Antibiotics

Tamar BarlamInfectious Disease

Director, Antimicrobial Stewardship

Why is antibiotic choice important?

Safe, broad-spectrum antibiotics are readily availableOne can easily cover most common infections with excellent therapeutic results

So what’s the big deal?

Infectious Disease Society of America: Bad Bugs, No Drugs

In 1990, half of the large pharmaceutical companies in the US and Japan had stopped or decreased antibiotic efforts.A 2004 analysis found only 5 new antibiotics in the R&D pipeline out of >500 drugs in development.

A Changing Landscape for Numbers of Approved Antibacterial Agents

Bars represent number of new antimicrobial agents approved by the FDA during the period listed.

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Num

ber o

f age

nts

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1983-87 1988-92 1993-97 1998-02 2003-05 2008

Infectious Diseases Society of America. Bad Bugs, No Drugs. July 2004; Spellberg

B et al. Clin Infect Dis. 2004;38:1279-1286;New antimicrobial agents. Antimicrob Agents Chemother. 2006;50:1912

Resistance

Between 1962 and 2000, no major classes of antibiotics were introduced

Fischbach

MA and Walsh CT Science 2009

Infectious Disease Society of America: Bad Bugs, No Drugs

Since 1998, only 10 new antibiotics have been approved, only 2 are novelIOM 2003 report: not one new class of antibiotics is in late-stage development.Most are broad-spectrum i.e. more likely to contribute to development of resistance.

Antibiotic ResistanceAntimicrobial-resistant infections can cause worse patient outcomes, longer hospital stays, and higher mortality rates than similar infections with antibiotic-susceptible bacteria.Annual hospital costs associated with AR infections have been estimated at $5 billion.Total costs related to AR infections are estimated as high as $30 billion.

Selection of Resistance

Inappropriate antibiotic use is believed to be the major contributor to the development and spread of AR bacteria.Studies have demonstrated approximately 30 to 50% of antibiotic treatments are inappropriate.

New Resistant Bacteria

Mutations

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Emergence of Antimicrobial Resistance

Susceptible Bacteria

Campaign to Prevent Antimicrobial Resistance in Healthcare Settings

Resistant Bacteria

Resistance Gene Transfer

Resistant Strains Rare

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Resistant Strains Dominant

Antimicrobial Exposure

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Selection for antimicrobial- resistant Strains

Campaign to Prevent Antimicrobial Resistance in Healthcare Settings

Choosing an Antibiotic

What is wrong with the patient?Is it an infection?Is it bacterial?What is the site of infection or portal of entry?How sick is the patient?

Host Factors – Impact on Likely Organisms

Age Immunization status Social history

Travel – diarrhea, malariaSmoking – H. influenzae, M. catarrhalisUnprotected sex – STD’s, HIVCompany picnic – Listeria, SalmonellaPets – Pasteurella, Bartonella

ResidenceHomeless – tuberculosis, bartonellosisNursing homeFreshman college dormitory

Host Factors – Impact on Likely Organisms

Co-morbid conditions Neutropenia – gram-negatives, AspergillusHIV – S. pneumoniae, H. influenzae, PCPDiabetes – S. aureus, gram-negativesTransplantation –Nocardia, Listeria, fungi, CMVSteroid treatments – fungi, mycobacteriaInjection drug use – S. aureus, gram-negativesSplenectomy – fulminant infection with encapsulated organisms, more severe disease with babesiosis

Host Factors that Might Limit Antibiotic Choices

AllergiesPregnancy and breast feedingAge – reduced renal function, increased risk for ototoxicity.Genetic determinants – G6PD deficiencyOther medications

Drug-drug interactionsAdditive toxicities – furosemide and aminoglycosides; vancomycin and aminoglycosides

Attributes of the drugWhat is its spectrum?

Gram positive or gram negative?Aerobic or anaerobic or both?

Does it reach adequate levels at site of infection?Bacteriostatic or bacteriocidal?

EndocarditisMeningitisOsteomyelitis

Case #1

54 yo female with poorly controlled diabetes comes to the ED with a buttock abscess with surrounding erythema. The abscess was I&D’d and material sent for culture.

Case #1

Patient was placed on clindamycin and discharged home.

Case #1

Case #1Inducible macrolide resistance. Encoded by plasmid-borne gene erm.Constitutive – all test resistantInducible – clindamycin can test susceptible

Bacteria Isolated from Culture of Abscess Material, Deep Tissue Specimens, or Blood.

Jenkins T C et al. Clin Infect Dis. 2010;51:895-903

©

2010 by the Infectious Diseases Society of America

Case #223 yo healthy male with tibial fracture after MVA. ORIF performed and patient was discharged after an uneventful hospital course. Pain persisted and after six weeks, there was complete non-union. One month later, a small pustule formed and drained purulent material. Patient was seen by orthoand taken back to OR.What is the patient’s diagnosis? Treatment?

Case #2

Case #2

What if these were the culture results?

Case #3

47 yo active IVDU, HCV positive, presents with severe left arm pain and swelling. The patient had injected heroin into the veins of that arm 1 day prior.

On the morning of admission, he had severe bilateral pleuritic chest pain

Case #3

Rest of exam: T103 Other VSS II/VI SEM at LSB, decreased breath sounds R>L base, rales bilaterallyNo HSM

WBC 18,000 w/ 26% B; H/H 13/40, plts 300K other labs wnl

Case #3

Case #3

Describe what the patient likely has.What would you do next?Antibiotics?

Case #3

Case #3

Antibiotic?Duration?

Case #3What if patient if this was his isolate and MRSA screen:

Case #4

83 yo female, PICC in place, has 1 day of fever and some erythema at site.Rest of exam unremarkable, VSS, currently afebrile.MRSA with same profile as previous case but only 1 day of positive blood culturesTreatment?Duration?

Case #4Duration of TherapyIf catheter is removed, 5-7 days of treatment is usually adequate for CoNS. If catheter is not removed, treat for 10-14 days and consider antibiotic lock therapy.Treat 7-14 days for other organisms if uncomplicated infection. If complicated infection, treat for 4-6 weeks. If osteomyelitis, treat 6-8 weeks.If bacteremia / fungemia persist > 3 days after catheter removal - evaluate for complicated infection and treat 4-6 weeks. Consider surgical evaluation for incision / drainage. Evaluate need for anticoagulation in circumstances of septic thrombosis.

For catheter-related infections caused by S. aureus:Short-term catheters: Remove catheter and treat for ≥ 14 daysLong-term catheter: Remove catheter and treat for 4-6 weeks UNLESS:

Patient is NOT diabetic, NOT immunosuppressed, and NOT neutropenic;Infected catheter is removed and patient has no prosthetic intravascular device;There is no evidence of endocarditis or septic thrombosis;And there is no evidence of metastatic infection;

Then consider shorter duration of therapy (i.e., minimum of 14 days)

Case #5

57 year old woman from Brewster, MA comes in with fever, malaise, joint pains and headache.Patient is febrile and tachycardic but the rest of the exam is unrevealing.Lab is notable for slightly increased transaminases.Patient started on vanco/zosyn

Case #5

She continues to worsen clinically.She becomes neutropenic, thrombocytopenic and ast/alt worsenTeam calls for imipenem approval. All culture data are negative.

Case #5

Case #5

ID consult recommends d/c all antibiotics and start doxycycline.

Case #6

A 78-year old man presents with fever, lower back pain, and motor weakness of the right leg. You determine that he has vertebral osteomyelitis of L1 and L2.

Case #6

Case #6

What most commonly causes vertebral osteomyelitis?What should you do next?

Case #6

What if he came from Russia and this was his MRI?

Case #6

You review the MRIs and the radiologist informs you that the intervertebral disk is fine, but the entire vertebral body is replaced with some process. He revises the MRI report to state that only L1 is involved.

Case #6

Case #7A 70 year old man develops right-sided abdominal pain, fever and leukocytosis.The pain appears localized to the right upper quadrant and his liver is enlarged.He has an elevated wbc of 25,000 with 70% PMNsand 24% bands. His LFTs are most notable for an elevated alk phos = 420 and ALT/AST in the 60s

Case #7

Case #7

What is his diagnosis?What organisms do you need to cover?How did he get this?

Case #7Pyogenic

Older >50 years oldComorbidities – DM, CaMultiple abscessesNegative serologyLower serum albuminCulture positive (if aspirated)

AmoebicEpidemiologyPositive serologyYoung malesSolitary lesion >80%Culture negative (if aspirated)

Case #8A 43-year old man presents with fevers, general malaise, and shortness of breath. He has had symptoms for over two months but they have been slowly progressing. On examination, most notable are the presence of a harsh systolic murmur at the apex and bilateral rales on pulmonary examination. He also has severe gingivitis and poor oral hygiene.

Case #8

The patients informs you that he has had a change in bowel habits, has been losing weight, and that those symptoms have preceded the fevers by six months.

Case #8

The patient reveals that he is an injection drug user. The patient is actually known to you. Two months ago, he was admitted for mitral valve replacement. The surgery went well, and he was discharged home peri-operatively without incident.

Case #9

A 35-year old woman is admitted to the hospital four hours following the sudden onset of fever, stiff neck, headache, and photophobia. She has no active medical problems and is on no medications. She has three young children at home and two are in daycare.

Case #9

It turns out that she has systemic lupus and is on immunosuppressive therapies. And you notice that she has a ventriculoperitoneal shunt and she now tells you she has a history of hydrocephalus.

Case #10A 23 year-old BU freshman is brought to the ED by her roommates. She has been febrile and now is lethargic. She was well in the morning before they left for class.On physical examination, she is easily arousable, and has no meningismus. The rest of the examination is normal except the intern notices 2 small petechiae on her abdomen.

Copyright ©2006 American Academy of Pediatrics

Case #10

Case #10

Copyright ©2006 American Academy of Pediatrics

Case #10

She had been camping on the cape a few days earlier. ●

Diagnostics

Availability of broad-spectrum, safe agents appears to have decreased the urgency of definitive diagnosis.Broad empiric coverage is more difficult to narrow or refine if appropriate samples are not taken pre-treatment.When culture data are available, correct interpretation is crucial.

Take-Home LessonsAntimicrobials affect not only the patient but the communityWhat you prescribe for one patient may impact his neighborThere are many ways to treat most infections.The availability of broad-spectrum, safe agents does not free you from carefully considering more “elegant” solutions.Empiricism is fine, but knowing what you’re doing is even better.