Appropriate Choice of Antibiotics

The Rational for the Use of Gentamicin for Short Term, Empiric Therapy is Different Than it is for Long Term Definitive Therapy.

If a person presents in an emergent manner with a fever, high white cell count, and other signs or symptoms of septicemia (a blood infection), the person must be aggressively treated with strong, broad spectrum antibiotics until blood cultures are obtained. Blood cultures are grown to determine which specific bacteria are causing the infection, and which antibiotics are effective against these bacteria. Generally, antibiotics must be given for 2-3 days before these culture results are available. Because the side effects of gentamicin are minimal when given for a very short period, its use in empiric situations for 2-3 days is much more justifiable than its use in definitive therapy requiring long term administration.

 

 

Culture and Sensitivity Studies Can Reveal, in Many Instances, the Pathogen that is Causing the Infection, and the Antibiotics to which the Pathogen is Sensitive.

Prior to administering antibiotics, a culture of blood, tissue, urine, or other potential source of infection may be obtained. Blood is obtained by venipuncture and placed in vials containing a special nutrient broth (Figure 1) and incubated (Figure 2).

Figure 1.

 

 Figure 2.

 

The cultured material is then placed on a Petri dish containing nutrient, and allowed to grow. The specific bacteria is identified using a microscope and information regarding the color, shape and appearance of the colonies plated on the Petri dish. Finally, tiny discs containing different antibiotics are introduced, and the size of the clear ring around each disc, which indicates killed bacteria, is measured. (Figure 3) The larger the ring, the better the antibiotic is at eradicating that particular bacteria. The results are reported to the treating physician in a report listing various antibiotics and whether the bacteria is resistant or susceptible to that particular antibiotic. (Figure 4)

 

Figure 3 - Plated Bacteria Exposed to Antibiotic Discs.

 

Figure 4 - Example of Culture and Sensitivity Report.

 

The treating physician uses this information, preferably combined with other clinical information regarding the presentation of the infection and information regarding the particular patient, to arrive at a rational choice for an antibiotic or combination of antibiotics to use. Even though a particular pathogen is shown by culture (in vitro) to be sensitive to a particular antibiotic, its rational use may be totally contradicted by the presentation of the infection or by host factors (characteristics of the patient)

 

The Standard of Care Applicable to the Use of Gentamicin Has Changed Significantly In the Past Ten to Twenty Years

Gentamicin is used as a primary antibiotic or it is used synergistically with other antibiotics. Aminoglycosides, including gentamicin, can be used as a primary agent against a specific organism or organisms, or can be used synergistically with another antibiotic to “boost” the efficacy of the other antibiotic. This distinction is important, because synergistic doses tend to be much lower, (usually less than 3mg/kg/day), potentially causing fewer side effects. When gentamicin is used as primary therapy, the dosing tends to be higher (4-7mg/kg/day) potentially causing greater side effects.

Use of Gentamicin as a Primary Antibiotic Agent. While still an important antibiotic under certain circumstances, there are only a few instances where the use of gentamicin may be justified outside of short-term empiric treatment. Because of the risk of nephrotoxicity, ototoxicity, and vestibulotoxicity associated with the use of aminoglycosides, and because ototoxicity and vestibulotoxicity are usually permanent and life altering, gentamicin can be only justified as a primary antibiotic agent when there are no reasonable alternatives available. In the past 20 or so years, many antibiotics have been developed that are equally or more efficacious than gentamicin as primary antibiotic agents.

Often, physicians will just look at a sensitivity report and pick an antibiotic without giving sufficient consideration to side effects or host factors that may preclude its use. For example, Staphylococcus aureus will often show sensitive in vitro when tested against gentamicin. Gentamicin is now considered a third rate agent to use against Staph. Tverdek et al (2008) reviewed antibiotic therapy of methicillin-resistant Staphylococcus aureus in a critical care setting. There was no recommendation for the use of gentamicin, even as a synergistic agent. Fowler et al (2006) compared Daptomycin with standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus. Standard therapy was low dose gentamicin plus an antistaphylococcal penicillin or vancomycin. They concluded that as compared with daptomycin therapy, standard therapy was associated with a nonsignificantly higher rate of adverse events that led to treatment failure due to the discontinuation of therapy (17 vs. 8, P = 0.06), and that clinically significant renal dysfunction occurred in 11.0 percent of patients who received daptomycin and in 26.3 percent of patients who received standard therapy (P = 0.004).

 

Gentamicin should be used for primary therapy only when there is no other viable alternative treatment.  Regardless of the expense of other antibiotic agents, there is no justification for subjecting a patient to the possibility of permanent vestibular loss unless gentamicin is the only antibiotic that would be effective against a particular organism.

Moreover, the use of gentamicin in these circumstances must also depend on how serious the infection is. We have represented at least two clients who developed lifelong, severe vestibulopathy because a physician used gentamicin to preserve an toe. Amputation of the toe would have had a miniscule impact on each of these individuals when compared with the devastating impact of gentamicin poisoning.

Gentamicin is no longer the "big gun" for Pseudomonal infections:In recent years, newer, less toxic anti-pseudomonal drugs have emerged that in most instances are equally or more efficacious than gentamicin. Ceftazidime (Fortaz, Tazicef, Tazidime), piperacillin-tazobactam (Zosyn) and Imipenum (Primaxin) are examples. The following is excerpted from Mandell, Bennett, & Dolin: Principles and Practice of Infectious Diseases, 6th ed at p. 2601: "Thus, none of the dogmas concerning the appropriate therapy for P. aeruginosa bacteremia can be considered to be established by blinded, controlled clinical studies. One firm conclusion appears to be that monotherapy with an aminoglycoside dosed in the approved way should not be the primary choice for antibiotic treatment. [emphasis supplied] Unquestionably, the majority of infectious disease experts still favor the use of combination therapy for P. aeruginosa bacteremia. However, it is difficult to indict the use of a single modern antipseudomonal -lactam antibiotic as being inadequate therapy. Even in the patients most at risk for dying rapidly from P. aeruginosa bacteremia (i.e., high-risk patients with fever and neutropenia), empirical monotherapy [referring to the antipseudomonal -lactam antibiotics such as ceftazidime, piperacillin-tazobactam, or imipenum] designed to treat P. aeruginosa is considered to be as efficacious as empirical combination therapy in the Practice Guidelines of the Infectious Diseases Society of America (IDSA)."

However, gentamicin has recently been recognized as appropriate in the treatment of serious pseudomonal infections under certain circumstances. The following is excerpted from Giamarellou and Antoniadou, Antibiotic therapy Antipseudomonal antibiotics, Med. Clin. N. Am. 85-1 (2001):

 

"Despite the advent of newer antipseudomonal compounds such as carbapenems and the fluoroquinolones, aminoglycosides have an important role in the therapy of serious P. aeruginosa infections. They continue to be used because of (1) their excellent and fast concentration-dependent bactericidal activity, a determining factor in the prognosis of severe P. aeruginosa infections in neutropenic patients or in ICU life-threatening nosocomial infections, particularly during the first 24 hours of treatment; (2) their limited tendency to develop resistance during therapy; (3) the synergistic effect when combined with antipseudomonal penicillins and antipseudomonal cephalosporins in vitro and in vivo; (4) the protective effect toward resistance development in the b-lactams whenever they are given simultaneously in vivo; (5) their lack of inoculum effect; (6) their prolonged and concentration-dependent postantibiotic effect (> 2 hours); (7) their antimicrobial activity at levels below their MICs; and (8) the possibility to be given once daily despite a half-life that demands twice-daily or thrice-daily administration. (9) The last-mentioned possibility is based on their prolonged PAE and the first exposure effect (i.e., the down-regulation of subsequent uptake of the drug after initial exposure of bacteria to it). All aminoglycosides share the same disadvantages, however: (1) nephrotoxic, ototoxic, and neuromuscular blockade potential: (2) poor kinetics in cerebrospinal fluid, eye compartments, prostate, and phagocyte with an intracellular-to-extracellular ratio of less than 1; (3) reduced in vitro activity under modification of environmental factors, such as divalent caution concentration, acidic pH, decreased arterial oxygen tension, and microaerobic or anaerophilic conditions, as happens in abscesses; and (4) in vivo inactivation by high concentration of penicillins and cephalosporins."

Therapeutic alternatives for pseudomonal infections was re-reviewed by Kanellakopoulou in 2008. (Current Therapies for Pseudononas Aeruginosa, Crit Care Clin 24). They note developing emergence of aminoglycoside resistance worldwide, and the lack of evidence for the efficacy of using combination therapy with an aminoglycoside:

  • The need to maintain the traditional antibiotic combination of a broad spectrum antipseudomonal β-lactam plus an aminoglycoside is still controversial.
  • Two recent meta-analyses on infections caused by susceptible strains showed that there was no advantage over monotherapy in terms of mortality, clinical efficacy, or prevention of resistance, whereas more adverse effects -- especially nephrotoxicity -- were observed in the combinations.
  • The analysis of P aeruginosa bacteremia subgroups showed a significant survival benefit for the combination [citations omitted].

 

Use of gentamicin with another antibiotic for synergistic effect

Another dosing issue relates to the concept of antibiotic synergy. Gentamicin kills bacteria by interfering with the bacteria’s ability to synthesize protein. Specifically, gentamicin binds tightly to ribosomes, which are located inside of the cell. Other antibiotics, including penicillin-like antibiotics, (beta-lactams), kill bacteria by interfering with cell wall synthesis, making the cell wall porous. When combined with gentamicin, the beta-lactam allows a lot more gentamicin to get inside the cell to attach to the ribosomes, which means that a lower concentration of gentamicin is needed to give the same bacteria-killing effect than without the beta-lactam.

Only certain organisms such as P. aeruginosa and certain enterococcal species exhibit synergistic killing with the addition of an aminoglycoside to other antibiotics. Gentamicin is most often used as a synergistic agent in the treatment of endocarditis.

 

Synergistic dosing is discussed here.

Antimicrobial Agents Used in Treatment of Infectious Disease. This is a short, comprehensive explanation of many of the aspects of antibiotic therapy.

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