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Antimicrobial Regimen Selection

Source: Burgess DS. Antimicrobial Regimen Selection. In: DiPiro, JT, Talbert RL, Yee GC, Matzke GR, Wells BG,
Posey LM. Pharmacotherapy: A Pathophysiologic Approach. 8 ed.
http://accesspharmacy.com.ezproxy4.library.arizona.edu/content.aspx?aid=8001114. Accessed June 23,
2012.

Definitions
“Empiric” regimen: initiated before o ending organism is identified and sometimes prior to documentation
of presence of infection.
“Definitive” regimen: instituted when causative organism is known.

Confirming Presence of Infection

Obtain careful history and physical.
Signs and Symptoms
Fever
Body temperature above normal range of 36.7–37°C (98.1–98.6°F; measured orally)
Hallmark of infectious disease
May be caused by drugs in absence of infection or other underlying condition.
Elevated white blood cell (WBC) count
Granulocytes and/or lymphocytes are mobilized to destroy invading microbes.
Bacterial infections associated with
Elevated granulocyte counts (neutrophils and basophils)
Increased band neutrophils in peripheral smear (le -shi )
Low neutrophil counts (neutropenia), indicating abnormal response; associated with poor prognosis
Tuberculosis, viral, or fungal infections associated with relative lymphocytosis even with normal or slightly
elevated total WBC count
Local signs
Pain and inflammation
Swelling
Erythema
Tenderness
Purulent drainage

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Identification of Pathogen
Collect infected body material.
Assess with Gram stain.
Perform blood cultures and sensitivities.
Perform serologic tests for presence of antibodies.
Collect suspected fluids or tissues (e.g., spinal fluid in meningitis).
Assess inflammation with deep-seated infections by examining tissues or fluids (e.g., examine sputum to
assess pneumonia).

Selection of Presumptive Therapy

Factors to consider
Severity and acuity of disease
Local susceptibility data rather than national compilations
Host factors
Allergy or history of adverse drug reactions
Age of patient
Pregnancy
Metabolic abnormalities
Renal and hepatic function: Adjust dosage with diminished renal and/or hepatic function to avoid drug
accumulation.
Concomitant drug therapy: Potential for drug interactions (Table 1)
Concomitant disease states
Drug factors
Use generally accepted drugs based on pathogen (Table 2)
Consider pharmacokinetic and pharmacodynamic properties of agent
Bactericidal e ects may be concentration-dependent (aminoglycosides and fluoroquinolones) or time-
dependent (β-lactams).
Treatment outcome can be predicted by area under concentration-time curve (AUC) and maximal plasma
concentration.
Duration that drug concentration exceeds minimal inhibitory concentration (MIC) is most important
pharmacodynamic relationship for antimicrobials that display time-dependent bactericidal e ects.
Antibiotic tissue penetration varies with site of infection.
Clinically relevant drug concentrations found in blood, urine, synovial fluid, and peritoneal fluid.
Combination therapy should be considered to:
Broaden the spectrum of coverage for empiric therapy
Important when multiple aerobic and anaerobic bacteria are likely to be present (e.g., in intraabdominal and
female pelvic infections)
Achieve synergistic activity against infecting organism

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Advantageous for infections caused by gram-negative bacilli in immunosuppressed patients.

May produce better results in infections caused by Pseudomonas aeruginosa and certain infections caused
by Enterococcus spp.
Prevent the emergence of resistance

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Table 1. Major Drug Interactions with Antimicrobials

Clinical
Antimicrobial Other Agent(s) Mechanism of Action/E ect
Management

Aminoglycosides Neuromuscular blocking Additive adverse e ects Avoid

agents

Nephrotoxins (N) or Additive adverse e ects Monitor

ototoxins (O) (e.g., aminoglycoside
amphotericin B (N) cisplatin SDC and renal
(N/O), cyclosporine (N), function
furosemide (O), NSAIDs (N),
radio contrast (N),
vancomycin (N)

Amphotericin B Nephrotoxins (e.g., Additive adverse e ects Monitor renal

aminoglycosides, cidofovir, function
cyclosporine, foscarnet,
pentamidine)

Azoles Numerous possible drug interactions for individual agents; consult prescribing
information for specifics.

Chloramphenicol Phenytoin, tolbutamide, Decreased metabolism of Monitor

ethanol other agents phenytoin SDC,
blood glucose

Foscarnet Pentamidine IV Increased risk of severe Monitor renal

nephrotoxicity/hypocalcemia function/serum
calcium

Isoniazid Carbamazepine, phenytoin Decreased metabolism of Monitor drug

other agents (nausea, SDC
vomiting, nystagmus, ataxia)

Macrolides/azalides Digoxin Decreased digoxin Monitor digoxin

bioavailability and SDC; avoid if
metabolism possible

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Clinical
Antimicrobial Other Agent(s) Mechanism of Action/E ect
Management

Theophylline Decreased metabolism of Monitor

theophylline theophylline
SDC

Metronidazole Ethanol (drugs containing Disulfiram-like reaction Avoid

ethanol)

Penicillins and Probenecid, aspirin Blocked excretion of β- Use if

cephalosporins lactams prolonged high
concentration
of β-lactam
desirable

Ciprofloxacin/norfloxacin Theophylline Decreased metabolism of Monitor

theophylline theophylline

Quinolones Classes Ia and III Increased Q-T interval Avoid

antiarrhythmics

Multivalent cations Decreased absorption of Separate by 2

(antacids, iron, sucralfate, quinolone hr
zinc, vitamins, dairy, citric
acid) didanosine

Rifampin Azoles, cyclosporine, Increased metabolism of Avoid if

methadone propranolol, other agent possible
PIs, oral contraceptives,
tacrolimus, warfarin

Sulfonamides Sulfonylureas, phenytoin, Decreased metabolism of Monitor blood

warfarin other agent glucose, SDC,
PT

Tetracyclines Antacids, iron, calcium, Decreased absorption of Separate by 2

sucralfate tetracycline hr

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Clinical
Antimicrobial Other Agent(s) Mechanism of Action/E ect
Management

Digoxin Decreased digoxin Monitor digoxin

bioavailability and SDC; avoid if
metabolism possible

PI, protease inhibitor; PT, prothrombin time; SDC, serum drug concentrations.

Azalides: azithromycin; azoles: fluconazole, itraconazole, ketoconazole, and voriconazole; macrolides: erythromycin, clarithromycin;
protease inhibitors: amprenavir, indinavir, lopinavir/ritonavir, nelfinavir, ritonavir, and saquinavir; quinolones: ciprofloxacin, gemifloxacin,
levofloxacin, moxifloxacin.

Reprinted with permission from Wells BG, DiPiro JT, Schwinghammer TL, et al. Pharmacotherapy Handbook. 8th ed. New York: McGraw-
Hill, 2012.

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Table 2. Drugs of Choice, First Choice, and Alternative(s)

Gram-positive cocci

Enterococcus faecalis (generally not as resistant to antibiotics as Enterococcus faecium)

• Serious infection (endocarditis, meningitis, pyelonephritis with bacteremia)

• Ampicillin (or penicillin G) + (gentamicin or streptomycin)

• Vancomycin + (gentamicin or streptomycin), daptomycin,linezolid, telavancin, tigecyclinea

• Urinary tract infection (UTI)

• Ampicillin, amoxicillin

• Fosfomycin or nitrofurantoin

E. faecium (generally more resistant to antibiotics than E. faecalis)

• Recommend consultation with infectious disease specialist

• Linezolid, quinupristin/dalfopristin, daptomycin, tigecyclinea

Staphylococcus aureus/Staphylococcus epidermidis

• Methicillin (oxacillin)-sensitive

• Nafcillin or oxacillin

• FGC,b,c trimethoprim-sulfamethoxazole, clindamycin, BL/BLIj

• Hospital-acquired methicillin (oxacillin)–resistant

• Vancomycin ± (gentamicin or rifampin)

• Daptomycin, linezolid, telavancin, tigecycline,a trimethoprim-sulfamethoxazole, or quinupristin-dalfopristin

• Community-acquired methicillin (oxacillin)-resistant

• Clindamycin, trimethoprim-sulfamethoxazole, doxycylcinea

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• Daptomycin, linezolid, telavancin, tigecycline,a or vancomycin

Streptococcus (groups A, B, C, G, and Streptococcus bovis)

• Penicillin G or V or ampicillin

• FGC,b,cerythromycin, azithromycin, clarithromycin

Streptococcus pneumoniae

• Penicillin-sensitive (MIC <0.1 mcg/mL)

• Penicillin G or V or ampicillin

• FGC,b,cdoxycycline,aazithromycin, clarithromycin, erythromycin

• Penicillin intermediate (MIC 0.1–1.0 mcg/mL)

• High-dose penicillin (12 million units/day for adults) or ce riaxonec or cefotaximec

• Levofloxacin,amoxifloxacin,agemifloxacin,a or vancomycin

• Penicillin-resistant (MIC ≥1.0 mcg/mL)

• Recommend consultation with infectious disease specialist.

– Vancomycin ± rifampin

– Per sensitivities: cefotaxime,cce riaxone,clevofloxacin,amoxifloxacin,a or gemifloxacina

Streptococcus, viridans group

• Penicillin G ± gentamicind

• Cefotaxime,cce riaxone,cerythromycin, azithromycin, clarithromycin, or vancomycin ± gentamicin

Gram-negative cocci

Moraxella (Branhamella) catarrhalis

• Amoxicillin-clavulanate, ampicillin-sulbactam

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• Trimethoprim-sulfamethoxazole, erythromycin, azithromycin, clarithromycin, doxycycline,a

SGC,c,ecefotaxime,cce riaxone,cor TGC POc,f

Neisseria gonorrhoeae (also give concomitant treatment for Chlamydia trachomatis)

• Disseminated gonococcal infection

• Ce riaxonec or cefotaximec

• Oral follow-up: cefpodoxime,cciprofloxacin,a or levofloxacina

• Uncomplicated infection

• Ce riaxone,c cefotaxime,c or cefpodoximec

• Ciprofloxacina or levofloxacina

Neisseria meningitides

• Penicillin G

• Cefotaximecor ce riaxonec

Gram-positive bacilli

Clostridium perfringens

• Penicillin G ± clindamycin

• Metronidazole,a clindamycin, doxycycline,a cefazolin,c carbapenemg,h

Clostridium di icile

• Oral metronidazolea

• Oral vancomycin

Gram-negative bacilli

Acinetobacter spp.

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• Doripenem, imipenem or meropenem ± aminoglycosidei (amikacin usually most e ective)

• Ampicillin-sulbactam, colistin,h or tigecyclinea

Bacteroides fragilis (and others)

• Metronidazolea

• BL/BLI,jclindamycin, cefoxitin,ccefotetan,cor carbapenemg,h

Enterobacter spp.

• Carbapenem,g or cefepime ± aminoglycosidei

• Ciprofloxacin,alevofloxacin,apiperacillin-tazobactam, ticarcillin-clavulanate

Escherichia coli

• Meningitis

• Cefotaxime,c ce riaxone,c meropenem

• Systemic infection

• Cefotaximec or ce riaxonec

• BL/BLI,jfluoroquinolone,a,k carbapenemg,h

• Urinary tract infection

• Most oral agents: check sensitivities

• Ampicillin, amoxicillin-clavulanate, doxycyline,a or cephalexinc

• Aminoglycoside,i FGCb,cnitrofurantoin, fluoroquinolonea,k

Gardnerella vaginalis

• Metronidazolea

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• Clindamycin

Haemophilus influenzae

• Meningitis

• Cefotaximec or ce riaxonec

• Meropenemh

• Other infections

• BL/BLI,j or if β-lactamase-negative, ampicillin or amoxicillin

• Trimethoprim-sulfamethoxazole, cefuroxime,cazithromycin, clarithromycin, or fluoroquinolonea,k

Klebsiella pneumoniae

• BL/BLI,j cefotaxime,c ce riaxone,c cefepimec

• Carbapenem,g,hfluoroquinolonea,k

Legionella spp

• Azithromycin, erythromycin ± rifampin, or fluoroquinolonea,k

• Trimethoprim-sulfamethoxazole, clarithromycin, or doxycyclinea

Pasteurellamultocida

• Penicillin G, ampicillin, amoxicillin

• Doxycycline,a BL/BLI,j trimethoprim-sulfamethoxazole, or ce riaxonec

Proteus mirabilis

• Ampicillin

• Trimethoprim-sulfamethoxazole

Proteus (indole-positive) (including Providencia rettgeri, Morganella morganii, and Proteus vulgaris)

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• Cefotaxime,c ce riaxone,c or fluoroquinolonea,k

• BL/BLI,jaztreonam,l aminoglycosides,i carbapenemg,h

Providencia stuartii

• Amikacin, cefotaxime,c ce riaxone,c fluoroquinolonea,k

• Trimethoprim-sulfamethoxazole, aztreonam,lcarbapenemg,h

Pseudomonas aeruginosa

• UTI only

• Aminoglycosidei

• Ciprofloxacin,alevofloxacina

• Systemic infection

• Cefepime,c ce azidime,c doripenem,h imipenem,h meropenem,h piperacillin-tazobactam, or ticarcillin-

clavulanate + aminoglycosidei

• Aztreonam,lciprofloxacin,alevofloxacin,a colistinh

Salmonella typhi

• Ciprofloxacin,a levofloxacin,a ce riaxone,c cefotaximec

• Trimethoprim-sulfamethoxazole

Serratia marcescens

• Ce riaxone,c cefotaxime,c cefepime,c ciprofloxacin,a levofloxacina

• Aztreonam,l carbapenem,g,hpiperacillin-tazobactam, ticarcillin-clavulanate

Stenotrophomonas(Xanthomonas) maltophilia (generally very resistant to all antimicrobials)

• Trimethoprim-sulfamethoxazole

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• Check sensitivities to ce azidime,cdoxycycline,aminocycline,a and ticarcillin-clavulanate

Miscellaneous microorganisms

Chlamydia pneumoniae

• Doxycyclinea

• Azithromycin, clarithromycin, erythromycin, or fluoroquinolonea,k

Chlamydia trachomatis

• Azithromycin or doxycyclinea

•Levofloxacin,aerythromycin

Mycoplasmapneumoniae

• Azithromycin, clarithromycin, erythromycin, fluoroquinolonea,k

• Doxycyclinea

Spirochetes

Treponemapallidum

• Neurosyphilis

• Penicillin G

• Ce riaxonec

• Primary or secondary

• Benzathine penicillin G

• Ce riaxonecor doxycyclinea

Borreliaburgdorferi (choice depends on stage of disease)

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• Ce riaxonec or cefuroxime axetil,c doxycycline,a amoxicillin

• High-dose penicillin, cefotaximec

MIC, minimal inhibitory concentration; PO, orally.

aNot for use in pregnant patients or children.

bFirst-generation cephalosporins—IV: cefazolin; PO: cephalexin, cephradine, or cefadroxil.

cSome penicillin-allergic patients may react to cephalosporins.

dGentamicin should be added if tolerance or moderately susceptible (MIC >0.1 g/mL) organisms are encountered; streptomycin is used but
can be more toxic.

eSecond-generation cephalosporins—IV: cefuroxime; PO: cefaclor, cefditoren, cefprozil, cefuroxime axetil, and loracarbef.

fThird-generation cephalosporins—PO: cefdinir, cefixime, cefetamet, cefpodoxime proxetil, and ce ibuten.

gCarbapenem: doripenem, ertapenem, imipenem/cilastatin, meropenem.

hReserve for serious infection.

iAminoglycosides: gentamicin, tobramycin, and amikacin; use per sensitivities.

jβ-lactam/β-lactamase inhibitor combination—IV: ampicillin–sulbactam, piperacillin–tazobactam, ticarcillin–clavulanate; PO: amoxicillin–

clavulanate.

kFluoroquinolones—IV/PO: ciprofloxacin, levofloxacin, and moxifloxacin.

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lGenerally reserved for patients with hypersensitivity reactions to penicillin.

Reprinted with permission from Wells BG, DiPiro JT, Schwinghammer TL, et al. Pharmacotherapy Handbook. 8th ed. New York: McGraw-
Hill, 2012.

Monitor Therapeutic Response

Review
Culture and sensitivity reports: Narrow antibiotic spectrum of activity if indicated
WBC count
Temperature
Signs and symptoms of infection
Appetite
Radiologic studies as appropriate
Serum antimicrobial concentrations
Reevaluate route of administration as patient improves
Consider changing to oral therapy if
Clinically improved
No fever for 8–24 hours
WBC is decreased
Gastrointestinal (GI) tract is functioning
Assess if apparent lack of response to therapy.
Drug selection
Inappropriate drug, dosage, or route of administration
Malabsorption due to GI disease or drug interaction may lead to subtherapeutic serum concentrations.
Accelerated drug elimination
Poor penetration into site of infection
Host factors
Immunosuppressed patient
Need for drainage of abscess or removal of foreign body and/or necrotic tissue
Microorganisms
Development of drug resistance during therapy

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