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Microbiology and Antibiotic Therapy of Oral and Maxillofacial Infections

Thomas R. Flynn, DMD

CALAOMS Meeting: January 18, 2015 1

MICROBIOLOGY AND ANTIBIOTIC THERAPY OF ORAL AND

MAXILLOFACIAL INFECTIONS (Bugs and Drugs)

CALAOMS Annual Meeting

January 18, 2015

Palm Springs, CA

Thomas R. Flynn, D.M.D., Reno, NV

[email protected]

GOALS OF THIS SESSION

•  Update and review microbiology

•  Discuss the 10 principles of antibiotic therapy •  Provide for informal discussion

Objectives: Better Practice

1.  The changing microbiology of orofacial infections

2.  Today’s and tomorrow’s culturing techniques

3.  Cost-effective use of new and old antibiotics

4.  Pharmacology of the commonly used antibiotics

PRINCIPLES OF ANTIBIOTIC THERAPY

1.  Surgery to remove the cause and establish drainage is primary; antibiotics are adjunctive treatment.

2.  Use therapeutic antibiotics only when clinically indicated.

3.  Use specific antibiotic therapy as soon as possible, based on culture and sensitivity testing.

4.  Follow the guidance of evidence-based recommendations and professional guidelines when they are available.

5.  Use the narrowest spectrum empiric antibiotic effective against the most likely pathogens.

PRINCIPLES OF ANTIBIOTIC THERAPY (cont.)

6.  Use the least toxic indicated antibiotic, considering interaction with concurrent medications.

7.  Avoid the use of combination antibiotics, except in specific situations where they are shown to be necessary.

8.  Minimize the duration of antibiotic therapy, as appropriate to the presenting type of infection.

9.  Use the most cost-effective appropriate antibiotic.

10. Use prophylactic antibiotics only where proved effective or according to professional guidelines.

THE CHANGING MICROBIOLOGY OF

ODONTOGENIC INFECTIONS

•  MAJOR PATHOGENS •  CHANGING NOMENCLATURE •  BACTERIAL INTERACTIONS •  ANAEROBIC PROGRESSION •  IMMUNE SYSTEM COMPROMISE




MAJOR PATHOGENS OF OROFACIAL INFECTIONS

Type of Infection Early Lesions

Mature Lesions

Microorganism Streptococcus milleri group

S. viridans group

Peptostreptococcus spp

Prevotella spp

Fusobacterium spp

Most Frequent Pathogens in Orofacial Infections

Species Sakamoto(‘98) Heimdahl(‘85)

Strep milleri group 65% 31%

Peptostreptococci 65 31

Other anaerobic streps 9 38

Prevotella spp 74 35

Porphyromonas spp 17

Fusobacterium nucleatum 52 43

Bacterial Interactions in Odontogenic Infections

*Brook, Int J Pediatr Otorhinolaryngol 74:447, 2010

•  The streptococcus-anaerobe combination •  Dependence of anaerobes on other organisms •  Anaerobic progression •  Release of penicillinase •  Bacterial interference

•  Non-pathogens can inhibit colonization by pathogens

–  Smokers and their children have more pathogens! *

ORAL STREPTOCOCCI New Species Nomenclature

Old Name Streptococcus viridans

New name Streptococcus anginosus

intermedius

constellatus

mutans

sanguis

mitis

salivarius

vestibularis

Brown= abscesses; Green = caries; Red = endocarditis

STREPTOCOCCUS MILLERI New Species Nomenclature

Old Name Streptococcus milleri

New name Streptococcus

anginosus

intermedius

constellatus

(Also known as S. milleri group)

ORAL ANAEROBIC STREPTOCOCCI

New Genus Nomenclature

Old Name Peptococcus

Newer name Peptostreptococcus

Newest name Anaerococcus

or Parvimonas




ORAL BACTEROIDES New Genus Nomenclature

Prevotella melaninogenica

Intermedia

oralis

buccae (Ohio State)

loeschii

denticola

ruminicola

nigrescens (new)

Porphyromonas asaccharolyticus

gingivalis

endodontalis

circumdentaria (new)

salivarius (new)

Molecular methods have further changed nomenclature

Gemella morbillorum -alpha-hemolytic streptococcus

•  May be mistaken for S. viridans

•  Oral flora: gingival sulcus

•  Found in 22% of odontogenic infections (90% perio-related)

•  Also endocarditis, sinus, respiratory infections

•  May be Penicillin resistant

•  In severe infections: use Vancomycin + β-lactam + aminoglycoside or Metronidazole

Kuriyama et al. Oral Micro Immun 17:132, 2002; Vashistha et al. Clin Infect Dis 22:1084, 1996

MICROBIOLOGY OF OROFACIAL INFECTIONS

AEROBES ONLY 6%

MIXED 44%

ANAEROBES ONLY 50%

Brook, Frazier, & Gher: Oral Microbiol Immunol, 1991

MAJOR PATHOGENS OF OROFACIAL INFECTIONS

Type of Infection Early Lesions

Mature Lesions

Microorganism Streptococcus milleri group

S. viridans group

Peptostreptococcus spp

Prevotella spp

Fusobacterium spp

MICROBIOLOGY OF SINUSITIS

Brook, Proc Am Thorac Soc 8:90, 2011

MICROBIOLOGY OF SINUSITIS

Brook, Proc Am Thorac Soc 8:90, 2011

• Normal - No growth in 25-50%

• Acute – Aerobes –  (MRSA = 60-70% of S. aureus)

• Chronic – Anaerobes

• Nosocomial – Enteric Gram-negative rods – Pseudomonas, Klebsiella, Enterobacter,

Proteus, Serratia




MICROBIOLOGY OF OTHER HEAD AND NECK

INFECTIONS Brook, et al.

•  Cellulitis – streps and staph, still some anaerobes, esp. head and neck

•  Odontogenic sinusitis – same organisms but fewer

•  Rhinogenic orbital infections – same organisms but fewer

MICROBIOLOGY OF MEDIASTINITIS

Brook, et al.

• Post-sternotomy – Staph aureus

• Other mediastinitis (odontogenic, gunshot wounds)

– Same as orofacial pathogens

MICROBIOLOGY OF NECROTIZING FASCIITIS

Brook, et al.

•  Polymicrobial (Local flora) –  4.6 isolates per case –  Head and neck:

orofacial pathogens –  Perineal: abdominal

and G-U pathogens •  Group A beta-hemolytic

streptococci •  Clostridial •  MRSA •  Klebsiella

Microbiology of Orofacial Infections in Immunocompromised

Patients

• Diabetes – Klebsiella*

•  I.V. Drug Abuse – MRSA • HIV - Intracellular pathogens (M. avium)

– Multi drug resistant TB – HIV-P and HIV-G (same flora as periodontitis)

*Huang TT, et al. Acta Otolaryngol 126:396, 2006 * Lee, et al.: Yongsei Med J 2007:48:55-62

Practical Culturing Techniques

• When is culturing necessary?

• The use of culturettes • Gram stains

• What if antibiotics are already in use? • New bacterial identification techniques

Molecular methods may soon be more rapid and accurate

When is Culturing Necessary?

• Serious, potentially life-threatening infections

• Chronic, recalcitrant infections • Previous, multiple antibiotic therapy

•  Immunocompromised patient

Principle 3: Use specific antibiotic therapy as soon as possible, based on culture and sensitivity testing.




Culturettes

• Aerobic and anaerobic

– watch expiration dates

• More practical for the office than syringes

The Role of the Gram Stain

•  Accurate early diagnosis

•  A guide for antibiotic therapy

The “True” Flora of Orofacial Odontogenic Infections

• 69% unculturable

• 6-18 species per case

• Dialister pneumosintes, Parvimonas micra, Fusobacterium in 78%

• Eubacterium brachy, Prevotella oris in 67%

Flynn, et al. JOMS 70:1854, 2012

Molecular Techniques for Diagnosis of OMF Infections

Even Newer Techniques • Real-time PCR: results in 1 hour

• Screening for MRSA, epidemic pathogens • Rapid culture and sensitivity testing by molecular methods

• Problem: which resistance genes are “turned on”?

When antibiotic therapy has already begun

• Oral antibiotics only (PCN 5.6 v. 20 µg/mL)

• Penetration of antibiotics into abscess cavities

– Clindamycin is best abscess penetrator – Abscess concentration = 33% of serum

concentration

• Yield of cultures is still good

“Normal Oral Flora” - So what??

• Medicolegal protection • Empiric antibiotics should be effective • Severe (hospitalized) cases:

–  Eikenella corrodens grows on clindamycin –  Penicillin-resistant strains in 55% of cases –  Penicillin failure in 21% of cases –  Clindamycin-resistant strains in 17% of cases




ANTIBIOTIC RESISTANCE

• Resistance Rates Among Oral Pathogens

• Penicillin Resistance in Hospitalized Cases

• Highly Resistant Organisms

Principle 2: Use therapeutic antibiotics only when clinically indicated.

INCREASING ANTIBIOTIC RESISTANCE RATES IN ODONTOGENIC INFECTIONS

Year % of Cases PCN Resistant

Country

1991 (Brook, et al.) 33 USA

1992 (von Konow, et al.) 38 Sweden

1995 (Lewis, et al.) 55 UK

1999 (Flynn, et al.) 54 USA

ANTIBIOTIC RESISTANCE IN ORAL STREPTOCOCCI

Erythromycin resistance rates high

Organism(s) PCN Clindamycin S. milleri

group

(abscesses) 0 – 3% 0 –17%

and rising! S. mitis, oralis,

sanguis (endocarditis)

58% 0%

ANTIBIOTIC RESISTANCE IN PREVOTELLA AND PORPHYROMONAS

• Historically 23-25% (PCN)

• Recently 38% -Pediatric study (prior antibiotics)

-Brook: J Med Microbiol 42:340, 1995

Montefiore study overview

• Prospective case series of 37 patients

• Pen G IV unless allergic (allergic pts. placed on clindamycin)

• Prompt I&D and C&S by aspiration of pus/wound fluid

• Species identification and PCN and Clindamycin sensitivity testing in 24 cases

Flynn, et al.: JOMS 64:1093-1103, 2006; Flynn, et al.: JOMS 64:1104-1113, 2006

Penicillin Therapeutic Failure Failure of improvement in temp, WBC, and

swelling after:

•  48 h of IV PCN 2 m.u. q4h •  Postop CT demonstrating adequate

drainage •  Isolation of PCN-resistant organisms •  Toxicity or allergic reaction

Principle 1: Surgery to remove the cause and establish drainage is primary; antibiotics are adjunctive treatment. Principle 3: Use specific antibiotic therapy as soon as possible, based on culture and sensitivity testing.




Montefiore Study Results

Penicillin Failure

•  PCN used in 33 pts., clindamycin in 3 pts., triple AB’s in 1 with necrotizing fasciitis

•  PCN therapeutic failure in 7/33 pts = 21%.

•  All 7 had PCN resistant strains = 100%.

•  PCN resistance in 13/24 pts. = 54%

•  Therapeutic failure of PCN in pts. with PCN-resistant bacteria: 6/10 pts. = 60%

Flynn, et al: JOMS 2006;64:1093-1103 and 1104-1113

Montefiore Study Results Clindamycin resistant cases

• Clindamycin-resistant strains in 4/24 pts. = 17%

• Therapeutic failure of clindamycin in 0/3 pts. = 0%

Flynn, et al: JOMS 2006;64:1093-1103 and 1104-1113

Penicillin and Clindamycin

Resistant Strains

• Bacterial strains isolated (N=90)

• % of Isolates – PCN resistant strains = 17/90 = 19%

– Clindamycin resistant strains = 4/90 = 5% – PCN and Clindamycin resistant = 1/90 = 1%

CLINDAMYCIN RESISTANCE IN ORAL INFECTIONS RECENT EXPERIENCE AT

MASS GENERAL HOSPITAL

• Clindamycin was the antibiotic of choice, regardless of penicillin allergy

• 11 cases of treatment failure or postoperative infection after prophylactic clindamycin

• All successfully rescued with penicillins

Effect of antibiotic therapy on PCN resistance in

upper respiratory tract infections PCN treatment for pharyngitis (7days) % resistant

(cases)

Before treatment 12

End of Treatment: Patient 46

End of Treatment: Parents and sibs 45

3 months after treatment 27

Brook, Arch Otolaryngol Head Neck Surg 114:667, 1988

Effect of antibiotic therapy on PCN resistance

in upper respiratory tract infections

Throat swab cultures in children: Monthly variation in PCN resistance

% PCN resistant (cases)

September (trough) 13

April (peak) 60

Brook, et al., Pediatr Infect Dis J 16:255, 1997




Antibiotic Resistance Mechanisms Mechanism Example

Antibiotic inactivation Betalactamases, adenylyl transferases (aminoglycosides)

Receptor site modification

PBP’s, D-ala-D-ala (vancomycin), DNA gyrase (fluoroquinolones), methylated RNA, (macrolides)

Membrane pore deletion

Deleted porins in K. pneumoniae & E. coli (cephalosporins, imipenem, aztreonam)

Active transport pumps tet A (tetracyclines), erm (erythromycin)

Sundsfjord, et al: APMIS 112:815, 2004; Jacoby G, et al: NEJM 352:380-391, 2005

Mechanisms of PCN Resistance

Mechanism Pathogens

Betalactamases

S. aureus, S. epidermidis, H. influenzae, Prevotella, Porphyromonas, Capnocytophaga, Eikenella, Fusobacterium

Altered PBP’s (trans-, carboxy-, and endopeptidases)

MRSA, S. pneumoniae, S. sanguis

Reduced permeability K. pneumoniae, P. aeruginosa, S. marcescens, E. coli

ANTIBIOTICS FOR COMMUNITY-ACQUIRED MRSA

Gilbert, et al: Sanford Guide to Antimicrobial Therapy, 2012

Outpatient, Immunocompetent* Febrile,

Immunocompetent Bacteremia/Sepsis or Endocarditis

TMP/SMX- DS (160 – 320 bid) Vancomycin or

Linezolid (IV) Vancomycin ↔ Daptomycin (IV)

Doxy- or minocycline (100 po bid)

*If abscess, I&D is most important

Daptomycin + Naf-, Oxacillin or

Ceftaroline or Telavancin

Clindamycin (300-450 tid)

*If complicated switch to Vanco after 2-3 d Linezolid (bacteriostatic)


Principle 7: Avoid the use of combination antibiotics, except in specific situations where they are shown to be necessary.

VRSA

• Community transmission of van A gene from enterococci to MRSA has been reported

• Linezolid or telavancin • Daptomycin +/- ceftaroline or

oxacillin, based on C&S

MULTIDRUG RESISTANT VIRIDANS STREPTOCOCCI

MDRVS •  19 yr old female with congenital and valvular heart

disease, kidney and liver transplants •  On daily penicillin & T/S prophylaxis, prednisone •  Osteomyelitis after extractions •  Resistant to PCN, clinda, cephs, vanco, macrolides •  Treated with moxifloxacin

Ang, et al: Southern Medical Journal 101:539, 2008

VANCOMYCIN RESISTANT ENTEROCOCCI:

VRE •  ENDOCARDITIS •  PROSTHETIC IMPLANT INFECTIONS •  “BROKER” OF ANTIBIOTIC

RESISTANCE GENES




OTHER HIGHLY RESISTANT ORGANISMS

• KPC and NDM-1 Enterobacteriaceae (Superbugs)

• S. pneumoniae

– PCN and multi-resistant types – Altered PBP’s (PCN binding proteins)

• S. epidermidis

KLEBSIELLA PNEUMONIAE CARBAPENEMASE AND NDM-1 • Metallobetalactamases (bla gene)

• New Delhi metalloproteinase-1 = NDM-1 • NDM-1 associated with medical care in India

• Resistance to all betalactams except monobactams

• Monobactam resistance carried on the plasmid by a separate gene, however

• Carbapenem + Polymixin E (Colistin)

A NEW SUPERBUG EPIDEMIC?

• 8% of Klebsiella pneumoniae strains are KPC formers (increasing)

• Highest concentration in Northeast; expected to be “prominent mechanism”

• E. coli, K. pneumoniae, Enterobacter, Proteus, Citrobacter, Acinetobacter, Pseudomonas

• Resistant to all antibiotics except carbapenem + Polymixin E (Colistin)

• KPC has been found in meat CDC. MMWR 59:750, June 25, 2010; Hirsch & Tam. J Antimicrob Chemother doi: 10.1093/jac/dkq108, accessed 9.18.10

NON-ANTIBIOTIC STRATEGIES FOR HRO’s

• HANDWASHING !!!!! •  Isolation and aseptic technique • Limit # of caregivers • Minimize/remove colonizing sites (devices,

esp. in VRE) • Minimize patient transport • Minimize LOS in ICU’s, etc. • Disinfect entire units

EMPIRIC ANTIBIOTICS OF CHOICE FOR

ODONTOGENIC INFECTIONS

• Outpatient infections • Severe (hospitalized) infections

Why Amoxicillin Is the Empiric Drug of Choice for Outpatient

Odontogenic Infections

Principle 5: Use the narrowest spectrum empiric antibiotic effective against the most likely pathogens

Principle 9: Use the most cost-effective appropriate antibiotic.




Systematic Review

Trials of Antibiotics in Odontogenic Infections

Randomized Clinical Trial Antibiotics Tested Result

Gilmore WC, Jacobus NV, Gorbach SL, et al. 1988 PEN V v. CLINDA NSD

von Konow L, Nord CE, 1983 ORNIDAZOLE v. PEN V NSD

Mangundjaja S, Hardjawinata K, 1990 CLINDA v. AMPICILLIN NSD

Lewis MA, Carmichael F, MacFarlane TW, et al., 1993 AMOX/CLAV v. PEN V NSD

Davis WM Jr, Balcom JH 3rd, 1969 LINCO (im&po) v. PCNG (im&po) NSD

Matijević S, Lazić Z, Kuljić-Kapulica N, , et al., 2009 AMOXICILLIN v. CEPHALEXIN NSD - Antibiotic groups had shorter treatment time than surgery alone (NSD)

Ingham HR, Hood FJ, Bradnum P, , et al., 1977 METRONIDAZOLE v. PENG (IM QD) NSD

Al-Nawas B, Walter C, Morbach T, et al., 2009 MOXIFLOXACIN v. AMOX/CLAV NSD

Systematic Review of Effectiveness

Conclusions

1.  The usual antibiotic choices are generally equally effective, given appropriate surgery

2.  Surgery alone may be effective, but time to cure may be shorter when antibiotics are used.

3.  Antibiotic selection is appropriately based on pharmacologic safety, cost, and past medical history.

Flynn: OMS Clinics N. America, Nov. 2011

Principle 5: Use the least toxic indicated antibiotic, considering interaction with concurrent medications. Principle 9: Use the most cost-effective appropriate antibiotic.

Does an antibiotic prescription prevent severe infection?

In patients with toothache •  Randomized clinical trial of Penicillin V or placebo in patients

presenting to ER with toothache (Vicodin given for pain relief)

– 13 of 134 patients with toothache developed severe infection (swelling, fever, pus drainage, or trismus) = 10%

– No difference between PCN and placebo groups for these parameters

– No difference in pain between antibiotic and placebo groups

– Positive correlation with developing severe infection: Existing amalgam, PAP > 1.5 mm

• Conclusion: Definitive dental treatment for toothache with existing amalgam and large PAP within 5-7d, not antibiotics (Grade A)

Brennan, et al: JADA 137:62-66, 2006

Comparative Costs of Oral Antibiotics

Antibiotic Cost per week Amoxicillin Cost Ratio

Amoxicillin 500 tid $11.99 1.00

Penicillin V 500 qid $13.99 1.17

Augmentin 875 bid $49.69 4.14

Ceftin® 500 tid $64.99 5.42

Clindamycin 150x2 qid $43.99 3.67

Metronidazole 500 qid $22.89 1.91

Moxifloxacin 400 qd $96.99 8.09

Linezolid 600 bid $2,311.99 192.83

Comparative Costs of I.V. Antibiotics

Includes $4.00 per dose I.V. administration cost

Antibiotic Cost per week Clinda Cost Ratio

Pen G 2 m.u. q4h $721.89 3.11

Ampicillin 1 g q6h $345.24 1.49

Unasyn 3 g q6h $656.88 2.83

Ceftriaxone 1 g q24h $57.26 0.25

Clindamycin 900 q8h $231.91 1.00

Metronidazole 500 q6h $182.00 0.78

Moxifloxacin 400 qd $322.00 1.39

Vancomycin 1g q12h $159.88 0.69

Linezolid 600 q12h $1,757.34 7.49

AMOXICILLIN vs. PENICILLIN

•  EFFECTIVENESS –  Amoxicillin: less swelling d 1 and 7 in children

(Paterson, et al., 1993) –  20-30% of oral anaerobes Amoxicillin – resistant*

•  Up to 81% of oral anaerobes PCN – resistant * •  COMPLIANCE – TID vs. QID DOSING •  COST - SLIGHTLY CHEAPER

*Boyanova, et al. J Med Microbiol 55:1285, 2006




Empiric Antibiotics of Choice

Outpatient Infections

Inpatient Infections

Amoxicillin

Clindamycin

Azithromycin

Ampicillin + Sulbactam

Clindamycin

Ampicillin + Metronidazole

Empiric Antibiotics of Choice Penicillin Allergy

Outpatient Infections

Inpatient Infections

Clindamycin

Azithromycin

Moxifloxacin

Clindamycin

Ceftriaxone

Moxifloxacin (E. corrodens)

Vanco + Levo + Metronidazole?

ANTIBIOTICS FOR PARAPHARYNGEAL (sic)

INFECTIONS • CLINDAMYCIN

• PENICILLIN + METRONIDAZOLE • AMPICILLIN + SULBACTAM

– OR OTHER β-LACTAM + BLI • MAY ADD METRONIDAZOLE TO

OTHER ANTIBIOTICS Gilbert, et al: Sanford Guide to Antimicrobial Therapy, 2014

ANTIBIOTICS FOR SEVERE ODONTOGENIC INFECTIONS

• AMPICILLIN + SULBACTAM

• CLINDAMYCIN • CEFTRIAXONE (Rocephin®)

• MOXIFLOXACIN

Considerations: Blood-brain barrier, IV vs. PO absorption, Resistance, Drug interactions

ANTIBIOTICS FOR NECROTIZING FASCIITIS

•  POLYMICROBIAL (odontogenic)

–  Carbapenem (imi-, meropenem)

•  STREPTOCOCCAL (Group A, C, G)

–  Penicillin G + Clinda

•  CLOSTRIDIAL

–  Penicillin G + Clinda

•  MRSA

–  Imipenem + vanco- daptomycin

•  KLEBSIELLA

–  Carbapenem (+ Colistin if KPC/ESBL+)

EMPIRIC THERAPY:

Carbapenem + Vancomycin


Gram stain + C&S

Principle 7: Avoid the use of combination antibiotics, except in specific situations where they are shown to be necessary.

ANTIBIOTICS FOR OSTEOMYELITIS BASED ON BONE CULTURES

•  BONE SPECIMENS FOR CULTURE –  Extraoral harvest ideal –  Culturettes or sterile cup

•  LONG TERM ANTIBIOTICS (6 weeks?) –  Fluoroquinolones, Augmentin helpful in avoiding PICC

line, e.g. in IVDA –  Decreasing urine Lysylpyridinoline (LP) → treatment

success –  Normalization of CRP?, ESR?

•  REALLY LONG TERM FOR ACTINOMYCOSIS (6 months)

*Springer, et al: IJOMS 2007;36:527-32




MRONJ: DENOSUMAB BLACK-PIGMENTED BONE + SINUS = AUGMENTIN

ANTIBIOTICS FOR ACUTE BACTERIAL RHINOSINUSITIS

• FIRST LINE ANTIBIOTICS (LOW RISK OF RESISTANCE)

– Amoxicillin/clavulanate 2000 mg po bid x 5-7d

• PENICILLIN ALLERGY – Doxycycline 100 mg po bid

– Levofloxacin 750 mg po qd (anaphylactic PCN allergy, or clinda 30-40 mg/kg/d in children)

– Cefpodoxime (non-anaphylactoid PCN allergy in children)

Gilbert DN, Chambers, HF, et al: Sanford Guide to Antimicrobial Therapy, 2014

ANTIBIOTICS FOR ACUTE BACTERIAL RHINOSINUSITIS

• SECOND LINE ANTIBIOTICS FOR ↑ RISK OF RESISTANCE

•  (↕AGE, RECENT AB’S, RECENT HOSP., IMMUNOCOMPROMISE, COMORBIDITIES)

– High-dose amoxicillin/clavulanate 2g or 90mg/kg/day po bid

– Moxifloxacin 400 mg po qd (or other FQ)


Principle 4: Follow the guidance of evidence-based recommendations and professional guidelines when they are available.

ANTIBIOTIC STRATEGY IN FEBRILE NEUTROPENIA

Absolute Neutrophil Count < 500; T > 38o C

•  Low risk (no mucositis) –  Cipro + Augmentin

•  High risk (with mucositis) –  Cefepime, carbapenem, piperacillin-

tazobactam, or –  Add vanco for IV site infection, MRSA –  Add vanco- + tobramycin + echinocandin

for sepsis/shock •  Persistent fever > 5d (think fungi)

–  Echinocandin or voriconazole Gilbert, et al: Sanford Guide to Antimicrobial Therapy, 2014

DURATION OF ANTIBIOTIC THERAPY

SHORT COURSES MINIMIZE RESISTANCE

Amoxicillin: 3d vs. 7d course had equally good results. Chardin, et al.: J Med Microbiol 2009;58:1092-7

Type of Infection Duration of Antibiotic Odontogenic 3 - 4 d Sinusitis 5d (adults) - 10 d (kids) Osteomyelitis 42 d (until ESR WNL?) Actinomycosis 42 (Sanford) - 180 d (OMS)

Principle 8: Minimize the duration of antibiotic therapy, as appropriate to the presenting type of infection.

WHEN TO CHANGE ANTIBIOTICS

•  ALLERGIC OR TOXIC REACTION

•  AT LEAST 48 h OF I.V. ANTIBIOTIC (72 h FOR ORAL)

•  DETERIORATION AFTER REPEAT I&D AND/OR POSTOP CT

•  C&S REPORT INDICATING RESISTANCE

•  NECROTIZING FASCIITIS




A QUESTION FOR YOU

WHEN DO YOU USE ANTIBIOTICS FOR 3M SURGERY?

A. H/o pericoronitis B. Difficult impactions C. A and B D. Always E. Never

A QUESTION FOR YOU

WHEN DO YOU START ANTIBIOTICS FOR 3M SURGERY?

A. 2 days or more preop B. Orally, 2h or less preop C. At start of the IV D. Take-home prescription E. Not unless infection develops postop

EVIDENCE BASE FOR PROPHYLACTIC ANTIBIOTICS IN

THIRD MOLAR SURGERY

• Prior pericoronitis increases infection risk

• Topical tetracycline decreases risk of infection and dry socket

• Preop antibiotic decreases infection risk • Short postop course decreases infection risk

Ren, et al. Antibiotic Prophylaxis in Third Molar Surgery. JOMS 65:1909-21 2007. Halpern, et al. Inflammatory Complications After Third Molar Surgery. JOMS 65:177, 2007. Lodi G, et al. Antibiotics to prevent complications following tooth extractions. Cochrane Database Syst Rev. 2012 Nov 14;11:CD003811

POLICY ON ANTIBIOTIC RESISTANCE

ADA Council on Scientific Affairs

• Antibiotic resistance is a growing problem • Narrow spectrum antibiotics for simple cases

– Penicillin – Metronidazole – Clindamycin in PCN allergy

ADA Council on Scientific Affairs. JADA 135:484-7, 2004

Principle 10: Use prophylactic antibiotics only where proved effective or according to professional guidelines.

POLICY ON ANTIBIOTIC RESISTANCE

ADA Council on Scientific Affairs

•  Broad spectrum antibiotics for complex cases

–  Amoxicillin, ampicillin

–  Augmentin for sinus infections

–  Cephalosporins

–  Macrolides

–  Tetracyclines

ADA Council on Scientific Affairs. JADA 135:484-7, 2004

SIMPLE VS. COMPLEX ODONTOGENIC INFECTIONS

•  SIMPLE

–  Swelling limited to the alveolar process and vestibular space

–  First attempt at treatment

–  Nonimmunocompromised patient

•  COMPLEX

–  Swelling extending beyond the vestibular space

–  Failed prior treatment

–  Immunocompromised patient

Flynn: Principles of mgmt of odont infections, Peterson, Contemporary OMS, 2008




SYSTEMATIC REVIEW ON PROPHYLACTIC ANTIBIOTICS IN

DENTISTRY

•  Follow AHA/AAOS Guidelines •  Late prosthetic joint infection risk < anaphylactic

shock risk •  Indications for wound infection prophylaxis:

–  Immunocompromise, including fair/poor IDDM control (Hgb A1c < 7.0)

–  Cranial shunts: VA shunts, not VP shunts –  Dialysis shunts

Tong DC, Rothwell BR. JADA 131:366-74, 2000

SYSTEMATIC REVIEW ON PROPHYLACTIC ANTIBIOTICS IN

DENTISTRY

“Aside from the specific situations described, there is little or no scientific basis for the use of antibiotic prophylaxis in dentistry. The risk of inappropriate use of antibiotics and widespread antibiotic resistance appear to be far more important than any possible perceived benefit.

“Dentists are wise to use antibiotic prophylaxis in only those specific situations in which there is a valid scientific basis for it.”

Tong DC, Rothwell BR. JADA 131:366-74, 2000

WEAKNESSES OF STUDIES ON LPJI

•  TWO RECENT CASE CONTROL STUDIES:

–  Dental Procedures + Antibiotic Prophylaxis followed by LPJI

–  OUTCOME VARIABLE = ALL CASES OF LPJI

–  No significant difference between cases with and without prophylaxis

•  INFECTING BACTERIA IN THE SUBSEQUENT LPJI:

–  Staphylococci = 58%

–  Oral flora = 15%

•  SUBSET OF LPJI DUE TO ORAL BACTERIA – INSUFFICIENT DATA

–  No microbiologic data in JADA study (Medicare data set)

–  Insufficient statistical power in CID study

•  IT IS UNFAIR TO EXPECT AMOXICILLIN OR CLINDAMYCIN TO PREVENT LPJI DUE TO RESISTANT BACTERIA!

Skaar DD, et al.: JADA 142:1343, 2011; Berbari EF, et al: Clinical Infectious Diseases 50:8, 2010.

REVISED GUIDELINES ON LPJI 12/18/2012

•  The practitioner might consider discontinuing the practice of routinely prescribing prophylactic antibiotics for patients with hip and knee prosthetic joint implants undergoing dental procedures.

• Grade of Recommendation: Limited = quality of evidence unconvincing or quality studies show little clear advantage of one approach vs. another.

• Implications: Practitioners should be cautious in deciding whether to follow a recommendation classified as Limited, and should exercise judgment and be alert to emerging publications that report evidence. Patient preference should have a substantial influencing role.

A QUESTION FOR YOU

WHEN WILL YOU USE PROPHYLACTIC ANTIBIOTICS IN PATIENTS WITH PROSTHETIC JOINTS?

A. With h/o LPJI B.  In immunocompromised patients C. For joints < 2 years old D. A, B, and C E. Never

Indications for therapeutic antibiotics Swelling Fever Osteomyelitis

USE OF ANTIBIOTICS

Indications for prophylactic antibiotics Endocarditis risk Prosthetic joint infection risk Infection-prone surgery

Orofacial infection present

Risk of infection

Inpatient

Outpatient

Osteomyelitis

Infection-prone surgery

Endocarditis Risk

Prosthetic Joint Infection Risk

Clindamycin

Ampicillin/Sulbactam*

3rd/4th Generation Fluoroquinolone

Penicillin*

Clindamycin

Moxifloxacin

Clindamycin

Ampicillin/Sulbactam*

3rd/4th Generation Fluoroquinolone

Culture and sensitivity

Failure of empiric antibiotic

Culture and sensitivity

Culture and sensitivity at debridement

Specific antibiotic therapy based on:

Culture and sensitivity results

Response to empiric antibiotic

Transoral

Transcutaneous

Follow AHA/ADA guidelines

Follow AAOS/ADA guidelines

Penicillin*

Clindamycin

Cefazolin**

Clindamycin

*Avoid in Penicillin Allergy ** Caution in PCN Allergy




NEW ANTIBIOTICS Useful to OMS: oral administration

• Macrolides: Azithro- vs. Clarithromycin • Fluoroquinolones: Cipro- vs.

Moxifloxacin • Ketolides: Telithromycin, Cethromycin

(hepatotoxic) • Oxazolidinone: Linezolid

CLARITHROMYCIN vs. AZITHROMYCIN

•  MACROLIDE ANTIBIOTICS (Biaxin® & Zithromax®)

•  LESS GI UPSET THAN ERYTHROMYCIN

•  ONCE OR TWICE PER DAY DOSING

•  BACTERIOSTATIC OR – CIDAL PROTEIN SYNTHESIS INHIBITOR – AZITHROMYCIN CONCENTRATES IN PHAGOCYTES 10-15X

•  CYTOCHROME P450 DRUG INTERACTIONS WITH BIAXIN ONLY

•  AZITHROMYCIN MORE EFFECTIVE FOR PEPTOSTREPTOCOCCI

•  AZITHROMYCIN EFFECTIVE IN OMF INFECTIONS*

* Al-Belasy, et al. JOMS 61:310, 2003

Principle 6: Use the least toxic indicated antibiotic, considering interaction with concurrent medications.

MOXIFLOXACIN (AVELOX®)

•  NEW 4th GENERATION FLUOROQUINOLONE (w/ gemi-, sparfloxacin)

•  STREPS, ANAEROBES, EIKENELLA

•  ONCE PER DAY DOSING PO AND IV; WELL ABSORBED: AVOID ANTACIDS, DAIRY, IRON

•  LIGHTHEADEDNESS, CONFUSION, SEIZURES, N &V

•  INSULIN RELEASE IN NIDDM: HYPOGLYCEMIA

•  PREGNANCY CATEGORY C AND CHONDROTOXIC: AVOID IN CHILDREN

Culley C, et al.: Am J Health Syst Pharm 58:379-388, 2001

MOXIFLOXACIN (AVELOX®)

• DRUG INTERACTIONS: PROLONGS QT INTERVAL IN 48%* (TORSADES)

– ANTIBIOTICS: MACROLIDES, PENTAMIDINE, et al.

– ANTIARRHYTHMICS: AMIODARONE, PROCAINAMIDE, SOTALOL, et al.

– OTHER DRUGS: TCA’S, SSRI’S, HALO-, RIS-, DROPERIDOL, TAMOXIFEN

• AS EFFECTIVE AS CEFUROXIME IN SINUSITIS

*Ng T, et al.: Crit Care Med 32SupplA:40, 2004

TELITHROMYCIN

(Ketek®)

NOW RESTRICTED USE DUE TO HEPATOTOXICITY

•  Ketolides: new family related to MLSB group of antibiotics

–  Protein synthesis inhibitor at 23S ribosomal RNA

–  Gm +, Prevotella and Peptostreptococcus

–  Concentrates in alveolar macrophages (146X)

–  Macrolide-like drug interactions: CYP3A4 inhibitor, prolongs QT slightly

–  Severe hepatotoxicity has caused Ketek to be withdrawn and delayed Phase III trials of cethromycin

LINEZOLID

(Zyvox®) •  Oxazolidinones: new family of peptide AB’s

–  Protein synthesis inhibitor at 23S ribosomal RNA –  Gm+ aerobes, including streps and enterococci

–  MRSA, VRE (including E. faecalis) –  S. viridans, Fusobacterium, Peptostreptococcus, Prevotella –  Twice-daily dosing: 600 mg BID po or IV –  Absorbed well po and IV, crosses BBB –  Myelosuppression, thrombocytopenia

–  Reduce epinephrine; confusion, tremor with SSRI’s, MAOI’s –  Does not involve CYP 450 system; renal excretion –  As effective as comparators for MRSA, VRE, CAP, & NP Paladino JP: Am J Health Syst Pharm 59:2413-2425, 2002




CEFTRIAXONE (Rocephin®)

• Third generation • Parenteral only • Streps, anaerobes • Cross-allergy with penicillins • Crosses blood-brain barrier • Pseudocholelithiasis (sludging)

New Antibiotics Parenteral use only

• Daptomycin (MRSA endocarditis)

• Telavancin (MRSA) • Tigecycline (KPC superbugs)

New Antibiotics Parenteral use only

• Cefipime - Maxipime®

• Carbapenems: imipenem, meropenem, ertapenem, doripenem

• Teicoplanin (for VISA, not GISA) • Synercid® (for VRE)

• Daptomycin (Cubicin ®)

• Tigecycline (for KPC)

IMIPENEM, MEROPENEM, ERTAPENEM & DORIPENEM •  CARBAPENEM ANTIBIOTICS •  BACTERICIDAL CELL WALL DISRUPTOR •  P. AERUGINOSA BECOMES RESISTANT DURING

TREATMENT •  RARE CROSS-ALLERGY WITH PENICILLIN •  SEIZURES AT HIGH DOSES OF IMPENEM •  CILASTATIN ADDED TO DECREASE RENAL

EXCRETION OF IMIPENEM •  MEROPENEM SAFEST, CROSSES BBB

TEICOPLANIN

! GLYCOPEPTIDE ANTIBIOTIC (like Vancomycin)

! BACTERICIDAL CELL WALL DISRUPTOR

! GRAM POSITIVE COCCI

! EFFECTIVE AGAINST

–  MRSA

–  VISA

–  NOT GISA (Glycopeptide intermediate S. aureus)

–  VRE with van B phenotype

SYNERCID ®

! 2 STREPTOGRAMIN ANTIBIOTICS ! QUINUPRISTIN + DALFOPRISTIN ! PROTEIN SYNTHESIS INHIBITOR ! GRAM POSITIVE COCCI, ANAEROBES !  INDICATED FOR:

–  GLYCOPEPTIDE-RESISTANT E. FAECIUM, BUT NOT FAECALIS

–  S. AUREUS, NOT MRSA – RESISTANCE DURING TREATMENT?

– CYP3A4 INHIBITOR – DRUG INTERACTIONS – REQUIRES CENTRAL LINE INFUSION




Even Newer Antibiotics Parenteral use only

• Daptomycin (MRSA endocarditis)

• Telavancin (MRSA) • Tigecycline (KPC superbugs)

DAPTOMYCIN (CUBICIN®)

! CYCLIC LIPOPEPTIDE ! MEMBRANE DEPOLARIZATION - ↓ DNA & RNA ! GRAM +, (Staph, Strep, Enterococci) ! GRAM - ARE RESISTANT ! ANAEROBES NOT SENSITIVE? ! MODERATE COST 250 mg q24h = $44 ! PREGNANCY CATEGORY B ! MUSCLE TOXICITY (↑ CPK) ! PHLEBITIS, GI UPSET ! ADJUST DOSE IN RENAL FAILURE

Antifungal Antibiotics

• Nystatin – cheap • Clotrimazole (Mycelex®) – tastes good • Fluconazole (Diflucan®) – $$ • Itra-, Vori-, Posaconazole – $$$, CYP3A4 • Echinocandins (caspo-, micafungin) • Amphotericin B (Lipid-based less toxic)

Antiherpes Antibiotics Comparison

• Acyclovir – 5 doses/d; I.V. not available

• Valacyclovir – 2 doses/d; oral only – Prodrug of acyclovir

–  In non-immunosuppressed patients: symptoms ↓ by ½-1 d @ $25-70/d

– TTP with high dose

• Similar results with fami- and penciclovir topical and oral: < 2d ↓ symptoms

Principle 2: Use therapeutic antibiotics only when clinically indicated.

Pharmacology of the Commonly Used Oral

Antibiotics

PENICILLIN vs. AMOXICILLIN

PENICILLIN AMOXICILLIN QID dosing TID dosing

Streps Gram negative rods

Beta-lactamase susceptible Beta-lactamase susceptible

$13.99 $11.99 (-3%)

Boring Antibiotic-associated colitis

More effective in peds? Interferes w/OCP’s?




GI ISSUES

• Cephalosporins generally well tolerated, but less effective

• Azithromycin vs. Erythromycin

• Augmentin: take at the beginning of a meal for ↑ absorption, ↓ GI upset

• Fluoroquinolones: avoid dairy, Ca++

• No known benefit of antacids, bismuth, H2-blockers

REDUCED DOSING INTERVALS Augmentin TID or BID Cefadroxil BID Cefdinir QD Azithromycin QD Clarithromycin BID Moxifloxacin QD Doxycycline BID Linezolid BID

QD = once; BID = twice; TID = thrice daily

ANTIBIOTIC ASSOCIATED COLITIS •  CLINICAL SIGNS OF AAC

–  Diaharrhea (mucoid or bloody)

–  Abdominal cramping

–  Fever

–  Sloughing of mucosa on sigmoidoscopy

–  C. difficile culture

–  C. difficile exotoxin assay

!  ANTIBIOTICS ASSOCIATED WITH AAC

–  Amoxicillin

–  Clindamycin

–  Oral cephalosporins

ANTIBIOTIC ASSOCIATED COLITIS

RISK FACTORS FOR AAC •  Antibiotic therapy •  G.I. surgery •  Hospitalized patient •  Female •  Inflammatory bowel disease •  Cancer chemotherapy •  Renal disease


C. difficile most frequent cause of nosocomial diaharrhea

• Clostridium difficile exotoxin assay X3

• Colonoscopy • Discontinue antibiotic

• Vancomycin or metronidazole


Fulminant AAC • ~ 5% of cases

• Elderly, hospitalized, operated patient • Rapid onset of acute abdomen

• WBC > 18,000 • Total colectomy lifesaving in 60%; Diverting

loop ileostomy with colonic lavage in 80% (new procedure)

Kazanowski M, et al. Tech Coloproctol. 18:223, 2014




DRUGS ASSOCIATED WITH CONTRACEPTIVE FAILURE

•  ANTIBIOTICS –  Rifampin –  Ampicillin –  Tetracyclines

•  OTHER DRUGS –  Barbiturates –  Phenylbutazone

Probably due to induction of microsomal enzymes in the liver

Antibiotics With Significant Risk in Pregnancy

• Category D: Evidence of human risk

– Tetracyclines, tigecycline – Aminoglycosides

– Voriconazole – Thalidomide

Antibiotics With Significant Risk in Pregnancy (cont.)

•  Category C: Animal toxicity; human studies inadequate

–  Clarithromycin (Biaxin®), not Azithromycin –  Fluoroquinolones (Cipro®, moxifloxacin, etc.) –  Sulfonamides/trimethoprim –  Vancomycin –  Imipenem/cilastatin –  Telithromycin –  Flu- Itra- Ketoconazole

Antibiotics Not Approved for Pediatric Use

• Fluoroquinolones (moxi-, ciprofloxacin, etc.)

• Tetracyclines

DRUGS THAT PROLONG QT Potential for Torsades and V. Fib.

•  Antibiotics: macrolides, fluoroquinolones, TMP-SMX, flu-, itra-, ketoconazole, pentamidine, quinine

•  Antiarrhythmics: amiodarone, procainamide, sotalol, disopyramide, quinidine

•  Psychiatric drugs: TCA’s, SSRI’s, phenothiazines, lithium, butyrophenones (Haldol, Risperdal)

•  Anticonvulsants: felbamate, fosphenytoin

•  Miscellaneous: diphenhydramine, droperidol, tacrolimus, tamoxifen, serotonin receptor agonists (Imatrex, Zomig) smoking


Antibiotic Drug Interactions





Macrolide-Drug Interactions Azithromycin not included in most of them

Other Drug Effect Result Theophylline ↑ Theophylline Seizures, apnea,

N&V Lova-, simvastatin ↑ Statin Rhabdomyolysis

Warfarin ↑ Warfarin INR

Carbamazepine ↑Carbamazepine Nystagmus, ataxia, N&V

Pimozide (Orap) (Azithromycin included)

↑ QT interval Torsades (V. fib)

AVOID


Moxifloxacin-Drug Interactions Other Drug Effect Result

Cations (dairy, antacids, vitamins) ↓ Moxifloxacin ↓ Antibiotic effect

Oral hypoglycemics ↑Hypoglycemc

Hypoglycemia

Antimicrobials (macrolides, pentamidine)


Antiarrhythmics (procainamide, amiodarone, sotalol)


Other drugs (TCA’s, SSRI’s butyrophenones, tamoxifen, serotonin agonists)



Telithromycin-Drug Interactions Other Drug Effect Result Digoxin ↑ Digoxin Digitalis toxicity

Lova-, simvastatin ↑ Statin Rhabdomyolysis

Midazolam ↑ Midazolam Oversedation

Metoprolol ↑ Metoprolol Hypotension, Bradycardia

Ergot alkaloids ↑ Ergotamine Peripheral vasoconstriction

Pimozide (Orap) ↑ QT interval Torsades (V. fib) AVOID


Linezolid-Drug Interactions Other Drug Effect Result

Adrenergic agents (epinephrine)

↑ Sympathetic effect

Hypertension

Serotonergic drugs (SSRI’s, MAOI’s)

↑ Serotonin Serotonin syndrome (confusion, tremor, sweating, fever)

Aged, fermented, pickled, or smoked foods

↑ Tyramine Hypertension


Miscellaneous Antibiotic-Drug Interactions

Antibiotic Other Drug Effect Clindamycin Muscle relaxants ↑ Duration of paralysis

Doxycycline Sunlight Photosensitivity

Doxycycline Warfarin ↑ INR

Tetracyclines Digoxin Digitalis toxicity (prolonged in 10%)

Metronidazole Alcohol Antabuse effect

Metronidazole Warfarin ↑ INR

Metronidazole Hydantoins CNS depression


Azole-Drug Interactions Flu-, Itra-, and Ketoconazole

Other Drug Effect Result Phenytoin, Dilantin ↑ Phenytoin CNS depression

Midazolam ↑ Midazolam Oversedation

Warfarin ↑ Warfarin Nystagmus, ataxia, N&V

Calcium channel blockers

↑ Ca++ blocker Hypotension, bradycardia

Lova-, simvastatin (itraconazole only)

↑ Statin Rhabdomyolysis

Oral hypoglycemics (not ketoconazole)

↑ Hypoglycemic Hypoglycemia

Protease Inhibitors (not fluconazole)

↑ Protease Inhibitor Specific toxicity





THE END

THANK YOU VERY MUCH!

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