Effect of Intraoperative Phenylephrine Infusion on Redistribution Hypothermia During Cesarean Delivery Under Spinal Anesthesia.

An observational clinical study to evaluate the effect of phenylephrine infusion on maternal temperatures during scheduled cesarean delivery under spinal anaesthesia was conducted in 40 ASA physical status II parturients. Following placement of spinal anesthesia, phenylephrine infusion was initiated at 40 µg/min and titrated to maintain mean arterial pressure within 20 percent of baseline. Maternal oral temperature, heart rate, and blood pressure were measured at baseline, spinal placement, every 10 minutes thereafter for 60 minutes. Phenylephrine dose received was documented every ten minutes. The range in maternal temperature change was 0.06-0.29°C. The lowest recorded temperature was 36.3°C. Decreased maternal temperature was associated with duration of anesthesia and cumulative phenylephrine dose in a univariate model (P<0.001 for all). The multivariable model showed an association between a greater decrease in maternal temperature with larger doses of phenylephrine being administered.

Increased polymorphonuclear leukocyte respiratory burst function in type 2 diabetes.

The predisposition to infection and chronic inflammation in diabetes may in part be related to the effects of hyperglycemia or other metabolic abnormality on polymorphonuclear leukocytes (PMN). We evaluated oxidative respiratory burst activity (superoxide production) in non-stimulated and stimulated PMN from 70 stable type 2 Hispanic diabetic patients, as compared to 70 healthy Hispanic individuals without diabetes. The influences of protein kinase C (PKC) inhibitors and certain antibiotics on superoxide production were examined. Both resting and stimulated (PMA, zymosan) PMN from diabetic individuals produced more superoxide than PMN from controls. Inhibitors of PKC, a possible mediator of the augmented respiratory burst activity, decreased superoxide production in all (resting and stimulated) diabetic and control PMN. Azithromycin, which is markedly concentrated by PMN, profoundly inhibited superoxide generation in all groups of diabetic and control cells. PMN from Hispanic diabetic patients produced greater quantities of superoxide than non-diabetic controls. This increased oxidative respiratory burst activity may predispose to infection and chronic inflammation in diabetes. PKC inhibitors and azithromycin inhibited this respiratory burst response. The possible role of PKC (especially PKC beta) as the mediator of this augmented respiratory burst response requires further evaluation, and may lead to therapeutic studies with appropriate inhibitors.

Risk factors for hepatitis C on the Texas-Mexico border.

OBJECTIVES: Our clinical experience suggested that hepatitis C virus (HCV) infection in this Texas-Mexico border area might have features, especially risk factors, that differ from some other areas of the United States. Therefore, we conducted a prospective analysis to investigate the epidemiology, risk factors, and certain other characteristics of HCV infection in the El Paso region. METHODS: During a 2-yr period, individuals with a positive HCV serology were considered as "patients" and those with a negative hepatitis serology panel were "controls." A questionnaire survey was conducted in person or by telephone with individuals (patients and controls) who agreed to participate in the interview process. RESULTS: We identified and interviewed 320 patients and 307 controls. All of the contacted patients and controls agreed to be interviewed. Many established and potential risk factors for HCV transmission were documented in the patients. Furthermore, multiple potential risk factors were often present in individual patients. However, on multivariate analysis only injection drug use, blood transfusion, and tattooing were found to be significant independent risk factors for HCV infection. In the great majority of patients, tattoos were applied by friends (including gang members), inmates in jail/prison, or self, rather than commercial parlors. CONCLUSIONS: Tattooing is an independent risk factor for HCV infection in this United States-Mexico border area. The role of nonsterile tattooing practices in HCV transmission merits additional examination in regard to precise risk settings, frequency, and mechanisms of infection.

[Mechanisms of azithromycin accumulation and efflux in human polymorphonuclear leukocytes]. / Mekhanizmy nakopleniia i vybrosa azitromitsina v polimorfnoiadernykh leikotsitakh cheloveka.

Azithromycin achieves prolonged, high tissue concentrations in spite of low serum levels and obviously must be effective at tissue sites of infection. These unique features prompted us to evaluate the interactions of azithromycin and human polymorphonuclear leukocytes (PMN). Uptake of radiolabeled antibiotic by PMN was determined by a velocity-gradient centrifugation technique and expressed as the ratio of cellular to extracellular drug concentration (C/E). Azithromycin was massively accumulated by human PMN (C/E = 387.2 at 2 h). Uptake was not influenced by inhibitors of cellular metabolism, but phagocytosis slightly inhibited the entry of azithromycin into PMN. After removal of extracellular drug, the release (efflux) of azithromycin from PMN was extremely slow. Agents which neutralize lysosomal pH, preventing protonation and trapping of azithromycin, markedly increased antibiotic efflux. Active concentration and prolonged retention of azithromycin by phagocytic cells should allow delivery and subsequent release of accumulated drug at sites of infection.

Characteristics and mechanisms of azithromycin accumulation and efflux in human polymorphonuclear leukocytes.

Azithromycin achieves prolonged, high tissue concentrations in spite of low serum levels and obviously must be active at tissue sites of infection to be effective. These unique features prompted us to evaluate the interactions of azithromycin and human polymorphonuclear leukocytes (PMN). Uptake of radiolabeled antibiotic by PMN was determined by a velocity-gradient centrifugation technique and expressed as the ratio of cellular to extracellular drug concentration (C/E). Azithromycin was massively accumulated by human PMN (C/E=387.2 at 2 h). Uptake was not influenced by inhibitors of cellular metabolism, but phagocytosis slightly inhibited the entry of azithromycin into PMN. After removal of extracellular drug, the release (efflux) of azithromycin from PMN was extremely slow. Agents which neutralize lysosomal pH, preventing protonation and trapping of azithromycin, markedly increased antibiotic efflux. Active concentration and prolonged retention of azithromycin by phagocytic cells should allow delivery and subsequent release of accumulated drug at sites of infection.

Current challenges in antibiotic resistance.

The striking, widespread increase in bacterial resistance to antibiotics is an issue of great concern. Worldwide emergence of antibiotic resistances in our common gram-positive coccal pathogens is probably the most serious problem we have in the realm of bacterial infections. The most important of these organisms are penicillin-resistant Streptococcus pneumoniae, vancomycin-resistant Enterococcus, and methicillin- (and now vancomycin-) resistant Staphylococcus aureus. Although known by the above names, all of these organisms are multidrug-resistant. Beta-lactam and vancomycin resistances in gram-positive cocci are caused by altered cell wallñbinding sites with decreased affinity for the drug. Another serious problem is that of resistance in certain gram-negative bacilli due to extended-spectrum beta-lactamase production. These antibiotic resistances in common pathogens have made antimicrobial therapy of many infections extremely difficult or virtually impossible in some instances. The extensive, and often inappropriate, use of antibiotics in the U.S. and worldwide is the major factor in the emergence and spread of antimicrobial resistance. Microbial mechanisms, epidemiology, clinical importance, treatment, and prevention of these antibiotic resistance problems are discussed.

A cost analysis: general endotracheal versus regional versus monitored anesthesia care.

A prospective study was conducted to compare the total cost of all consumable products used to perform a general endotracheal anesthetic (GETA), a regional anesthetic, and a monitored anesthetic (MAC). For 1 month, providers completed a survey for each anesthetic rendered identifying type and quantity of consumables used. The mean cost of each type of anesthetic was identified. Analysis of variance was conducted using SPSS (version 7.5.1) to compare the mean costs of the three groups. Of 936 anesthetics performed, 536 surveys were returned (57%). The breakdown by type was GETA, 60% (N = 319); regional, 35% (N = 189); and MAC, 5% (N = 28). The mean cost per case type was GETA, $61.74; regional, $34.99; and MAC, $26.27. The cost of rendering a GETA was significantly greater (p < 0.0005) than that of either regional or MAC. Clinical practice guidelines were established to address areas in which cost savings could be realized and were provided to all anesthesia practitioners to assist in providing the safest and most cost-effective method of rendering an anesthetic.

Influence of pentoxifylline and its derivatives on antibiotic uptake and superoxide generation by human phagocytic cells.

Pentoxifylline modulates multiple activities of stimulated polymorphonuclear neutrophils (PMNs), including the respiratory burst response and membrane transport of certain substances (e.g., nucleosides). We found that several weakly basic antibiotics are highly concentrated by human PMNs and that these drugs also inhibit the respiratory burst response (by a mechanism different from that of pentoxifylline). Since both pentoxifylline and antibiotics will be administered to some patients with serious infections, we have evaluated several types of interactions between these drugs and human PMNs and have attempted to identify the mechanisms that produce alterations in cellular function. Roxithromycin, dirithromycin, and clindamycin were avidly concentrated by PMNs. Pentoxifylline and two derivatives (HWA-448 [torbafylline] and HWA-138 [albifylline]) increased the uptake of these antibiotics by PMNs, both in the resting state and during phagocytosis. Pentoxifylline, HWA-448, HWA-138, and the highly concentrated antibiotics each exerted an inhibitory effect on the stimulated respiratory burst response in PMNs. The combination of both pentoxifylline and a modulatory antibiotic (roxithromycin or clindamycin) inhibited superoxide production to a greater extent than either agent alone. This additive effect might be expected, since pentoxifylline and the modulatory antibiotics influence the respiratory burst activation pathway at different sites. The ability of pentoxifylline to augment the entry of antibiotics into neutrophils has important therapeutic implications. The consequences of this phenomenon might include improved intracellular bactericidal activity as well as efficient antibiotic delivery and release at sites of infection.

Interactions of dirithromycin with human polymorphonuclear leukocytes.

Dirithromycin, a new macrolide antibiotic, achieves prolonged, high levels in tissue. We previously demonstrated that certain macrolides are highly concentrated within phagocytic cells. This background information prompted us to evaluate the interactions of dirithromycin and human polymorphonuclear leukocytes (PMNs). After incubation with radiolabeled dirithromycin, antibiotic uptake by PMNs was determined by a velocity-gradient centrifugation technique and was expressed as the ratio of the cellular to the extracellular drug concentration (C/E). Dirithromycin was avidly accumulated by PMNs (C/E, 5 at 15 min, 10 at 30 min, 19 at 1 h, and 35 at 2 h). Uptake was dependent on cell viability, physiologic environmental temperature, and pH (optimum 8.6), but was not influenced by potential competitive inhibitors of membrane transport. Incubation with sodium cyanide caused an increase in dirithromycin accumulation by PMNs. Ingestion of microbial particles (mimicking in vivo infection) modestly inhibited the entry of dirithromycin into PMNs. After removal of extracellular drug, the efflux (release) of dirithromycin from PMNs was slow; only 10% was released within the first 30 min. This prolonged retention of dirithromycin within phagocytic cells might allow delivery and release of accumulated drug at sites of infection. The impact of intraphagocytic dirithromycin on cellular function was also evaluated. In a manner similar to that of other highly concentrated, weakly basic antibiotics, dirithromycin inhibited the respiratory burst response (superoxide production) in stimulated PMNs. The presence of dirithromycin slightly increased the intraphagocytic killing of Staphylococcus aureus in human PMNs. These interactions of dirithromycin with phagocytic cells may promote the extraphagocytic, and possibly the intraphagocytic, killing of infecting organisms.

Role of phospholipase D-derived diradylglycerol in the activation of the human neutrophil respiratory burst oxidase. Inhibition by phosphatidic acid phosphohydrolase inhibitors.

An agonist-activated phospholipase D/phosphatidic acid phosphohydrolase (PAH) pathway was recently demonstrated in human neutrophils, and evidence suggests that phosphatidic acid (PA) and/or diradylglycerol (DG) generated from this pathway participates in activation of the O2(-)-generating respiratory burst. We have used a series of cationic amphiphilic compounds (sphingosine, propranolol, chlorpromazine, and desipramine) and antibiotics (clindamycin, trimethoprim, and roxithromycin) all of which inhibit the respiratory burst, to investigate the role of the phospholipase D/PAH pathway in neutrophil activation. The phosphatidylcholine (PC) pool in intact cells was first labeled using [3H]-1-O-alkyl-lysoPC; released [3H]-PA and [3H]-DG were then quantified after the addition of either chemo-attractant or PMA. Using either agonist, all compounds showed a dose-dependent inhibition of [3H]-DG generation which correlated with inhibition of O2- generation, but compounds failed to inhibit directly the NADPH oxidase in a cell-free system. For either activator, a plot of the ID50 values for O2- generation vs those for DG generation was linear over four orders of magnitude. In many cases, inhibition of [3H]-DG generation corresponded to an increase in [3H]-PA, implicating PAH as the locus of inhibition. Superoxide generation was inhibited under conditions where PA was either elevated or minimally affected. Neither O2- release nor DG generation showed any selectivity for stereoisomers of propranolol, suggesting that this inhibition does not act via a specific binding site on PAH. No evidence was obtained for an effect of the inhibitors on PA mobility as monitored by electron spin resonance studies of spin-labeled PA in a model membrane system. Data are consistent with an effect of the inhibitors at the level of the interaction of PAH with the membrane and/or its substrate. These data imply that DG produced via the phospholipase D/PAH pathway functions in the activation or maintenance of the respiratory burst.

Uptake of antibiotics by human polymorphonuclear leukocyte cytoplasts.

Enucleated human polymorphonuclear leukocytes (PMN cytoplasts), which have no nuclei and only a few granules, retain many of the functions of intact neutrophils. To better define the mechanisms and intracellular sites of antimicrobial agent accumulation in human neutrophils, we studied the antibiotic uptake process in PMN cytoplasts. Entry of eight radiolabeled antibiotics into PMN cytoplasts was determined by means of a velocity gradient centrifugation technique. Uptakes of these antibiotics by cytoplasts were compared with our findings in intact PMN. Penicillin entered both intact PMN and cytoplasts poorly. Metronidazole achieved a concentration in cytoplasts (and PMN) equal to or somewhat less than the extracellular concentration. Chloramphenicol, a lipid-soluble drug, and trimethoprim were concentrated three- to fourfold by cytoplasts. An unusual finding was that trimethroprim, unlike other tested antibiotics, was accumulated by cytoplasts more readily at 25 degrees C than at 37 degrees C. After an initial rapid association with cytoplasts, cell-associated imipenem declined progressively with time. Clindamycin and two macrolide antibiotics (roxithromycin, erythromycin) were concentrated 7- to 14-fold by cytoplasts. This indicates that cytoplasmic granules are not essential for accumulation of these drugs. Adenosine inhibited cytoplast uptake of clindamycin, which enters intact phagocytic cells by the membrane nucleoside transport system. Roxithromycin uptake by cytoplasts was inhibited by phagocytosis, which may reduce the number of cell membrane sites available for the transport of macrolides. These studies have added to our understanding of uptake mechanisms for antibiotics which are highly concentrated in phagocytes.

Antibiotic inhibition of the respiratory burst response in human polymorphonuclear leukocytes.

Recently we found that certain antibiotics which are markedly concentrated by human polymorphonuclear leukocytes (PMN) failed to kill susceptible, intraphagocytic Staphylococcus aureus, even though cellular drug levels were quite high. The possibility that specific antibiotics might adversely affect phagocyte antibacterial function was considered. Thus, we studied the effects of multiple antibiotics and adenosine, a known modulator of the PMN respiratory burst response, on neutrophil antibacterial function. At nontoxic concentrations, these drugs had no effect on degranulation in stimulated PMN. Adenosine was a potent inhibitor of formyl-methionyl-leucyl-phenylalanine (FMPL)-stimulated superoxide and hydrogen peroxide generation in PMN but produced less inhibition of microbial particle-induced respiratory burst activity. Three of the tested antibiotics, all of which reach high concentrations in phagocytic cells, had a marked modulatory effect on the PMN respiratory burst. Clindamycin, which enters phagocytes by the cell membrane adenosine (nucleoside) transport system, had only a modest effect on FMLP-mediated superoxide production but inhibited the microbial particle-induced response by approximately 50%. Roxithromycin and trimethoprim were efficient inhibitors of PMN superoxide generation stimulated by FMLP and concanavalin A (also inhibited by erythromycin) but had less effect on zymosan-mediated respiratory burst activity. Antibiotics which entered phagocytes less readily had no effect on the respiratory burst response in PMN. These results, as well as those of experiments with inhibitors of cell membrane nucleoside receptors, indicated that the antibiotic effect is mediated through intraphagocytic pathways. The possibility that antibiotic-associated inhibition of the PMN respiratory burst response might alter leukocyte antimicrobial and inflammatory function deserves further evaluation.

Pentoxifylline modulation of plasma membrane functions in human polymorphonuclear leukocytes.

Pentoxifylline is known to have major effects on cell membrane function in mammalian cells, including human leukocytes. The protective effects of this agent in animal models of infection and inflammation may be due to alterations in phagocyte (neutrophil and macrophage) function. However, the exact mechanism of action of pentoxifylline is unknown. In this study, we evaluated the effect of the drug on several membrane-associated activities in human polymorphonuclear neutrophils and investigated possible mechanisms for the observed changes in neutrophil function. Pentoxifylline inhibited ingestion of microbial particles (Staphylococcus aureus and zymosan); decreased superoxide generation activated by zymosan, formyl-methionyl-leucyl-phenylalanine, and concanavalin A (but not phorbol myristate acetate); and decreased uptake (transport) of adenosine stimulated by formyl-methionyl-leucyl-phenylalanine and zymosan. In contrast, pentoxifylline actually increased clindamycin uptake in zymosan-stimulated polymorphonuclear neutrophils. However, pentoxifylline had no effect on uptake of adenosine or clindamycin in unstimulated neutrophils. In comparison with known inhibitors of nucleoside transport (nitrobenzylthioinosine and dipyridamole), the results suggested that pentoxifylline does not bind to membrane nucleoside transport receptors. At concentrations which inhibit neutrophil function, pentoxifylline activity is not mediated through external membrane nucleoside regulatory sites. Thus, pentoxifylline affects the activation signal chain at a point beyond the membrane receptors. Whatever its precise mechanism of action, pentoxifylline has a striking modulatory effect on cell membrane-associated responses in stimulated leukocytes and may prove useful for control of injurious inflammatory states.

The entry of antibiotics into human monocytes.

Effective therapy of infections due to facultative intracellular micro-organisms, which persist after ingestion by mononuclear phagocytic cells, requires the use of antibiotics with the ability to inactivate these intra-phagocytic bacteria. Since entry of antibiotics into mononuclear phagocytes is a pre-requisite for activity against such intracellular organisms, we have determined the uptake of 11 radiolabelled antibiotics by human peripheral blood monocytes. beta-Lactams (penicillin G, cefamandole and cefotaxime), gentamicin, and metronidazole had a limited ability to enter monocytes, achieving cellular concentrations which were equal to or less than extracellular levels (C/E less than or equal to 1). Imipenem, a novel beta-lactam antibiotic, rapidly bound to monocytes, but cell-associated drug progressively declined during further incubation. Chloramphenicol, a lipid-soluble drug, and trimethoprim were concentrated three-fold by human monocytes. In comparison with the other antibiotics, roxithromycin (C/E = 14), clindamycin (C/E = 6 to 7) and erythromycin propionate (C/E = 4 to 5) were markedly concentrated by human monocytes. In contrast to our findings in other phagocytes, there was no evidence that active membrane transport was involved in monocyte uptake of clindamycin, erythromycin and roxithromycin. We have demonstrated that several antibiotics are highly concentrated within human monocytes, and it will be important to evaluate the effects of this antibiotic uptake on various monocyte functions, including intra-phagocytic antibacterial activity.

Entry of roxithromycin (RU 965), imipenem, cefotaxime, trimethoprim, and metronidazole into human polymorphonuclear leukocytes.

Entry of antibiotics into phagocytes is necessary for activity against intracellular organisms. Therefore, we examined the uptake of five of the newer antibiotics--roxithromycin (RU 965), imipenem, cefotaxime, trimethoprim, and metronidazole--by human polymorphonuclear leukocytes (PMN). Antibiotic uptake by PMN was determined by a velocity gradient centrifugation technique and expressed as the ratio of the cellular concentration of antibiotic to the extracellular concentration (C/E). Cefotaxime, like other beta-lactam antibiotics, was taken up poorly by phagocytes (C/E less than or equal to 0.3). The metronidazole concentration within PMN was similar to the extracellular level. Imipenem bound rapidly to phagocytes (C/E = 3), but cell-associated drug progressively declined during the incubation period. Trimethoprim was well concentrated by PMN (C/E = 9 to 13), and uptake was unexpectedly greater at 25 degrees C than at 37 degrees C. The most striking finding was that roxithromycin was more avidly concentrated by PMN (C/E = 34) than any other antibiotic we studied. Entry of roxithromycin into phagocytes was an active process and displayed saturation kinetics characteristic of a carrier-mediated membrane transport system. Ingestion of microbial particles by PMN slightly decreased the ability of these cells to accumulate roxithromycin (C/E = 24 to 31). These studies identified two antibiotics, trimethoprim and especially roxithromycin, which are markedly concentrated within human PMN and may prove useful in treatment of infections caused by susceptible intracellular organisms.

Spontaneous peritonitis: a reappraisal.

Spontaneous bacterial peritonitis occurs frequently in cirrhotic patients. In order to define more accurately the spectrum of this disease, 55 cases of spontaneous peritonitis were compared with 56 controls (patients with negative ascitic fluid cultures). Of several presenting symptoms, only vomiting (p less than 0.01), fever (p less than 0.05), and severe gastrointestinal bleeding (p less than 0.05) were more prevalent in cases than controls. There were no physical signs and no laboratory studies that separated the two groups except for elevated serum amylases in controls. Studies of peritoneal fluid were rarely helpful and cell counts overlapped in the cases and controls. Spontaneous peritonitis is usually seen in patients with severe liver disease, but there are few distinctive symptoms, signs, or laboratory findings. The mortality rate is high, and it is uncertain from our data that antibiotic therapy alters this prognosis.

Effect of phagocyte membrane stimulation on antibiotic uptake and intracellular bactericidal activity.

Phagocytosis stimulated a substantial increase in clindamycin uptake and a smaller increase in rifampin accumulation by polymorphonuclear leukocytes. The effect of this increased antibiotic uptake on intraphagocytic bactericidal activity was evaluated. Although zymosan stimulated antibiotic uptake by polymorphonuclear leukocytes, neither zymosan nor formyl-methionyl-leucyl-phenylalanine enhanced the ability of clindamycin or rifampin to kill ingested staphylococci. Properties other than antibiotic uptake are important in determining intraphagocytic bactericidal activity.

Contrasts between phagocyte antibiotic uptake and subsequent intracellular bactericidal activity.

An ideal antibiotic for therapy of infections due to facultative intracellular organisms would enter phagocytes readily and kill intracellular bacteria. We have examined the consequences of antibiotic uptake by human polymorphonuclear lymphocytes (PMN) on intraphagocytic bactericidal activity, using antibiotics which differ markedly in their ability to enter PMN. After ingestion of Staphylococcus aureus, PMN were evaluated in regard to uptake of antibiotics and survival of intraphagocytic bacteria in the presence or absence of these drugs. Except for erythromycin, the uptake of which was slightly decreased, the entry of tested antibiotics into PMN was increased or unchanged after ingestion of S. aureus. Clindamycin and erythromycin, which achieved high cellular levels in PMN, failed to produce a significant reduction in viable intraphagocytic S. aureus during 3 h of antibiotic exposure. In contrast, rifampin, which was concentrated severalfold by phagocytes, was able to kill intracellular staphylococci. Gentamicin and penicillin G penetrated PMN rather poorly. However, while gentamicin demonstrated efficient intraphagocytic killing of bacteria, penicillin had no intracellular effect during the 3-h incubation period. These observations document that the ability to enter phagocytes is only one of the factors which determine the intracellular antibacterial activity of an antibiotic.

Antibiotic uptake by alveolar macrophages of smokers.

Cigarette smoking, particularly when associated with chronic pulmonary disease, increases the risk of respiratory tract infection. Thus, we elevated the uptake of antibiotics by alveolar macrophages (AM) obtained by bronchoalveolar lavage from persons who smoke and have associated pulmonary abnormalities, circumstances which adversely affect certain macrophage functions. The entry of radiolabeled drugs into AM was determined by a velocity-gradient centrifugation technique, and uptake was expressed as the ratio of cellular to extracellular antibiotic concentration (C/E). Cefamandole and penicillin G were taken up poorly by the AM obtained from smokers (C/E less than or equal to 1). Cellular levels of isoniazid, gentamicin, and tetracycline were similar to their extracellular concentrations. The lipid-soluble drugs lincomycin, chloramphenicol, and rifampin were concentrated severalfold by the AM from smokers (C/E = 3 to 11). Ethambutol also entered macrophages readily (C/E = 11). Erythromycin and clindamycin were massively concentrated by the AM from smokers (C/E = 23 to 56). The AM of smokers accumulated a lipid-soluble antibiotic (rifampin) and actively transported agents (erythromycin propionate, clindamycin) more avidly than did the AM of nonsmokers. Augmented uptake of these antibiotics by the AM of smokers may be related to structural and functional alterations induced by smoking.

Uptake of antibiotics by human alveolar macrophages.

To provide additional criteria for therapy of pulmonary infections caused by facultative intracellular bacteria, we studied the uptake of 12 antibiotics by alveolar macrophages (AM) obtained from healthy, young volunteers by bronchoalveolar lavage. These human AM were incubated with radiolabeled antibiotics for periods as long as 2 h. Entry of antimicrobials into the cells was determined by means of a velocity-gradient centrifugation technique. Antibiotic uptake was expressed as the ratio of the cellular to the extracellular drug concentration (C/E). Penicillin G, cefamandole, and gentamicin were taken up poorly by human AM (C/E = 0.5 to 0.8). Isoniazid achieved a cellular concentration similar to the extracellular level of the drug (C/E = 0.9). Chloramphenicol, rifampin, tetracycline, and lincomycin, drugs that are lipid-soluble, were concentrated several-fold by AM (C/E = 2 to 5). The remaining antibiotics tested, clindamycin, erythromycin, erythromycin propionate, and ethambutol, were markedly concentrated by AM (C/E = 9 to 23). Accumulation of clindamycin (C/E = 23) was a rapid, active, energy-requiring process, which appeared to be dependent upon mitochondrial oxidative metabolism. The ability of the tested antimicrobial agents to enter human AM correlates well with the efficacy of these drugs in treatment of certain intracellular pulmonary infections.