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THE MERCK MANUAL MEDICAL LIBRARY: The Merck Manual of Diagnosis and Therapy
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Introduction

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Bacteria are microorganisms that have circular double-stranded DNA and (except for mycoplasmas) cell walls. Most bacteria live extracellularly. Some bacteria (eg, Salmonella typhi; Neisseria gonorrhoeae; Legionella, Mycobacterium, Chlamydia, and Chlamydophila spp) preferentially reside and replicate intracellularly. Some bacteria such as chlamydiae and rickettsiae are obligate intracellular pathogens (ie, able to grow, reproduce, and cause disease only within the cells of the host); others (eg, Salmonella typhi, Brucella sp, Francisella tularensis, N. gonorrhoeae, N. meningitidis, Legionella and Listeria spp, Mycobacterium tuberculosis) are facultative intracellular pathogens.

Many bacteria are present in humans as normal flora, often in large numbers and in many areas (eg, in the GI tract). Only a few bacterial species are human pathogens.

Bacteria are classified by the following criteria (see Table 1: Bacteria and Antibacterial Drugs: Classification of Common Pathogenic BacteriaTables).

Morphology: Bacteria may be cylindric (bacilli), spherical (cocci), or spiral (spirochetes). A few coccal, many bacillary, and most spirochetal species are motile.

Staining: The most common stain for general bacterial identification is Gram stain. Gram-positive bacteria retain crystal violet dye (appearing dark blue) after iodine fixation and alcohol decolorization; gram-negative bacteria do not. Gram-negative bacteria have an additional outer membrane containing lipopolysaccharide (endotoxin), increasing the virulence of these bacteria. (For other factors that enhance bacterial pathogenicity, see Biology of Infectious Disease: Factors Facilitating Microbial Invasion)

Ziehl-Neelsen stain (acid-fast stain) is used to identify mainly mycobacteria, particularly M. tuberculosis. It also can identify Nocardia sp. Carbolfuchsin is applied with heat, followed by decolorization with hydrochloric acid and ethanol and counterstaining with methylene blue Some Trade Names
UROLENE BLUE
Click for Drug Monograph
.

Encapsulation: Some bacteria are enclosed in capsules; for some encapsulated bacteria (eg, Streptococcus pneumoniae, Haemophilus influenzae), the capsule helps protect them from ingestion by phagocytes. Encapsulation increases bacterial virulence.

Oxygen requirements: Aerobic bacteria (obligate aerobes) require O2 to produce energy and to grow in culture. They produce energy using aerobic cellular respiration.

Anaerobic bacteria (obligate anaerobes) do not require O2 and do not grow in culture if air is present. They produce energy using fermentation or anaerobic respiration. Anaerobic bacteria are common in the GI tract, vagina, dental crevices, and wounds when blood supply is impaired.

Facultative bacteria can grow with or without O2. They produce energy by fermentation or anaerobic respiration when O2 is absent and by aerobic cellular respiration when O2 is present. Microaerophilic bacteria prefer a reduced O2 tension (eg, 2 to 10%). Chlamydiae are obligate intracellular parasites that acquire energy from the host cell and do not produce it themselves.

Table 1

Classification of Common Pathogenic Bacteria

Type

Bacteria

Obligate aerobic

Gram-negative cocci

Moraxella catarrhalis, Neisseria gonorrhoeae, N. meningitidis

Gram-positive bacilli

C. jeikeium

Acid-fast bacilli

Mycobacterium avium complex, M. kansasii, M. leprae, M. tuberculosis, Nocardia sp

Nonfermentative, non-Enterobacteriaceae

Acinetobacter calcoaceticus, Flavobacterium meningosepticum, Pseudomonas aeruginosa, P. alcaligenes, other Pseudomonas sp, Stenotrophomonas maltophilia

Fastidious gram-negative coccobacilli and bacilli

Brucella, Bordetella, Francisella, and Legionella spp

Treponemataceae (spiral bacteria)

Leptospira sp

Obligate anaerobic

Gram-negative bacilli

Bacteroides fragilis, other Bacteroides sp, Fusobacterium sp, Prevotella sp

Gram-negative cocci

Veillonella sp

Gram-positive cocci

Peptococcus niger, Peptostreptococcus sp

Non–spore-forming gram-positive bacilli

Actinomyces, Bifidobacterium, Eubacterium, and Propionibacterium spp

Endospore-forming gram-positive bacilli

Clostridium botulinum, C. perfringens, C. tetani, other Clostridium sp

Facultative anaerobic

Gram-positive cocci, catalase-positive

Staphylococcus aureus (coagulase-positive), S. epidermidis (coagulase-negative), other coagulase-negative staphylococci

Gram-positive cocci, catalase-negative

Enterococcus faecalis, E. faecium, Streptococcus agalactiae (group B streptococcus), S. bovis, S. pneumoniae, S. pyogenes (group A streptococcus), viridans group streptococci (S. mutans, S. mitis, S. salivarius, S. sanguis), S. anginosus group (S. anginosus, S. milleri, S. constellatus), Gemella morbillorum

Gram-positive bacilli

Bacillus anthracis, Erysipelothrix rhusiopathiae, Gardnerella vaginalis (gram-variable)

Gram-negative bacilli

Enterobacteriaceae (Citrobacter sp, Enterobacter aerogenes, Escherichia coli, Klebsiella sp, Morganella morganii, Proteus sp, Providencia rettgeri, Salmonella typhi, other Salmonella sp, Serratia marcescens, Shigella sp, Yersinia enterocolitica, Y. pestis)

Fermentative, non-Enterobacteriaceae

Aeromonas hydrophila, Chromobacterium violaceum, Pasturella multocida, Plesiomonas shigelloides

Fastidious gram-negative coccobacilli and bacilli

Actinobacillus actinomycetemcomitans, Bartonella bacilliformis, B. henselae, B. quintana, Eikenella corrodens, Haemophilus influenzae, other Haemophilus sp

Mycoplasma

Mycoplasma pneumoniae

Treponemataceae (spiral bacteria)

Borrelia burgdorferi, Treponema pallidum

Microaerophilic

Curved bacilli

Campylobacter jejuni, Helicobacter pylori,

Vibrio cholerae, V. vulnificus

Obligate intracellular parasitic

Chlamydiaceae

Chlamydia trachomatis, Chlamydophila pneumoniae, C. psittaci

Coxiellaceae

Coxiella burnetii

Rickettsiales

Rickettsia prowazekii, R. rickettsii, R. typhi, R. tsutsugamushi, Ehrlichia chaffeensis, Anaplasma phagocytophilum

Antibacterial Drugs

Antibacterial drugs are derived from bacteria or molds or are synthesized de novo. Technically, “antibiotic” refers only to antimicrobials derived from bacteria or molds but is often (including in The Manual) used synonymously with “antibacterial drug.”

Antibiotics have many mechanisms of action, including inhibiting cell wall synthesis, activating enzymes that destroy the cell wall, increasing cell membrane permeability, and interfering with protein synthesis and nucleic acid metabolism.

Antibiotics sometimes interact with other drugs, raising or lowering serum levels of other drugs by increasing or decreasing their metabolism or by various other mechanisms (see Table 2: Bacteria and Antibacterial Drugs: Common Effects of Antibiotics on Other DrugsTables). The most clinically important interactions involve drugs with a low therapeutic ratio (ie, toxic levels are close to therapeutic levels). Also, other drugs can increase or decrease levels of antibiotics.

Many antibiotics are chemically related and are thus grouped into classes. Although drugs within each class share structural and functional similarities, they often have different pharmacology and spectra of activity.

Table 2

Common Effects of Antibiotics on Other Drugs

Drug

Toxicity Enhanced By

No Change With

Digoxin Some Trade Names
DIGITEK
LANOXIN
Click for Drug Monograph

Azithromycin Some Trade Names
ZITHROMAX
Click for Drug Monograph

Clarithromycin Some Trade Names
BIAXIN
Click for Drug Monograph

Doxycycline Some Trade Names
PERIOSTAT
VIBRAMYCIN
Click for Drug Monograph

Erythromycin Some Trade Names
ERY-TAB
ERYTHROCIN
Click for Drug Monograph

Tetracycline Some Trade Names
ACHROMYCIN V
TETRACYN
TETREX
Click for Drug Monograph

Trimethoprim Some Trade Names
PROLOPRIM
TRIMPEX
Click for Drug Monograph

Aminoglycosides

Cephalosporins

Clindamycin Some Trade Names
CLEOCIN
Click for Drug Monograph

Fluoroquinolones

Ketoconazole Some Trade Names
NIZORAL
Click for Drug Monograph

Linezolid Some Trade Names
ZYVOX
Click for Drug Monograph

Metronidazole Some Trade Names
FLAGYL
Click for Drug Monograph

Penicillins

Quinulpristine/dalfopristin

Sulfonamides

Vancomycin Some Trade Names
VANCOCIN
Click for Drug Monograph

Phenytoin Some Trade Names
DILANTIN
Click for Drug Monograph

Chloramphenicol Some Trade Names
CHLOROMYCETIN
Click for Drug Monograph

Ciprofloxacin Some Trade Names
CILOXAN
CIPRO
Click for Drug Monograph

Isoniazid Some Trade Names
INH
NYDRAZID
Click for Drug Monograph

Macrolides ( erythromycin Some Trade Names
ERY-TAB
ERYTHROCIN
Click for Drug Monograph
, clarithromycin Some Trade Names
BIAXIN
Click for Drug Monograph
, dirithromycin Some Trade Names
DYNABAC

)

Rifampin Some Trade Names
RIFADIN
RIMACTANE
Click for Drug Monograph
(decreased phenytoin Some Trade Names
DILANTIN
Click for Drug Monograph
levels)

Sulfonamides

Azithromycin Some Trade Names
ZITHROMAX
Click for Drug Monograph

Aminoglycosides

Cephalosporins

Clindamycin Some Trade Names
CLEOCIN
Click for Drug Monograph

Doxycycline Some Trade Names
PERIOSTAT
VIBRAMYCIN
Click for Drug Monograph

Linezolid Some Trade Names
ZYVOX
Click for Drug Monograph

Metronidazole Some Trade Names
FLAGYL
Click for Drug Monograph

Penicillins

Other fluoroquinolones

Quinulpristine/dalfopristin

Tetracycline Some Trade Names
ACHROMYCIN V
TETRACYN
TETREX
Click for Drug Monograph

Trimethoprim Some Trade Names
PROLOPRIM
TRIMPEX
Click for Drug Monograph

Vancomycin Some Trade Names
VANCOCIN
Click for Drug Monograph

Theophylline Some Trade Names
ELIXOPHYLLIN
THEO-DUR
Click for Drug Monograph

Clarithromycin Some Trade Names
BIAXIN
Click for Drug Monograph

Erythromycin Some Trade Names
ERY-TAB
ERYTHROCIN
Click for Drug Monograph

Fluoroquinolones ( ciprofloxacin Some Trade Names
CILOXAN
CIPRO
Click for Drug Monograph
)

Rifampin Some Trade Names
RIFADIN
RIMACTANE
Click for Drug Monograph
(decreased theophylline Some Trade Names
ELIXOPHYLLIN
THEO-DUR
Click for Drug Monograph
levels)

Aminoglycosides

Azithromycin Some Trade Names
ZITHROMAX
Click for Drug Monograph

Cephalosporins

Clindamycin Some Trade Names
CLEOCIN
Click for Drug Monograph

Doxycycline Some Trade Names
PERIOSTAT
VIBRAMYCIN
Click for Drug Monograph

Linezolid Some Trade Names
ZYVOX
Click for Drug Monograph

Metronidazole Some Trade Names
FLAGYL
Click for Drug Monograph

Penicillins

Quinulpristine/dalfopristin

Sulfonamides

Tetracycline Some Trade Names
ACHROMYCIN V
TETRACYN
TETREX
Click for Drug Monograph

Trimethoprim Some Trade Names
PROLOPRIM
TRIMPEX
Click for Drug Monograph

Vancomycin Some Trade Names
VANCOCIN
Click for Drug Monograph

Warfarin Some Trade Names
COUMADIN
Click for Drug Monograph
*

Cefoperazone

Cefotetan Some Trade Names
CEFOTAN
Click for Drug Monograph

Chloramphenicol Some Trade Names
CHLOROMYCETIN
Click for Drug Monograph

Clarithromycin Some Trade Names
BIAXIN
Click for Drug Monograph

Dirithromycin Some Trade Names
DYNABAC

Doxycycline Some Trade Names
PERIOSTAT
VIBRAMYCIN
Click for Drug Monograph

Erythromycin Some Trade Names
ERY-TAB
ERYTHROCIN
Click for Drug Monograph

Fluoroquinolones ( ciprofloxacin Some Trade Names
CILOXAN
CIPRO
Click for Drug Monograph
, levofloxacin Some Trade Names
IQUIX
LEVAQUIN
QUIXIN
Click for Drug Monograph
, ofloxacin Some Trade Names
FLOXIN
Click for Drug Monograph
)

Metronidazole Some Trade Names
FLAGYL
Click for Drug Monograph

Rifampin Some Trade Names
RIFADIN
RIMACTANE
Click for Drug Monograph
(decreased PT)

Sulfonamides

Aminoglycosides (IV)

Azithromycin Some Trade Names
ZITHROMAX
Click for Drug Monograph

Cephalosporins (some)

Clindamycin Some Trade Names
CLEOCIN
Click for Drug Monograph

Doxycycline Some Trade Names
PERIOSTAT
VIBRAMYCIN
Click for Drug Monograph

Linezolid Some Trade Names
ZYVOX
Click for Drug Monograph

Penicillins

Quinulpristine/dalfopristin

Tetracycline Some Trade Names
ACHROMYCIN V
TETRACYN
TETREX
Click for Drug Monograph

Trimethoprim Some Trade Names
PROLOPRIM
TRIMPEX
Click for Drug Monograph

Vancomycin Some Trade Names
VANCOCIN
Click for Drug Monograph

*see Table 4: Pulmonary Embolism (PE): Drug, Herbal Preparation, and Food Interactions With WarfarinTables

These drugs interfere with vitamin K–dependent clotting factors and, when used with antiplatelet drugs and thrombolytics, may increase risk of bleeding.

Selection and Use of Antibiotics

(See also the Johns Hopkins Point of Care Information Technology Antibiotic Guide and The Sanford Guide to Antimicrobial Therapy.) Antibiotics should be used only if clinical or laboratory evidence suggests bacterial infection. Use for viral illness or undifferentiated fever is inappropriate, subjects patients to drug complications without any benefit, and contributes to bacterial resistance. Certain bacterial infections (eg, abscesses, infections with foreign bodies) require surgical intervention and do not respond to antibiotics alone.

Spectrum of activity: Cultures and antibiotic sensitivity testing are essential for selecting a drug for serious infections. However, treatment must often begin before culture results are available, necessitating selection according to the most likely pathogens (empiric antibiotic selection). Whether chosen according to culture results or not, drugs with the narrowest spectrum of activity that can control the infection should be used. For empiric treatment of serious infections that may involve any one of several pathogens (eg, fever in neutropenic patients) or that may be due to multiple pathogens (eg, polymicrobial anaerobic infection), a broad spectrum of activity is desirable. The most likely pathogens and their susceptibility to antibiotics vary according to geographic location (within cities or even within a hospital) and can change from month to month.

For serious infections, combinations of antibiotics are often necessary because multiple species of bacteria may be present or because combinations act synergistically against a single species of bacteria. Synergism is usually defined as a more rapid and complete bactericidal action from a combination of antibiotics than occurs with either antibiotic alone. A common example is a cell wall–active antibiotic (eg, a β-lactam, vancomycin Some Trade Names
VANCOCIN
Click for Drug Monograph
) plus an aminoglycoside.

Effectiveness: In vivo antibiotic effectiveness involves many factors, including

  • Pharmacology (eg, absorption, distribution, concentration in fluids and tissues, protein binding, rate of metabolism or excretion)
  • Pharmacodynamics (ie, the time course of antibacterial effects exerted by drug levels in blood and at the site of infection)
  • Drug interactions or inhibiting substances
  • Host defense mechanisms
  • In vitro killing power but usually only if the site of infection (eg, in meningitis or endocarditis) is resistant to treatment or if systemic host defenses are weak (eg, in neutropenic or other immunocompromised patients)

Bactericidal drugs kill bacteria in vitro. Bacteriostatic drugs slow or stop in vitro bacterial growth. These definitions are not absolute; bacteriostatic drugs may kill some bacteria, and bactericidal drugs may not kill all of the bacteria in vitro. More precise quantitative methods identify the minimum in vitro concentration at which an antibiotic can inhibit growth (minimum inhibitory concentration, or MIC) or kill (minimum bactericidal concentration, or MBC).

The predominant determinant of bacteriologic response to antibiotics is the time that blood levels of the antibiotic exceed the MIC (time-dependence) or the peak blood level relative to MIC (concentration-dependence).

β-Lactams and vancomycin Some Trade Names
VANCOCIN
Click for Drug Monograph
exhibit time-dependent bactericidal activity. Increasing their concentration above the MIC does not increase their bactericidal activity, and their in vivo killing is generally slow. In addition, because there is no or very brief residual inhibition of bacterial growth after concentrations fall below the MIC (postantibiotic effect, or PAE), β-lactams and vancomycin Some Trade Names
VANCOCIN
Click for Drug Monograph
are most often effective when serum levels of free drug (drug not bound to serum protein) exceed the MIC for 50% of the time. Because ceftriaxone Some Trade Names
ROCEPHIN
Click for Drug Monograph
has a long serum half-life, free serum levels exceed the MIC of very susceptible pathogens for the entire 24-h dosing interval. However, for β-lactams that have serum half-lives of 2 h, frequent dosing or continuous infusion is required. For vancomycin Some Trade Names
VANCOCIN
Click for Drug Monograph
, trough levels should be maintained at least at 10 to 15 μg/mL.

Aminoglycosides, fluoroquinolones, and daptomycin Some Trade Names
CUBICIN
Click for Drug Monograph
exhibit concentration-dependent bactericidal activity. Increasing their concentrations from levels slightly above the MIC to levels far above the MIC increases their rate of bactericidal activity and decreases the bacterial load. In addition, if concentrations exceed the MIC even briefly, aminoglycosides and fluoroquinolones have a PAE on residual bacteria; duration of PAE is also concentration-dependent. If PAEs are long, drug levels can be below the MIC for extended periods without loss of efficacy, allowing less frequent dosing. Consequently, aminoglycosides and fluoroquinolones are usually most effective as intermittent boluses that reach peak free serum levels 10 times the MIC of the bacteria.

Route: For many antibiotics, oral administration results in therapeutic blood levels nearly as rapidly as IV administration. However, IV administration is preferred in the following circumstances:

  • Oral antibiotics cannot be tolerated (eg, because of vomiting).
  • Oral antibiotics cannot be absorbed (eg, because of malabsorption after intestinal surgery).
  • Intestinal motility is impaired (eg, because of opioid use).
  • No oral formulation is available (eg, for aminoglycosides).
  • Patients are critically ill, possibly impairing GI tract perfusion or making even the brief delay with oral administration detrimental.

Special populations: Doses and scheduling of antibiotics may need to be adjusted for the following:

Pregnancy and breastfeeding affect choice of antibiotic. Penicillins, cephalosporins, and erythromycin Some Trade Names
ERY-TAB
ERYTHROCIN
Click for Drug Monograph
are among the safest antibiotics during pregnancy; tetracyclines are contraindicated. Most antibiotics reach sufficient concentrations in breast milk to affect a breastfed baby, sometimes contraindicating their use in women who are breastfeeding.

Duration: Antibiotics should be continued until objective evidence of systemic infection (eg, fever, symptoms, abnormal laboratory findings) is absent for several days. For some infections (eg, endocarditis, TB, osteomyelitis), antibiotics are continued for weeks or months to prevent relapse.

Complications: Complications of antibiotic therapy include superinfection by nonsusceptible bacteria or fungi and cutaneous, renal, hematologic, and GI adverse effects. Adverse effects frequently require stopping the causative drug and substituting another antibiotic to which the bacteria are susceptible; sometimes, no alternatives exist.

Table 3

PDF Usual Doses of Commonly Prescribed Antibiotics

This table is presented as a PDF and requires the free Adobe PDF reader. Get Adobe Reader

Antibiotic Resistance

Resistance to an antibiotic may be inherent in a particular bacterial species or may be acquired through mutations or acquisition of genes for antibiotic resistance that are obtained from another organism. Different mechanisms for resistance are encoded by these genes (see Table 4: Bacteria and Antibacterial Drugs: Common Mechanisms of Antibiotic ResistanceTables). Resistance genes can be transmitted between 2 bacterial cells by the following mechanisms:

  • Transformation (uptake of naked DNA from another organism)
  • Transduction (infection by a bacteriophage)
  • Conjugation (exchange of genetic material in the form of either plasmids, which are pieces of independently replicating extrachromosomal DNA, or transposons, which are movable pieces of chromosomal DNA). Plasmids and transposons can rapidly disseminate resistance genes.

Antibiotic use preferentially eliminates nonresistant bacteria, increasing the proportion of resistant bacteria that remain. Antibiotic use has this effect not only on pathogenic bacteria but also on normal flora; resistant normal flora can become a reservoir for resistance genes that can spread to pathogens.

Table 4

Common Mechanisms of Antibiotic Resistance

Mechanism

Example

Decreased cell wall permeability

Loss of outer membrane D2 porin in imipenem-resistant Pseudomonas aeruginosa

Enzymatic inactivation

Production of β-lactamases that inactivate penicillins in penicillin-resistant Staphylococcus aureus, Haemophilus influenzae, and Escherichia coli

Production of aminoglycoside-inactivating enzymes in gentamicin Some Trade Names
GARAMYCIN
Click for Drug Monograph
-resistant enterococci

Changes in target

Decreased affinity of penicillin-binding proteins for β-lactam antibiotics (eg, in Streptococcus pneumoniae with reduced penicillin sensitivity)

Decreased affinity of methylated ribosomal RNA target for macrolides, clindamycin Some Trade Names
CLEOCIN
Click for Drug Monograph
, and quinupristin in MLSB-resistant S. aureus

Decreased affinity of altered cell wall precursor for vancomycin Some Trade Names
VANCOCIN
Click for Drug Monograph
(eg, in Enterococcus faecium)

Decreased affinity of DNA gyrase for fluoroquinolones in fluoroquinolone-resistant S. aureus

Increased antibiotic efflux pump

Increased efflux of tetracycline Some Trade Names
ACHROMYCIN V
TETRACYN
TETREX
Click for Drug Monograph
, macrolides, clindamycin Some Trade Names
CLEOCIN
Click for Drug Monograph
, or fluoroquinolones (eg, in S. aureus)

Bypass of antibiotic inhibition

Development of bacterial mutants that can subsist on products (eg, thymidine) present in the environment, not just products synthesized within the bacteria (eg, in certain bacteria exposed to trimethoprim/sulfamethoxazole Some Trade Names
BACTRIM
SEPTRA
Click for Drug Monograph
)

MLSB = macrolide, lincoside, streptogramin B.

Last full review/revision July 2009 by Matthew E. Levison, MD

Content last modified July 2009

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