CLINICAL USE OF BETA-LACTAMS

Douglas Black, Pharm.D.Associate ProfessorSchool of Pharmacy

University of Washingtondblack@u.washington.edu

WHY IS INFECTIOUS DISEASE PHARMACOTHERAPY SO CONFUSING?

• Learning the antibiotics is not enough

• Microbial taxonomy constantly changes

• New antimicrobials are continually being developed

• Empiric therapy is especially difficult

• Antibiotic resistance complicates everything!

• There are many reasonable treatment choices but usually only one best choice

MASTERING TREATMENT OF AN INFECTIOUS DISEASE

• Know the most common pathogens in rank order

• Know the resistance patterns of the pathogens in question

• Know the drug(s) of choice in a patient with a classic case

• Know the best alternative for a patient unable to receive the drug of choice

• Know the drug of choice in pregnancy

“BY THE YEAR 2000, NEARLY ALL EXPERTS AGREE THAT BACTERIAL AND VIRAL DISEASES WILL HAVE BEEN VIRTUALLY WIPED OUT…”

THE FUTURISTS: LOOKING TOWARD A.D. 2000(TIME MAGAZINE, FEBRUARY 25, 1966)

“IN THE RACE FOR SUPREMACY, MICROBES ARE SPRINTING

AHEAD…”WORLD HEALTH ORGANIZATION

ACUTE INFECTIOUS DISEASES ACCOUNT FOR 25% OF DEATHS WORLDWIDE, AND FOR 45%

IN DEVELOPING COUNTRIES

NOSOCOMIAL BLOODSTREAM ISOLATES

Edmond, et al Clin Infect Dis. 1999;29:239-244

SCOPE Project (n=10,935)

Other (11%)

Coagulase-neg

Staphylococcus (32%)

Enterococci (11%)

Gram-negative

(21%)

Candida (8%)

Viridans strep (1%)

S. aureus (16%)

NEW ANTIBACTERIAL AGENTS APPROVED IN THE U.S. (1983-2002)

CASE 1. A 5-year-old boy presents with fever, purulent tonsillar exudate, and cervical lymphadenopathy. No rash is evident.

Dx: Tonsillopharyngitis

CASE 1: BUGS AND DRUGS

• Most likely pathogens:– Virus– Streptococcus pyogenes (Group A

ß-hemolytic Streptococcus)– Arcanobacterium haemolyticum

• Drug of choice– Penicillin VK (won’t cover A.

haemolyticum)

CASE 2. A 20-month-old girl comes to the clinic with a cough and runny nose. She is very fussy and continually tugs at her left ear. Her temperature is 102 F, her left ear drum is red and immobile, and bony landmarks are not visible.

Dx: Acute otitis media

Most likely pathogens: Streptococcus pneumoniae, Hemophilus influenzae, Moraxella catarrhalis

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1988 1990 1992 1994 1996 1998 2000 2002

% o

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YearBreiman RF, et al. JAMA. 1994;271:1831-1835. Doern GV, et al. AAC. 1996;40:1208-1213. Thornsberry C, et al. DMID. 1997;29:249-257.

Thornsberry C, et al. JAC. 1999;44:749-759. Thornsberry C, et al. CID 2002;34(S1):S4-S16. Karlowsky, et al. CID. 2003;36:963-970. Sahm, et al. IDSA 2003, abstract 201. Data on file, Ortho-McNeil Pharmaceutical, Inc. In vitro activity does not necessarily correlate with clinical results.

Trend for PenicillinTrend for Penicillin--Resistant (MIC Resistant (MIC 2 2 g/ml) g/ml) S. pneumoniaeS. pneumoniae in the US (1988in the US (1988--2002)2002)

Global Susceptibility ofGlobal Susceptibility ofS. pneumoniaeS. pneumoniae:: 20012001--20022002

No. ofNo. of Percent SusceptiblePercent SusceptibleCountryCountry IsolatesIsolates PenicillinPenicillin AzithromycinAzithromycin LevofloxacinLevofloxacin

ASIAASIASouth KoreaSouth Korea 283283 2424 1818 9797ThailandThailand 168168 2929 4545 9999Hong KongHong Kong 188188 3131 2323 92 (98 in 2003)92 (98 in 2003)JapanJapanaa 218218 4646 3232 9999ChinaChina 180180 8383 1818 9898EUROPEEUROPEFranceFrance 760760 4747 4545 9999SpainSpain 649649 4949 6060 9999ItalyItaly 813813 8282 6969 9999UKUK 505505 9292 8787 100100GermanyGermany 1,1881,188 9595 8585 100100

a: Japan data (1998) from Sahm, et al. JAC, 2000;45:457-466. Data on file, Ortho-McNeil Pharmaceutical, Inc.

CASE 2: BUGS AND DRUGS

• Most likely pathogens:– Streptococcus pneumoniae– Hemophilus influenzae– Moraxella catarrhalis

• Drug of choice– Amoxicillin

CASE 3. Same 20-month-old girl, 48 hours later, no improvement.

Dx: Refractory AOM

CASE 3: BUGS AND DRUGS

• Most likely pathogens:– Hemophilus influenzae– Moraxella catarrhalis– Could be something weird

• Drug of choice– Amoxicillin/clavulanate

(Augmentin)

CASE 4. A 46-year-old male complains of headache and facial pain aggravated by stooping, and continuous nasal discharge. He says he caught a cold ten days ago and has had symptoms ever since. Decongestants provide little relief.

Dx: Acute bacterial sinusitis

THE PARANASAL SINUSES

(The sphenoid sinuses are between the eyes and located posteriorly)

CASE 4: BUGS AND DRUGS

• Most likely pathogens:– Streptococcus pneumoniae– Hemophilus influenzae– Moraxella catarrhalis

• Drug of choice– Amoxicillin– Some would use Augmentin

CASE 5. A 35-year-old construction worker complains of a tender and swollen right arm. The arm is erythematous and warm to the touch.

Dx: Cellulitis

Most likely pathogens: Staphylococcus aureus, Streptococcus pyogenes

CELLULITIS

ERYSIPELAS

IMPORTANT MILESTONES IN THE HISTORY OF RESISTANT

STAPHYLOCOCCUS AUREUS

EVENTYEA

RCOMMENT

Penicillinase-producing S. aureus appears in

an Oxfordshire constable

1942Penicillin introduced

into clinical practice in 1942

Emergence of MRSA 1961Methicillin approved

in 1961

Emergence of VISA (GISA)

1996Vancomycin approved

in 1958

Emergence of VRSA 2002Reported 3 times so

far

INCREASE IN RESISTANT NOSOCOMIAL INFECTIONS: MRSA

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60

89 90 91 92 93 94 95 96 97 98 99 00

ICU Patients

Non-ICU

Patients

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http://www.cdc.gov/drugresistance/healthcare/ha/slideset.htm

Year

20.3

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MSSA MRSA

Mo

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%

Overall risk = 2.97 (95% CI: 1.12 - 7.88)*

IMPACT OF MRSA ON BACTEREMIA

P = .03

Methicillin resistance is an independent predictor for shock and risk factor for death in S aureus bacteremia†

MRSA is also associated with increased length of stay and higher hospital costs, although data are conflicting (Engemann et al, CID 2003; 36: 592)

*Talon D, et al. Eur J Intern Med. 2002; †Soriano A, et al. Clin Infect Dis. 2000.

S aureus bacteremia: mortality

CASE 5: BUGS AND DRUGS

• Most likely pathogens:– Staphylococcus aureus – Streptococcus pyogenes

• Drug of choice (if using oral therapy)– Cephalexin– Dicloxacillin

• Drug of choice (if using IV therapy)– Cefazolin– Nafcillin

CASE 6. A 67-year-old man is seen by his physician for fever, chills, malaise, and night sweats. A new heart murmur is audible. The man mentions a visit to the dentist a month ago. He has poor dentition.

Dx: Bacterial endocarditis

A GOOD EXAMPLE OF POOR DENTITION

CASE 6: BUGS AND DRUGS

• Most likely pathogens:– Viridans group Streptococcus– Fastidious Gram-negative bacillus

(part of oral flora)

• Drug of choice– Penicillin G (± gentamicin)– Ceftriaxone

CASE 7. A 24-year-old woman develops fever, chills, flank pain, abdominal pain, nausea, and vomiting. She is barely able to get out of bed. She is flushed and diaphoretic.

DX: acute pyelonephritis

Most likely pathogens: E. coli, maybe another enteric Gram-negative bacillus

AUGUST 2003 NNIS REPORT for the period 1/98-6/03

ORGANISM ICU (%)Non-ICU

(%)

Outpt areas (%)

Methicillin-resistant S. aureus 51.6 42.0 25.9

Vancomycin-resistant Enterococcus

12.7 11.5 4.6

Ciprofloxacin-resistant P. aeruginosa

35.8 27.2 23.1

Imipenem-resistant P. aeruginosa 19.4 12.4 7.5

Ceftazidime-resistant P. aeruginosa

13.8 8.5 4.7

3rd-gen ceph resistant Enterobacter

26.6 20.3 9.6

3rd-gen ceph resistant Klebsiella 5.8 5.5 1.8

3rd-gen ceph resistant E. coli 1.2 1.3 0.4

Fluoroquinolone-resistant E. coli 6.2 6.1 2.7NNIS. Am J Infect Control 2003; 31: 481-98

CASE 7: BUGS AND DRUGS

• Most likely pathogens:– E. coli– Maybe another enteric Gram-

negative bacillus

• Drug of choice– Ceftriaxone– Levofloxacin is cheaper

CASE 8. A 56-year-old intubated patient in the ICU recovering from heart surgery spikes to 39.9 C. His WBC is 25,900 with a neutrophil predominance and he has impressive infiltrates on chest x-ray. Sputum Gram stain reveals 4+ WBC, 4+ GNR, 2+ GPC.

Dx: Hospital-acquired pneumonia

PULMONARY INFILTRATES

CASE 8: BUGS AND DRUGS

• Most likely pathogens:– Enteric Gram-negative bacilli,

especially resistant strains– Pseudomonas aeruginosa– Staphylococcus aureus, possibly

MRSA

• Drug of choice– Imipenem/cilastatin or meropenem– Vancomycin might be added

CASE 9. A 55-year-old diabetic male complains of fevers to 38.3, worsening erythema, and purulent drainage from a chronic foot ulcer. His WBC is 14,800 with 83% neutrophils. ESR (erythrocyte sedimentation rate) is 76 mm/hr.

Dx: Diabetic foot ulcer, possible osteomyelitis

CASE 9: BUGS AND DRUGS

• Most likely pathogens:– Just about anything: Gram-

negative bacilli including Pseudomonas, Gram-positive cocci, anaerobes

• Drug of choice– Piperacillin/tazobactam– Ticarcillin/clavulanate