Antimicrobial Regimen Selection

Introduction

A generally accepted systematic approach to the selection and evaluation of an antimicrobial regimen is shown in Table Systematic Approach for Selection of Antimicrobials. An «empiric» antimicrobial regimen is begun before the offending organism is identified, while a «definitive» regimen is instituted when the causative organism is known.

Confirming the presence of infection

Fever

Fever is defined as a controlled elevation of body temperature above the normal range of 36.7 to 37.0В°C. Fever is a manifestation of many disease states other than infection.
Many drugs have been identified as causes of fever. Drug-induced fever is defined as persistent fever in the absence of infection or other underlying condition. The fever must coincide temporally with the administration of the offending agent and disappear promptly upon its withdrawal, after which it remains normal.

Signs and symptoms

White Blood Cell Count

Most infections result in elevated white blood cell counts (leukocytosis) because of the mobilization of granulocytes and/or lymphocytes to destroy invading microbes. The generally accepted range of normal values for white blood cell counts is between 4000 and 10,000/mm³.

TABLE. Systematic Approach for Selection of Antimicrobials

Confirm the presence of infection Careful history and physical Signs and symptoms Predisposing factors Identification of the pathogen Collection of infected material Stains Serologies Culture and sensitivity Selection of presumptive therapy considering every infected site Host factors Drug factors Monitor therapeutic response Clinical assessment Laboratory tests Assessment of therapeutic failure

Bacterial infections are associated with elevated granulocyte counts (neutrophils, basophils), often with increased numbers of immature forms (band neutrophils) seen in peripheral blood smears (left-shift). With infection, peripheral leukocyte counts may be very high, but are rarely higher than 30,000 to 40,000/mm³. Low neutrophil counts (neutropenia) after the onset of infection indicate an abnormal response and are generally associated with a poor prognosis for bacterial infection.
Relative lymphocytosis, even with normal or slightly elevated total white blood cell counts, is generally associated with viral or fungal infections. Lymphocytopenia occurs with AIDS.
Many types of infections, however, may be accompanied by a completely normal white blood cell count and differential.

Pain and Inflammation

Pain and inflammation may accompany infection and are sometimes manifested by swelling, erythema, tenderness, and purulent drainage. Unfortunately, these signs may be apparent only if the infection is superficial or in a bone or joint.
The manifestations of inflammation with deep-seated infections such as meningitis, pneumonia, endocarditis, and urinary tract infection must be ascertained by examining tissues or fluids. For example, the presence of polymorphonuclear leukocytes (neutrophils) in spinal fluid, lung secretions (sputum), and urine is highly suggestive of bacterial infection.

Identification of the pathogen

Infected body materials must be sampled, if at all possible or practical, before the institution of antimicrobial therapy, for two reasons. First, Gram stain of the material may rapidly reveal bacteria or acid-fast stain may detect mycobacteria or actinomycetes. Second, a delay in obtaining infected fluids or tissues until after therapy is started may result in false-negative culture results or alterations in the cellular and chemical composition of infected fluids.
Blood cultures should be performed in the acutely ill, febrile patient. Less accessible fluids or tissues must be obtained based on localized signs or symptoms (e.g., spinal fluid in meningitis, joint fluid in arthritis). Abscesses and cellulitic areas should also be aspirated.
Caution must be used in the evaluation of positive culture results from normally sterile sites (e.g., blood, cerebrospinal fluid, joint fluid). The recovery of bacteria normally found on the skin in large quantities (e.g., coagulase-negative staphylococci, diphtheroids) from one of these sites may be a result of contamination of the specimen rather than a true infection.

Selection of presumptive therapy

To select rational antimicrobial therapy for a given infection, a variety of factors must be considered. These include the severity and acuity of the disease, host factors, factors related to the drugs used, and the necessity for use of multiple agents.
There are generally accepted drugs of choice for the treatment of most pathogens (Table Drugs of Choice, First Choice, Alternative(s)). The drugs of choice are compiled from a variety of sources and are intended as guidelines rather than specific rules for antimicrobial use.

TABLE. Drugs of Choice, First Choice, Alternative(s)

GRAM-POSITIVE COCCI Enterococcus faecalis (generally not as resistant to antibiotics as E. faecium) Serious infection (endocarditis, meningitis, pyelonephritis with bacteremia) Ampicillin (or penicillin G) + (gentamicin or streptomycin) Vancomycin + (gentamicin or streptomycin), linezolid Urinary tract infection Ampicillin, amoxicillin Doxycycline^a fosfomycin, or nitrofurantoin E. faecium (generally more resistant to antibiotics than E. faecalis) Recommend consultation with infectious disease specialist. Linezolid, quinupristin/dalfopristin Staphylococcus aureus/Staphylococcus epidermidis Methicillin (oxacillin)-sensitive PRP^c FGC,^d^,e trimethoprim-sulfamethoxazole, clindamycin,^f ampicillin-sulbactam, amoxicillin-clavulante, or fluoroquinolone Methicillin (oxacillin)-resistant Vancomycin + (gentamicin or rifampin) Linezolid, quinupristin-dalfopristin, daptomycin Per sensitivities: Trimethoprim-sulfamethoxazole, doxycycline,^a or clindamycin Streptococcus (groups A, B, C, G, and S. bovis) Penicillin G^h or Vⁱ or ampicillin FGC,^d^,e erythromycin, azithromycin, clarithromycin,^j S. pneumoniae Penicillin-sensitive (minimum inhibitory concentration < 0.1 mcg/mL) Penicillin G or V or ampicillin Erythromycin, FGC,^d^,e azithromycin, or clarithromycin^j Penicillin intermediate (minimum inhibitory concentration 0.1-1.0 mcg/mL) High-dose penicillin (12 million units/day for adults) or ceftriaxone^e or cefotaxime^e Gatifloxacin^b, levofloxacin^b, moxifloxacin^b, or vancomycin Penicillin-resistant (minimum inhibitory concentration в‰Ґ 1.0 mcg/mL) Recommend consultation with infectious disease specialist. Vancomycin В± rifampin Per sensitivities: TGC,^e^,k levofloxacin,^b gatifloxacin,^b or moxifloxacin^b Streptococcus, viridans group Penicillin G В± gentamicin^l TGC,^d^,e erythromycin, azithromycin, clarithromycin,^j or vancomycin В± gentamicin GRAM-NEGATIVE COCCI Moraxella (Branhamella) catarrhalis Amoxicillin-clavulanate, ampicillin-sulbactam Trimethoprim-sulfamethoxazole, erythromycin, azithromycin, clarithromycin,^j doxycycline,^a SGC,^e^,m TGC,^e^,k or TGCpo^e^,n Neisseria gonorrhoeae (also give concomitant treatment for Chlamydia trachomatis) Disseminated gonococcal infection Ceftriaxone^e or cefotaxime^e Oral follow-up: Cefixime,^e cefpodoxime,^e ciprofloxacin,^b or ofloxacin^b Uncomplicated infection Ceftriaxone^e or cefotaxime,^e cefixime,^e or cefpodoxime^e Ciprofloxacin^b or ofloxacin^b N. meningitides Penicillin G TGC^e^,k GRAM-POSITIVE BACILLI Clostridium perfringens Penicillin G В± clindamycin Metronidazole, clindamycin, doxycycline,^a cefazolin,^e imipenem,^o meropenem,^o or ertapenem^o C. difficile Oral metronidazole Oral vancomycin GRAM-NEGATIVE BACILLI Acinetobacter spp. Imipenem or meropenem either В± aminoglycoside^p (amikacin usually most effective) Ciprofloxacin,^b trimethoprim-sulfamethoxazole, or ampicillin-sulbactam Bacteroides fragilis (and others) Metronidazole BLIC,^g clindamycin, cephamycin,^e^,q or carbapenem^o Enterobacter spp. Imipenem, meropenem, ertapenem, or cefepime В± aminoglycoside^p Ciprofloxacin,^b levofloxacin,^b piperacillin-tazobactam, ticarcillin-clavulanate, or trimethoprim-sulfamethoxazole Escherichia coli Meningitis TGC^e^,k or meropenem Systemic infection TGC^e^,k Ampicillin-sulbactam, FGC,^d^,e BL/BLI,^g trimethoprim-sulfamethoxazole, SGC,^e^,m fluoroquinolone,^b^,o,r imipenem,^o meropenem^o Urinary tract infection Most oral agents: Check sensitivities. Ampicillin, amoxicillin-clavulanate, trimethoprim-sulfamethoxazole, or cephalexin^e Aminoglycoside, FGC^d^,e nitrofurantoin, fluoroquinolone^b^,o,r Gardnerella vaginalis Metronidazole Clindamycin Hemophilus influenzae Meningitis Cefotaxime^e or ceftriaxone^e Meropenem^o or chloramphenicol^r Other infections BLIC,^g or if β- lactamase-negative, ampicillin or amoxicillin Trimethoprim-sulfamethoxazole, cefuroxime,^e erythromycin, azithromycin, clarithromycin,^j or fluoroquinolone^b^,o,r Klebsiella pneumoniae TGC^e^,k (if Urinary tract infection only: Aminoglycoside^p) Trimethoprim-sulfamethoxazole, cefuroxime,^e fluoroquinolone,^b^,r BLIC,^g imipenem,^o or meropenem^o Legionella spp. Erythromycin В± rifampin or fluoroquinolone^b^,r Trimethoprim-sulfamethoxazole, clarithromycin,^j azithromycin, or doxycycline^a Pasteurella multocida Penicillin G, ampicillin, amoxicillin Doxycycline,^a BLIC,^g trimethoprim-sulfamethoxazole or ceftriaxone^e^,k Proteus mirabilis Ampicillin Trimethoprim-sulfamethoxazole, most antibiotics except PRP^c Proteus (indole-positive) (including Providencia rettgeri, Morganella morganii, and Proteus vulgaris) TGC^e^,k or fluoroquinolone^b^,r Trimethoprim-sulfamethoxazole, BLIC,^g aztreonam,^t imipenem,^o or TGCpo^e^,n Providencia stuartii TGC^e^,k or fluoroquinolone^b^,r Trimethoprim-sulfamethoxazole, aztreonam,^t imipenem,^o or meropenem^o Pseudomonas aeruginosa Cefepime, ceftazidime, piperacillin-tazobactam, or ticarcillin-clavulanate plus aminoglycoside^p Ciprofloxacin,^b levofloxacin,^b aztreonam,^t imipenem,^o or meropenem^o Urinary tract infection only: Aminoglycoside^p Ciprofloxacin,^b levofloxacin,^b or gatifloxacin^b Salmonella typhi Ciprofloxacin,^b levofloxacin,^b ceftriaxone,^e or cefotaxime^e Trimethoprim-sulfamethoxazole Serratia marcescens Piperacillin-tazobactam, ticarcillin-clavulanate, or TGC,^e^,kВ± gentamicin Trimethoprim-sulfamethoxazole, ciprofloxacin,^b levofloxacin,^b aztreonam,^t imipenem,^g meropenem,^a or ertapenem Stenotrophomonas (Xanthomonas) maltophilia Trimethoprim-sulfamethoxazole Generally very resistant to all antimicrobials; check sensitivities to ceftazidime,^e ticarcillin-clavulanate, doxycycline,^a and minocycline^a MISCELLANEOUS MICROORGANISMS Chlamydia pneumoniae Doxycycline^a Erythromycin, azithromycin, clarithromycin,^j or fluoroquinolone^b^,r C. trachomatis Doxycycline^a or azithromycin Levofloxacin^b or ofloxacin^b Mycoplasma pneumoniae Erythromycin, azithromycin, clarithromycin^j Doxycycline^a or fluoroquinolone^b^,r SPIROCHETES Treponema pallidum Neurosyphilis Penicillin G Ceftriaxone^e Primary or secondary Benzathine penicillin G Doxycycline^a or ceftriaxone^e Borrelia burgdorferi (choice depends on stage of disease) Ceftriaxone^e or cefuroxime axetil,^e doxycycline,^a amoxicillin High-dose penicillin, cefotaxime,^e azithromycin, or clarithromycin^j

^a Not for use in pregnant patients or children younger than 8 yr. ^b Not for use in pregnant patients or children younger than 18 yr. ^c Penicillinase-resistant penicillin: nafcillin or oxacillin. ^d First-generation cephalosporins – intravenous: cefazolin; PO: cephalexin, cephradine, or cefadroxil. ^e Some penicillin-allergic patients may react to cephalosporins. ^f Not reliably bactericidal; should not be used for endocarditis. ^g β- Lactamase inhibitor combination – intravenous: ampicillin-sulbactam, piperacillin-tazobactam, ticarcillin-clavulante; PO: amoxicillin-clavulanate. ^h Either aqueous penicillin G or benzathine penicillin G (pharyngitis only). ⁱ Only for soft tissue infections or upper respiratory infections (pharyngitis, otitis media). ^j Do not use in pregnant patients. ^k Third-generation cephalosporins – intravenous: cefotaxime, ceftriaxone. ^l Gentamicin should be added if tolerance or moderately susceptible (minimum inhibitory concentration >0.1 g/mL) organisms are encountered; streptomycin is used but may be more toxic. ^m Second-generation cephalosporins – intravenous: cefuroxime; PO: cefaclor, cefditoren, cefprozil, cefuroxime axetil, and loracarbef. ⁿ Third-generation cephalosporins – PO: cefdinir, cefixime, cefetamet, cefpodoxime proxetil, and ceftibuten. ^o Reserve for serious infection. ^p Aminoglycosides: gentamicin, tobramycin, and amikacin; use per sensitivities. ^q Cefoxitin, cefotetan. ^r intravenous/PO: ciprofloxacin, ofloxacin, levofloxacin, gatifloxacin, and moxifloxacin. ^s Reserve for serious infection when less toxic drugs are not effective. ^t Generally reserved for patients with hypersensitivity reactions to penicillin.

When selecting antimicrobial regimens, local susceptibility data should be considered whenever possible rather than information published by other institutions or national compilations.
Empiric therapy is directed at organisms that are known to cause the infection in question.

Host factors

In evaluating a patient for initial or empiric therapy, the following factors should be considered:
- Allergy or history of adverse drug reactions
- Age of patient
- Pregnancy
- Metabolic abnormalities
- Renal and hepatic function
- Concomitant drug therapy
- Concomitant disease states
Patients with diminished renal and/or hepatic function will accumulate certain drugs unless dosage is adjusted. Any concomitant therapy the patient is receiving may influence the selection of drug therapy, the dose, and monitoring.
A list of selected drug interactions involving antimicrobials is provided in Table Major Drug Interactions with Antimicrobials.

Drug factors

Integration of both pharmacokinetic and pharmacodynamic properties of an agent is important when choosing antimicrobial therapy to ensure efficacy and prevent resistance.
The importance of tissue penetration varies with the site of infection. The central nervous system is one body site where the importance of antimicrobial penetration is relatively well defined and correlations with clinical outcomes are established. Drugs that do not reach significant concentrations in cerebrospinal fluid should be avoided in treating meningitis.
Apart from the bloodstream, other body fluids where drug concentration data are clinically relevant include urine, synovial fluid, and peritoneal fluid.
Certain pharmacokinetic parameters such as area under the concentration-time curve and maximal plasma concentration (C_max can be predictive of treatment outcome when specific ratios of area under the concentration-time curve or C_max to the minimum inhibitory concentration are achieved. For some agents, the ratio of area under the concentration-time curve to minimum inhibitory concentration, peak to minimum inhibitory concentration ratio, or the time that the drug concentration is above the minimum inhibitory concentration may predict efficacy.
Antimicrobials that affect cell wall synthesis (e.g., β- lactams and vancomycin) display time-dependent bactericidal effects. Therefore, the most important pharmacodynamic relationship for these antimicrobials is the duration that drug concentrations exceed the minimum inhibitory concentration (T greater than minimum inhibitory concentration).
- The costs of drug therapy are increasing dramatically, especially as new products derived from biotechnology are introduced. The total cost of antimicrobial therapy includes much more than just the acquisition cost of the drugs.

Combination antimicrobial therapy

Combinations of antimicrobials are generally used to broaden the spectrum of coverage for empiric therapy, achieve synergistic activity against the infecting organism, and prevent the emergence of resistance.

TABLE. Major Drug Interactions with Antimicrobials

Antimicrobial	Other Agent(s)	Mechanism of Action/Effect	Clinical Management
Aminoglycosides	Neuromuscular blocking agents	Additive adverse effects	Avoid
	Nephrotoxins (N) or ototoxins (O) (e.g., amphotericn B (N) cisplatin (N/O), cyclosporine (N), furosemide (O), nonsteroidal anti-inflammatory drugs (N), radio contrast (N), vancomycin (N)	Additive adverse effects	Monitor aminoglycoside SDC and renal function
Amphotericin B	Nephrotoxins (e.g., aminoglycosides, cidofovir, cyclosporine, foscarnet, pentamidine)	Additive adverse effects	Monitor renal function
Azoles
Chloramphenicol	Phenytoin, tolbutamide, ethanol	Decreased metabolism of other agents	Monitor phenytoin SDC, blood glucose
Foscarnet	Pentamidine intravenous	Increased risk of severe nephrotoxicity/ hypocalcemia	Monitor renal function/serum calcium
Isoniazid	Carbamazepine, phenytoin	Decreased metabolism of other agents (nausea, vomiting, nystagmus, ataxia)	Monitor drug SDC
Macrolides/azalides	Digoxin	Decreased digoxin bioavailability and metabolism	Monitor digoxin SDC; avoid if possible
Macrolides/azalides	Theophylline	Decreased metabolism of theophylline	Monitor theophylline SDC
Metronidazole (also cefamandole, cefoperazone)	Ethanol (drugs containing ethanol)	Disulfiram-like reaction	Avoid
Penicillins and cephalosporins	Probenecid, aspirin	Blocked excretion of β- lactams	Use if prolonged high concentration of β- lactam desirable
Ciprofloxacin/ norfloxacin	Theophylline	Decreased metabolism of theophylline	Monitor theophylline
Quinolones	Class la and III Antiarrhythmics	Increased Q-T interval	Avoid
Quinolones	Multivalent cations (antacids, iron, sucralfate, zinc, vitamins, dairy, citric acid) didanosine	Decreased absorption of quinolone	Separate by 2 h
Rifampin	Azoles, cyclosporine, methadone propranolol, protease inhibitors (Pl), oral contraceptives, tacrolimus, warfarin	Increased metabolism of other agent	Avoid if possible
Sulfonamides	Sulfonylureas, phenytoin, warfarin	Decreased metabolism of other agent	Monitor blood glucose, SDC, PT
Tetracyclines	Antacids, iron, calcium, sucralfate	Decreased absorption of tetracycline	Separate by 2 h
Tetracyclines	Digoxin	Decreased digoxin bioavailability and metabolism	Monitor digoxin SDC; avoid if possible
Azalides: azithromycin; azoles: fluconazole, itraconazole, ketoconazole, and voriconazole; macrolides: erythromycin, clarithromycin; protease inhibitors: aprenavir, indinavir, lopinavir/ritonavir, nelfinavir, ritonavir, and saquinavir; quinolones: ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin. SDC = serum drug concentrations.

Broadening the spectrum of coverage

Increasing the coverage of antimicrobial therapy is generally necessary in mixed infections where multiple organisms are likely to be present. This is the case in intraabdominal and female pelvic infections in which a variety of aerobic and anaerobic bacteria may produce disease.
Another clinical situation in which increased spectrum of activity is desirable is with nosocomial infection. Hospital-acquired infections, except as previously noted, are generally caused by only one organism, but many different organisms may be possible.

Synergism

The achievement of synergistic antimicrobial activity is advantageous for infections caused by gram-negative bacilli in immunosuppressed patients.
Traditionally, combinations of aminoglycosides and β- lactams have been used since these drugs together generally act synergistically against a wide variety of bacteria. However, the data supporting superior efficacy of synergistic over nonsynergistic combinations are weak.
Synergistic combinations may produce better results in infections caused by Pseudomonas aeruginosa, in certain infections caused by Enterococcus spp., and, perhaps, in patients with profound, persistent neutropenia.

Preventing resistance

The use of combinations to prevent the emergence of resistance is widely applied but not often realized. The only circumstance where this has been clearly effective is in the treatment of tuberculosis.

Disadvantages of combination therapy

Although there are potentially beneficial effects from combining drugs, there are also potentially serious liabilities. Examples include additive nephrotoxicity from drugs such as aminoglycosides, amphotericin, and possibly vancomycin. Inactivation of aminoglycosides by penicillins may be clinically significant when excessive doses of penicillin are given to a patient in renal failure.
Some combinations of antimicrobials are potentially antagonistic. Such combinations should probably be avoided whenever possible, unless the clinical situation warrants the use of both drugs for different pathogens. Agents that are capable of inducing β- lactamase production in bacteria may antagonize the effects of enzyme-labile drugs such as penicillins.

Failure of antimicrobial therapy

A variety of factors may be responsible for apparent lack of response to therapy. Factors include those directly related to the host, those related to the pathogen, and, although unlikely, laboratory error in identification and/or susceptibility testing. Factors directly related to the antimicrobial agents being utilized are only a small proportion of the possibilities.

Failures Caused by Drug Selection

Factors directly related to the drug selection include an inappropriate selection of drug, dosage, or route of administration. Malabsorption of a drug product because of gastrointestinal disease (e.g., short-bowel syndrome) or a drug interaction (e.g., complexation of fluoroquinolones with multivalent cations resulting in reduced absorption) may lead to potentially subtherapeutic serum concentrations.
Accelerated drug elimination is also a possible reason for failure and may occur in patients with cystic fibrosis or during pregnancy, when more rapid clearance or larger volumes of distribution may result in low serum concentrations, particularly for aminoglycosides.
Finally, a common cause of failure of therapy is poor penetration into the site of infection. This is especially true for the so-called privileged sites such as the central nervous system, the eye, and the prostate gland.

Failures Caused by Host Factors

Patients who are immunosuppressed (e.g., granulocytopenia from chemotherapy, AIDS) may respond poorly to therapy because their own defenses are inadequate to eradicate the infection despite seemingly adequate drug regimens.
Other host factors are related to the necessity for surgical drainage of abscesses or removal of foreign bodies and/or necrotic tissue. If these situations are not corrected, they result in persistent infection and, occasionally, bacteremia, despite adequate antimicrobial therapy.

Failures Caused by Microorganisms

Factors related to the pathogen include the development of drug resistance during therapy. Primary resistance refers to the intrinsic resistance of the pathogens producing the infection. However, acquisition of resistance during treatment has become a major problem as well.
The increase in resistance among pathogenic organisms is believed to be due, in large part, to continued overuse of antimicrobials in the community, as well as in hospitals, and the increasing prevalence of immunosuppressed patients receiving long-term suppressive antimicrobials for the prevention of infections.