Multiple Small Feedings Of The Mind

Emerging Antibiotic Resistance

Ronald W. Flenner, MD, FACPVice Dean for Academic Affairs

James E. Etheridge Jr. Distinguished ProfessorshipEastern Virginia Medical School

64yo female PMHx significant for HTN, prior CVA, CAD, CHF, and

CKD but negative for previous recurrent infectious illnesses

Presents to the ED with 3d history of dizziness, hematuria, R flank pain, and n/v

VS: T 96.7, HR 85, RR 18, BP 95/50, SpO2 98% WBC 25.1K CT abd/pelvis: (+) evidence of acute pyelonephritis

The patient…

IV ceftriaxone begun while awaiting cultures

Febrile to 102F after admission

Urine cultures returned E. coli sensitive to only amikacin, meropenem, nitrofurantoin, pip/tazo

Blood cultures returned GNB Ceftriaxone stopped; meropenem 500mg IVPB Q12h

started

The admission…

ID consulted, on detailed history she had two MD appointments the preceding Wednesday—one was to OB/GYN.

“[She] noted that it was ‘very hot’ in the exam room and she felt very bad.”

That night, she started having fevers, abdominal pain, vomiting which worsened over the next few days

The consult

Blood cultures returned same organism—E. coli with same susceptibilities

Maintained on Meropenem 500mg IV Q12h

Tmax peaked at 103F on hospital day 4 (Abx day 3) Defervesced slowly

WBCs peaked day of admission but remained elevated without thrombocytosis (range 14.2-23.4)

Cr baseline 1.4-1.6 During admission, peaked at 6.4 on hospital day 5 (abx day 4) but has

trended down since

Clinical course

Expected risk factors: Immunocompromised status Prolonged hospital/SNF stay Chronic indwelling urinary catheter Repeated courses of abx

Her risk factors: none of the above exposure to healthcare a few hours before

symptom onset

So why is this case clinically important?

What are beta-lactams?

First penicillinase in 1944 Early 1980s: 3rd-gen cephalosporins developed in

response to spread of beta-lactamases 1983: first report of a beta-lactamase able to

hydrolyze new cephalosporins 1986: first big outbreak of ESBL-producing bacteria

in France (first in Germany & England, but majority of occurrences in France)

1988: first reports of ESBL-producing bacteria in US

The rise of the beta-lactamases

Extended-spectrum beta-lactamase-producing organisms

Most often Escherichia coli and Klebsiella pneumoniae (>75% of studies on ESBL have addressed K. pneumoniae)

Produces an enzyme (beta-lactamase) via plasmid that destroys the drug—most ESBLs able to hydrolyze penicillins, broad-spectrum cephalosporins, monobactams

ESBL-producing bacteria

Serine-based mechanism of action (classed by amino acid sequence—Ambler classes A, C, D) Serine residue near active site of enzyme irreversibly reacts

with beta-lactam ring This inactivates the beta-lactam and regenerates the enzyme Can be inhibited by clavulanic acid

Ambler class B use a metalloenzyme as a substrate and can hydrolyze 3rd-gen cephalosporins E.g., Stenotrophomonas maltophilia Not inhibited by clavulanic acid, tazobactam Inhibited by EDTA (heavy metal chelator)

The way they work

The rise of the beta-lactamase

TEM-1, TEM-2, SHV-1: “classic” beta-lactamases Oft found in Enterobacteriaceae Active against early penicillins and 1st-gen cephalosporins

SHV-2: G238S this mutation single-handedly accounts for ES properties

TEM-3: extended substrate profile, likely due to overuse of 3rd-gen cephalosporins and aztreonam

Over 100 TEM variants; most qualify as ESBL most are susceptible to suicide inhibitors (clavulanic acid)

CMT1-4: able to hydrolyze 3rd-gen cephalosporins but also have inhibitor resistance

Types of beta-lactamases

MIC of cephalosporins often within susceptible range Variations due to:

genetic differences in resistance determinants varying levels of gene expression variations in spectra of enzymatic activity inoculum effect

In vitro: directly proportional rise in MIC of cephalosporins with increase in ESBL-organism inoculum

The problems with cultures

Plasmids are transferable from strain to strain and between bacterial species

Often occur with: plasmids causing aminoglycoside resistance AmpC beta-lactamase

Associated with increasing fluoroquinolone resistance

Co-resistance

Theoretically beta-lactamase inhibitors should be effective, BUT: Hyperproducing strains may overcome

inhibition Possible presence of AmpC enzyme will make it

resistant to inhibitors

Drug of choice: Carbapenems

Treatment

Increasing incidence of carbapenem-resistant bacterial species, especially Stenotrophomonas and Pseudomonas

CRE: carbapenem-resistant Enterobacteriaceae

IMP-1, IMP-7: Beta-lactamases capable of carbapenem hydrolysis Plasmid-mediated Two types, both metalloenzymes

KPC-1: found in a strain also harboring SHV-29 (ESBL) Possible mechanism: change in affinity of PBPs for carbapenems

Concerns for the future

Study by Ahmad, et al: 8 patients with carbapenem-resistant K. pneumoniae following imipenem No other antibiotic options; six of the eight patients died

Seattle’s Virginia Mason Medical Center 32 cases, 11 deaths Transmitted via endoscopes

Consider tigecycline, polymixins if treating carbapenem-resistant klebsiellae No cross-resistance; mechanisms of resistance are

different

CREs in the community

Extended-spectrum beta-lactamases pose a significant risk to our ability to combat infections with the antibiotics we have

ESBLs come in a variety of types that affect their sensitivities to different drugs

Carbapenems are your drug of choice when treating ESBLs

If you’re facing a carbapenem-resistant ESBL, use tigecycline or Colistin (or something that has a different mechanism of resistance)

Always promote good antibiotic stewardship!

Take-home points

MRSA

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MRSA

Described in 1961 Increase in both Healthcare and Community

settings HA- MRSA

Infections occurring > 48 hours following hospitalization

Surgical site infections

HA- MRSA

Routinely implicated in nearly every type of hospital –acquired infection Biofilm

Risk factors: Antibiotic use Prolonged hospitalization ICU Hemodialysis

HA- MRSA

Risk factors – continued MRSA colonization Proximity to those with MRSA infection or

colonization

HA- MRSA

Higher mortality, longer hospital stays, higher costs vs. MSSA BSI secondary to MRSA – 1.5 – 2.0 fold more

likely to die compared with BSI due to MSSA Higher rates of AKI, hemodynamic instability ,

and prolonged ventilator dependence compared to MSSA

CA- MRSA

Occurs in the absence of healthcare exposure Initially reported in the 1980’s in IVDA population

Now most common cause of SSTI in U.S. Most carry SCCmec type IV or V genes for

cytotoxin Panton- Valentine lukocidin – confers enhanced virulence

CA- MRSA

Risks Animals – may carry MRSA Many patients have no risk factors

HA- MRSA/CA- MRSA

Blurred epidemiologic distinction CA- MRSA may be replacing traditional

hospital-acquired strains

MRSA

Antibiotic use Cephalosporins Fluoroquinolones

HIV InfectionHemodialysisLTCF

MRSA

Transmission HC- MRSA

Transiently contaminated hands of HCW Contaminated environmental surfaces

CA- MRSA Direct contact with colonized or infected individual

Staphylococcal Colonization Ecologic niche of S.aureus is the anterior nares. Carriage rates average 20-25% (increased in

diabetes, dialysis, IVDA). Carriers have a 2 to 10- fold increased risk of

surgical site or IV catheter infections. 30-100% of SSI in nasal carriers are caused by the

strain carried in the nose. 40 different decolonization regimens have been

studied over the last 60 years.

MRSA Colonization Decolonization was attempted with rifampin as part of a comprehensive program to control MRSA in a VA Nursing Home Care Unit.

For rifampin, 92% of baseline isolates were sensitive; after treatment only 43% were sensitive.

Decolonization was “ineffective and potentially hazardous”.

Strausbaugh LJ. Infect Control Hosp Epidemiol 1992;13:151-9.

Mupirocin Decolonization for MRSA

Mupirocin applied to the anterior nares for 5 days can reduce colonization by 90-95%.

Especially valuable in the treatment of HCW’s linked to nosocomial MRSA infections.

Significantly better than bacitracin (94 vs. 44% eradication).

May be much lower clearance with multisite carriage (wounds,etc.): 21-44%.

MRSA Colonization: Mupirocin

All 321 residents of a VA LTCF (Ann Arbor) were cultured; MRSA (+) received mupirocin ointment to nares and wounds.

MRSA was rapidly eliminated by the end of 1 week. Even with weekly maintenance mupirocin, 40%

recurred and 10.8% became mupirocin resistant. Facility colonization rates did not change.

Kauffman CA. Am J Med 1999;94:371-8.

Mupirocin for MRSA

Prevention of CAPD catheter infections (exit site): decreases GPC exit site infections, increases GNR infections. Ritzau J. Perit Dial Int 2001;21:471-9.

Cardiac Surgery: 67% reduction in surgical site infections compared to historic controls; cost $12.47/patient vs. $81,018/deep infection) Ann Thorac Surg 2001;71:1572-8.

Take Home: MRSA and Mupirocin

Highly effective for individuals with nasal colonization, esp. HCW assoc with nosocomial infections.

Less successful with colonization other than nares and attempts at decreasing facility wide colonization rates.

Resistance most likely with long term use. Areas of interest: preoperative to decrease SSI’s

and dialysis (CAPD and HD).

Enterococci

Normal intestinal flora of almost all animals from cockroaches to humans with typical concentrations of 108/gram of stool.

2 predominant species: E. faecalis and E.faecium. E.faecalis causes 80% of human infections, but

only 2% are Vancomycin resistant (VRE). E.faecium causes 20% of human infections, but

52% are VRE. Huycke M. Emerg Infect Dis 1998;4:239-49.

Enterococci and Synercid

E. faecium are almost always sensitive to Synercid (90% of VRE isolates).

E.faecalis are almost always resistant to Synercid (10% of all VRE).

Mechanism of resistance is unknown but similar observations have been reported for Virginiamycins M and S.

Collins L. AAC 1993;37:598-601.

Linezolid (Zyvox)

First antibiotic from the oxazolidinone class.

Inhibits protein synthesis at the bacterial ribosome and is bacteriostatic against Staphylococci and Enterococci.

Active against VRE (both E. faecium and E. faecalis), MRSE and MRSA.

Cure rates have been comparable to vancomycin. Medical Letter 2000;42:45-6 (issue #1079)

Linezolid (Zyvox)

Usual dose is 600 mg. Q12H. Available in 600 mg. tablets, oral solution

and IV formulation. Each 600 mg. tablet is $53 and a 600mg. IV

vial is $72. No dosage adjustment with renal or hepatic

failure.

Linezolid (Zyvox)

Most common adverse events have been nausea, vomiting and diarrhea.

Reversible thrombocytopenia has been reported with prolonged use; monitoring of platelet counts has been recommended if treatment is >2 weeks.

Weak non-selective reversible inhibitor of monoamine oxidase; patients should avoid foods rich in tyramine which could result in severe hypertension.

Linezolid Resistant VRE

Liver transplant recipient with VRE infection treated with linezolid which became linezolid resistant, but remained synercid sensitive.

Strain was transmitted to 6 others, none had overt infection or were treated with linezolid.

Associated with a 23S rDNA mutation which has also been described in a linezolid resistant S. aureus.

Herrero I.NEJM 2002;346:868-9.

Is there ever justification in attempting to eradicate colonization of VRE/MRSA in a patient?

Where are patients colonized with VRE?

For patients with VRE bacteremia:

100% had stool colonization.

86% had skin colonization.

Beezhold D. Clin Infect Dis 1997;24:704-6

VRE Colonization

70% of patients colonized with VRE go undetected without active surveillance.

VRE colonized and VRE infected have similar amounts of VRE in stool (108/gm of stool).

Some remain colonized for > 1 year.

Bacitracin for VRE Colonization Not routinely used to treat systemic infection.

Non-absorbable antibiotic first isolated from a Bacillus species.

Highly active against gram positives.

Acquired resistance unusual.

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Bacitracin for VRE

8 patients treated with bacitracin 25,000u BID x 10d; 5 were repeatedly negative after one course

(1 required 2 courses).

Chia J. Clin Infect Dis 1995;21:1520.

4 LTC facility residents received bacitracin 75,000u QID x 14d; 3 of 4 cleared VRE during therapy, 2 became (+) after 48hrs.

Armstrong-Evans M. Infect Control Hosp

Epidem 1999;20:312-17.

Bacitracin for VRE

All colonized inpatients were treated with bacitracin 25k or 50k units QID.

VRE was suppressed in stools in 50% and 75% in the low and high dose arms ,respectively.

Long term eradication was only 25% and 40%.

McGeer A. 35th ICAAC San Fran 1995 Ab# J142.

Bacteria are Survivors

Many beta lactam antibiotics are natural products of microorganisms (Penicillin from Penicillium notatum and Cephalosporins from Cephalosporium acremonium).

No slackers, others produced beta-lactamases to inactivate the beta lactams gaining a survival advantage over non-producers.

Not to be outdone, other microorganisms counter attacked with beta-lactamase inhibitors (Clavulanic acid was derived from Streptomyces clavuligerus).

Resistant Pneumococcus: How Did It Happen?

Pneumococci imported and integrated DNA sequences for penicillin resistance from other bacterial species through recombination; the most likely suspects are the viridans streptococci in the mouth.

Aminoglycoside resistance gene is the same as the one present in Enterococci and Staphylococci.

Erythromycin resistance gene is the same as the one found in Escherichia coli.

Resistance traits are perfectly stable and allow normal rates of growth.

Pneumococcus Does It All

35% of S. pneunoniae are now PCN resistant; 60% are high level resistant (MIC>2 ug/ml).

High rates of asymptomatic colonization (5-10% of adults and 20-40% of children) and person to person transmission (esp. day care centers).

Driven by the selective pressure of antibiotic use (prior treatment with antibiotics is the #1 risk factor for DRSP infection).

Antibiotic Use and Resistance

Antibiotic use creates a competitive advantage for resistant organisms. Forces the acquisition of resistance by sensitive strains

in self defense. Selects out resistant subpopulations.

Quinolone Resistance in Pneumococcus

Resistance occurs by mutations in the parC and gyrA genes which encode topoisomerase enzymes, the target of quinolones.

Resistance occurs as a stepwise process with mutation in the primary target followed by a second step mutation (occurs much more easily than first step mutations).

Spontaneous mutations occur at a rate of 1 in 106 -109 . Mutants are much more likely to be selected when

quinolones are used to treat patients with pneumococcal pneumonia (up to 1010 organisms/ml of sputum) than with simple colonization.

Levofloxacin and MPC Mutant Prevention Concentration (MPC) is the level of

antibiotic at which no mutant can be recovered from >10 billion cells exposed to the drug.

For levofloxacin, the MPC for the pneumococcus is near or above the maximal serum concentration.

MPC for moxifloxacin is below the serum level for 90% of isolates.

Rate of selection of first step mutants is 1000x higher for levofloxacin than moxifloxacin.

AAC 2002;46:522-4. Has led some to suggest that levofloxacin may become a

“class killer”.

Lancet Infect Dis 2001;1:145-6.

Beginning of the End or the End of the Beginning

4 cases of levofloxacin failure with pneumococcal pneumonia.

2 isolates were sensitive at baseline ( acquired resistance during therapy) and 2 patients had prior courses of quinolones (selection of resistant subpopulation).

Davidson R N Engl J Med 2002;346:747-50.

Levofloxacin Resistant Pneumococcus

National Committee for Clinical Laboratory Standards (NCCLS) does not currently recommend routine quinolone susceptibility testing for pneumococci.

Current ATS and IDSA guidelines for treatment of CAP do not mention prior quinolone exposure as a potential problem.

“In our opinion,the current data indicate that recent exposure to a fluoroquinolone should be a contraindication to the use of another fluoroquinolone for the empirical treatment of community acquired pneumonia.”

Davidson R N Engl J Med 2002;346:747-50.

Macrolide Resistant Group A Streptococcus

No macrolide resistance was noted in Group A Streptococci from Oct 1998 to May 2000 in Pittsburgh during a longitudinal study at an elementary school.

48% of isolates were resistant to erythromycin from Oct 2000 to May 2001., all were the same strain.

Occurred during a time of increased macrolide use. Strep throat often diagnosed with a non-culture technique

and even if cultured routine sensitivities are not performed. Martin J. N Engl J Med 2002;346:1200-6.

Lessons Learned

Bacteria are promiscuous.

Bacteria are survivors.

Antibiotic use adds to the natural selection pressure giving an advantage to resistant strains.

Take Home Message

The More You Use It, The Faster You Lose It!