FIGURE 42-1 Model depicting the interaction among components mediating resistance to ft-lactam antibiotics in Pseudomonas aeruginosa. (Courtesy of Hiroshi Nikaido.) Most ^-lactam antibiotics are hydrophilic and must cross the outer membrane barrier of the cell via outer membrane protein (Omp) channels, or porins. The channel has size and charge selectivity such that some Omps slow or block transit of the drug. If an Omp permitting drug entry is altered by mutation, is missing, or is deleted, then drug entry is slowed or prevented. ^-Lactamase concentrated between the inner and outer membranes in the periplasmic space constitutes an enzymatic barrier that works in concert with the porin permeability barrier. If the antibiotic is a good substrate for ^-lactamase, it will be destroyed rapidly even if the outer membrane is relatively permeable to the drug. If the rate of drug entry is slow, then a relatively inefficient ^-lactamase with a slow turnover rate can hydrolyze just enough drug that an effective concentration cannot be achieved. If the target (PBP, penicillin-binding protein) has low binding affinity for the drug or is altered, then the minimum concentration for inhibition is elevated, further contributing to resistance. Finally, ^-lactam antibiotics (and other polar antibiotics) that enter the cell and avoid ^-lactamase destruction can be taken up by an efflux transporter system (e.g., MexA, MexB, and OprF) and pumped across the outer membrane, further reducing the intracellular concentration of active drug.

transporter system

FIGURE 42-1 Model depicting the interaction among components mediating resistance to ft-lactam antibiotics in Pseudomonas aeruginosa. (Courtesy of Hiroshi Nikaido.) Most ^-lactam antibiotics are hydrophilic and must cross the outer membrane barrier of the cell via outer membrane protein (Omp) channels, or porins. The channel has size and charge selectivity such that some Omps slow or block transit of the drug. If an Omp permitting drug entry is altered by mutation, is missing, or is deleted, then drug entry is slowed or prevented. ^-Lactamase concentrated between the inner and outer membranes in the periplasmic space constitutes an enzymatic barrier that works in concert with the porin permeability barrier. If the antibiotic is a good substrate for ^-lactamase, it will be destroyed rapidly even if the outer membrane is relatively permeable to the drug. If the rate of drug entry is slow, then a relatively inefficient ^-lactamase with a slow turnover rate can hydrolyze just enough drug that an effective concentration cannot be achieved. If the target (PBP, penicillin-binding protein) has low binding affinity for the drug or is altered, then the minimum concentration for inhibition is elevated, further contributing to resistance. Finally, ^-lactam antibiotics (and other polar antibiotics) that enter the cell and avoid ^-lactamase destruction can be taken up by an efflux transporter system (e.g., MexA, MexB, and OprF) and pumped across the outer membrane, further reducing the intracellular concentration of active drug.

cell membrane, resistance can result from mutations that inhibit this transport mechanism. For example, gentamicin, which targets the ribosome, is actively transported across the cell membrane using energy provided by the membrane electrochemical gradient. This gradient is generated by respiratory enzymes that couple electron transport and oxidative phosphorylation. A mutation in this pathway or anaerobic conditions slows entry of gentamicin into the cell, resulting in resistance. Bacteria also have efflux pumps that can transport drugs out of cells. Resistance to numerous drugs (e.g., tetracycline, chloramphenicol, fluroquinolones, macrolides, and ^-lactam antibiotics) is mediated by an efflux pump mechanism. Figure 42-1 depicts the multiple membrane and periplasm components that reduce the intracellular concentrations of ^-lactam antibiotics and cause resistance.

Drug inactivation. Bacterial resistance to aminoglycosides and ^-lactam antibiotics usually results from production of enzymes that modify or destroy the antibiotic, respectively. A variation in this mechanism—the failure of bacteria to activate a prodrug—commonly underlies resistance of Mycobacterium tuberculosis to isoniazid.

Target alteration. This can include mutation of the natural target (e.g., fluoroquinolone resistance), target modification (e.g., ribosomal protection from macrolides and tetracyclines), or acquisition of a resistant form of the susceptible target (e.g., staphylococcal resistance to methicillin caused by production of a low-affinity variant of penicillin-binding protein).

ACQUISITION OF DRUG RESISTANCE Drug resistance may be acquired by mutation and selection, with passage of the trait vertically to daughter cells, or by horizontal transfer of resistance determinants. For mutation and selection to generate resistance, the mutation cannot be lethal, should not appreciably impair virulence, and the cell carrying the mutation must disseminate and replicate. Resistance acquired by horizontal transfer of resistance determinants can disseminate rapidly either by clonal spread of the resistant strain or by subsequent transfers to other susceptible recipient strains. Horizontal transfer offers several advantages over mutation-selection. Lethal mutation of an essential gene is avoided; the level of resistance often is higher than that produced by mutation, which tends to yield incremental changes; the gene can be mobilized and rapidly amplified within a population by transfer to susceptible cells; and the resistance gene can be eliminated when no longer required.

Mutation-Selection. Mutation and antibiotic selection of the resistant mutant are the molecular basis for resistance to streptomycin (ribosomal mutation) quinolones (gyrase or topoisomerase IV mutations) rifampin (RNA polymerase mutation), and linezolid (ribosomal RNA mutation). This mechanism underlies all drug resistance in M. tuberculosis. The mutations are not caused by drug exposure per se, but are random events that confer a survival advantage when the drug is present. High-level resistance can either emerge from a sequential series of mutations that alter susceptibility incrementally (more commonly) or from a mutation that confers high-level resistance in a single step.

Horizontal Gene Transfer. Horizontal gene transfer of resistance genes is greatly facilitated by and is largely dependent on mobile genetic elements. Of these, plasmids play the most important role, with lesser importance of transposable elements, integrons, and gene cassettes. Other mechanisms may play important roles in the horizontal transfer of resistance in certain bacteria. Conjugation, the direct transfer of genes by cell-to-cell contact though a sex pilus or bridge, is an extremely important mechanism because multiple resistance genes can be transferred in a single event. Genetic transfer by conjugation is common among gram-negative bacilli and resistance is conferred on a susceptible cell in a single event. Enterococci and staphylococci are gram-positive bacteria that also transfer antibiotic resistance by conjugative transfer.

Selection of an Antimicrobial Agent

Optimal selection of antimicrobial agents requires clinical judgment and detailed knowledge of pharmacological and microbiological factors. Antibiotics have three general uses: empirical therapy, definitive therapy, and phophylactic therapy. When used as empirical therapy, the antibiotic(s) should cover all the likely pathogens, because the infecting organism has not been identified. Either combination therapy or, preferably, treatment with a single broad-spectrum agent may be employed. Once the infecting microorganism is identified, the course is completed with a narrow-spectrum, low-toxicity drug. Failures to identify the infecting microorganism and to narrow the antibiotic spectrum thereafter are common misuses of antibiotics.

The first consideration in selecting an antibiotic is whether it is even indicated. The reflex action to associate fever with treatable infections and prescribe antimicrobial therapy without further evaluation is irrational and potentially dangerous. The diagnosis may be masked if therapy is started before appropriate cultures are obtained. Antibiotics are potentially toxic, and may promote selection of resistant microorganisms. Of course, definitive identification of a bacterial infection before treatment is initiated often is not possible. In the absence of a clear indication, antibiotics often may be used if disease is severe and it seems likely that withholding therapy will result in failure to manage a serious or life-threatening infection.

Initiation of optimal empiric antibiotic therapy requires knowledge of the most likely infecting organisms and their antibiotic susceptibilities. Selection of an antibiotic regimen should rely on the clinical presentation, which may suggest a specific microorganism, and knowledge of the microorganisms most likely to cause a specific infection in a given host. In addition, simple and rapid laboratory tests may provide important clues to the possible infectious microorganism (e.g., Gram's stain of infected secretion or body fluid), thereby permitting more rational selection of initial antibiotic therapy. In many situations, it is not possible to arrive at a specific bacteriological diagnosis, and the selection of a single narrow-spectrum antibiotic may be inappropriate, particularly if the infection is severe. Broad-spectrum antibiotic coverage is then indicated, pending isolation and identification of the microorganism. Whenever the clinician is faced with initiating therapy on a presumptive bacteriological diagnosis, cultures of the presumed site of infection and blood should be taken prior to the institution of drug therapy. For definitive therapy, the regimen should be changed to a more specific and narrow-spectrum antibiotic once an organism has been identified and its susceptibility is known.

TESTING FOR MICROBIAL SENSITIVITY TO ANTIMICROBIAL AGENTS Bacterial strains, even from the same species, may vary widely in sensitivity to antibiotics. Information about the antibiotic sensitivity of the infecting microorganism is important for appropriate drug selection. Various methods are used to assess susceptibility, including disk-diffusion, dilution test, and automated broth dilution. The results are either reported on a semi-quantitative scale (i.e., resistant, intermediate, or susceptible) or in terms of the minimal inhibitory concentration (MIC).

PHARMACOKINETIC FACTORS In vitro activity, although critical, is only a guide to whether an antibiotic is likely to be effective, and successful therapy also depends on achieving a drug concentration sufficient to inhibit or kill bacteria at the site of infection without harming the host.

The location of the infection may dictate the choice of drug and the route of administration. The minimal drug concentration achieved at the infected site should be approximately equal to the MIC for the infecting organism, although it usually is advisable to achieve multiples of the MIC if possible. Even subinhibitory concentrations of antibiotics may be effective, perhaps by enhancing phagocytosis. Nonetheless, the aim of antibiotic therapy always should be to produce antibacterial concentrations of the drug at the site of the infection during the dosing interval.

Antibiotic access to sites of infection depends on multiple factors. If the infection is in the central nervous system (CNS), the drug must pass the blood-brain barrier. Antibiotics that are polar at physiological pH generally penetrate poorly; some, such as penicillin G, are actively transported out of the cerebrospinal fluid (CSF) by an anion transport mechanism in the choroid plexus. The concentrations of penicillins in the CSF usually are only 0.5-5% of those determined simultaneously in plasma. If the integrity of the blood-brain barrier is diminished by active bacterial infection, antibiotic penetration is increased considerably, permitting the use of penicillins in infectious meningitis. As the inflammatory reactions subside, penetration returns to normal; the drug dosage therefore should not be decreased as the patient improves. In a similar manner, antibiotics that are highly protein bound may penetrate less well into the site of infection than those that are largely unbound.

The dose and dosing frequency of antibiotics traditionally have been selected to achieve antibacterial activity at the site of infection for most of the dosing interval. This may not always be necessary, and superior results may even be obtained with high peak concentrations followed by periods of subinhibitory activity. For example, aminoglycosides are at least as efficacious and less toxic when given in a single large daily dose than when given more frequently in divided doses.

Knowledge of an individual patient's renal and hepatic function also is essential, as the dose of certain antibiotics must be adjusted to avoid toxicity when their elimination is impaired.

HOST FACTORS A critical determinant of antibiotic efficacy is the status of the host humoral and cellular defense mechanisms. In the immunocompetent host, merely halting the multiplication of the microorganism with a bacteriostatic agent frequently is sufficient to cure the infection. If host defenses are impaired, bacteriostatic activity may be inadequate and a bactericidal agent is required for cure. Examples where this applies include bacterial endocarditis, bacterial meningitis, and disseminated bacterial infections in neutropenic patients. Patients with HIV-1 infection and acquired immunodeficiency syndrome have impaired cellular immune responses. Therapy for opportunistic infection therefore often is suppressive but not curative; disseminated infections with Salmonella or atypical mycobacteria typically require prolonged antibiotic therapy to prevent relapse.

LOCAL FACTORS Antibiotic activity may be reduced significantly in pus, which contains phagocytes, cellular debris, and proteins that can bind drugs or create conditions unfavorable to drug action. The low pH that is characteristically found in abscesses and many confined infected sites can markedly reduce the activity of some agents, particularly the aminoglycosides.

The presence of a foreign body in an infected site markedly reduces the likelihood for successful antibiotic therapy. Prosthetics such as cardiac valves, artificial joints, pacemakers, vascular grafts, and various shunts promote the formation of a bacterial biofilm that impairs phagocytosis; within the film, the slower growth of bacteria may also reduce antibiotic activity and favor bacterial persistence. Infections associated with foreign bodies thus are characterized by frequent relapses and failure, even with long-term antibiotic therapy. Successful therapy usually requires removal of the foreign material.

Intracellular pathogens (e.g., Salmonella, Brucella, Toxoplasma, Listeria, and M. Tuberculosis) are protected from the action of antibiotics that penetrate into cells poorly. Certain antibiotics (e.g., fluoroquinolones, isoniazid, trimethoprim-sulfamethoxazole, and rifampin) penetrate cells well and can achieve intracellular concentrations that inhibit or kill pathogens residing within cells.

OTHER FACTORS Age may play an important role in antibiotic therapy; newborn babies and the elderly often have impaired mechanisms of elimination of antibiotics and thus are uniquely susceptible to certain drug toxicities. Genetic polymorphisms that affect drug metabolism are increasingly appreciated as important factors in interindividual differences in toxic effects of many drugs, including antibiotics. Pregnancy may impose an increased risk of reaction to antibiotics for both mother and fetus. Similarly, lactating females can pass antibiotics to nursing babies, sometimes with adverse effects. Drug allergy is a common event with many antibiotics, especially ^-lactam antibiotics.

Therapy with Combined Antimicrobial Agents

The simultaneous use of two or more antibiotics is recommended in specifically defined situations based on pharmacological rationale. Such combination therapy requires an understanding of the potential for interaction between the antibiotics. For example, vancomycin given alone typically has minimal nephrotoxicity, but it may be nephrotoxic when combined with an aminoglycoside.

To determine the antiomicrobial activity of drug combinations, bacteria are incubated in broth with serial dilutions of antibiotics, either individually or in combination. Synergism of the antibiotics is defined as inhibition of growth by the drug combination at concentrations less than or equal to 25% of the MIC of each drug acting alone. This finding implies that one drug is affecting the microorganism so as to increase the susceptibility to the other antibiotic. If one half of the inhibitory concentration of each drug is required to produced inhibition, the result is called additive, suggesting that the two drugs are working independently of each other. If more than one-half of the MIC of each drug is necessary to produce an inhibitory effect, the drugs are said to be antagonistic.

Bacteriostatic antibiotics (e.g., tetracyclines, erythromycin, and chloramphenicol) frequently antagonize the action of bactericidal drugs (e.g., ^-lactam antibiotics, vancomycin, and aminogly-cosides); this probably is because they inhibit cell division and protein synthesis, which are required for the effect of most bactericidal drugs. Bactericidal drugs from different classes in combination tend to be additive or synergistic. For example, an inhibitor of cell wall synthesis and an aminoglycoside are synergistic against many bacterial species, and such combinations are frequently used. It is important to remember that these antibiotic sensitivities are determined in vitro, and the clinical relevance of synergy and antagonism in vivo is often much less clearly defined.

INDICATIONS FOR THE CLINICAL USE OF COMBINATIONS OF ANTIMICROBIAL AGENTS Use of antibiotics in combination may be justified: (1) for empirical therapy of an infection for which the cause is unknown; (2) for treatment of polymicrobial infections; (3) to enhance antimicrobial activity for a specific infection (i.e., for synergy); or (4) to prevent emergence of resistance.

Empirical Therapy of Severe Infections in Which a Cause is Unknown. Empirical therapy of infection is the most common reason for using a combination of antibiotics. Severe illness and less certainty as to the particular infection or causative agent may mandate broad coverage initially, and more than one agent may be required to ensure that the regimen includes a drug that is active against the potential pathogens. In the treatment of community-acquired pneumonia, a macrolide may be used for atypical organisms such as Mycoplasma in combination with cefuroxime for pneumococci and gramnegative pathogens. Prolonged administration of empirical broad-spectrum coverage or multiple antibiotics should be avoided because it often is unnecessary, is expensive, may select for antibiotic resistance against multiple agents, and may cause additional adverse effects due to the multiple agents. Inappropriately broad coverage often is continued because adequate cultures were not obtained prior to the initiation of therapy or because of the misconception that a broad-spectrum regimen is superior to a narrow-spectrum regimen. Although reluctance to narrow therapy after a favorable initial response has occurred is understandable, the goal should be to use the most selectively active drug that produces the fewest adverse effects, which includes adverse effects on normal host flora.

Treatment of Polymicrobial Infections. Treatment of intra-abdominal, hepatic, and brain abscesses, and some genital tract infections may require the use of a drug combination to eradicate these typically mixed aerobic-anaerobic infections. These and other mixed infections may be caused by two or more different microorganisms that are sufficiently different in antibiotic sensitivity that no single agent can provide the required coverage.

Enhancement of Antibacterial Activity in the Treatment of Specific Infections. Antibiotics administered together may produce a synergistic effect. Such synergistic combinations have been shown to be better than single-agent therapy in relatively few infections. Perhaps the best-documented example of the utility of synergistic combinations is in the treatment of enterococcal endocarditis. The clinical outcome clearly is better in patients treated with a combination of penicillin and streptomycin or gentamicin versus treatment with penicillin alone. The same combination has shown clinical benefit in the treatment of endocarditis caused by strains of viridans streptococci, with more rapid eradication of bacteria. Combinations of ^-lactam antibiotics and aminoglycosides also have been recommended for the treatment of serious infections with gram-negative rods, especially Pseudomonas aeruginosa; the benefits of these combinations in vivo are less well established.

Another frequently employed combination is that of a sulfonamide and an inhibitor of dihydro-folate reductase, such as trimethoprim; this combination is synergistic because the drugs block sequential steps in microbial folate synthesis.

Finally, the combination of flucytosine and amphotericin B is synergistic against Cryptococcus neoformans and is often employed in AIDS patients with cryptococcal meningitis.

Prevention of the Emergence of Resistant Microorganisms. The theoretical basis for combination therapy of tuberculosis is to prevent the emergence of resistant mutants that might result from monotherapy; clinical experience amply documents the utility of concomitant use of two or more agents in this setting. Combination therapy to prevent the emergence of resistance also frequently is used when rifampin is used in other infections.

DISADVANTAGES OF COMBINATIONS OF ANTIMICROBIAL AGENTS Disadvantages of antibiotic combinations include increased risk of toxicity, selection of multiple-drug-resistant microorganisms, eradication of normal host flora with subsequent superinfection, and increased cost. Although antibiotic antagonism is frequently observed in vitro, well-documented clinical examples are relatively rare; the most notable is pneumococcal meningitis, where penicillin alone is much more effective than a penicillin-tetracycline combination. Concerns of antagonism are most important in situations where achieving a bactericidal effect is critical for cure of the infection (e.g., meningitis, endocarditis, and gram-negative infections in neutropenic patients).

Antibiotic Prophylaxis

In general, if a single, effective, nontoxic drug is used to prevent infection by a specific microorganism or to eradicate an early infection, then chemoprophylaxis frequently is successful. On the other hand, if the aim of prophylaxis is to prevent colonization or infection by any or all organisms present in the environment of the patient, then prophylaxis often fails.

Prophylaxis may be used to protect healthy persons from acquisition of or invasion by specific microorganisms to which they are exposed. Successful examples of this practice include rifampin administration to prevent meningococcal meningitis in close contacts of a known case, prevention of gonorrhea or syphilis after contact with an infected person, and the intermittent use of trimethoprim-sulfamethoxazole to prevent recurrent urinary tract infections.

Antibiotic prophylaxis, often with an oral fluoroquinolone, is used to prevent a variety of infections in patients undergoing organ transplantation or receiving cancer chemotherapy. Prophylaxis is recommended for primary and secondary prevention of opportunistic infections in AIDS patients whose CD4 counts are below certain thresholds (e.g., <200 cell/mm3 for the prevention of Pneumocystis pneumonia and <50 cells/mm3 for prevention of atypical mycobacterial infections).

Chemoprophylaxis against endocarditis is recommended for patients with valvular or other structural lesions of the heart who are undergoing dental, surgical, or other procedures that may produce a high incidence of bacteremia. Therapy, generally as a single dose, should begin 1 hour before the procedure for oral drugs and 30 minutes before for parenteral drugs. Criteria are established for the selection of specific drugs and patients who should relieve prophylaxis for various procedures (Table 42-1).

The most extensive and probably best-studied use of chemoprophylaxis is to prevent wound infections after various surgical procedures (Table 42-1). Wound infections occur when a critical number of bacteria are present in the wound at the time of closure; factors that influence the size of innoculum needed include: virulence of the bacteria, the presence of devitalized or poorly vascularized tissue, the presence of a foreign body, and the status of the host. Antibiotic agents directed against the invading microorganism may prevent infection by reducing the number of viable bacteria below the critical level.

Several factors are important for effective chemoprophylaxis in surgical procedures. Antimicrobial activity must be present at the wound site at the time of closure. Thus, the drug should be given preoperatively (and perhaps intraoperatively for prolonged procedures) to ensure that therapeutic levels are maintained throughout the procedure. The antibiotic, often a cephalosporin, must be active against the most likely contaminating microorganisms. Prolonged administration of the drug after the surgical procedure is unwarranted, and no data support a lower incidence of wound infections if antibiotics are continued after the day of surgery. Clinical trials support chemoprophylaxis for dirty or contaminated surgical procedures (e.g., resection of the colon) but not for clean surgical procedures. When the surgery involves insertion of a prosthetic implant (e.g., prosthetic valve, vascular grant, prosthetic joint), cardiac surgery, or neurosurgical procedures, the complications of infection are so drastic that most authorities currently advocate antibiotic prophylaxis.

Guidelines for Prophylactic Antibiotics in Surgical Procedures

Antibiotics should be administered 30-60 minutes prior to incision and may need to be readministered to maintain effective serum drug concentrations during prolonged procedures. A single preoperative antibiotic dose is usually sufficient prophylaxis. Continuation of antibiotics for up to 24 hours may be considered in some cases (e.g., contaminated cases, surgery of long duration, implantation of prosthetic material).

Nature of Surgery

Probable Pathogen(s)

Recommended Drug(s) (Adult Dosage)

Time of Administration

I. Clean

A. Thoracic, cardiac, vascular, and orthopedic; neurosurgery

B. Ophthalmic

S. aureus*, coagulase-negative staphylococci, gram-negative bacilli, Pseudomonas

Cefazolin (1 g IV) At induction of anesthesia

Vancomycin* (1 g IV)

Gentamicin or neomycin-gramicidin-polymyxin B ophthalmic drops; multiple drugs at intervals for first 24 hours

II. Clean-Contaminated

3 A. Head and neck (potentially entering esophageal lumen)

B. Abdominal—cholecystectomy and high-risk gastroduodenal or biliary

C. Abdominal—appendectomy

D. Colorectal

Preoperative lavage recommended, plus antimicrobial treatment 1. Oral antimicrobial prophylaxis

2. Parenteral antimicrobial prophylaxis

S. aureus and oral anaerobes

Patients who have not received lavage and oral prophylaxis should receive parenteral antibiotics for <24 hours to cover enteric aerobes (including Escherichia coli, Klebsiella spp.) and enteric anaerobes (including Bacterodes fragilis, Clostridium spp., anaerobic cocci, and Fusobacterium spp.)

Cefazolin (1-2 g IV) or clindamycin (600 mg IV) ± gentamicin (1.5 mg/kg IV) Cefazolin (1 g IV)

Cefoxitin or cefotetan (1 g IV) Go-Lytely electrolyte solution (4 liters)

Erythromycin stearate (1 g PO) or metronidazole (500 mg PO) plus neomycin (1 g PO) Cefotetan (1 g every 12 hours for 2 doses) Ceftizoxime (1 g every 12 hours for 2 doses) Cefoxitin (1 g every 4-8 hours for 3 doses)

At induction of anesthesia

At induction of anesthesia

At induction of anesthesia Preoperative day

At 1 PM, 2 PM, and 11 PM on the preoperative day

Guidelines for Prophylactic Antibiotics in Surgical Procedures (Continued)

Nature of Surgery

Probable Pathogen(s)

Recommended Drug(s) (Adult Dosage)

Time of Administration

II. Clean-Contaminated

E. Gynecological

1. Vaginal or abdominal hysterectomy and high-risk cesarean section (following labor or ruptured membrane only)

2. High-risk abortion, first trimester

3. High-risk abortion, second trimester

F. Urology

Cefazolin (1 g IV)

At induction of anesthesia or postcord clamp

Penicillin G (2 million units IV) or doxycycline (300 mg PO) Cefazolin (1 g IV)

Prophylactic antibiotics not shown to reduce incidence of wound infection after urological procedures. Bacteriuria is most common postoperative complication; only patients with evidence of infected urine should be treated with antibiotics directed against the specific pathogens isolated.

III. Trauma-Contaminated Wounds

A. Extremity

B. Ruptured viscus—abdomen/bowel injury

C. Bites (cats and human)

Antimicrobial coverage for Group A streptococci, staphylococci, and Clostridium spp.

Aerobic and anaerobic streptococci from skin and oral flora. Infection of animal bites additionally may be caused by Pasteurella multocida, which is penicillin-sensitive

Cefazolin (1 g every 8 hours IV) Vancomycin (1 g every 12 hours IV)*

Cefotetan (1 g every 12 hours) or ceftizoxime (1 g every 12 hours) or cefoxitin (1 g every 6 hours) or clindamycin (600 mg IV every 8 hours) + gentamicin (1.5 mg/kg IV every 8 hours)* for < 5 days Amoxicillin/clavulanate (750/125 mg twice a day for 5 days or doxycycline 100 mg PO twice a day for 5 days)

*Recommended for hospitals with a high prevalence of infections caused by methicillin-resistant staphylococci or for serious allergy to ^-lactams. ^For serious ^-lactam allergy.

abbreviations: IV. intravenous administration; PO, oral administration.


All individual who receive therapeutic doses of antibiotics undergo alterations in the normal microbial population of the GI, upper respiratory, and genitourinary tracts; as a result, some develop superinfection, or the appearance of bacteriological and clinical evidence of a new infection during the chemotherapy of a primary one. Such superinfection is due to the removal of the normal flora, which produces antibacterial substances and competes for essential nutrients. Of concern, the microorganisms responsible for the new infection can be drug-resistant strains of bacteria or fungi. The broader the spectrum and the longer the period of antibiotic treatment, the greater the risk of superinfection. The most specific and narrowest spectrum antibiotics should be chosen to treat infections whenever feasible.

Misuses of Antibiotics

TREATMENT OF NONRESPONSIVE INFECTIONS Most viral diseases are self-limited and do not respond to any of the currently available anti-infective compounds. Thus, antibiotic therapy of at least 90% of infections of the upper respiratory tract and many GI infections is ineffective.

THERAPY OF FEVER OF UNKNOWN ORIGIN Fever of short duration in the absence of localizing signs usually is associated with undefined viral infections. Antimicrobial therapy is unnecessary, and resolution of fever usually occurs spontaneously within a week. Fever persisting for 2 or more weeks, commonly referred to as fever of unknown origin, has a variety of causes; only about one quarter of these are infections. Moreover, some of these infections (e.g., tuberculosis, disseminated fungal infections) may require antibiotics that are not typically used for bacterial infections. Inappropriately administered antibiotics may mask an underlying infection, delay the diagnosis, and prevent the identification of the infectious pathogen by culture.

IMPROPER DOSAGE Dosing errors with antibiotics are common. Excessive dosing can result in significant toxicities, while too low a dose may result in treatment failure and is most likely to select for antibiotic resistance.

INAPPROPRIATE RELIANCE ON CHEMOTHERAPY ALONE Infections complicated by abscess formation or the presence of necrotic tissue or a foreign body often cannot be cured by antibiotic therapy alone. Drainage, debridement, and removal of the foreign body are at least as important as the choice of antibiotic agent. As a general rule, when an appreciable quantity of pus, necrotic tissue, or a foreign body is present, the most effective therapy is an antimicrobial agent given in adequate dose plus a properly performed surgical procedure.

LACK OF ADEQUATE BACTERIOLOGICAL INFORMATION Antibiotic therapy too often is given in the absence of supporting microbiological data. Bacterial cultures and Gram stains of infected material are obtained too infrequently, and, when available, the results often are disregarded in the selection and application of drug therapy. Frequent use of drug combinations or drugs with broadest spectra is a cover for diagnostic imprecision.

For a complete Bibliographical listing see Goodman & Gilman's The Pharmacological Basis of Therapeutics, 11th ed., or Goodman & Gilman Online at



10 Ways To Fight Off Cancer

10 Ways To Fight Off Cancer

Learning About 10 Ways Fight Off Cancer Can Have Amazing Benefits For Your Life The Best Tips On How To Keep This Killer At Bay Discovering that you or a loved one has cancer can be utterly terrifying. All the same, once you comprehend the causes of cancer and learn how to reverse those causes, you or your loved one may have more than a fighting chance of beating out cancer.

Get My Free Ebook

Post a comment