current use for old antibacterial agents-polymixins,rifampin and aminoglycosides

Infect Dis Clin N Am 18 (2004) 669–689

Current use for old antibacterial agents:polymyxins, rifampin, and aminoglycosides

Donald Kaye, MD*Department of Medicine, Drexel University, College of Medicine,

3300 Henry Avenue, Philadelphia, PA 19129, USA

The polymyxins, rifampin, and the aminoglycosides may be consideredspecial-use antibacterial agents. They are all old agents and are rarelyconsidered the drugs of choice for common bacterial infections. Thepolymyxins are important because of the recent emergence of multidrug-resistant (MDR) bacteria, such as strains of Pseudomonas aeruginosa, whichare susceptible only to the polymyxins. Rifampin is only considered innonmycobacterial infections where its role is limited and sometimescontroversial. The aminoglycosides are discussed as to their current rolein nonmycobacterial systemic infections with an emphasis on the use ofsingle-daily dosage.

Polymyxins (polymyxin B and colistin)

The two parenteral polymyxins that have been available are polymyxin Band polymyxin E (colistin, formulated as colistimethate sodium). They arecyclic cationic polypeptide detergents with molecular weights of greater thanor equal to 1000 kDa. Polymyxin B was initially isolated from Bacilluspolymyxa, and colistin was isolated from Bacillus colistinus. The sulfome-thylated formulation of colistin (colistimethate sodium) must be hydrolyzedto be active as an antibiotic. Hydrolysis occurs both at body temperatureand in in vitro testing systems [1].

The polymyxins were discovered in 1947. They were frequently used totreat serious infections caused by gram-negative bacilli from 1962 untilaminoglycosides active against strains of P aeruginosa (eg, gentamicin) cameinto common use after the mid to late 1960s.The polymyxins fell into disuseby 1980 because of their nephrotoxicity and subsequently have been mainly

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670 D. Kaye / Infect Dis Clin N Am 18 (2004) 669–689

reserved for topical and oral use [1–5]. The recent increasing emergence ofP aeruginosa and other gram-negative bacilli resistant to all otherantimicrobial agents, however, has resulted in the occasional need for useof an injectable polymyxin. Colistimethate sodium is less active in vitro andless nephrotoxic than polymyxin B [6].

These agents have been used to treat patients with bacteremia, pneumo-nia, and other systemic infections caused by gram-negative bacilli [1]. Inrecent years, colistimethate sodium has been the most commonly used formof polymyxin for parenteral therapy. Colistimethate has also been used fornebulization therapy in patients with cystic fibrosis.

Colistin has been available as colistin sulfate for use topically and orallyand as colistimethate sodium for intramuscular and intravenous use.Polymyxin B sulfate is available for topical use (discussed elsewhere in thisissue). There is also a parenteral preparation that can be given intramus-cularly and intravenously; it has been used intrathecally and intraventric-ularly for central nervous system infections.

Mechanism of action and antimicrobial activity

The polymyxins are surface-active amphipathic agents containing bothlipophilic and lipophobic groups. They penetrate into cell membranes andinteract with phospholipids in the membranes, leading to permeabilitychanges that quickly disrupt the membranes leading to cell death. They arerapidly bactericidal in a concentration-dependent manner and have a post-antibiotic effect [6,7]. They also bind to the lipid A portion of endotoxin orlipopolysaccharide, and in animal studies block many of the biologic effectsof endotoxin [8]. Resistance of gram-negative bacteria to the polymyxinsis most likely related to a change in architecture of the membrane [9]. Theactivity of the polymyxins is diminished in the presence of high concen-trations of divalent cations, such as calcium and magnesium [9].

The polymyxins are active against commonly isolated gram-negativeaerobic bacilli with the exception of Proteus spp. Proteus spp are generallyvery resistant to the polymyxins. The polymyxins also have poor activityagainst Providencia, Burkholderia, and Serratia spp [5,10]. When the sulfatesalt is used for testing, most gram-negative bacilli are inhibited by 1 lg/mL;P aeruginosa strains are more resistant, but most strains are inhibited by2 lg/mL [5]. Strains with a minimal inhibitory concentration (MIC) greaterthan 4 lg/mL are generally defined as resistant; some consider strains re-quiring 4 lg/mL for inhibition to be resistant [5,9].

It is important to recognize that the sulfate forms of colistin andpolymyxin B (usually used for in vitro testing) are much more active invitro than the sulfomethyl form, often a fourfold to eightfold difference [9].Gram-positive organisms and most anaerobes are resistant to these agents.The polymyxins have retained activity against many MDR gram-negative

671D. Kaye / Infect Dis Clin N Am 18 (2004) 669–689

bacilli, such as MDR P aeruginosa and Acinetobacter baumannii. There iscomplete cross-resistance between the polymyxins.

Studies of in vitro synergy have been limited to relatively few organisms.Using colistin-susceptible strains of MDR bacteria, synergism has beendemonstrated between colistin and ceftazidime, colistin and rifampin, andcolistin and trimethoprim-sulfamethoxazole [7,11].

Pharmacokinetics and pharmacodynamics

The basic and clinical evaluation of the polymyxins took place manyyears ago, and the pharmacokinetic and pharmacodynamic informationavailable is limited. Review articles often have internally inconsistent dataconcerning pharmacokinetics, especially blood levels [12].

None of the polymyxins are absorbed when given orally. According tothe old literature, following intramuscular injection of 2 to 4 mg/kg poly-myxin B, peak serum levels of 1 to 8 lg/mL were achieved. There are little orno reliable data on serum levels after intravenous administration of poly-myxin B. According to the old literature, when colistimethate, 2.5 mg/kg,was given intramuscularly to adults, a peak serum level of 5 to 7 lg/mL wasachieved. When colistimethate was given intravenously, the peak was about20 lg/mL. The package insert for colistimethate shows peak levels of about8 lg/mL and 20 lg/mL, respectively, following intramuscular and in-travenous administration of 150 mg. The excretion of both polymyxin B andcolistin is primarily by glomerular filtration. There is a 12- to 24-hour lagperiod after the initial dose of polymyxin B (but not colistimethate) beforesignificant amounts appear in the urine. With subsequent doses, urine levelsof both polymyxin B and colistimethate exceed 15 lg/mL for at least 6 hoursafter injection. The half-life of polymyxin B in serum is about 4.5 to 6 hoursand that of colistimethate is about 3 hours [13]; half-lives are prolongedwhen the agents are given to patients with renal insufficiency. Accumulationof both drugs occurs with repeated dosing. Distribution to the cerebrospinalfluid, biliary tract, pleural fluid, and joint fluid is poor. In one report,however, the peak cerebrospinal fluid levels following the intravenousadministration of colistimethate were 25% of the peak serum levels [14]. Thepolymyxins are poorly dialyzed.

Toxicity

Hypersensitivity is unusual. There is dose-related nephrotoxicity, dam-aging the convoluted tubular epithelium; this is usually reversible afterdiscontinuing the drug [12,15]. There is also dose-related reversibleneurotoxicity, which can be manifested by neuromuscular blockade; thiscan result in muscle weakness and even apnea [12,15]. Neuromuscularblockade is most likely to occur with drug overdosage and in patients withrenal insufficiency or who are receiving curariform drugs. With respiratory


paralysis, support of respiratory function is required until the effects of thepolymyxin wear off. Aminoglycosides may potentiate the neurotoxic effects.Perioral paresthesias, paresthesias of the tongue and extremities, peripheralneuropathy, and other neurotoxic side effects are not uncommon [13].Toxicity is less likely to occur with colistimethate than with polymyxin B.

Clinical indications

Polymyxin B is very painful when given intramuscularly, and this route ofadministration should be avoided. If intramuscular injection is necessary,the usual intramuscular dose is 2.5 to 3 mg/kg/d in divided doses every 4 to6 hours. The intravenous dose is 1.5 to 2.5 mg/kg/d by continuousintravenous infusion or in divided doses every 12 hours over a period of60 to 90 minutes. For treatment of gram-negative bacillary meningitis,polymyxin B has been given intrathecally in doses of 5 to 10 mg/d for theinitial 3 days of therapy and then every other day. There is a recent report ofsuccessful intraventricular use [16].

The recommended dosage of colistimethate in patients with normal renalfunction is 2.5 to 5 mg/kg (depending on the severity of infection) each dayintramuscularly or intravenously in two to four divided doses. The doseshould be based on ideal body weight and should not exceed 300 mg/d.Doses must be decreased in patients with impaired renal function to avoiddrug accumulation and toxicity. When given intravenously, colistimethateis administered over 3 to 5 minutes. Administration of doses as high as8 mg/kg/d has been reported recently [17]. The question of use of colistimeth-ate as a single daily dose theoretically to lower the risk of toxicity has beenraised but clinical validation is lacking [7].

Colistin sulfate has been used orally for intestinal decontamination. Theoral preparation is not available in the United States.

Inhalation therapy with aerosolized colistimethate has been used withvarying results to treat colonization or infection of the bronchial systemin patients with cystic fibrosis, especially with MDR P aeruginosa [18,19].Systemic blood levels are not achieved with inhalation therapy.

Most of the literature on the use of the polymyxins for parenteral therapyis old. In recent years, colistimethate has been used parenterally to treatsystemic infections caused by MDR gram-negative bacilli, mainly ventilator-associated pneumonia [1,3,14,20]. In contrast with the old experience, recentreports claim little in the way of nephrotoxicity or neurotoxicity [1,3,17,20].More modern-day experience is necessary, however, before colistimethatecan be considered a relatively nontoxic systemic agent. Modern day reportsof use of polymyxin B have been sparse [21].

Recent observations have indicated emergence of resistance of Paeruginosa to the polymyxins, probably in relationship to the use ofnebulized colistimethate in patients with cystic fibrosis [6,22].


Until more clinical data become available, parenteral polymyxin B andcolistimethate should be reserved for use only when no other less toxic orpotentially more effective drug can be used.

Rifampin

Rifampin was first synthesized in 1965 from a fermentation product ofStreptomyces mediterranei. It is the 3-4-methyl-piperazinyl-iminomethylderivative of rifamycin. It and other rifamycin derivatives (such as rifabutin)are valuable drugs for treatment of mycobacterial infections. This sectiondeals only with rifampin and its use as an agent against nonmycobacterialorganisms.

Rifampin is unusual in its ability readily to enter cells and haveantibacterial activity at intracellular sites. It also has a broad range ofantibacterial activity, but cannot be used as a single therapeutic agentbecause of rapid emergence of resistance. For this reason, there are verylimited and special circumstances in which rifampin is used for non-mycobacterial infections.


Rifampin acts by suppressing initiation of RNA synthesis by inhibitingDNA-dependant RNA polymerase after binding to the beta subunit ofthe enzyme [23]. This interferes with protein synthesis by preventing chaininitiation. Its activity is usually bactericidal, but may be bacteriostaticdepending on the organism and the concentration of drug. In general mostgram-positive cocci (including staphylococci and streptococci) are highlysusceptible (MICs \1 lg/mL) to rifampin; enterococci, which are onlymoderately sensitive, are an important exception [24,25].

Meningococci, gonococci, and Hemophilus influenzae are susceptible torifampin. Most gram-negative bacilli, however, are resistant. Rifampin ishighly active against Legionella spp [26].

Microorganisms inhibited by less than or equal to 1 lg/mL areconsidered to be susceptible to rifampin, those inhibited by 2 lg/mL areintermediate, and those greater than or equal to 4 lg/mL are resistant.

Resistance to rifampin often develops by mutations in the gene (rpoB) thatencodes the beta subunit of DNA-dependant RNA polymerase; in addition,resistance can be mediated by alterations in membrane permeability [27].

The effect of adding rifampin to other antibiotics is a difficult andcomplicated issue, because the results are unpredictable. When rifampin isadded to other bactericidal agents, the effect may be synergistic, additive,indifferent, or antagonistic depending on the drugs, their concentrations, theorganisms being studied, and the model. Examples of some of the resultsfollow.


Addition of rifampin to penicillinase-resistant penicillins in vitro in-hibited the bactericidal activity of the penicillins against Staphylococcusaureus [28]. In a study in the rabbit model of S aureus endocarditis, thecombination of a penicillinase-resistant penicillin and rifampin was syner-gistic for some strains and indifferent or antagonistic for other strains [29].The addition of rifampin to vancomycin or to vancomycin plus gentamicinimproved the effectiveness of therapy in a rabbit model of Staphylococcusepidermidis endocarditis [30]. Similarly, substantial improvements in curerates for S epidermidis prosthetic valve endocarditis were achieved by addingrifampin, gentamicin, or both to vancomycin [31].

Experimental meningitis studies with limited number of strains ofpneumococci have demonstrated that addition of rifampin to vancomycinor ceftriaxone may have differing effects on the rate of killing of pneumococciin cerebrospinal fluid. One study showed a beneficial effect [32]. In contrast,another study demonstrated no increase in killing rate against pneumococciwhen rifampin was added to vancomycin [33]. Interestingly, an in vitro studyshowed that the addition of rifampin to ceftriaxone resulted in a markeddecrease in killing rates of ceftriaxone-susceptible pneumococci comparedwith ceftriaxone alone [34].

Synergism has been demonstrated between colistin and rifampin in vitroagainst strains of Stenotrophomonas maltophilia [11].


Rifampin is available orally and for intravenous administration. It is wellabsorbed when given orally with peak serum concentrations of 7 to 10 lg/mL following a dose of 600 mg. Food interferes with absorption and itshould be administered with an empty stomach. Following intravenousadministration of 300 or 600 mg over 30 minutes, mean peak serum levels of9 or 17.5 lg/mL, respectively, are achieved.

Rifampin is 80% protein bound. It is highly lipid soluble and is widelydistributed into body fluids including saliva, bile, pleural fluid, andcerebrospinal fluid. It also penetrates into tissues, such as liver, lung,prostate, and bone. The cerebrospinal fluid concentrations achieved withinflamed meninges are 10% to 20% of simultaneous serum concentrations.Given the lipophilic nature of rifampin, it penetrates relatively well acrossthe blood-brain barrier, even in the absence of meningeal inflammation.

Rifampin is excreted mainly by the liver. It is desacetylated in the liver toan active metabolite and excreted in the bile. There is significant entero-hepatic circulation. The half-life in serum is 2 to 5 hours but becomesshorter with repeated dosing because of enhanced biliary excretion relatedto rifampin’s property of inducing P-450 enzymes in the liver. Most of thedrug is eventually excreted in the stool. Blood levels are elevated in thepresence of hepatic insufficiency. The presence of renal insufficiency does nothave much of an effect on serum levels. With doses of over 450 mg there is


a disproportionate rise in blood levels related to saturation of the excretorycapacity of the liver for rifampin.

Rifampin readily enters phagocytic cells and can kill microorganisms inthe cells. Although there is relatively little information available about thepharmacodynamics of rifampin per se, this information is of little useclinically. This is because rifampin cannot be used therapeutically as a soleagent because of the rapid emergence of resistance [35]. The pharmacody-namics of rifampin are unusual; for example, there was a paradoxicaldecrease in bacterial killing rate of pneumococci in spinal fluid of rabbits atdoses of 20 mg/kg compared with 10 mg/kg [36]; this may have been theresult of the need for some protein synthesis for bacterial killing. Rifampinhas a very long postantibiotic effect [37].

Toxicity

With administration of rifampin, the urine and sweat may have an orangetinge and soft contact lenses may be stained. Rash may occur in up to 5%of patients, but the flulike syndrome associated with long-term intermittentuse is not associated with the short courses used for nonmycobacterialinfections. Gastrointestinal side effects occur in up to 5% of patients (eg,nausea, vomiting, diarrhea, heartburn). Abnormalities in liver chemistriesare common but frank hepatitis is uncommon (\1%), especially with theshort courses used for nonmycobacterial infections.

The major problem with the use of rifampin is its potent induction ofhepatic microsomal enzymes with consequent multiple drug interactions.Some of the drugs with altered metabolism related to rifampin are oralcontraceptives, cyclosporine, digoxin, fluconazole, sulfonylureas, theophyl-line, thyroxine, warfarin, many of the agents used in patients with HIV, andmany others [38,39].

Clinical indications

Rifampin can be administered either orally or intravenously. It shouldbe given orally 1 hour before a meal. The only Food and Drug Administra-tion (FDA) approved uses for rifampin are for therapy of mycobacterialinfections and for prophylaxis of meningococcal infection.

The only situation in which rifampin can be considered for use as a soleantibacterial agent is in prophylaxis of infection. It is indicated forprophylaxis of invasive meningococcal infection. It has also been used forprevention of H influenzae infection in children by administration to familymembers who were close contacts of patients with serious infections causedby these organisms. The principle of chemoprophylaxis is to eradicate theorganism from the nasopharynx. The widespread use ofH influenzae vaccinehas decreased the need for use for prevention of H influenzae infection.

Resistance to rifampin was recently reported in 3% of isolates ofNeisseria meningitidis in the United States [40]. Rifampin is administered


in a dose of 10 mg/kg (not to exceed 600 mg) in patients greater than orequal to 1 month of age, twice a day for 2 days for prevention ofmeningococcal disease; this generally has an efficacy of more than 90%.Rifampin has several shortcomings, however, including nasopharyngealeradication rates of only about 70% to 80% in some studies; adverse effects;necessity for multiple doses over 2 days; and emergence of resistantorganisms (up to 10%–27% of N meningitidis isolates). Ciprofloxacin maybe more effective in eradicating meningococci [41]. To protect childrenunder 4 years of age who have been incompletely immunized againstH influenzae type B, all household contacts who have been in contact witha case of severe infection should receive rifampin prophylaxis. The dose inadults is 600 mg once daily for 4 days.

Rifampin used alone intermittently has also been shown to decrease thefrequency of infections of the shunt and catheter in patients undergoinghemodialysis and peritoneal dialysis [42,43].

The situations for which rifampin has been used in combination withother antibacterial agents for treatment of nonmycobacterial infections arelimited. The major uses have been in staphylococcal infections especially onforeign bodies (eg, prosthetic valve endocarditis); meningitis caused bypenicillin- or cephalosporin-resistant S pneumoniae; for infections caused byBrucella spp; and for infection caused by Legionella spp [44]. Rifampin hasalso been used alone or in combinations for therapy of some other infectionsthat are not discussed here, such as Q fever, chancroid, bartonellosis, andRhodococcus infections [44].

Staphylococcal infectionClinical studies in serious S aureus infection treated with a combination

of rifampin and penicillinase-resistant penicillin versus the penicillin alonehave been inconclusive in terms of a beneficial effect of the rifampin.Although it is common practice to add rifampin to an antistaphylococcalregimen when the patient is not responding, reports of better response afteraddition of rifampin are difficult to evaluate.

Substantial improvements in cure rates for S epidermidis prosthetic valveendocarditis have been reported by adding rifampin, gentamicin, or both tovancomycin [31]. The dose of rifampin recommended by the AmericanHeart Association in this situation is 300 mg orally every 8 hours [45]. Ina study of right-sided S aureus endocarditis, patients were treated success-fully orally with ciprofloxacin plus rifampin [46]. Use of a fluoroquinolonefor S aureus infection, however, is questionable.

Because of the excellent penetration of rifampin into tissues and spaces,there is a general enthusiasm for including rifampin in regimens whentreating staphylococcal infections in the presence of abscesses or foreignbodies. In animal models of S aureus osteomyelitis, there is a benefit ofadding rifampin to the regimen [47], but clinical studies have not been


convincing. In the presence of a foreign body, however, it is reasonable toadd rifampin [48,49].

Rifampin alone or in combination with another drug (eg, trimethoprim-sulfamethoxazole) has been used to eradicate nasal carriage of S aureusincluding methicillin-resistant strains. These combinations have also beenused for oral treatment of infections from non–life-threatening methicillin-resistant strains.

Pneumococcal meningitisDespite high in vitro susceptibility against Streptococcus pneumoniae,

rifampin should never be used alone to treat pneumococcal meningitis.When the infecting organism is highly resistant to ceftriaxone andcefotaxime, but is rifampin susceptible, combination therapy with vanco-mycin plus ceftriaxone plus rifampin might be effective [32]. In thesecircumstances, vancomycin concentrations should be maximized to ensureadequate central nervous system penetration. Steroid therapy can reduceantimicrobial penetration into the cerebrospinal fluid by decreasing in-flammation; in animal models, steroid therapy has been associated withfailure of cephalosporin or vancomycin monotherapy, although this has notbeen observed in all experimental studies. The combination of these agentswith rifampin was an effective regimen, however, even when given con-comitantly with steroids [33,50,51].

There are no reliable clinical data concerning results of the addition ofrifampin to vancomycin or a third-generation cephalosporin in patients withpneumococcal meningitis. Because there are conflicting results of thebenefits of rifampin in in vitro and animal model studies, it has beensuggested that rifampin be used for patients in whom the pneumococcalisolate is sensitive to rifampin in vitro and who are not respondingappropriately to standard therapy (discussed elsewhere in this issue).

BrucellosisRifampin in combination with doxycycline has been used successfully to

treat brucellosis [52,53].

LegionellosisLegionella pneumophila and micdadei are highly sensitive to rifampin in

vitro, and it has been suggested that rifampin be added to a macrolide intreatment of infections that are responding poorly to the macrolides alone[54]. There are no convincing clinical data, however, to support this.

Aminoglycosides

The aminoglycosides are a class of bactericidal antibiotics characterizedby the presence of a six-carbon aminocyclitol ring, covalently bonded to


multiple amino sugar groups. Aminoglycosides were once widely used asprimary agents in the therapy of gram-negative bacillary infections.Because of their toxicity and the availability of newer effective agents,however, their use has significantly diminished. The current use of systemicaminoglycosides in adults is primarily as companion drugs to eitherbroaden coverage against gram-negative aerobic bacilli or to providesynergistic killing against gram-positive cocci or certain gram-negativebacilli.

The major change in the use of the aminoglycosides has been a trendtoward single-daily dosage. FDA-approved dosing regimens for aminoglyco-side antibiotics require division of the total daily dose into multiple doses inindividuals with normal renal function. Improvements in the understandingof the pharmacodynamics of aminoglycosides and mechanisms of toxicity,however, have prompted the evaluation and use of once-daily dosingregimens. Gentamicin, the most widely administered of the aminoglycosidesand the most studied, is used as the prototype for discussion.


The aminoglycosides act in part by impairing bacterial protein synthesisthrough irreversible binding to the 30S subunit of the bacterial ribosome.They are rapidly bactericidal against a broad range of aerobic gram-negative bacilli (including P aeruginosa), but lack activity against anaerobes.Although there is activity against some gram-positive aerobic cocci, it isunreliable. The aminoglycosides are generally used against gram-positivecocci, such as enterococci and staphylococci, only in combination with cell-wall active antibiotics to achieve synergistic bactericidal activity.

Resistance to the aminoglycosides in normally susceptible bacteria isusually by means of bacterial elaboration of aminoglycoside-inactivatingenzymes. These enzymes are widely distributed in both gram-positive andgram-negative bacteria, and usually are plasmid-mediated [55]. Perhaps themost clinically significant resistance occurs in enterococci where thesynergistic killing activity of gentamicin is required for a high cure rate ofendocarditis. Although all enterococci are intrinsically resistant to lowconcentrations of aminoglycosides, the clinical problem arises with high-level gentamicin-resistant enterococci [56]. High-level gentamicin-resistantenterococci are highly resistant to all other aminoglycosides in clinical usein the United States, with the possible exception of streptomycin, and donot demonstrate synergistic killing of enterococci when aminoglycosidesare combined with penicillin or vancomycin [57]. Detection of high-level gentamicin resistance requires either special susceptibility wells orscreening plates with high concentrations of gentamicin or streptomycin(eg, �500 lg/mL) (discussed elsewhere in this issue).

When aminoglycosides are combined with cell-wall active agents, such asb-lactam drugs or vancomycin, there is a synergistic killing effect against


susceptible bacteria (aerobic gram-negative bacilli and gram-positive cocci).This phenomenon has been demonstrated with multiple organisms and inmultiple animal models [58]. This activity has been best demonstrated to beimportant clinically in infective endocarditis caused by enterococci and in Sepidermidis endocarditis on a prosthetic valve. It has been suggested thatcontribution to this activity may also be important in serious P aeruginosainfections, and in infections caused by gram-negative bacilli in neutropenicpatients.


Aminoglycosides are poorly absorbed orally. After intravenous infusionof 1.7 mg/kg gentamicin (every 8-hour dosage), peak serum levels (Cmax) are4 to 10 lg/mL. After infusion of 5 mg/kg (once-daily dosage), peak levels areabout 20 lg/mL serum. The half-life of all of the aminoglycosides is about 2to 3 hours. Protein binding is low (\10%) and because the agents are watersoluble, they are distributed in the intravascular space and into interstitialfluid. The drugs diffuse into synovial, pleural, and peritoneal fluids, butpenetration into the cerebrospinal fluid and into bile is poor.

In general, in the absence of large effusions and edema, the volume ofdistribution is low. Increases in the volume of distribution tend to decreasethe Cmax and area under the serum concentration-time curve (AUC), andincreases in clearance tend to decrease the AUC. For example, the volumeof distribution tends to be elevated and peak serum levels decreased inpatients with large effusions, fever, burns, or congestive heart failure and incritically ill patients [59,60]. Excretion of aminoglycosides is primarily byglomerular filtration; clearance is decreased with renal insufficiency and in-creased in children, in pregnancy, and in patients with cystic fibrosis.

The pharmacodynamics of aminoglycosides has been extensively studied(discussed elsewhere in this issue). Bacterial killing by aminoglycosides invitro is concentration dependent [61–64]. In vivo, higher doses of the drugnot only increase the rate of reduction of bacteria, but also the length oftime of drug exposure to bactericidal concentrations as measured by theAUC. In animal studies, aminoglycoside efficacy is correlated with the ratioof Cmax to the MIC of the infecting organism [65] and also with the AUC[66]. These pharmacodynamic properties stand in contrast to those of b-lactam antibiotics, whose efficacy correlates best with time above MIC [66].In animal studies, effective dosing regimens for concentration-dependentantibiotics require that either the 24-hour AUC/MIC be 80 to 100 againstgram-negative bacilli or the Cmax/MIC of the causative pathogen be 8 to 10[63].

Some clinical studies have demonstrated a relationship between peakaminoglycoside concentrations and response to therapy [67,68]. Forconcentration-dependent drugs, such as aminoglycosides, giving the totaldaily dose as a single dose every 24 hours rather than giving smaller divided


doses maximizes the Cmax and possibly allows for comparable or betterefficacy at greater convenience and lower cost. A Cmax/MIC of greater thanor equal to 10 seems to be a reasonable goal [63,68].

Aminoglycoside antibiotics have a significant postantibiotic effect forstaphylococci and gram-negative bacilli, meaning that suppression ofbacterial growth persists despite concentrations of antibiotic below theMIC [66,69–71]. This permits longer intervals before another dose ofaminoglycoside is given. The postantibiotic effect tends to be longer in vivothan in vitro even in neutropenic animals [72]. The postantibiotic effect isextended by higher doses of aminoglycosides [65,71] and concurrent ad-ministration of a cell-wall active antibiotic [72].

Enhanced phagocytosis of aminoglycoside-exposed bacteria by hostleukocytes has also been observed in vitro [73]. This has been referred toas ‘‘postantibiotic leukocyte enhancement.’’ The absence of postantibioticleukocyte enhancement may help explain the decreased efficacy of once-daily dosing that has been described in neutropenic animals as comparedwith nonneutropenic animals [71].

The term ‘‘adaptive resistance’’ refers to the transient reduction in rate ofbacterial killing by an antibiotic following pre-exposure to that drug [74].Adaptive resistance to aminoglycoside agents has been observed principallyin P aeruginosa, but also in other gram-negative bacilli [75]. Once-dailydosing may circumvent the possibility of adaptive resistance through theprovision of a drug-free interval.

Toxicity

The well known major toxic side effects of the aminoglycosides are forthe renal proximal convoluted tubules, the cochlear and vestibular bodies ofthe ear, and for the neuromuscular junction. The nephrotoxicity is usuallyreversible as is the neuromuscular blockade [76].

The uptake of aminoglycosides by renal cortical cells seems to bea saturable process [76]. Once proximal tubular cells are saturated withaminoglycoside, the higher peak serum concentrations seen with once-dailydosing should not cause greater intracellular accumulation of drug than isseen with multiple lower doses. In fact, renal cortical accumulation ofgentamicin in rodents is lower following once-daily dosing regimens thanafter multiple-daily doses, and greater increases in serum creatinine are seenwith multiple-daily dosing regimens [77].

Correlation of increased renal cortical accumulation of aminoglycosideswith dosing frequency rather than peak serum concentrations has beendemonstrated in a cohort of human subjects undergoing nephrectomy forcancer [78]. Increased nephrotoxicity has been observed with elevated troughlevels; with prolonged use; in patients with diabetes mellitus; with concurrentuse of vancomycin, loop diuretics, cyclosporine, and cisplatin; and when thedrug is administered at time of rest as opposed to activity [79–82].


There have been many clinical studies of nephrotoxicity of aminoglyco-sides. A recent review [63] compiled a summary of the results of meta-analyses of once-daily dosing of aminoglycosides versus multiple-dailydosing. Although some of these reported a decrease in nephrotoxicity withonce-daily dosing, most of the meta-analyses demonstrated no significantdecrease in nephrotoxicity.

Aminoglycoside therapy may result in both vestibular and cochleartoxicity. In rats, (but not in guinea pigs) gentamicin uptake into perilymph,endolymph, and inner ear tissues seems to be a saturable process, as in thekidney [83]. It is unknown if gentamicin uptake is a saturable process inhumans, and it is unclear whether aminoglycoside accumulation in the innerear predicts ototoxicity [83].

Risk of ototoxicity has been associated with elevated trough levels ofaminoglycoside, although some authors have found no association betweendrug levels and ototoxicity after controlling for age [84]. Nonetheless, thesuggestion that aminoglycoside uptake into inner ear fluids is saturable hasraised the possibility that once-daily dosing of aminoglycosides may de-crease ototoxicity. Most published meta-analyses, however, have reported nodifference in ototoxicity between once- and multiple-daily dosing [63].

Clinical use

The indications for parenteral use of aminoglycosides have not changedin many years. Their use in mycobacterial infections and in infections causedby unusual pathogens, such as Yersinia pestis, Brucella spp, and Francisellatularensis, is beyond the scope of this article.

Outside of these uses aminoglycosides are generally reserved for seriousgram-negative bacillary infections, almost always in combination with otherantimicrobial agents (usually b-lactam antibiotics). They are included tobroaden coverage against resistant gram-negative bacilli, such as Paeruginosa, and to provide potential synergistic bactericidal activity againstthese organisms. They are also used in combination with cell-wall activeantibiotics to provide synergistic bactericidal activity in treatment of seriousgram-positive coccal infections, such as staphylococcal, enterococcal, andstreptococcal endocarditis [85].

The major change in use of aminoglycosides has been the consideration ofuse of single-daily dosage versus divided-daily doses. For example, the dailydose of gentamicin is usually 5 mg/kg. It can be given as 1.7 mg/kgintramuscularly or intravenously every 8 hours (FDA approved) or as 5 mg/kg in one single-daily intravenous dose over 30 to 60 minutes. Once-dailydosing should be performed in a manner that ensures a high Cmax/MIC ratiofor the pathogen being treated and ensures that trough levels are low enoughtominimize toxicity and permit the loss of adaptive resistance. Higher rates ofbactericidal action result in lower residual bacterial counts and longer intervalsbefore significant regrowth occurs. Maximizing serum concentrations of


aminoglycosides by using the single large dose maximizes the rate and extentof bactericidal activity.

The possibility of increased efficacy with once-daily aminoglycosidedosing has been evaluated in a multitude of randomized clinical trials. Ingeneral, these individual trials have lacked sufficient power to determinewhether observed differences in efficacy between once-daily and multiple-daily dosage regimens were caused by chance alone. Meta-analysis has beenused to synthesize the data contained in these multiple studies. Many ofthese [86–94] were reviewed in a recent publication [63]. Most of these meta-analyses demonstrated an improvement (albeit usually small) in the clinicalefficacy of once-daily aminoglycoside dosing.

Overall, existing clinical data suggest that once-daily administration ofaminoglycosides may be more efficacious and less nephrotoxic, or at leastnot more nephrotoxic, than multiple-daily dosing. Giving the total 24-hourdose as a single dose, rather than in smaller divided doses, and usingextended dosing intervals has now become the standard in many clinicalsettings [63]. This strategy may be especially appropriate for treatment ofinfections caused by borderline susceptible pathogens (eg, P aeruginosa),with MICs that are close to the breakpoint [95].

Dosages used in clinical trials of once-daily administration of gentamicin,netilmicin, and tobramycin have varied from 4 to 7 mg/kg/d [95]. A startingdose of 5 mg/kg has been suggested for adults 30 to 60 years of age withdoses of 6 mg/kg for adults below 30 years and 4 mg/kg for those over 60[63]. It has been pointed out that, because of patient-to-patient variability,4 mg/kg dosing does not always ensure sufficiently high peak concentrationsto provide optimal activity against such organisms as P aeruginosa [95]. Theuse of 7 mg/kg dosing of gentamicin in 2148 adult inpatients was associatedwith only 27 incidents of nephrotoxicity and three of vestibulotoxicity;however, the median duration of therapy was only 3 days [95]. It has beensuggested that once-daily doses should be based on FDA-approvedmaximum daily doses of aminoglycoside antibiotics (ie, 5 mg/kg/d forgentamicin) [96].

Once-daily dosage should not be used with creatinine clearances of lessthan 20 mL/min. Two approaches have been advanced for initial dosing ofonce-daily aminoglycosides in individuals with mild to moderate renalimpairment: reduction of drug dosage, and increase in dosing interval. Prinset al [97] suggested that gentamicin and tobramycin be administered ata dose of 4 mg/kg/d when estimated creatinine clearance is greater than80 mL/min, and that the daily dose be decreased when renal function iscompromised. Nicolau et al [95] have suggested that a fixed 7 mg/kg dose beadministered, and that the dosing interval be extended beyond 24 hours inindividuals with impaired renal function. Recommendations on dosing withrenal insufficiency are discussed in more detail elsewhere in this issue. Whenrenal function is decreased, it is important subsequently to monitor amino-glycoside serum levels.


The doses of aminoglycosides used for synergistic bactericidal activity inthe treatment of gram-positive coccal endocarditis have been lower thanthose used for serious gram-negative infections (target serum peak levels3–4 mg/L). Furthermore, although a significant postantibiotic effect has beendemonstrated against enterococci with aminoglycoside–b-lactam combina-tions in vitro, no postantibiotic effect was demonstrated in an animal modelof enterococcal endocarditis [85]. Some have found multiple-daily dosingregimens to be superior to once-daily regimens in the treatment of experi-mental enterococcal endocarditis [98,99].

Once-daily gentamicin dosing for streptococcal endocarditis was used ina clinical trial, comparing 4 weeks of ceftriaxone with 2 weeks of ceftriaxonecombined with gentamicin; the two regimens were equivalent [100]. Atpresent, the use of once-daily dosing of aminoglycosides for the treatment ofgram-positive coccal endocarditis remains controversial, and further dataare needed before such regimens can be recommended.

Aminoglycoside antibiotics are commonly used in the treatment ofpulmonary exacerbations in individuals with cystic fibrosis and P aeruginosacolonization. Antibiotic treatment of such exacerbations is typicallyprolonged, and often occurs in the home setting; once-daily dosing forhome therapy has obvious advantages. Individuals with cystic fibrosis clearaminoglycosides at an increased rate. Higher doses of aminoglycosides (eg,tobramycin at doses up to 15 mg/kg/d) once daily have been usedsuccessfully, with little or no increase in nephrotoxicity [101–105], althoughtransient ototoxicity has been associated with these doses [102].

Several different methods of monitoring once-daily dosing aminoglyco-side have been suggested. Some authors have suggested monitoring troughconcentrations only, with dose adjustments for troughs greater than 2 lg/mL. This approach does not allow clinicians to appreciate underdosage ofdrug, however, and trough levels of 2 lg/mL are too high and indicatereduced clearance with once-daily dosing.

Another proposed approach to monitoring of once-daily dosage is witha drug level taken 6 to 14 hours after infusion and adjusting the dosesaccording to a nomogram [93,95]. Suboptimal peaks are not recognized bythis method. A third approach measures two levels (at 0.5–1 hour and 6–14hours) and calculates the AUC [106,107].

It has been proposed that aminoglycoside levels need not be measuredwith once-daily dosing in patients with creatinine clearance greater than60 mL/min who receive less than 5 days of therapy [95,96]. Levels shouldbe checked in patients at increased risk for toxicity or clinical failure,however, such as the elderly, those receiving other nephrotoxic drugs,those with severe infections, or those expected to require longer than 5days of treatment. In patients on long-term therapy, aminoglycoside levelsshould be measured weekly as long as the serum creatinine is stable[95,96].


Summary

This article reviews three classes of antibacterial agents that are un-commonly used in bacterial infections (other than mycobacterial infections)and can be thought of as special-use agents. The polymyxins are reserved forgram-negative bacilli that have become resistant to virtually all other classesof drugs. Rifampin is used therapeutically, mainly as a companion drug intreatment of refractory gram-positive coccal infections especially involvingforeign bodies. The aminoglycosides are used mainly as companion drugsfor the therapy of resistant gram-negative bacillary infection and for gram-positive coccal endocarditis. The major change in use of aminoglycosideshas been a shift to once-daily dosing in many situations.

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current use for old antibacterial agents-polymixins,rifampin and aminoglycosides

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