Overview of Antimicrobial Therapy

Burke A. Cunha; Cheston B. Cunha

Overview of Antimicrobial TherapyChapter 1

Cheston B. Cunha, MD, Burke A. Cunha, MD

Factors in Antibiotic Selection ……………… 2
- Spectrum ……………… 2
- Tissue Penetration ……………… 2
- Antibiotic Resistance Potential (Table 1.1) ……………… 3
- Safety Profile ……………… 4
- Cost ……………… 4
Hemodialysis Dosing Strategies (Table 1.2) ……………… 4
Microbiology and Susceptibility Testing ……………… 5
- In Vitro vs. In Vivo Susceptibility (Table 1.3) ……………… 5
PK/PD and Other Considerations in Antimicrobial Therapy ………………6
- Concentration vs. Time Dependent Kinetics (Table 1.4) Bactericidal vs. Bacteriostatic Therapy ……………… 7
- Monotherapy vs. Combination Therapy. ……………… 7
- IV to PO Switch Therapy ……………… 7
- Bioavailability of Oral Antimicrobials (Table 1.5) ……………… 8
- OPAT ……………… 8
- Duration of Antibiotic Therapy ……………………… 9
Colonization vs. Infection ………………9
- Urine (AUC and CAB) (Table 1.6) ………………………9
- Respiratory Secretions (Table 1.7) …………………… 10
- Wounds (Table 1.8) ……………………………… 10
- Sacral Decubitus Ulcers and Diabetic Foot Ulcers (Table 1.9) ……………………………… 11
- Positive Blood Cultures vs. Bacteremia (MSSA, MRSA, CoNS) (Table 1.10). ……………………………… 11
Drug Fever (Table 1.11). ……………………………… 12
- Relative Bradycardia (Table 1.12) ……………………………… 12
Antibiotic Failure (Table 1.13). ……………………………… 13
Antimicrobial Stewardship: Principles and Practice (Table 1.14). ……………………………… 132

Overview of Antimicrobial Therapy

FACTORS IN ANTIBIOTIC SELECTION

Spectrum

Antibiotic spectrum refers to the range of microorganisms an antibiotic is usually effective against, and is the basis for empiric antibiotic therapy.
In vitro susceptibility does not always predict in vivo effectiveness.

Tissue Penetration

Antibiotics unable to reach the site of infection will be ineffective. Antibiotic tissue penetration depends on antibiotic properties, e.g., lipid solubility, molecular size, adequacy of blood supply and presence of inflammation.
Antibiotics cannot be expected to eradicate organisms from difficult to penetrate areas. Abscesses usually require surgical drainage for cure.
Device associated infections usually need device removal for cure.

Antibiotic Resistance

Bacterial resistance to antimicrobial therapy may be classified as natural/intrinsic or acquired relative or absolute.
Pathogens not covered by the usual spectrum of an antibiotic are termed naturally/intrinsically resistant, e.g., 25% of S. pneumoniae are naturally resistant to macrolides.
Acquired resistance refers to a previously susceptible pathogen that is no longer susceptible to an antibiotic, e.g., ampicillin resistant H. influenzae. Organisms with intermediate level (relative) resistance manifest as an increase in minimum inhibitory concentrations (MICs), but are susceptible if achievable serum/tissue concentrations > MIC, e.g., penicillin resistant S. pneumoniae and PCN.
Organisms with high level (absolute) resistance cannot be overcome by higher-than-usual antibiotic doses, e.g., gentamicin resistant P. aeruginosa.
Most acquired antibiotic resistance is agent specific, not class related resistance (usually limited to one or two species).
Resistance is not related, per se, to volume or duration of use, e.g., doxycycline, ceftriaxone.
Some antibiotics have little resistance potential, i.e., “low resistance” potential even when used in high volume. Other antibiotics can induce resistance, e.g., “high resistance” potential even with limited use.3

Table 1.1 Resistance Potential of Selected Antibiotics

“High Resistance Potential” Antibiotics to Avoid	Usual Organism(s) Resistant to Each Antibiotic	Preferred “Low Resistance Potential” Antibiotic Alternatives in Same Class	Preferred “Low Resistance Potential” Antibiotic Alternatives in Different Classes
Aminoglycosides
Gentamicin or Tobramycin	P. aeruginosa	Amikacin	Levofloxacin, Colistin, Cefepime
Cephalosporins
Ceftazidime	P. aeruginosa	Cefepime	Levofloxacin, Colistin, Polymyxin B
Tetracyclines
Tetracycline	S. pneumoniae S. aureus	Doxycycline, Minocycline	Levofloxacin, Moxifloxacin
Quinolones
Ciprofloxacin	S. pneumoniae	Levofloxacin, Moxifloxacin	Doxycycline
Ciprofloxicin	P. aeruginosa	Levofloxacin	Amikacin, Colistin, Cefepime
Glycopeptides
Vancomycin	MSSA MRSA	None	Linezolid, Daptomycin, Minocycline, Tigecycline
Carbapenems
Imipenem	P. aeruginosa	Meropenem, Doripenem	Amikacin, Cefepime, Colistin, Polymyxin B
Macrolides
Azithromycin	S. pneumoniae	None	Doxycycline, Levofloxacin, Moxifloxacin
Dihydrofolate Reductase Inhibitors
TMP-SMX	S. pneumoniae	None	Doxycycline, Levofloxacin, Moxifloxacin

Safety Profile

Whenever possible, avoid antibiotics with serious/frequent side effects.

Mode of Antibiotic and Excretion/Excretory Organ Toxicity

The mode of elimination/excretion does not predispose to excretory organ toxicity per se, e.g., nafcillin (hepatically eliminated) is not hepatotoxic, and it's main side effect is nephrotoxicity (interstitial nephritis). In contrast, oxacillin (renally eliminated), is not nephrotoxic, it's main side effect is hepatotoxicity (hepatitis).
The primary route of antibiotic elimination is protective and does not predispose to excretory organ toxicity.

Cost

Switching early from IV to PO antibiotics is the single most important cost saving strategy in hospitalized patients.
Institutional cost of IV administration (~ $10/dose) may exceed the cost of the antibiotic.
Antibiotic costs can also be minimized by using antibiotics with long half-lives, by choosing monotherapy over combination therapy, and decreasing duration of therapy.

HEMODIALYSIS (HD) DOSING STRATEGIES

Intra-HD Dosing

For renally eliminated antibiotics, begin therapy with the usual initial dose, then decrease the maintenance doses/intervals for a CrCl < 10 mg/min (for specific antibiotics, see Chapter 11, Drug Summaries).
For antibiotics partially/totally removed by HD, a post-HD is needed (for specific antibiotics, see Chapter 11, Drug Summaries).

HD Dosing Only

For selected antibiotics with the requisite PK/PD properties, treatment may be given at each HD (Table 1.2).

Table 1.2 Selected Antibiotics for Dialysis Dosing (Regimens that do not require Intra-HD Dosing)

Antibiotic	ESRD (t½h)	Clinical Spectrum	Resistance Potential	Dialysis Dosing
Cefazolin	40 hours	MSSA, Klebsiella pneumoniae, E. coli	Low	2 gm (IV) q HD
Cefepime	18 hours	P. aeruginosa, Aerobic GNBs	Low	2 gm (IV) q HD5
Ceftazidime	21 hours	P. aeruginosa, Aerobic GNB	High (P. aeruginosa)	2 gm (IV) q HD
Daptomycin	30 hours	MSSA, MRSA, VSE, VRE	Low	6-12 mg/kg (IV) q HD*
Levofloxacin	40 hours	P. aeruginosa, Aerobic GNBs, MSSA	Low	500 mg (IV/PO) q HD
Meropenem	7 hours	P. aeruginosa, Aerobic GNBs, MSSA, VSE	Low	2 gm (IV) q HD
* For bacteremia due to MSSA/MRSA use 6 mg/kg, for VSE/VRE use 12 mg/kg.

MICROBIOLOGY AND SUSCEPTIBILITY TESTING

Limitations of Microbiology Susceptibility Testing

In vitro data do not differentiate between colonizers and pathogens.
In vitro data do not necessarily translate into in vivo efficacy.
Antibiotic activity-effectiveness depends on body site concentrations local pH, degree of inflammation, cellular debris, local oxygen levels, blood supply and penetrability.
In vitro susceptibility testing is dependent on the microbe, methodology, pH, and antibiotic concentration.
In vitro susceptibility testing assumes the isolate was recovered from blood, using serum concentrations of an antibiotic given in the usual dose.
Since some body site, e.g., bladder urine contains higher antibiotic concentrations than found in serum, and other body sites, e.g., CSF levels may be lower than in serum, i.e., in vitro susceptibility may be misleading for non-bloodstream infections.
Antibiotics should be prescribed at the usual recommended doses; attempts to lower cost by reducing dosage may decrease antibiotic efficacy, e.g., cefoxitin 2 gm IV inhibits ~ 85% of B. fragilis, whereas 1 gm IV inhibits only ~ 20%.6

Table 1.3 Antibiotic-Organism Combinations for Which In Vitro Susceptibility Testing Does Not Predict In Vivo Effectiveness

Antibiotic	“Susceptible” Organism
Penicillin	H. influenzae, Yersinia pestis, VSE*
TMP–SMX	Klebsiella, VSE, Bartonella
Polymyxin B	Proteus, Salmonella
Imipenem	Stenotrophomonas maltophilia
Vancomycin	Erysipelothrix rhusiopathiae
Gentamicin	Mycobacterium tuberculosis
Aminoglycosides	Streptococci, Salmonella, Shigella
Clindamycin	Fusobacteria, Clostridia, Listeria
Macrolides	P. multocida
1^st, 2^nd generation cephalosporins	Salmonella, Shigella, Bartonella
3^rd, 4^th generation cephalosporins	Listeria, Bartonella, MRSA^†
Quinolones	MRSA^†
^† In spite of apparent in vitro susceptibility of antibiotics against MRSA, only vancomycin, minocycline, quinupristin/dalfopristin, linezolid, tedizolid, daptomycin, ceftaroline fosamil, telavancin, dalbavancin, oritavancin, and tigecycline are effective in vivo. * Effective penicillin therapy for systemic enterococcal infections due to VSE requires an aminoglycoside, e.g., gentamicin.

PK/PD AND OTHER CONSIDERATIONS IN ANTIMICROBIAL THERAPY

Antibiotic Dosing: Concentration vs. Time Dependent Kinetics

Table 1.4 Pharmacokinetic/Pharmacodynamic (PK/PD) Considerations

Antibiotics		Optimal Dosing Strategies
Concentration Dependent Antibiotics (Cmax: MIC)
Quinolones Aminoglycosides Vancomycin (if MIC ≥ 1 mcg/ml) use 2 gm (IV) q12h	Doxycycline Tigecycline Colistin/ Polymyxin B	Use highest effective dose (without toxicity)7
Time Dependent Antibiotics (T > MIC)
PCN: maintain concentrations > MIC for ≥ 60% of the dosing interval β-lactams: maintain concentrations > MIC for ≥ 75% of the dosing interval Carbapenems: maintain concentrations > MIC for ≥ 40% of the dosing interval Vancomycin (if MIC ≤ 1 mcg/mL) use 1 gm (IV) q12h		Use high doses (which increase serum concentrations which also increase T > MIC for more of the dosing interval)
Other Antibiotics (Cmax: MIC/T>MIC and or AUC _0-24/MIC)
Quinolones > 125 (effective) > 250 (more effective)		Use highest effective dose (without toxicity)

Bactericidal vs. Bacteriostatic Therapy

For most infections, bacteriostatic and bactericidal antibiotics inhibit/kill organisms at the same rate, and should not be a factor in antibiotic selection.
Bactericidal antibiotics have an advantage in certain infections, such endocarditis, meningitis, and febrile leukopenia, but there are exceptions even in these cases.

Monotherapy vs. Combination Therapy

Monotherapy is preferred to combination therapy for nearly all infections.
In addition to cost savings, monotherapy results in less chance of medication error and fewer missed doses/drug interactions.
Combination therapy may be useful for drug synergy or for extending spectrum beyond what can be obtained with a single drug.
Combination therapy is not effective in preventing antibiotic resistance, except in very few situations.

IV to PO Switch Therapy

Patients admitted to the hospital are usually started on IV antibiotic therapy, then switched to equivalent oral therapy after clinical improvement/defervescence (usually within 72 hours).
Advantages of early IV-to-PO switch programs include reduced cost, early hospital discharge, less need for home IV therapy, and virtual elimination of IV line infections.
Drugs well-suited for IV-to-PO switch or for treatment entirely by the oral route have high bioavailibility, e.g., doxycycline, minocycline, clindamycin, metronidazole, chloramphenicol, amoxicillin, trimethoprim-sulfamethoxazole, quinolones, and linezolid.8

Table 1.5 Bioavailability of Oral Antimicrobials

Bioavailability		Antimicrobials
Excellent (> 90%)	Amoxicillin Cephalexin Cefprozil Cefadroxil Clindamycin Quinolones Chloramphenicol	TMP TMP–SMX Doxycycline Minocycline Fluconazole Metronidazole Cycloserine	Linezolid Tedizolid Isavuconazole Voriconazole Rifampin Isoniazid Pyrazinamide
Good (60–90%)	Cefixime Cefpodoxime Ceftibuten Cefuroxime	Valacyclovir Famciclovir Valganciclovir Macrolides Cefaclor Nitrofurantoin	Ethambutol 5-Flucytosine Posaconazole Itraconazole (solution) Nitazoxanide (with food)
Poor (< 60%)	Vancomycin Acyclovir	Cefdinir Cefditoren	Nitazoxanide (without food) Fosfomycin

Oral Antibiotic Therapy for Serious Systemic Infections

Most infectious diseases should be treated orally unless the patient is critically ill, cannot take antibiotics by mouth, or there is no equivalent oral antibiotic.
If the patient is able to take/absorb oral antibiotics, there is no difference in clinical outcome using equivalent IV or PO antibiotics.
It is more important to think in terms of antibiotic spectrum, bioavailability and tissue penetration, rather than route of administration.
Nearly all non-critically ill patients may be treated in part or entirely with oral antibiotics.
When switching from IV to PO therapy, oral antibiotic chosen should have the same spectrum/degree of activity against the presumed/known pathogen and achieve the same blood and tissue levels as the equivalent IV antibiotic.

OPAT (outpatient parenteral antibiotic therapy)

OPAT has been used to treat infections IV on an outpatient basis or to complete IV therapy begun during hospitalization. Preferred OPAT antibiotics are those with few adverse effects and those with a long serum half life. The most frequently used OPAT antibiotics are ceftriaxone and vancomycin.9
Other agents with long t_1/2 ideal for OPAT of Gram positive cSSSIs due to MRSA are telavancin 10 mg (IV) q 24 h, dalbavancin 1 gm (IV) × 1 doses then 500 mg (IV) × 1 dose 7 days later; tedizolid 200 mg (IV)q 24 h × 6 days, then 200 mg (PO) q 24 h × 6 days; and oritavancin 1200 mg (IV) × 1 dose.
The preferred alternative to OPAT is oral antibiotic therapy, e.g., for MRSA, minocycline or linezolid are equally efficacious as OPAT regimens.

Duration of Therapy

Most bacterial infections in normal hosts are treated with antibiotics for 1–2 weeks.
The duration of therapy may need to be extended in patients with impaired immunity, e.g., diabetes, SLE, alcoholic liver disease, neutropenia, diminished splenic function, etc., chronic bacterial infections e.g., endocarditis, osteomyelitis, chronic viral and fungal infections, or certain bacterial intracellular pathogens.

COLONIZATION VS. INFECTION

Table 1.6 Colonization vs. Infection†: Acute Uncomplicated Cystitis (AUC) and Catheter Associated Bacteriuria (CAB)*

Inflammation

Pyuria (> 30 WBCs/hpf) with no or low grade bacteriuria (< 50 cfu/mL).

Colonization

AUC: bacteriuria with minimal pyuria (< 10 WBCs/hpf) and low grade bacteriuria (< 50 cfu/mL).
CAB: bacteriuria with pyuria (> 10 WBCs/hpf)^§ and bacteriuria (> 50 cfu/mL)

Infection

AUC with moderate – high grade pyuria (>10 WBCs/hpf) and high grade bacteriuria (>100 cfu/mL)*.
CAB (UA/UC after Foley removed/replaced) with >10 WBCs/hpf and high grade bacteriuria (> 100 cfu/mL)*

* If indwelling urinary catheter, change/replace catheter and repeat AU/UC before considering treatment ^† UTI = high grade pyuria with high grade bacteriuria. Pyuria ≠ UTI; Dysuria ≠ UTI; Bacteriuria ≠ UTI ^§ clumps = high grade pyuria.10

COLONIZATION VS. INFECTION

Table 1.7 Colonization vs. Infection: Respiratory Secretions

Colonization of respiratory secretions in ventilated patients is the rule and a function of days intubated.
GNB from the ICU milieu colonize respiratory secretions.
Common GNB colonizers include Klebsiella, Enterobacter, Serratia, S. maltophilia, B. cepacia and P. aeruginosa.
Most GNB colonizing organisms rarely, if ever, cause NP/VAP, e.g., Enterobacter, S. maltophilia, B. cepacia.
In ventilated patients with fever, leukocytosis, and infiltrates on CXR organisms cultured from respiratory secretions should be considered as airway colonizers and not the cause of NP/VAP unless accompanied by the characteristic clinical features of the pathogen.
Klebsiella pneumonia presents with fevers and rapid cavitation (3-5 days after infiltrates) P. aeruginosa pneumonia presents with high spiking fevers, and rapid cavitation (<3 days after infiltrates).

Ventilated patients treated with antibiotics with minimal S. aureus activity, e.g., ciprofloxacin, ceftazidime are often colonized with MSSA or MRSA, but do not develop S. aureus NP/VAP.
S. aureus (MSSA or MRSA) may cause CAP with influenza pneumonia but rarely, if ever, causes NP/VAP.
Data suggesting that S. aureus in ventilated patients with fever, leukocytosis and infiltrates on CXR is a common cause of NP/VAP is based on respiratory secretion cultures and represents colonization and not the cause of NP.
Such data represents colonization of respiratory secretions in ventilated patients. Without the distinctive clinical features of MSSA or MRSA pneumonia, e.g., high fevers, clinical deterioration and rapid cavitation (<3 days) on CXR the patients should be considered as colonized or may have tracheobronchitis.

COLONIZATION VS. INFECTION

Table 1.8 Colonization vs. Infection: Draining Wounds

Wound drainage	Wound Gram stain	Wound culture	Diagnosis
Clear	Few or some WBCs	+	Colonization
Serous	Few or some WBCs	+	Colonization
Serosanguineous	Few or some WBCs	+	Colonization
Purulent	Abundant WBCs	+	Infection

Table 1.9 Colonization vs. Infection: Sacral Decubitus (Stage III/IV) and Diabetic Foot Ulcers (± osteomyelitis)

Always treat the usual pathogens (related to body site flora) rather than just “covering the cultured organism” (particularly if the specimen is not representative of the infected tissue).

Diabetic foot ulcers with infections at the body site, chronic osteomyelitis

Cover the usual pathogens: GAS, GBS, common coliforms, S. aureus, and B. fragilis (not P. aeruginosa)

Do not cover surface ulcer colonizers cultured: P. aeruginosa, Acinetobactor, VSE/VRE, Enterobacter, Burkholderia, Stenotrophomonas
- Do not rely on deep ulcer/fistula cultures (which represent skin flora) and are not reflective of bone pathogens, i.e., osteomyelitis.
- If P. aeruginosa is cultured from deep ulcer/fistula, do not cover only for P. aeruginosa. Over 95% of diabetic foot ulcers/fistulas will be culture positive from P. aeruginosa (due to P. aeruginosa colonization from wet socks, wet dressings, whirlpool baths). In aseptically collected bone specimens in the OR, P. aeruginosa is NOT a bone pathogen in diabetics with chronic osteomyelitis.
Sacral decubitus ulcers (stage III/IV) = chronic osteomyelitis

Cover the usual pathogens:

GAS, GBS, S. aureus, common coliforms, and B. fragilis.

Do not cover ulcer surface colonizers cultured:

Stenotrophomonas, Acinetobacter, Enterobacter, P. aeruginosa, Burkholderia

Table 1.10 Positive Blood Cultures vs. Bacteremia (MSSA, MRSA, CoNS)

Factors Favoring + Blood Cultures (not bacteremia)	Factors Favoring Bacteremia (not BC skin contaminants)
MSSA/MRSA + BCs (skin contamination likely) with:	MSSA/MRSA Bacteremia with:
Intermittently positive BCs Low level/low grade BC positivity (1/4 – 2/4 BCs +) TTPC = > 2 days No clinical source of MSSA/MRSA bacteremia (CVC, abscesses, osteomyelitis, ABE)	Persistently positive BCs High level/high grade bacteremia (3/4 – 4/4 BCs +) TTPC = < 2 days Clinical source of MSSA/MRSA bacteremia clinically apparent (CVC, abscesses, osteomyelitis, ABE)
CoNS (skin contamination likely) with: Intermittently positive BCs Low level/low grade BC positivity (1/4 − 2/4 + BCs) TTPC = > 2 days No clinical source of CoNS + BCs (CVC, implanted orthopedic/cardiac devices, prosthetic materials, severe/prolonged neutropenia)	CoNS Bacteremia (infection likely) with: Persistently positive BCs High level/high grade bacteremia (3/4 – 4/4 BCs +) TTPC = < 2 days Clinical source of + BCs for CoNS apparent (CVC, implanted orthopedic/cardiac devices, pros- thetic materials, severe/prolonged neutro- penia) 12
Implanted/prosthetic device associated: Dx = gallium or indium scan. ABE: Dx = cardiac vegetation. Abscess Dx = Gallium scan or CT scan. CVC associated: Dx = SQ removed CVC tip culture with > 15 col of same organism as in BCs not drawn from the CVC. TTPC = time to positive culture

Table 1.11 Clinical Features of Drug Fever

History

Many but not all individuals are atopic
Patients have been on a sensitizing medication for days or years “without a problem”

Physical exam

Relative bradycardia
Fevers may be low- or high-grade, but usually range between 102°–104°F and may exceed 106°F
Patient appears “inappropriately well” for degree of fever

Laboratory tests

Elevated WBC count (usually with left shift)
Eosinophils almost always present, (but eosinophilia is uncommon)
Elevated erythrocyte sedimentation rate in most
Early, transient, mild elevations of serum transaminases (common)
Negative blood cultures (excluding contaminants)

Table 1.12 Relative Bradycardia: Pulse/Temperature-Pulse Relationships*

Temperature	Appropriate Pulse Response (beats/min)	If Relative Bradycardia Pulse (beats/min)
106°F (41.1°C) 105°F (40.6°C) 104°F (40.7°C) 103°F (39.4°C) 102°F (38.9°C)	150/min 140/min 130/min 120/min 110/min	< 140/min < 130/min < 120/min < 110/min < 100/min
* Relative bradycardia refers to heart rates that are inappropriately slow relative to body temperature (pulse must be taken simultaneously with temperature elevation). Applies to adult patients with temperature ≥ 102°F Does not apply to patients with second/third-degree heart block, pacemaker-induced rhythms, or those taking beta-blockers, diltiazem, or verapamil. 13

ANTIBIOTIC FAILURE

Table 1.13 Causes of Apparent/Actual Antibiotic Failure

Microbiologic Factors

In vitro susceptibility but ineffective in vivo
Antibiotic “tolerance” with Gram-positive cocci
Treating colonization (vs. infection)

Antibiotic Factors

Inadequate antimicrobial spectrum
Inadequate antibiotic blood/tissue levels
Decreased antibiotic activity in tissue
Drug-drug interactions (inactivation/antagonism)

Antibiotic Penetration Problems

Undrained abscess
Foreign body associated infection
Protected focus e.g., cerebrospinal fluid
Organ hypoperfusion/diminished blood supply, e.g. DM, PVD

Non-infectious Diseases

Medical disorders mimicking infection e.g., SLE, malignancies
Drug fever

Antibiotic Unresponsive Infectious Diseases

Viral or fungal infections

ANTIMICROBIAL STEWARDSHIP: PRINCIPLES AND PRACTICE

Table 1.14 Antimicrobial Stewardship: Principles and Practice

Colonization vs. Infection (see also Tables 1.6–1.10)

Treat infection, not colonization.
Provide empiric coverage primarily directed against the most probable pathogens causing the infection at the body site.
Avoid “covering” or “chasing” multiple organisms cultured that are (pathogens and non-pathogens) at the body site cultured.
Selectively treat CAB in immunocompromised hosts. Avoid treating CAB in normal hosts.
Colonization of respiratory secretions, wounds, or urine with “water” (S. maltophilia, B. cepacia, P. aeruginosa) or skin organisms (MSSA, MRSA, CoNS, VSE, VRE) is the rule.

Narrow vs. Broad Spectrum Therapy

Narrow vs broad spectrum doesn't prevent resistance, e.g., in treating E. coli urosepsis switching from a carbapenem (broad spectrum) to ampicillin (narrow spectrum) may actually increase resistance potential.14
Narrow spectrum vs broad spectrum is not clinically superior to well chosen broad spectrum therapy, e.g., switching from ceftriaxone (broad spectrum) to penicillin (narrow spectrum in treating S. pneumoniae has no clinical rationale or clinical advantage and has no effect on controlling resistance.
Antibiotic resistance potential is related to individual antibiotics and not antibiotics class, e.g., meropenem (low resistance potential) vs. imipenem (high resistance potential).
Antibiotic resistance is not related to spectrum narrowness or broadness, e.g., levofloxacin (broad spectrum but “low resistance potential”) vs ampicillin (narrow spectrum but “high resistance potential”).

Antibiotic Resistance (see also Table 1.1)

The best way to control resistance is a selectively restricted formulary; restricted only to “high resistance potential” antibiotics, e.g., ciprofloxacin (not levofloxacin or moxifloxacin), imipenem (not meropenem or ertapenem), cefazidime (not other 3rd of 4th GC), gentamicin/tobramycin (not amikacin).
Some antibiotics may be restricted for other reasons, e.g., excessive vancomycin (IV not PO) use predisposes to VRE emergence and vancomycin may cause cell wall thickening in S. aureus resulting in permeability related resistance (to vancomycin and other antibiotics, e.g., daptomycin).
Over-restriction of antibiotics may impair timely effective therapy and does not, per se, decrease resistance.
Preferentially select antibiotics (all other things being equal) with a “low resistance potential”. Avoid, if possible, “high resistance potential” antibiotics, e.g., macrolides (for respiratory infections), TMP-SMX (for UTIs).
Except for TB therapy, combination therapy doesn't prevent resistance. The only examples of combination therapies that prevent resistance are carbenicillin + gentamicin and FC + amphotericin B.
Since resistance is, in part, concentrations dependant, subtherapeutic or low antibiotic tissue concentrations, (all other things being equal) predisposes to resistance.
Suboptimal dosing or usual dosing with inadequate tissue penetration, e.g., into the body fluids or undrained abscesses (source control is key) also predisposes to resistance.
Treat for the shortest duration of therapy that is effective in eliminating the infection.

Monotherapy vs. Combination Therapy

Preferably use monotherapy whenever possible to cover the most likely pathogen or cultured pathogen clinically relevant to the site of infection.
Combination therapy should be avoided if possible. Always tty to preferentially use monotherapy.
Monotherapy is usually less expensive than combination therapy and has less potential for adverse effects and drug-drug interactions.15
Combination therapy is often used for potential synergy (rarely occurs and if used must be based on microbiology laboratory synergy studies), to increase spectrum (preferable to use monotherapy with same spectrum), or to prevent resistance (except for TB, ineffective in nearly all contributors).

PO and IV-to-PO Switch Antibiotic Therapy (see also Table 1.5)

Wherever possible, treat with entirely oral antibiotic therapy instead of IV therapy.
Switch from IV-to-PO antibiotic therapy after clinical defervescence (usually < 72 hours).
Early IV-to-PO switch therapy eliminates phlebitis and IV line associated infections.

Antibiotic De-escalation

De-escalation is problematic if based on microbiology data alone without site-pathogen correlation.
De-escalation is appropriate in the setting of broad spectrum coverage of “presumed urosepsis” which can be narrowed after the uropathogen is identified in blood/urine.
In intubated/ventilate patients, microbiology data from respiratory secretion cultures are usually misleading and not representative of NP or VAP lung pathogens.
In patients with NP or VAP, it is more prudent to treat the most likely pathogen, e.g., P. aeruginosa (even if not cultured from respiratory secretions) than to be misguided into treating multiple colonizing organisms in respiratory secretions.
De-escalation can be harmful if microbiology data is misleading, e.g., represents colonization rather than being reflective of the pathogen (underlying bone pathogen, not ulcer organisms), e.g., diabetic foot ulcers/chronic osteomyelitis or sacral ulcers/chronic osteomyelitis.

C. difficile Diarrhea/Colitis

Preferentially select antibiotics (all other things being equal) with low C. difficile potential.
Predisposing factors to C. difficile include relatively few antibiotics, e.g., clindamycin, b-lactams, ciprofloxacin.
Most antibiotics have little/no C. difficile potential, e.g., aminoglycosides, aztreonam, maerolides, TMP-SMX, colistin, polymyxin B, daptomycin, Q/D, doxycycline, minocycline, tigecycline, vancomycin, linezolid.
Some antibiotics are protective against C. difficile, e.g., doxycycline, tigecycline.
Always consider non-antibiotic factors that may predispose to C. difficile, e.g., cancer chemotherapy, anti-depressants, statins, PPIs.
Also consider person to person spread or acquisition for the environment.

Empiric Antibiotics for Fever and Leukocytosis

Avoid treating unexplained fever/leukocytosis. If due to infection, let the infection declare itself and then initiate early therapy.
Try to diagnose the many non-infectious causes of fever/leukocytosis rather than treating empirically with antibiotics.16
Avoid prolonged antibiotic therapy of fever/leukocytosis in the presence of a device associated infection or undrained/inadequately drained abscesses.
Avoid antibiotic therapy of non-infectious fevers or non-antibiotic responsive infections, e.g., drug fevers, malignancies, hematomas, rheumatic/inflammatory disorders, viral infections.

Pharmacoeconomic Considerations

The least expensive therapy is usually not the best therapy.
The least expensive antibiotic (acquisition cost) may, in fact, be expensive (re: total cost) when considering the cost implications to the institution of dosing frequency, C. difficile potential, resistance potential, and degree of activity against the known or likely pathogen, and the cost of potential therapeutic failure vis-à-vis ↑ LOS and medicolegally.
Stewardship savings are best achieved by decreasing duration of antibiotic therapy, and by treating entirely with oral antibiotic therapy or early IV-to-PO switch therapy.

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Chapter Notes

Overview of Antimicrobial TherapyChapter 1