebitis.
-Prevotella spp; mouth upper respiratory, lower respiratory; not as common as bactericides which is the common GN anaerobe.

20

Summary

GN historically are in the hospital, but with drug resistant gonorrhea and other organisms we are seeing more GN in the community; significant resistance in community setting.
Superbugs are primarily GN because very resistant.
The most serious are health care associated and the most common pathogens are Enterobacteriaceae, Pseudomonas aeruginosa, and acinetobacter baumanii.
AB stewardship: a way to combat these problems and use AB more effectively in the right patients; key to reducing spread and development of resistance; appropriate AB and infection control measures; try to maintain AB pipeline.